About Course
INTRODUCTION
Antidepressants remain among the most common agents used in medicine. Despite a drop in
antidepressant prescriptions from 2003 to 2005, commonly attributed to the U.S. Food and Drug
Administration (FDA) black box warning on pediatric suicide risk, the number of antidepressant
prescriptions appears to be rebounding. The increasing availability of relatively inexpensive generic
antidepressants is likely to continue the trend toward more antidepressant prescriptions in the coming
years. In fact, 9 of the 10 most commonly prescribed antidepressants either are now generically
available or will be generically available by 2012.
Selective serotonin reuptake inhibitors (SSRIs) remain the dominant class of antidepressants. Their
ease of use, versatility, and safety have favored the SSRIs in both psychiatric and general medical
practice. Fluoxetine, citalopram, paroxetine, and sertraline are now available generically. Only
escitalopram currently has a patent extending to 2012. Although not all SSRIs are approved in all
anxiety disorders, the SSRIs have emerged as the first-line treatment for generalized anxiety disorder
(GAD), posttraumatic stress disorder (PTSD), panic disorder, and obsessive-compulsive disorder
(OCD). Most recently, escitalopram received an FDA-approved indication for GAD, but the
manufacturer did not receive approval for indications for panic and social anxiety. Despite this
nonapproval, the data supporting the use of escitalopram for the treatment of anxiety beyond GAD
appears substantial.
The serotonin-norepinephrine reuptake inhibitors (SNRIs) venlafaxine and duloxetine have also
become common first- or second-line agents and appear to be more useful than SSRIs in treating
neuropathic pain conditions. There has been the suggestion that the SNRIs may be more effective than
SSRIs in treating patients to remission, but the data are controversial and inconclusive in this regard.
Bupropion, which appears to have both noradrenergic and dopaminergic properties, became available
in a sustained-release formulation (Wellbutrin SR) in 1998 and a once-a-day XL preparation in 2004. In
addition, bupropion received an FDA indication for smoking cessation under the trade name Zyban.
Bupropion remains the most commonly added agent in the augmentation of serotonergic
antidepressants among partial responders. Findings from studies such as STAR*D (Sequenced
Treatment Alternatives for Resistant Depression; Trivedi et al. 2006) appear to support the
effectiveness of adding bupropion to an SSRI, but STAR*D also suggested that the much less
commonly used buspirone might be about as effective.
The use of other agents, such as mirtazapine, has flattened in their growth. Mirtazapine was
increasingly used in combination with other antidepressants for treatment-resistant depression and in
the treatment of depression in the elderly. It is now off patent. Nefazodone is more rarely used now,
since it has a black box warning of the risks of hepatoxicity, and is available on a more limited basis
(only available as a generic formulation). Along with bupropion, nefazodone and mirtazapine, unlike
virtually all other antidepressants, share a low proclivity for sexual side effects.
The FDA, following the lead of European regulatory agencies, recommended labeling changes for
SSRIs, venlafaxine, bupropion, nefazodone, and mirtazapine. The labels of these antidepressants now
advise close monitoring of pediatric patients for worsening depression and increased suicidality and
potentially will also soon warn about use in young adults (ages 18–25 years). This has been a
controversial recommendation. While there had been reports of increased suicidality associated with
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http://www.psychiatryonline.com/popup.aspx?aID=231806&print=yes_chapterthe SSRIs since the early 1990s, it had been difficult to discern an antidepressant-induced effect on
suicidal thoughts versus a progression of the underlying illness. Suicidality is often vaguely defined in
clinical trials, and the risk of suicidality in these studies is difficult to interpret. In studies in children, no
suicides have actually been observed. While effective antidepressant therapy is associated with the
reduction of suicidal ideation in most patients, there may be a few patients who are at risk for
worsening suicidality. These include partial responders who become energized enough with
antidepressant therapy to act on suicidal impulses. Patients with a latent bipolar disorder may also
worsen while taking an antidepressant alone without a mood stabilizer. Finally, it has been argued that
some patients may develop akathisia while taking serotonergic antidepressants, and this could lead to
suicidal ideation and a worsening course. Close monitoring of patients while they are taking
antidepressants is never a bad idea. However, the FDA recommendation has dissuaded some patients
or families from pursuing a needed therapy.
A recent analysis of manufacturers’ databases regarding adults revealed an increase in suicidal-like
activity in patients 18–25 years of age taking active medication compared with placebo. Other adult
age groups did not show a similar increased risk while taking the medication. In fact, the elderly (>65
years of age) demonstrate a significant decrease in suicidal activity.
The older antidepressants, the tricyclic antidepressants (TCAs) and the monoamine oxidase inhibitors
(MAOIs), continue to have an important but more limited role in modern clinical practice. There are
patients who respond to these older antidepressants who do less well with SSRIs or newer drugs. The
debate continues as to whether the TCAs and other agents with complex pharmacologies, such as
venlafaxine, are more effective than the SSRIs for more serious forms of depression or for depression
in elderly persons. Still, the TCAs and MAOIs are now considered second-line, or more commonly third
line, agents because of their potential drug interactions, toxicity, and difficulty in titration. Although
drug costs for the TCAs and MAOIs are generally much less than for newer drugs, these drugs still tend
to be less cost-effective overall because of the need for more frequent visits, additional laboratory
tests, morbidity of overdoses, and more frequent discontinuation secondary to adverse effects.
A number of antidepressants have been under recent investigation. These include the first transdermal
antidepressant, transdermal selegiline (Emsam), which was approved for the treatment of major
depressive disorder in February 2006. Transdermal selegiline is an MAOI that is applied via a patch.
The absorption of the drug through the skin obviates to some extent a number of the problems
associated with traditional oral MAOIs, including tyramine-induced hypertension and reduced
bioavailability from first-pass effects. In the pivotal trials, transdermal selegiline also appears to have
lower rates of sexual side effects, weight gain, and orthostatic hypotension than was commonly seen
with oral MAOIs. Another SNRI currently being investigated in the treatment of fibromyalgia in the
United States is milnacipran. Milnacipran has been shown to be effective as an antidepressant in a
number of trials and is on the market in France and Japan. If milnacipran is approved for the treatment
of fibromyalgia, it will represent an off-label option in the treatment of depression. Gepirone is a
serotonin 5-HT1A partial agonist that appears to be somewhat effective in the treatment of depression.
It lacks significant sexual side effects and, therefore, could be a useful alternative for the many
patients who cannot tolerate the side effects of SSRIs. However, the FDA decided not to approve
gepirone for major depression. Desmethylvenlafaxine, the major metabolite of venlafaxine, is currently
in development and could be released in 2007. It remains unclear what benefits in efficacy or side
effect profile it may have over venlafaxine. Agomelatine is perhaps the most novel antidepressant in
current development. It is a serotonin 5-HT2C antagonist and a melatonin MT1 and MT2 agonist.
Studies in Europe suggest antidepressant and anxiolytic benefits with a favorable side-effect profile.
Phase III trials are under way in the United States.
HISTORY
The modern antidepressants were discovered serendipitously. In the early 1950s, investigators noted
that tuberculosis patients showed prolonged elevation of mood when treated with iproniazid (Marsilid),
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http://www.psychiatryonline.com/popup.aspx?aID=231806&print=yes_chapteran MAOI thought to be an antituberculosis agent. Iproniazid proved ineffective for tuberculosis, but its
impact on mood led to some of the earliest double-blind studies in psychopharmacology,
demonstrating that MAOIs were effective antidepressant agents. The biological and pharmacological
observations that MAOIs were antidepressants and that monoamine oxidase degraded norepinephrine
and serotonin (5-HT) became cornerstones of the so-called biogenic amine theories of depression.
Iproniazid was taken off the U.S. market some time ago because of fear that it causes hepatic
necrosis. For many years the use of other MAOIs declined, partly because of the introduction of TCAs
and partly because of the occurrence in patients of significant hypertensive crises.
The TCAs were also discovered serendipitously. The first reports on TCA efficacy in depression came
from Professor Kuhn (1958) in Switzerland, who astutely noted that a three-ringed compound,
imipramine, which was being investigated as a treatment for schizophrenia, appeared to elevate mood
even though it did not relieve psychosis. The drug was similar in structure to the phenothiazines, but a
simple substitution of nitrogen for sulfur in the central ring appeared to confer unique antidepressant
properties.
Two antidepressants with a four-ringed structure, maprotiline and amoxapine, have pharmacological
effects similar to those of the more traditional TCAs. These effects are not unexpected, because the
development of many of the earlier antidepressant compounds was based on the similarity of their
activity in certain animal models to that of prototypical TCAs—a similarity that led some to call them
“me-too drugs.” However, there are both subtle and pronounced differences among many of the so
called me-too drugs. For example, amoxapine is a potent 5-HT2 antagonist.
The success of traditional antidepressants in treating depression led to a search in the pharmaceutical
industry for compounds that would have the efficacy of the TCAs without many of the adverse effects,
such as cardiotoxicity. In 1972, a research team composed of Bryan Malloy, Dave Wong, and Ray
Fuller synthesized an agent at Eli Lilly labeled LY86032 that possessed these properties. This
compound was altered somewhat to produce fluoxetine hydrochloride (Prozac). After an initial release
in Belgium and South Africa, fluoxetine was released to the U.S. market in 1988. The first serotonergic
agent, trazodone, had been released in 1981, but it did not have nearly the impact of fluoxetine. No
other drug in the history of psychiatry has received as much attention, both positive and negative, as
has fluoxetine. In any case, fluoxetine offered an alternative to traditional agents because it retained
the efficacy of traditional antidepressants but did not have many of their side effects. In addition,
fluoxetine appeared safe in overdose. As a result, fluoxetine and related antidepressants have
supplanted the TCAs as the first-line agents in the treatment of major depression. Sales for fluoxetine
alone topped $2 billion in 2000 in the United States. (Fluoxetine went off patent in mid-2001.) This
success prompted other pharmaceutical companies to investigate agents that selectively enhance 5 HT
function, and several other new agents were later released.
The search for selective medications has also led to the introduction of new classes of antidepressants.
Venlafaxine, which is a selective serotonin-norepinephrine reuptake inhibitor (SSNRI), appears to
possess much of the efficacy of TCAs without the overdose risks and the myriad side effects of the
TCAs. Mirtazapine appears to increase norepinephrine release by blocking presynaptic 2 receptors.
This release also appears to, in turn, stimulate serotonin release. Selegiline, a selective monoamine
oxidase B (MAO-B) agent at low oral doses, circumvents some of the problems of traditional MAOI
when given transdermally or, for that matter, sublingually. Selective and reversible inhibitors of
monoamine oxidase A (RIMAs) represent another attempt to render difficult-to-tolerate MAOIs in a
more manageable form.
Despite the tremendous success of the newer classes of antidepressants in enhancing safety and
tolerability, there has been no appreciable success in improving the efficacy and the latency of onset of
the antidepressants. As with the traditional agents, no more than 50%–65% of patients with major
depression will respond to any given trial with a newer antidepressant, and no agent has been able to
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http://www.psychiatryonline.com/popup.aspx?aID=231806&print=yes_chapterreduce reliably the 3 weeks or longer it appears to take for the drugs to work. Reducing the latency of
antidepressant effects and enhancing efficacy will be important foci of future research efforts.
GENERAL PRINCIPLES OF ANTIDEPRESSANT USE
Although the antidepressants vary considerably in their mechanisms of action, toxicity, dosing, and
potential for drug interactions, some clinical decisions apply to the use of all antidepressants. These
include the criteria for choosing an antidepressant, deciding what dose is adequate, and determining
the optimal duration of treatment.
Choosing an Antidepressant
As the number of antidepressants available has steadily increased, choosing an agent has become
somewhat more difficult. Although side-effect profile is generally mentioned as the primary factor in
choosing an antidepressant, optimally matching an antidepressant to a specific patient is as much art
as science. Patient parameters, including subtype of depression, age, sex, and medical status, are
matched with drug parameters such as side effects, safety, and cost.
The general wisdom is that all antidepressants on the market are equally efficacious in the treatment
of depression. This is unlikely. Depression is much too heterogeneous to suggest that agents with
diverse actions all work equally well for all types of depression.
The notion that antidepressants are equally efficacious is based on the fact that it has not been
possible to show that any antidepressant is reliably more than 50%–70% effective in a given clinical
trial. In contrast, placebos tend to be about 30% effective in outpatient trials. Efficacy is usually
defined as a 50% improvement on a standard depression rating scale such as the Hamilton Depression
Rating Scale (HDRS). When remission, rather than more general improvement, is the criterion for
efficacy, differences between antidepressants may begin to emerge. There had been some speculation
that antidepressants with more complex neurotransmitter effects, such as the TCAs, venlafaxine,
duloxetine, mirtazapine, and MAOIs, may achieve more complete remissions than SSRIs, and this
hypothesis has been investigated. Some, such as the meta-analysis by Thase et al. (2001), indicated
that venlafaxine was significantly more likely to effect a remission than were the SSRIs with which it
was compared. However, this area is controversial. The FDA has chided Wyeth for using the Thase
study in their marketing, pointing out that venlafaxine superiority may only be inferred against
fluoxetine. Indeed, a more recent meta-analysis by Nemeroff et al. (2003) of an additional 20 studies
failed to show superiority of venlafaxine over paroxetine. One major problem is that the original
venlafaxine studies were not designed to compare maximum doses over time or to treat to remission.
When subtypes of depression such as atypical, melancholic, and psychotic depressions are evaluated,
differences between antidepressant classes appear. Atypical depressions, which are characterized by
mood reactivity along with reverse vegetative symptoms such as increased sleep and appetite, have
long been shown to respond better to MAOIs than to TCAs. Since atypical depression may also respond
well to SSRIs and bupropion, these agents still would be first-line agents in the treatment of this
subtype. However, it may be quite reasonable to consider an MAOI for a patient with treatment
resistant depression with atypical features. The availability of transdermal selegiline, with its favorable
side-effect profile and lack of dietary restrictions, should probably now be the first MAOI that is
considered in either atypical or treatment-resistant depression.
There continues to be a debate as to whether melancholic or psychotic depression responds better to
TCAs or SNRIs than to SSRIs. Although most studies of antidepressant efficacy in these subtypes have
involved TCAs, prospective, head-to-head comparisons have never been done, and the literature
remains inconclusive. Melancholic depression clearly appears to respond to TCAs, and it may be more
reasonable to start with venlafaxine or mirtazapine, which are TCA-like in their dual actions, than with
an SSRI. Likewise, psychotic depression has responded to electroconvulsive therapy (ECT);
amoxapine, which is a tetracyclic agent; or the combination of a TCA and an antipsychotic. There are
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effective, and this would be the recommended first-line strategy because of safety and ease of use.
The age of the patient is an important consideration in antidepressant choice. In geriatric patients,
toxicity is more likely because of the number of concurrent medications they are taking, increased fat
to-muscle ratios, and reduced hepatic function and renal clearance. Among the SSRIs, escitalopram,
citalopram, and sertraline appear to be among the best tolerated and the least likely to have serious
pharmacokinetic interactions. Likewise, venlafaxine and mirtazapine have a low risk of interactions in
geriatric patients. However, there has been some concern about the safety of venlafaxine in frail
nursing home patients (Oslin et al. 2003). TCAs and MAOIs tend to be more poorly tolerated in
geriatric patients and would be second- or third-line agents in this population, although some
geriatricians still emphasize nortriptyline for elderly melancholic patients, and isocarboxazid was well
tolerated in geriatric studies done some years ago.
Gender is also an important factor in tolerability and efficacy of a given antidepressant class.
Substantial evidence suggests that men may respond to and tolerate the TCAs better than do women.
Conversely, premenopausal women appear to do better with serotonergic agents than do men. Thus,
men may be better treated with venlafaxine, duloxetine, or a TCA, and women may be better treated
with an SSRI or a 5-HT2 antagonist. Although clinicians would generally be advised not to start with a
TCA because of safety concerns, it may be better to start male patients with a more noradrenergic
agent than with an SSRI. Again, head-to head comparison studies are needed before clearer
recommendations can be made, and this area is still controversial.
The medical status of the patient is an important consideration in choosing an antidepressant. Patients
with pain conditions may do better with duloxetine, venlafaxine, or a TCA than with other agents.
There is some evidence that duloxetine, venlafaxine, and TCAs may be effective in treating both
depression and some types of pain conditions. Patients with a history of a seizure disorder, stroke, or
head trauma are more safely treated with an SSRI or venlafaxine than with a TCA or bupropion.
Likewise, patients with a history of arrhythmia or coronary artery disease are more safely treated with
serotonergic agents than with TCAs or MAOIs. Caution should be used in prescribing nefazodone for
AIDS patients who are taking protease inhibitors, since it may increase toxicity of the protease
inhibitors through pharmacokinetic interactions.
The primary drug parameters in choosing an antidepressant are side effects and safety. These are the
considerations that have made the SSRIs the most popular antidepressant choice for most clinicians.
The SSRIs are relatively safe in overdose and better tolerated than the TCAs and MAOIs for most
patients. From safety alone, it is difficult to justify using a TCA or an MAOI as a first treatment option.
Most of the SSRIs are given once per day, and the starting dose is sometimes the therapeutic dose.
Thus, the SSRIs are also among the easiest agents to use. Recently, the British equivalent of the FDA
warned that overdoses with fluoxetine were more likely to be lethal than overdoses with other SSRIs.
They advised against first-line use of the drug. The FDA has not agreed with this position.
Side effects differ considerably from class to class. Among the more important long-term side effects
that influence compliance are weight gain and sexual dysfunction. The TCAs, MAOIs, and mirtazapine
are probably the most problematic agents for weight gain, whereas fluoxetine and bupropion may be
the least problematic. Sexual dysfunction is common to most antidepressants, especially the MAOIs,
clomipramine, and the SSRIs. A number of agents are less likely to cause sexual side effects; these
include nefazodone, bupropion, and mirtazapine. In addition, novel antidepressants such as
agomelatine and transdermal selegiline also appear to have low risk for sexual side effects.
Another common approach to choosing an antidepressant is to target specific symptoms of a
depressive episode. For example, a patient with depression characterized by insomnia might benefit
from a sedating agent such as mirtazapine or a tertiary-amine tricyclic. Patients with significant anxiety
tend to be treated with an SSRI or SNRI. Patients with insomnia or anxiety may also be treated with
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http://www.psychiatryonline.com/popup.aspx?aID=231806&print=yes_chapterthe combination of an SSRI or SNRI and a hypnotic or benzodiazepine. Alternatively, many clinicians
will choose a more stimulating antidepressant such as bupropion or transdermal selegiline in treating
patients who are experiencing hypersomnia and fatigue. Patients with significant cognitive deficits or
executive functioning problems might be treated with a noradrenergic agent such as bupropion or
atomoxetine. This targeted approach to the treatment of depression is intuitively sound but not
necessarily supported by empirical data.
Thus, although there are many considerations in optimizing the choice of antidepressants, it is evident
that the SSRIs and newer antidepressants remain the first-line agents for most patients. However,
TCAs and MAOIs still have a role in selected populations of depressed patients and continue to
represent an important option.
Dosage and Administration
The optimal dose of an antidepressant is the smallest efficacious dose that has the least side effects.
The decision about how much to push the dose of an antidepressant always comes down to balancing
efficacy and side effects. If, with a given dose of antidepressant, there are no signs of improving
symptoms after 4 weeks, the chances are very small that that dose will ever be effective (Quitkin et al.
1996). On the other hand, partial response in the first 4 weeks predicts more complete response over
the next 8 weeks, even if the dose is held constant. If a given dose is tolerated and not producing
partial benefits at 4 weeks, the dose should be increased rather than the medication switched.
Generally, increasing the dose every 2 weeks gives some opportunity for the clinician to assess the
benefits and side effects of a given dose. If the increase in dose is tolerated and less than complete
remission is observed, the dose should be gradually increased to the maximum recommended dose.
Duration of Treatment
Although standard antidepressant trials in the 1960s and 1970s were often 4 weeks, 6- to 12-week
trials are the current standard. It is difficult to assess the efficacy of an antidepressant in less than 4
weeks. Furthermore, it is unlikely that 4 weeks will be adequate to assess higher doses in a tolerant
patient. Quitkin et al. (1984), in reviewing a large series of depressed patients who were treated with
traditional TCAs, concluded that relatively few patients demonstrated significant improvement after
only 2 weeks of therapy and that many required as long as 6 weeks to respond. Years ago, our group
(Schatzberg et al. 1981) reported that patients with slow response to maprotiline and those with rapid
response could be identified biologically by their pretreatment urinary levels of 3-methoxy-4-
hydroxyphenylglycol (MHPG), which are indicative of norepinephrine function. Patients with low MHPG
levels demonstrated rapid responses (in less than 14 days), and those with very high MHPG levels
needed 4–6 weeks of treatment. More recent reviews by Nierenberg et al. (1995), (2000) have also
suggested that failure to improve while taking a given dose of fluoxetine for 4 weeks predicts failure to
respond at 8 and 12 weeks.
All patients who respond to a given dose of an antidepressant should be maintained at that dose for at
least 6–12 months. The continuation of all antidepressants studied to date appears to substantially
reduce the risk of relapse. In a major National Institute of Mental Health collaborative study (Prien et
- 1984), imipramine was generally more effective than placebo or lithium in preventing relapse of
major depression over a 2-year maintenance period. In contrast to that study, two earlier major
studies, one in the United States and the other in the United Kingdom, found lithium to be as effective
as TCAs in preventing relapses in patients with unipolar depression. In the U.S. study by Prien et al.
(1984), the overall relapse rate in the unipolar group was relatively high (64%; 49% in the imipramine
group), and the authors argued for the need to develop newer, alternative strategies, perhaps with
drugs other than TCAs. (For further discussion of maintenance therapy in affective disorders, see
Chapter 4: “Antipsychotic Drugs.”) In the first edition of this manual, we indicated that after receiving
maintenance therapy for some 3–4 months at the doses at which they responded, many patients can
be maintained at lower doses (½ to ¾ that of the original dose) for the remaining months. However,
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http://www.psychiatryonline.com/popup.aspx?aID=231806&print=yes_chapterthe results of Frank et al. (1990) suggest that full doses are needed for successful maintenance
therapy. These investigators found that 80% of patients with recurrent depression were free from
relapse or recurrence for 3 years when full doses of imipramine (average of 200 mg/day) were
maintained. We second the recommendations of Frank and colleagues that patients be maintained at
their therapeutic dosage levels unless pronounced side effects are present. However, low versus high
doses of SSRIs in maintenance therapy have not been compared, so we do not know whether lower
doses of SSRIs are effective for maintenance. Since depression is a recurrent illness, long-term
maintenance therapy should be considered for anyone who has had three or more serious depressive
episodes or two episodes in the past 5 years.
Long-term treatment with antidepressants can represent a challenge for the patient in adhering to the
prescribed regimen. Several interventions can increase compliance. It is helpful to educate the patient
and family about the course of depressive illness, the length of time it takes for antidepressants to
work, and the need to continue treatment when the patient is feeling better. Reviewing potential side
effects is also helpful. Asking for feedback and answering any questions the patient may have allows
the clinician to check the patient’s understanding of the prescribed treatment. Instructing the patient
to not change the dosage or discontinue the medication without consulting his or her physician is often
helpful as well.
SELECTIVE SEROTONIN REUPTAKE INHIBITORS
Although the TCAs were the dominant class of antidepressants worldwide for more than 30 years, the
SSRIs overtook them in popularity in just a decade. Currently, this class includes fluoxetine,
paroxetine, sertraline, fluvoxamine, citalopram, and escitalopram (Figure 3–1). Fluvoxamine does not
have an FDA-approved indication for the treatment of depression. However, the drug is marketed in
many countries as an antidepressant. Unlike the TCAs or any other group of prescribed psychotropic
agents, the SSRIs, particularly fluoxetine, have had tremendous exposure in the scientific literature.
Figure 3–1.
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http://www.psychiatryonline.com/popup.aspx?aID=231806&print=yes_chapterThese drugs have been both vilified and praised in the lay press, but the popularity of the SSRIs
among patients and physicians has remained quite consistent. The enormous popularity of these
agents is due in no small part to their favorable safety and side-effect profile relative to the MAOIs and
the TCAs. The SSRIs have also proved to have a broad spectrum of activity in a variety of psychiatric
disorders, and they have an additional advantage in that it is easier to attain the optimal therapeutic
dose. However, not all patients tolerate or respond to the SSRIs, and, as suggested earlier (see
“Choosing an Antidepressant” subsection earlier in this chapter), they may not be as effective as the
more traditional antidepressants for some disorders.
Chemical structures of selective serotonin reuptake inhibitors (SSRIs).
Selective serotonin reuptake inhibitors (SSRIs): overview
Efficacy First-line treatment in
MDD (FDA approved for all except fluvoxamine), dysthymia
PD (FDA approved for fluoxetine, paroxetine, and sertraline)
OCD (FDA approved for all except citalopram and escitalopram)
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As the name of this class of antidepressants indicates, the SSRIs selectively block the reuptake of 5-HT
through their inhibiting effects on the Na+/K+ adenosine triphosphatase (ATPase)–dependent carrier in
presynaptic neurons. Compared with a standard TCA such as amitriptyline, which has about an equal
tendency to block neuronal reuptake of 5-HT and norepinephrine, fluoxetine is 200 times more
selective in blocking the reuptake of 5-HT than of norepinephrine. Fluoxetine is approximately 4 times
as potent a 5-HT reuptake inhibitor in vitro as is amitriptyline, and paroxetine is approximately 80
times as potent an inhibitor as amitriptyline. Of the five currently available SSRIs, paroxetine and
citalopram appear to be the most potent 5-HT uptake blockers.
Social anxiety disorder (FDA approved for sertraline and paroxetine)
PTSD (FDA approved for sertraline and paroxetine)
Bulimia (FDA approved for fluoxetine)
GAD (FDA approved for paroxetine and escitalopram)
PMDD (FDA approved for fluoxetine [Sarafem only], paroxetine [controlled
release only], and sertraline)
Side effects GI side effects (nausea, diarrhea, heartburn)
Sexual dysfunction ( libido, delayed orgasm)
Headache
Insomnia/somnolence
Safety in overdose Generally safe in overdose to 30–90 days’ supply; manage with vital sign
support, lavage
Seizures/status epilepticus (rare)
Dosage and
administration
Citalopram, paroxetine, fluoxetine: qd dosing, starting at 10–20 mg, increasing
to a maximum of 40 mg (citalopram), 50 mg (paroxetine), and 80 mg
(fluoxetine).
Escitalopram: qd dosing, starting at 10 mg, increasing to 20 mg after minimum
of 1 week.
Sertraline: starts at 25–50 mg and is increased, as needed, to 200 mg
maximum.
Full benefits in 4–8 weeks
Discontinuation Paroxetine, fluvoxamine, sertraline: discontinuation associated with
parasthesias, nausea, headaches, flulike symptoms 1–7 days after sudden
discontinuation
Drug interactions MAOI (contraindicated): serotonin syndrome
TCA levels (paroxetine, fluoxetine)
Carbamazepine, phenobarbital, phenytoin levels
Haloperidol, clozapine levels (fluvoxamine)
Theophylline levels (fluvoxamine)
Encainide, flecainide levels (avoid)
Note. FDA = U.S. Food and Drug Administration; GAD = generalized anxiety disorder; GI =
gastrointestinal; MAOI = monoamine oxidase inhibitor; MDD = major depressive disorder; OCD =
obsessive-compulsive disorder; PD = panic disorder; PMDD = premenstrual dysphoric disorder; PTSD
= posttraumatic stress disorder; TCA = tricyclic antidepressant.
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http://www.psychiatryonline.com/popup.aspx?aID=231806&print=yes_chapterHowever, selectivity is a relative term. Although the SSRIs are more selective than, say, the TCAs, all
the SSRIs impact other neurotransmitter systems, at least modestly. For example, there is in vitro
evidence that paroxetine at high dosages (>40 mg/day) may be as much, if not more, of a
norepinephrine reuptake blocker as is venlafaxine. Sertraline also appears to block the reuptake of
dopamine and may be more potent in this regard than bupropion. Likewise, paroxetine may have as
strong of an anticholinergic effect as desipramine.
The reuptake-blocking properties of the SSRIs enhance general serotonergic tone in at least two
distinct steps. Initially, the SSRIs contribute to a significant increase in the availability of 5-HT in the
synaptic cleft. However, it is unlikely that this effect has any bearing on antidepressant efficacy,
because the SSRIs share the delayed onset of action typical of all antidepressants. With recurrent
administration of the drugs, however, there is a reduction in the sensitivity of the somatodendritic and
terminal 5-HT1A autoreceptors, and the time course of this effect is associated more closely with
antidepressant response.
Unlike the TCAs, the SSRIs have relatively little affinity for histaminic (H1 , H2 ), muscarinic, or 1 –
adrenergic receptors. Although sertraline may have 25% of the in vitro affinity for 1 -adrenergic
receptors that imipramine has, this finding is of little clinical relevance. On the other hand, paroxetine
has weak but somewhat clinically meaningful antimuscarinic activity. The anticholinergic affinity for
paroxetine is roughly equivalent to that for desipramine. In general, however, the selective nature of
the SSRIs results in the very favorable side-effect profile and the large therapeutic index possessed by
these drugs.
The SSRIs are extensively metabolized by hepatic enzymes, especially the cytochrome P450 2D6
enzyme (Table 3–1). Sertraline is also metabolized via the cytochrome P450 3A3/4 enzyme. Only
fluoxetine and sertraline have pharmacologically active metabolites (Table 3–2). Fluoxetine is
demethylated to norfluoxetine, and sertraline is metabolized to N-desmethylsertraline and a
hydroxyketone. As a result, the functional half-lives of fluoxetine and sertraline are considerably longer
than those of paroxetine and fluvoxamine. Fluoxetine has a half-life of about 34 hours; the half-life of
norfluoxetine is at least 1 week. Sertraline has a half-life of about 26 hours, and the half-lives of its
metabolites tend to range from 48 to 72 hours. Both paroxetine and fluvoxamine have half-lives that
average under 20 hours, whereas citalopram has a half-life of around 35 hours. With repeated
administration of the drugs, the half-lives of all of the SSRIs, but particularly paroxetine and fluoxetine,
increase substantially, because the drugs appear to inhibit their own metabolism. Thus, the functional
half-lives of fluoxetine and norfluoxetine, with continued use, are closer to 2–3 weeks. Plasma level
monitoring of the SSRIs has not proved clinically useful. The variability of SSRI plasma levels among
individuals is so great that it has been nearly impossible to correlate efficacy or toxicity with plasma
levels.
Table 3–1. Inhibition of cytochrome P450 enzymes by antidepressant
Enzyme Drugs metabolized Antidepressant inhibitors
2D6 TCAs (hydroxylation) fluoxetine (norfluoxetine)
bupropion sertraline (desmethylsertraline)
venlafaxine paroxetine
thioridazine fluvoxamine and citalopram (weakest)
1C antiarrhythmics
-blockers
paroxetine
risperidone
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haloperidol
clozapine
benztropine
perphenazine
1A2 caffeine fluvoxamine
theophylline
phenacetin
TCAs (demethylation)
clozapine
diazepam
3A3/4 alprazolam fluoxetine
triazolam sertraline
TCAs (demethylation) fluvoxamine
terfenadine nefazodone
astemizole
carbamazepine
erythromycin
dexamethasone
citalopram
escitalopram
2C19 TCAs (demethylation) fluoxetine
warfarin fluvoxamine
tolbutamide sertraline
phenytoin
diazepam
Note. TCA = tricyclic antidepressant.
Table 3–2. Pharmacokinetics of selective serotonin reuptake inhibitors (SSRIs)
Ssri Half-life
(hours)
Metabolite and its half-life Peak plasma level
(hours)
% Protein
bound
fluoxetine 24–72 norfluoxetine, 7–14 days 6–8 94
sertraline 25
N-desmethylsertraline, 2–3
days
6–8 95
paroxetine <20 NA 2–8 99
fluvoxamine 15 NA 2–8 77
citalopram 35 NA 4–6 91
escitalopram 32
S-demethylcitalopram 5 56
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The SSRIs are indicated primarily for the treatment of major depression, and numerous studies have
supported this use. A large number of double-blind, placebo-controlled studies have established that
the SSRIs are useful in the treatment of mild to moderate major depression in outpatients (Rickels and
Schweizer 1990). The SSRIs are effective in atypical depression, in combination with standard
antipsychotics in the treatment of psychotic depression, and in the maintenance therapy of recurrent
depression in trials lasting 1 year. The SSRIs are also useful in the treatment of chronic major
depression with dysthymia. Some clinicians have come to regard these agents as the treatments of
choice for these disorders.
However, there is ongoing debate about the role of the SSRIs in more serious forms of depression,
including melancholia. Large meta-analyses and reviews have failed to show a significant difference in
efficacy between SSRIs and TCAs in the treatment of severe depression (Hirschfeld 1999; Nierenberg
1994). Still, relatively few studies of SSRIs have involved more severely depressed inpatients, and
some of the studies that did involve such patients did not directly compare the SSRIs with older agents
such as the TCAs. Some studies that made these direct comparisons suggested that paroxetine was
inferior to clomipramine in inducing remission in melancholic inpatients (Danish University
Antidepressant Group 1990) and that fluoxetine was much less effective than nortriptyline in treating
melancholic elderly cardiac patients who were hospitalized for depression (Roose et al. 1994). These
studies defined response not as a reduction in overall severity but rather as virtual remission. Other
studies have failed to find any difference in efficacy between the TCAs and SSRIs in more severely
depressed inpatients. This debate about the efficacy of the SSRIs in more severe depression is likely to
continue. The available data suggest that the SSRIs may not be quite as effective in treating some
seriously depressed elderly inpatients but that they do have a more favorable side-effect profile than
the TCAs.
The second indication for the SSRIs is the treatment of OCD. The utility of clomipramine (a
serotonergic TCA) in the treatment of OCD was first noted in 1968. Since that time it has become clear
that other serotonergic agents are also useful in the treatment of this historically difficult-to-treat
disorder (Chouinard et al. 1990; Tollefson et al. 1994). Fluvoxamine, fluoxetine, sertraline, and
paroxetine all have an FDA indication for the treatment of OCD, but all the SSRIs have demonstrated
efficacy in treating the disorder. SSRI doses for the treatment of OCD are usually higher than those
required for the treatment of depression, and the latency to response is usually longer.
A third indication for the SSRIs, and a fairly well studied one, is the treatment of eating disorders,
particularly bulimia nervosa. Fluoxetine has been shown to have a positive effect on the binge-purge
cycle in some bulimic patients (Fluoxetine Bulimia Nervosa Collaborative Study Group 1992). The
SSRIs may also ameliorate the carbohydrate craving and mood disturbance associated with bulimia
nervosa and obesity. Fluoxetine and sertraline have been shown to have a modest effect on weight and
food intake in obese patients. Unfortunately, most patients who lose weight in the course of therapy
with an SSRI gain it back over time. There are few data on the use of the SSRIs to treat classic
anorexia nervosa, but one report suggested that fluoxetine may be useful for this condition (Kaye et al.
1991). The largest controlled study to date of fluoxetine in the prevention of relapse in anorexic
patients failed to show any benefit for fluoxetine in preventing relapse relative to placebo (Walsh et al.
2006). However, this study involved adults with a more chronic form of the illness, and there may be
subsets of anorexic patients who appear to do better while taking an SSRI.
Finally, there appears to be a role for the SSRIs in the treatment of most other anxiety disorders,
including panic disorder, social phobia, GAD, and PTSD. Although patients with panic disorder may be
sensitive to the activating effects of some SSRIs, most are able to tolerate a slow titration of dosage
upward. For example, some reports indicate that although some patients do not tolerate an initial
Note. NA = not applicable.
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http://www.psychiatryonline.com/popup.aspx?aID=231806&print=yes_chapterdosage of 20 mg/day of fluoxetine, many patients are able to benefit if the starting dosage is 5 mg/day
(Schneier et al. 1990).
The SSRIs, including citalopram and fluvoxamine, all appear, on the basis of published data, to be
effective in treating panic disorder. Paroxetine, sertraline, and fluoxetine have received an FDA
approved indication for the treatment of panic disorder.
In 1999, paroxetine received an FDA-approved indication for treating social phobia, and preliminary
data support the use of other SSRIs in the treatment of this disorder. A number of double-blind studies
indicate that paroxetine at dosages of 20–50 mg/day is more effective than placebo in alleviating
symptoms, including undue fear and avoidance of interpersonal interaction. Further, paroxetine
appears to reduce the significant disability associated with more severe forms of this disorder (Stein et
- 1998).
Posttraumatic stress disorder is associated with a variety of comorbid conditions, especially depression
and substance abuse. SSRIs have been used since the late 1980s to treat some of the symptoms of
PTSD, including depression, insomnia, hyperarousal, and agitation. There is substantial evidence that
fluoxetine, paroxetine, and sertraline help alleviate these symptoms and may even impact comorbid
substance use. In 1999, sertraline became the first drug to be approved by the FDA for the treatment
of PTSD. Many PTSD patients treated with sertraline appear to require doses above 100 mg/day of
sertraline for maximum effects. With paroxetine, a dosage of 20 mg/day appears to be about as
effective as 40 mg/day in treating PTSD.
The SSRIs should help with GAD, and paroxetine and escitalopram have received FDA approval for this
indication. Paroxetine, at dosages of 20–50 mg/day, was effective in reducing anxiety by 60% on the
Hamilton Anxiety Rating Scale. Large-scale studies of escitalopram have also shown benefit in the
treatment of generalized anxiety.
Premenstrual dysphoric disorder (PMDD) is a very disruptive monthly occurrence for about 3% of the
female population. In 1995, in the first large study of fluoxetine in the treatment of PMDD (Steiner et
- 1995), 20- and 60-mg doses were more effective than placebo for treating symptoms over six
consecutive menstrual cycles. The effect was seen as early as the first cycle after initiation of the
medication. Since then, a number of studies have supported the use of SSRIs, especially fluoxetine and
sertraline, in treating this disorder. Both of these drugs have also been used as intermittent treatment
in the luteal phase of the cycle and appear to be effective (Jermain et al. 1999). In 1999, fluoxetine
(Sarafem) became the first medication approved for the treatment of PMDD.
The list of disorders in which the serotonergic system plays a part is long, and the potential role for the
SSRIs is continually expanding. The SSRIs appear to be useful in treating the anger or impulsive
aggression associated with some personality disorders (Kavoussi et al. 1994; Salzman et al. 1995) and
perhaps certain pain disorders such as diabetic neuropathy and fibromyalgia (Wolfe et al. 1994),
although here the mixed norepinephrine-serotonin reuptake blockers appear to be far more effective.
Side Effects
As noted previously, the SSRIs tend to be safer and better tolerated than their predecessors. There
have been many overdoses in clinical practice with the SSRIs, but these have rarely been eventful. In
fact, a review of 234 fluoxetine overdose attempts, with doses up to 1,500 mg, failed to reveal any
fatalities, and more than half the patients were completely asymptomatic (Borys et al. 1992). Nothing
more than supportive care was required for any patient. Moderate overdoses (5–30 times the total
daily dose) are rarely serious. Fatal overdose with any of the SSRIs is at least theoretically possible but
has been rare. The usual cause of death appears to be complications of seizures or status epilepticus
and typically involves ingesting thousands of milligrams (Barbey and Roose 1998). There is no question
that the SSRIs offer a significant safety advantage over the TCAs and MAOIs.
In early clinical studies, approximately twice as many patients were likely to drop out because of
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http://www.psychiatryonline.com/popup.aspx?aID=231806&print=yes_chapteradverse effects of TCAs as because of adverse effects of SSRIs. The SSRIs are largely devoid of the
anticholinergic side effects that plague the TCAs. Furthermore, orthostatic hypotension does not
typically occur with SSRI use. That is not to say that all people tolerate the SSRIs better than the
TCAs. Emerging data suggest that men may tolerate and respond to TCAs better than do women. The
basis for this finding has not been elucidated. However, even greater tolerability, if substantiated,
would not make TCAs safer, and they are still second-line agents.
The most common reasons patients discontinue the SSRIs early in treatment are gastrointestinal (GI)
side effects. These include nausea, diarrhea, cramping, heartburn, and other symptoms of GI distress.
The gut is lined with 5-HT receptors, including 5-HT3 , which appear to be responsible for SSRI-induced
GI distress. Whereas the earliest reports suggested that approximately 20%–30% of patients treated
with fluoxetine developed GI side effects, the incidence in clinical practice has been much lower. In
early studies, the dosage was often started at 20 mg/day but reached 60 mg/day by the end of the
first week. In clinical practice, the starting dosage of 20 mg/day is maintained for 3 weeks, and nausea
is both less common and less severe. Furthermore, the GI side effects tend to diminish over the first
2–4 weeks of treatment.
Several strategies may be useful in reducing SSRI-induced GI distress. The first is a slow titration of
the medication. Starting at half, or less than half, of the usual starting dose and moving the dose up
slowly in sensitive patients allows adaptation to occur. Another strategy is instructing patients to take
their medication with meals. A full stomach appears to mitigate some GI distress. Finally, there is a
case report on the use of cisapride, a 5-HT3 antagonist, 5 mg bid, to reduce SSRI-induced GI distress
(Bergeron and Blier 1994). Unfortunately, cisapride was removed from the market in 1999 because of
the risk of arrhythmia. Other 5-HT3 antagonists, such as dolasetron (Anzemet) and ondansetron
(Zofran), are also clearly helpful but are too expensive to use routinely. Mirtazapine (Remeron) is a
moderately potent 5-HT3 antagonist and could potentially be used in combination with SSRIs.
Another group of side effects commonly encountered with SSRIs is related to central nervous system
(CNS) activation. At least 10%–20% of patients receiving SSRI therapy complain of insomnia,
jitteriness, and agitation in the course of treatment. These side effects are not particularly surprising,
given the selective, but not specific, effect of SSRIs on CNS serotonergic transmission. That is, the
SSRIs affect diffuse serotonergic pathways, and some of these pathways contribute to CNS arousal.
For this reason, fluoxetine, which has a reputation for activating properties, should be taken in the
morning, when it is less likely to interfere with sleep. Likewise, if patients develop insomnia with other
SSRIs, it is often effective to have the patients take the dose earlier in the day. Occasionally, patients
require modest doses of a benzodiazepine (e.g., clonazepam 0.5 mg bid, lorazepam 0.5 mg bid,
alprazolam 0.25 mg bid) early in the course of therapy to help with agitation and sleep. Trazodone is
another commonly used agent shown to be helpful at doses of 50–100 mg at bedtime for SSRI-induced
insomnia. A number of case reports also suggest that trazodone may augment response in the SSRIs.
Conversely, some patients may become sedated on SSRIs. This effect is seen mostly with paroxetine.
When sedation occurs, taking the dose at about 8:00 P.M. is useful for matching the peak blood level
with the optimal time of sedation (about 2:00 A.M.). Some patients taking other SSRIs experience the
emergence of a numbed or anergic feeling in the context of a euthymic mood. Donald Klein has
recommended low dosages of bromocriptine (2.5 mg qd or bid) or stimulants to counteract this effect.
Modafinil (Provigil) has been applied to counteract antidepressant-induced hypersomnia. Modafinil is a
stimulant with low abuse potential and is FDA approved for the treatment of narcolepsy and idiopathic
hypersomnia. We have found that doses of 100–200 mg in the morning are helpful in alleviating
treatment-emergent somnolence (DeBattista et al. 2003).
In recent years, it has become clear that treatment-emergent sexual dysfunction is a much bigger
problem with SSRI treatment than was previously recognized. Premarketing studies suggested that the
incidence of sexual dysfunction—including delayed ejaculation, anorgasmia, impotence, and diminished
libido—was less than 4%. However, more recent reports suggested that the incidence may be closer to
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http://www.psychiatryonline.com/popup.aspx?aID=231806&print=yes_chapter30%–40% for all of the SSRIs. Although accommodation to sexual side effects does occur in some
patients, such improvement may take months or even years. Holding the dose of shorter-acting SSRIs,
such as paroxetine and sertraline, for 24 hours prior to anticipated sexual activity has been anecdotally
reported to be helpful in some 50% of patients. The long half-life of fluoxetine makes this approach
ineffective.
A number of interventions to counteract treatment-emergent sexual dysfunction have been described
(Table 3–3), but most have not been well studied. Virtually all the reported benefits of adjunctive
agents for treatment-emergent sexual side effects are based on case reports or open-label studies. A
few controlled studies have been completed, but their findings are not conclusive. In one of the few
double-blind studies of sexual dysfunction antidotes to be published, buspirone, a partial agonist of the
5-HT1A receptor, was shown to be useful in treating SSRI-induced sexual dysfunction in some patients
at dosages of 20–60 mg/day (Landen et al. 1999). However, another double-blind study of buspirone
in the treatment of SSRI-induced sexual side effects did not find buspirone to be useful in this regard
(Michelson et al. 2000). Mirtazapine was also ineffective in a controlled trial, although olanzapine, a 5-
HT2 /D2 antagonist, was significantly more effective than placebo (Michelson et al. 2002). Switching to
bupropion (Walker et al. 1993) or adding bupropion at dosages of 75–150 mg/day to the SSRI regimen
(Ashton and Rosen 1998; Hirschfeld 1999; Labbate and Pollack 1994) has proved useful in some
cases. We completed a double-blind study of bupropion as an add-on therapy (DeBattista 2001) and
found it helpful for mood but not for sexual performance at a fixed dosage of 150 mg/day (DeBattista
et al. 2004). Bupropion was found to be only marginally effective at increasing sexual arousal;
however, a dose of 300 mg or more may be needed to improve sexual function. Clayton and colleagues
(2004) found that bupropion at a dosage of 150 mg bid improved desire and interest in sexual activity
on some measures after 4 weeks.
The use of sildenafil (Viagra) has been reported to be significantly more effective than placebo in men
with SSRI-induced sexual dysfunction (Nurnberg et al. 2001; Fava et al. 2006a). The reported utility of
sildenafil in countering SSRI-induced sexual side effects is somewhat counterintuitive, since the most
common sexual side effects of SSRIs are decreased libido and delayed orgasm rather than erectile
problems. However, sildenafil has been reported to increase overall sexual satisfaction in both men and
women. We have found sildenafil at dosages of 50–100 mg/day to be more helpful with men than with
Table 3–3. Adjunctive agents for selective serotonin reuptake inhibitor (SSRI)–induced
sexual dysfunction
Adjunctive
agent
Dosage Studies
buspirone 20–60
mg/day
Landen et al. 1999; Norden 1994
bupropion 75–150
mg/day
Ashton and Rosen 1998; Labbate and Pollack 1994
sildenafil 50–100 mg
prn
Ashton and Bennett 1999; Gupta et al. 1999; Nurnberg et al.
1999a, 1999b; Fava et al. 2006a
vardenafil 10–209 mg Rosen et al. 2006
Ginkgo biloba
60–240
mg/day
Wheatley 2004
amantadine 100–300
mg/day
Balon 1996; Shrivastava et al. 1995
cyproheptadine 4–12 mg prn Aizenberg et al. 1995; Keller Ashton et al. 1997
yohimbine 5.4 mg tid Jacobsen 1992; Price and Grunhaus 1990
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http://www.psychiatryonline.com/popup.aspx?aID=231806&print=yes_chapterwomen. Similar agents such as vardenafil also appear to be effective in antidepressant-associated
sexual dysfunction, at least in men (Rosen et al. 2006). Cyproheptadine at dosages of 4–12 mg/day
may reverse some of the dysfunction. Unfortunately, cyproheptadine may also reverse the
antidepressant or antiobsessive effects of the SSRIs and is quite sedating. The -adrenergic agonist
yohimbine helps some patients (Jacobsen 1992) but was ineffective in a controlled trial (Michelson et
- 2002). Unfortunately, yohimbine can be quite anxiogenic for some patients, and this effect tends to
be counterproductive. Similarly, some case reports have suggested that dopaminergic agents such as
amantadine, amphetamine, and bromocriptine may be helpful for some patients. The ancient herb
Ginkgo biloba has been anecdotally reported to help some patients with SSRI-induced sexual
dysfunction. However, beneficial effects may require a higher dosage (e.g., 240 mg/day) for weeks,
and such dosages have sometimes been associated with GI side effects, increased bleeding, and
confusion in elderly patients. As is often the case, more carefully controlled studies have failed to show
a benefit of Ginkgo biloba in treating antidepressant-induced sexual dysfunction (Wheatley 2004).
Given the lack of evidence supporting ginkgo and the potential for some side effects, we do not
encourage patients to try it.
A number of other adverse effects are associated with the SSRIs, but these occur less consistently.
Headaches may occur early in the course of therapy with some patients. On the other hand, the SSRIs
have shown some utility in the prophylaxis of migraine when used long-term. Autonomic symptoms
such as excessive perspiration and dry mouth are frequently reported. Excessive perspiration is very
problematic for some patients. Anecdotal approaches to the treatment of SSRI-induced perspiration,
such as the use of -blockers and anticholinergic agents, are largely untested. 2 -Adrenergic agents
may be helpful here. Tremor may develop in a dose-related pattern and is often responsive to
propranolol in modest dosages (10 mg tid). Dry mouth is seen in some 20% of patients treated with
paroxetine, reflecting the mild anticholinergic effects of this medication.
The question of whether weight gain is associated with chronic use of SSRIs has become a focus of
interest. In general, it has been difficult to reliably correlate significant weight gain with SSRI
treatment. After a year of treatment, most of the SSRIs are associated with either no weight gain or
modest weight increases. Among the SSRIs, paroxetine may be somewhat more associated with
weight gain and fluoxetine somewhat less.
Teicher et al. (1990) reported the emergence of intense preoccupation with suicide in six patients early
in fluoxetine treatment. This phenomenon may also occur with other antidepressants. Subsequent
studies and analyses of data sets have failed to find any greater proclivity for suicide with fluoxetine
than with other antidepressants (Beasley et al. 1991). In addition, there has been no association of
fluoxetine with suicidality in bulimia (Wheadon et al. 1992) or OCD (Beasley et al. 1992). This suggests
that the phenomenon of treatment-emergent suicidal thoughts may be an artifact of the patient’s
underlying depression rather than the result of the medication. However, fluoxetine is associated with
agitation or perhaps akathisia-like side effects, and it is conceivable that some depressed patients may
become more suicidal when these effects occur (Rothschild and Locke 1991). Rothschild and Locke
(1991) reintroduced fluoxetine in three patients who had previously attempted suicide while taking
fluoxetine. They reported that all three patients developed severe akathisia with the reintroduction. In
two of the three cases, the suicidal distress was relieved by propranolol. Thus, switching to a less
activating antidepressant or using a benzodiazepine such as clonazepam or lorazepam or a -blocker
concurrently with the SSRI may be advisable in cases of treatment-emergent suicidal ideation. Some
patients who experience this phenomenon while taking a TCA may not experience it with fluoxetine.
The second author (J.O.C.) was involved in the Teicher et al. (1990) report on obsessive suicidal
thoughts associated with fluoxetine and still believes he sees in rare cases patients who experience this
phenomenon. Fisher et al. (1992), in a prescription-based survey, found that 0.5% of patients who had
recently filled a fluoxetine prescription called an 800 number to report a new suicidal drive; no patients
who had filled trazodone prescriptions reported such adverse effects. The rare incidence of treatment
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http://www.psychiatryonline.com/popup.aspx?aID=231806&print=yes_chapteremergent suicidal thoughts is not a justification for avoidance of SSRIs. The controversial FDA review
of antidepessants and suicidality in children found an increased risk of about 3% with the
antidepressants and 1.5% with placebo. This resulted in a black box warning regarding the risks of all
antidepressants used in adolescents and children. However, this increased risk must be balanced with
the improvement in suicidal ideation that occurs in many more patients while taking antidepressants.
Studies subsequent to the black box warning that have examined the risk of suicidal behavior with
antidepressant use have generally failed to find an association (Hammad et al. 2006a, 2006b; Kaizar et
- 2006; Simon et al. 2006; Sondergard et al. 2006a, 2006b). Of note was the study by Simon et al.
(2006), in which risk of suicide attempts was highest in the month before initiation of therapy. The
recent FDA-initiated study of 100,000 patients revealed a 2% risk of emergent suicidal-like behavior in
subjects 18–25 years of age versus 1% in subjects receiving placebo. Older patients appeared to not
show such increased risk, and elderly subjects showed a significant decrease. However, as with adults,
there may be small subsets of patients at greater risk for suicidal behavior (e.g., young adults) while
taking antidepressants. These could include patients with latent bipolar disorder, patients who
experience agitation while taking an antidepressant, and patients who become energized enough while
taking an antidepressant to act on suicidal impulses before their mood has substantially improved.
We continue to recommend that these drugs be used in both children/adolescents and adults, but with
appropriate warning and monitoring. In view of the clustering of adverse reports with paroxetine in
children, it does seem wise to use another agent before trying paroxetine in children.
Overdose
The popularity of the SSRIs rests in part on their safety in overdose (Barbey and Roose 1998).
Thousand of overdoses have occurred in the past 15 years, but very few fatalities have resulted from
overdosing on an SSRI alone. Fluoxetine, the first SSRI in the United States and the most commonly
used, has the most fatalities associated with its overdose. Moderate overdoses (at up to 30 times the
common daily dose) tend to be associated with minor symptoms. The most common symptoms of
large overdoses include vomiting, nausea, tremor, and sedation. At very high doses (more than 75
times the common daily dose), more serious adverse events, cardiovascular events, seizures, and
altered or decreased consciousness have been reported.
The most common causes of death in an SSRI overdose are typically complications of status epilepticus
and cardiovascular events such as arrhythmias.
Most fatalities have involved the co-ingestion of other drugs, particularly alcohol or drugs dependent on
the cytochrome P450 2D6 system, such as the TCAs (Dalfen and Stewart 2001).
In general, lavage and supportive care in the emergency room are all that is required in the vast
majority of SSRI overdoses. In severe overdoses or those involving other drugs, cardiac monitoring or
interventions for seizure control may be required.
Drug Interactions
The risk of serious drug interactions is fairly limited with SSRIs. However, several types of drug
interactions may occur. The most serious of these is the interaction with the MAOIs. Several fatalities
have been reported from serotonin syndrome when SSRIs were used in close proximity to MAOIs, even
if the drugs were not used concurrently. In two of these cases, fluoxetine had been stopped but an
MAOI had been started promptly thereafter. Therefore, an adequate washout must occur after the
SSRIs are discontinued before an MAOI is initiated (see “Discontinuation” subsection). Serotonin
syndrome has proved difficult to treat. The most important interventions in treating this syndrome are
stopping the offending agents and initiating medical support, including lowering of body temperature, if
needed. Beyond that, cyproheptadine at a dosage of 16 mg/day may be helpful in less severe cases in
which myoclonic jerking is present. Dantrolene may also be helpful (see Chapter 10: “Emergency
Room Treatment”).
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http://www.psychiatryonline.com/popup.aspx?aID=231806&print=yes_chapterAnother type of potential drug interaction occurs as a result of the tendency of the SSRIs to
competitively inhibit enzymes of the cytochrome P450 system (Table 3–1). The inhibition of the 2D6
enzyme by the SSRIs is perhaps the best understood. Many drugs are metabolized by this enzyme,
including the TCAs, type 1C antiarrhythmic agents, some -blockers, benztropine, and many
antipsychotic medications. Most of the SSRIs are capable of inhibiting the 2D6 enzyme, leading to
increased plasma levels of other agents. For example, fluoxetine may be associated with up to an
eightfold increase in TCA plasma levels when the two drugs are used concurrently. On a molar basis,
fluoxetine, paroxetine, and sertraline are fairly equal in their proclivity to competitively inhibit the 2D6
enzyme, whereas citalopram (and escitalopram) and fluvoxamine do not significantly inhibit this
enzyme. Sheldon Preskorn at the University of Kansas reported that 20 mg of fluoxetine raises
desipramine levels several times higher than does 50 mg of sertraline. However, other studies indicate
that higher dosages of sertraline (e.g., 150 mg/day) can produce significant increases in desipramine
levels. Fluvoxamine is about 10 times less potent a competitive inhibitor of the 2D6 enzyme than the
other SSRIs, yet it was associated with a twofold increase in amitriptyline levels in two patients and a
sevenfold increase in clomipramine levels in a third patient (Bertschy et al. 1991). Fluvoxamine has
also been associated anecdotally with significantly increasing clozapine levels, probably through its
inhibition of the cytochrome P450 1A2 enzyme. Thus, caution should be exercised when combining any
of the SSRIs with drugs predominantly dependent on the 2D6 enzyme, because the risk of toxicity
from the concurrent drug will be enhanced. For example, it is prudent to monitor TCA serum levels and
electrocardiograms (ECGs) when any of the TCAs are used in combination with an SSRI. However, in a
geriatric study, Murphy et al. (2003) failed to find a relationship between specific cytochrome P450
2D6 alleles and the risk of dropping out due to adverse events, even though patients were taking a
variety of medical drugs that were known substrates for the 2D6 enzyme.
Although the 2D6 enzyme is the best characterized of the cytochrome P450 enzymes, there are at
least five others, and the SSRIs may be associated with the competitive inhibition of some of them as
noted above. Fluvoxamine is known to inhibit the 1A2 enzyme, which is responsible for the metabolism
of theophylline, caffeine, certain benzodiazepines, and haloperidol. It would therefore be prudent to
use lower doses of theophylline when treating asthmatic patients with fluvoxamine. In addition,
fluoxetine and fluvoxamine are capable of inhibiting the 3A3/4 enzyme, which degrades such common
drugs as triazolo compounds, including alprazolam, triazolam, and trazodone. Increased drowsiness
has been reported in patients treated concurrently with SSRIs and alprazolam, but no serious reactions
have been reported. However, lower doses of the concomitant drugs may be required. At one point, H2
blockers were thought to be particularly problematic vis-à-vis untoward interactions, but this has not
been borne out.
Among the SSRIs, citalopram and escitalopram currently exhibit the least potential for pharmacokinetic
interactions. Citalopram and escitalopram are weak inhibitors of not only cytochrome P450 2D6 but
also 3A3/4, 1A2, and 2C19. With venlafaxine, citalopram shares a low risk of drug interactions, which
has made it popular in the treatment of geriatric patients.
Dosage and Administration
Among the factors that have contributed to the enormous popularity of the SSRIs is that the starting
dose of the drug is frequently the optimal dose as well (Table 3–4). Given the already lengthy latency
of onset of antidepressant action, the SSRIs typically do not require a prolonged titration period in
which to achieve a therapeutic dose, as is common with the TCAs and the MAOIs.
Table 3–4. Selective serotonin reuptake inhibitors (SSRIs) and other available
antidepressants: names, formulations and strengths, and dosages
Generic name Brand name
Formulationsa and
strengths
Usual therapeutic
dosage (mg/day)b
SSRIs
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http://www.psychiatryonline.com/popup.aspx?aID=231806&print=yes_chapterFluoxetine is usually initiated at 20 mg/day, and the maximum recommended dosage is 80 mg/day. A
citalopram Celexa Tablets: 10, 20, 40 mg 20–40
Oral solution: 10 mg/5 mL
(240-mL bottle)
escitalopram Lexapro Tablets: 5, 10, 20 mg
Oral solution: 5 mg/5 mL (240-
mL bottle)
fluoxetine Prozac Capsules: 10, 20, 40 mg
Capsule (weekly): 90 mg
Oral solution: 20 mg/5 mL
(120-mL bottle)
Tablets: 10, 20 mg
20–60
fluvoxamine Luvox Tablets: 25, 50, 100 mg 100–200
paroxetine Paxil Tablets: 10, 20, 30, 40 mg
Oral suspension: 10 mg/5 mL
(250-mL bottle)
20–50
Paxil-CR (controlled
release)
Tablets: 12.5, 25, 37.5 mg
sertraline Zoloft Tablets: 25, 50, 100 mg
Oral concentrate: 20 mg/mL
(60-mL bottle)
50–200
5-HT2
antagonists
nefazodone Generic only Tablets: 50, 100, 150, 200,
250 mg
300–500
trazodone Desyrel and generic
Tablets: 50, 100, 150,c 300c
mg
150–300
Other
bupropion Wellbutrin and generic
Wellbutrin SR
(sustained-release)
Wellbutrin XL
(extended-release)
Tablets: 75, 100 mg
Tablets: 100, 150, 200 mg
Tablets: 150, 300 mg
200–450
mirtazapine Remeron Tablets: 7.5, 15, 30, 45 mg
Soltabs: 15, 30, 45 mg
15–45
venlafaxine Effexor
Effexor-XR (sustained
release)
Tablets: 25, 37.5, 50, 75, 100
mg
Capsules: 37.5, 75, 150 mg
75–375
duloxetine Cymbalta Capsules: 20, 30, 60 mg 60–120
Note. 5-HT2 = serotonin2 receptor.
aNot available in an injectable form.
bDosage ranges are approximate. Many patients will respond at relatively low dosages (even dosages
below those in ranges given above); others may require higher dosages.
cTrazodone also available in 150- and 300-mg divided-dose formulations.
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http://www.psychiatryonline.com/popup.aspx?aID=231806&print=yes_chapterreview of the efficacy data from double-blind studies of the use of fluoxetine in the treatment of major
depression revealed that fluoxetine produced maximal benefits at 20–40 mg/day, with lesser benefit
noted at 60 mg/day. In fact, 60 mg/day appeared to be less effective and to have more side effects
than did 20–40 mg/day. Because 20 mg was often effective and the drug has a long half-life, the
manufacturer finalized the recommended initial dosing at 20 mg/day for 3 weeks, with subsequent
increases to 40–80 mg/day if indicated. Patients with significant psychomotor retardation often seem
to require at least 40 mg/day. In other patients, 10 mg/day may be effective. The drug is currently
available in 10-mg, 20-mg, and 40-mg capsules, as well as in 10- and 20-mg tablets and in a
suspension. Dosages as low as 2 mg/day can be obtained with the suspension, and this is particularly
useful in patients who cannot initially tolerate higher dosages. Patients who have failed to respond to a
lower dosage (20 mg) may subsequently improve if the dosage is increased to 40–60 mg/day (Fava et
- 1994).
A few years ago a 90-mg, once-weekly form of fluoxetine was introduced. This form was designed to
be an alternative to daily treatment with fluoxetine at 20 mg/day and is meant for use in the
maintenance phase of treatment only. There are patients who prefer taking one capsule weekly rather
than daily. Taking one capsule every 3 days appears roughly equivalent to 40 mg/day. Some patients
take two capsules per week on the same day to achieve the equivalent of 40 mg/day. (It is unclear
whether taking two 90-mg capsules equals 40 mg/day.) However, staggering the dose every 3 days
decreases side effects. Dosing the weekly form of fluoxetine every 3 days appears to be well tolerated.
Dosing of paroxetine is much like that of fluoxetine, with an initial dosage of 20 mg/day. The
immediate-release form of the drug is currently available in 10-mg, 20-mg, 30-mg, and 40-mg tablets.
The tablets are scored, and patients intolerant of a full tablet can have the dose reduced to a half
tablet for 2–3 weeks. If no response is seen, the dosage may then be increased each week by 10–20
mg/day until a maximum dosage of 50 mg/day is achieved. Data suggest that patients with more
serious depressions require higher dosages (30–50 mg/day). Controlled-release (CR) paroxetine is
currently available in 12.5-mg, 25-mg, and 37.5-mg tablets, which are equivalent to the 10-mg, 20-
mg, and 30-mg immediate-release tablets, respectively. (At one point since the last edition, the CR
formulation was taken off the market because of quality control issues during the manufacturing.)
Citalopram is dosed at 20–60 mg/day. The new version of citalopram, escitalopram (Lexapro), is more
potent and is generally dosed at 10–20 mg/day. The side effects of escitalopram at 20 mg/day roughly
equal those seen with citalopram at 40 mg/day.
The dosage range for sertraline is somewhat wider than that for fluoxetine, paroxetine, and citalopram.
In addition, a more linear dose-response curve separates sertraline from the other SSRIs, which have
a relatively flat dose-response curve. Therapy is usually initiated at 50 mg/day, although, as with the
other SSRIs, a lower starting dosage is sometimes required. The 50-mg dose may be continued for 2
weeks, and if no response is seen, the dosage may then be increased weekly by 50 mg/day until a
maximum dosage of 200 mg/day is achieved. Sertraline is available in 25-mg, 50-mg, and 100-mg
tablets as well as a concentrate. The different tablet strengths are priced similarly. Thus, it is typically
more economical to prescribe the scored 100-mg tablets and instruct patients to break them in half to
achieve a dosage of 50 mg/day.
Fluvoxamine has a wider dosage range. It is usually initiated at 50–100 mg/day. Because of
fluvoxamine’s short half-life, dosages higher than 100 mg/day require divided doses in order to
optimize drug availability. In premarketing studies, most patients with major depression required
dosages in the range of 100 to 200 mg/day. However, some patients required a dosage as high as
300 mg/day.
Discontinuation
Discontinuation symptoms may be less common with the SSRIs than with the TCAs. However, a
number of case reports and double-blind studies do indicate that a discontinuation syndrome may
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http://www.psychiatryonline.com/popup.aspx?aID=231806&print=yes_chapteroccur with the sudden discontinuation of some SSRIs, especially the shorter-acting agents paroxetine,
sertraline, and fluvoxamine.
The most common presentation of an SSRI discontinuation syndrome is a flulike condition with
malaise, nausea, and headaches occurring within 2–7 days of stopping an SSRI. Paresthesias,
dizziness, agitation, and rebound depression have also been reported when the drugs are suddenly
discontinued. The mechanism underlying these symptoms is unclear. Because of paroxetine’s greater
effect at the serotonin transporter, shorter half-life, and anticholinergic properties, discontinuation
symptoms may be more common with this agent than with the other SSRIs. Fluoxetine’s very long
half-life and citalopram’s medium half-life may diminish the risk of discontinuation symptoms with
these drugs. Of the SSRIs, fluoxetine may be stopped abruptly without much risk of difficulty.
However, for the shorter-acting SSRIs, it may be prudent to taper the drugs over several weeks,
particularly if the patient required a prolonged titration upward as a result of adverse effects. Tapering
by 25% of the dose per week for doses greater than 30 mg of paroxetine, 100 mg of sertraline, and
150 mg of fluvoxamine is quite reasonable if it is practical to do so. In trials of 4 weeks or less, faster
taper schedules can be tried, and most patients will not require a taper.
If discontinuation symptoms occur, the first step may be to increase the dose to the previous dose and
taper more gradually. Often, resuming the previous dose will resolve the discontinuation symptoms
within 48 hours. Occasionally, clinicians have substituted a longer-acting agent such as fluoxetine for a
shorter-acting agent such as paroxetine in patients with substantial discontinuation symptoms.
However, there are no good data on the safety or efficacy of this approach.
In starting an MAOI after discontinuing an SSRI, a safe washout period depends on the half-life of the
drug and its metabolites. For fluoxetine, the manufacturer has recommended waiting 5 weeks when
changing from fluoxetine to an MAOI. This period is five times the half-life of the active metabolite of
fluoxetine, norfluoxetine. It is conceivable that a shorter period (e.g., 3 weeks) may suffice, but no
data are available. The other SSRIs are shorter acting than fluoxetine, and a 2-week washout appears
adequate. When going from an MAOI to an SSRI, a period of 2 weeks of no MAOI is recommended
before starting the SSRI.
A common question in clinical practice is, Does it make sense to switch from one SSRI to another if
one is not working? Although the practice of switching from one SSRI to another is common, very few
prospective, controlled data are available to support the practice. Clearly, however, patients who are
intolerant of one SSRI may achieve benefit by being switched to another. Brown and Harrison (1995)
reported that patients may respond to sertraline after not responding to fluoxetine. The largest study
to date to examine the question of switching to another SSRI after failing the first is STAR*D (Rush et
- 2006). In that study, 727 patients who failed to achieve remission while taking citalopram were
switched to either sertraline, venlafaxine, or bupropion. The remission and response rates when
patients were switched to sertraline were about the same as those for when patients were switched to
venlafaxine or bupropion. While this open study design may contribute to one-comparison agents
tending to consistently look similar in outcome, the study does support that switching within the class
of SSRIs may be as good as switching outside the class. Thase and colleagues (1997) found that
patients who had a poor response to an initial trial of sertraline often achieved a good response when
switched to fluoxetine. As many as 50% of patients who do not respond to one SSRI may respond to
another. However, melancholic inpatients who do not respond to an adequate trial of an SSRI appear
to have a much lower chance of responding to another SSRI. Along the same lines, Sacchetti et al.
(1994) found that patients with recurrent major depression were far more likely to respond to the
same SSRI they had responded to in a previous episode than they were to respond to a different SSRI.
For example, if a patient had responded to fluoxetine in the index depressive episode, he or she had
about a 90% chance of responding to fluoxetine in a subsequent episode but only a 50% chance of
responding to fluvoxamine. It is unclear from the report whether patients were blinded to the
challenge. It is evident that many patients in clinical practice who start off taking one SSRI will end up
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http://www.psychiatryonline.com/popup.aspx?aID=231806&print=yes_chaptertaking another agent. In a retrospective review, at least 25% of patients treated with one SSRI
subsequently ended up taking another SSRI (Nurnberg et al. 1999c). The authors concluded that the
SSRIs were not interchangeable, since patients who discontinue one SSRI because of either lack of
efficacy or lack of tolerability may do well with another agent. Likewise, in another study, 91% of
patients who were intolerant to fluoxetine tolerated sertraline (Brown and Harrison 1995).
5-HT
2 RECEPTOR ANTAGONISTS (TRAZODONE AND NEFAZODONE)
Another class of antidepressants act as 5-HT2 antagonists (Figure 3–2; Table 3–5) and have a number
of other direct effects on 5-HT receptors that distinguish these agents from the SSRIs. The class
currently includes the phenylpiperazine nefazodone and the triazolopyride trazodone. Trazodone was
synthesized in Italy in the mid-1960s and eventually released to the U.S. market in 1981. It
represented the first 5-HT-specific agent in the United States. Nefazodone was synthesized in the
1980s by Bristol-Myers Squibb (BMS) with the specific intent of improving the side-effect profile of
trazodone. Nefazodone became available in the United States in 1995. In December 2001, the FDA
issued a “black box” warning about the risk of hepatoxicity associated with nefazodone, In late 2003,
BMS withdrew Serzone from markets in the United States and Canada, but nefazodone is still available
generically.
Pharmacological Effects
The pharmacology of the 5-HT2 antagonists is somewhat more complex than the name implies, and
questions still remain. The principal effect of both trazodone and nefazodone appears to be antagonism
of the postsynaptic 5-HT2A and 5-HT2C receptors. Nefazodone is the more potent antagonist. This
antagonism causes a paradoxical downregulation of 5-HT2 sites, which may explain the antidepressant
effects of such 5-HT2 antagonism. The 5-HT2 receptor is also linked with other receptors, including the
5-HT1A receptor, which is thought to be important in depression, anxiety, and violent behavior. There
Table 3–5. The serotonin
2 (5-HT2 ) antagonists
Drug Starting dosage(mg/day) Maximum dosage (mg/day)
trazodone (Desyrel) 50–100 600
nefazodone (Serzone) 50–100 600
Figure 3–2.
Chemical structures of serotonin2 (5-HT2 ) antagonists.
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http://www.psychiatryonline.com/popup.aspx?aID=231806&print=yes_chapteris growing evidence that both nefazodone and trazodone stimulate the 5-HT1A site, possibly through
antagonizing the 5-HT2 receptor. In addition to their effects as 5-HT2 antagonists, both trazodone and
nefazodone block the reuptake of 5-HT to some extent. Although the inhibition of the 5-HT transporter
with these two drugs is weak in comparison to that of the SSRIs, it may be clinically significant.
Finally, m-chlorophenylpiperazine (m-CPP), a major active metabolite of both nefazodone and
trazodone, is a potent direct agonist of 5-HT, mostly at the 5-HT2C receptor, which may contribute
both to the efficacy of the drugs and to their side effects.
Indications
The primary indication for both trazodone and nefazodone is major depression. There are more than
two dozen double-blind, placebo-controlled studies of trazodone and at least eight double-blind studies
of nefazodone that establish the efficacy of these drugs in the treatment of major depression. Most of
these studies suggest that trazodone and nefazodone are as effective as comparison drugs, primarily
the TCAs, in the treatment of major depression. However, many of the controlled studies have involved
outpatients with mild to moderate major depression, and there have been persistent questions about
the efficacy of trazodone in the treatment of more severely depressed patients. Some investigators
have suggested that trazodone is not particularly helpful for retarded depressions. However, a review
of efficacy studies (Schatzberg 1987) found that there appeared to be no difference between TCAs and
trazodone in the treatment of depressed inpatients and of those with more classic endogenous
features. Interestingly, the studies that reported the poorest results with trazodone used aggressive
dosing, with dosages that reached a total of 300–450 mg in the first week of treatment. Thus,
trazodone may be effective and is better tolerated at lower rather than higher doses, particularly at
first. At least one study has also concluded that nefazodone is effective in the treatment of more
severely depressed inpatients (Ansseau et al. 1994).
Both trazodone and nefazodone appear to be effective anxiolytic agents. The antianxiety effects of the
drugs are often evident earlier than the antidepressant effects. A comparison of low-dose trazodone
with chlordiazepoxide for general anxiety suggested that the two agents had equal efficacy (Schwartz
and Blendl 1974). Likewise, one study suggested that trazodone compared favorably to imipramine
and diazepam in the treatment of GAD (Rickels et al. 1993). In depressed patients, anxiolytic effects of
nefazodone were noted at dosages less than 250 mg/day (Fontaine et al. 1994), but trazodone, an
antidepressant, has shown significant utility as a hypnotic at doses of 25–100 mg at night. Because
trazodone is quite sedating and does not have an addiction potential, it offers a safe alternative to the
benzodiazepines. Likewise, trazodone has been used successfully to treat SSRI- and MAOI-induced
insomnia.
Next to depression, the best-studied disorder treated with nefazodone is PTSD. Currently, nefazodone
is among the more common agents prescribed in treating PTSD because of the sleep disturbance,
agitation, and comorbid problems of substance abuse and depression. At least six open-label studies of
nefazodone in the treatment of PTSD suggested that the drug can help ameliorate nightmares and
hyperarousal and decrease anger (Hidalgo et al. 1999). Dosages ranging from 300 to 600 mg/day
appear to be efficacious, and large controlled trials are under way to determine their efficacy.
Nefazodone does not share trazodone’s utility as a hypnotic, because the former is generally less
sedating. However, preliminary data (Armitage et al. 1994) suggested that nefazodone, unlike many
psychotropics, may enhance rapid eye movement (REM) sleep and therefore may increase restful sleep
in some patients.
Case reports suggest a number of other potential roles for nefazodone. Nefazodone has been reported
to be useful in the treatment of social phobia, panic disorder, and PMDD and as an adjunctive agent in
the treatment of negative symptoms of schizophrenia.
Side Effects
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http://www.psychiatryonline.com/popup.aspx?aID=231806&print=yes_chapterAlthough the 5-HT2 antagonists are 5-HT-specific agents, they differ from the SSRIs in mechanism of
action and thus in side-effect profile as well (Table 3–6). One common side effect of all currently
available serotonergic antidepressants is GI upset. The incidence of nausea with trazodone and
nefazodone is less than that found with the SSRIs. However, it was still the leading cause for
discontinuation of nefazodone in prerelease trials. Higher doses of trazodone, particularly when taken
on an empty stomach, may also be correlated with nausea. As with the SSRIs, the GI side effects of
these drugs are lessened by taking them with food.
As reported, neither trazodone nor nefazodone has particularly strong anticholinergic effects. They can,
however, produce dry mouth because of their 1 -adrenergic receptor blockade. (Salivation is controlled
by both the acetylcholinergic and the noradrenergic systems.) The 1 -adrenergic blockade may also
result in significant orthostasis with trazodone, especially in elderly persons. Dizziness and even frank
syncope may occur in patients taking large doses of trazodone on an empty stomach, as well as in
some elderly patients taking nefazodone. It is therefore useful to monitor blood pressures for
orthostasis with vulnerable patients and to encourage proper hydration. Support stockings may also be
helpful. The incidence of orthostasis with nefazodone is thought to be lower than with trazodone.
However, orthostasis has been reported with higher doses of nefazodone and in vulnerable patients.
Trazodone also differs from nefazodone in the amount of sedation it produces. As described, trazodone
is very sedating and is useful as a hypnotic at modest doses. Nefazodone may produce daytime
somnolence, but this usually occurs at higher doses. Shifting the bulk of the dose to bedtime will
mitigate this problem.
CNS activation is generally reported not to be a problem with either drug. However, patients who are
deficient in the cytochrome P450 2D6 enzyme or who are taking SSRIs may experience activation
secondary to the effects of the metabolite m-CPP, which is cleared by this enzyme. We have also seen
some patients develop dysphoric activation on nefazodone, even without recent exposure to the SSRIs.
Therefore, starting nefazodone at lower doses appears prudent.
Table 3–6. Common or troublesome side effects of trazodone and nefazodone
Gastrointestinal
Nausea
Dyspepsia
Liver failure (nefazodone—rare)
Adrenergic blockade
Orthostasis (trazodone >> nefazodone)
Dizziness
Neurological
Headaches
Visual trails (nefazodone > trazodone)
CNS depression
Sedation (trazodone >> nefazodone)
CNS activation
Restlessness (nefazodone > trazodone)
Sexual
Priapism (trazodone)
Note. >> = much greater than; CNS = central nervous system.
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http://www.psychiatryonline.com/popup.aspx?aID=231806&print=yes_chapterMore than 200 cases of priapism have been reported in males treated with trazodone. Although rare,
priapism—with an incidence of 1 per 6,000 patients—is very problematic. Risk of trazodone-associated
priapism is thought to be higher in younger males with prolonged erections in the morning upon
awakening or who can have frequent erections over a relatively short period (several hours). Some
patients may require surgical intervention. The acute treatment involves injection of an -adrenergic
receptor agonist (e.g., epinephrine) into the penis. If not treated promptly, priapism may result in
permanent impotence. Male patients should thus be warned to stop the drug immediately if they
experience any symptoms suggestive of priapism (occasional erections are not problematic) and to
seek emergency room treatment if the erection persists longer than 1 hour. At least one case of clitoral
priapism has also been reported (Pescatori et al. 1993).
Since priapism is mediated via adrenergic pathways, nefazodone is thought to present less of a
problem than trazodone in this regard. There have been no reports of nefazodone-induced priapism,
but there have been isolated reports of prolonged erections in men and reports of increased nocturnal
penile tumescence. A case of clitoral engorgement, but not priapism, with nefazodone has also been
reported.
Sexual side effects generally appear to be rare with nefazodone. In fact, it is difficult to demonstrate
that the rate of sexual dysfunction with nefazodone treatment is any higher than with placebo
treatment. Feiger and colleagues (1996) found that sertraline and nefazodone were comparable in
antidepressant efficacy. However, sertraline had negative effects on sexual function, whereas
nefazodone had none.
Visual side effects may also occur in up to 12% of patients taking nefazodone. These side effects often
take the form of an afterimage during tracking of moving objects. Interestingly, the afterimage during
tracking may be a serotonin-enhancing effect, because other agonists, such as lysergic acid
diethylamide (LSD), also produce this effect. Patients should be told that the visual side effects
generally improve with time.
In 1999, there was an isolated report at one center of three patients being treated with nefazodone
who sustained liver failure. The patients were all women between the ages of 16 and 57 who were
treated with 200–400 mg of nefazodone for a period averaging several months (Aranda-Michel et al.
1999). All patients showed significant hepatocellular damage, and two of the three underwent liver
transplants. The third recovered without transplantation. In at least one of the patients, a concomitant
medication could have contributed to hepatotoxicity. Since that first report, a number of other cases
have emerged that led the FDA to advise BMS that they must include a black box warning in the
package insert that alerts the public about the risk of severe liver toxicity. The risk is estimated at
about 1/250,000 for every patient-year of treatment with nefazodone. In other words, if a quarter
million patients were taking nefazodone for a year, one patient would be expected to develop
potentially severe liver damage. While these odds are very small, this is about three to four times the
background rate for severe liver damage, and use of nefazodone dropped dramatically with the black
box warning. BMS voluntarily removed Serzone from the market, but nefazodone is still available
generically. Many antidepressants, including TCAs, have rarely and idiosyncratically been associated
with fulminant hepatic failure. There do not appear to be clear demographic variables that predict
hepatic toxicity from a given antidepressant. However, in any patient with a history of hepatic
difficulties, it is prudent to obtain baseline liver enzymes and monitor these periodically. Nefazodone
should not be prescribed in any patient with a history of liver disease. We are frequently asked
whether a patient who has done well while taking nefazodone should continue the medication. We have
not routinely taken patients who have responded to the drug off the medication. If there is a
reasonable alternative to nefazodone, it should be considered. If alternatives have been unsuccessful
or poorly tolerated, it may be particularly reasonable to continue the nefazodone while informing the
patient of the known risk. Patients should also be educated about symptoms of liver illness, including
jaundice, anorexia, GI disturbance, and malaise, and the drug should be discontinued if there are any
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Overdose
Trazodone and nefazodone appear to have a wide safety margin in cases of overdose. Doses as high as
10 g of trazodone have been taken without untoward incidents. The lethal dose in animals averages
500 mg/kg.
Although the risk of fatal overdoses with nefazodone or trazodone is very small, a number of reports
suggest that the combination of trazodone and other CNS depressants, such as alcohol, can be lethal
when taken in overdose. The usual cause of death is respiratory depression. Although a trazodone
overdose alone can result in a seizure or respiratory arrest, the lethal dose in animals approaches half
of body weight, or about 500 mg/kg. Nefazodone has been taken in overdoses of up to 12 g, or 20
times the maximum daily dose, without serious effects.
Drug Interactions
The 5-HT2 antagonists are fairly safe in terms of drug interactions. Trazodone may potentiate the
effects of other CNS depressants and lead to excessive sedation. Similarly, the postural hypotension
associated with trazodone is exacerbated by concurrent antihypertensive agents, and such
combinations should be monitored with frequent checks of orthostatic blood pressure. Because both
the 5-HT2 antagonist drugs have proserotonergic effects, there is a theoretical risk of precipitating a
serotonin syndrome with the MAOIs, particularly at higher doses. However, neither trazodone nor
nefazodone is a potent catecholamine reuptake inhibitor (although nefazodone has some reuptake
inhibition); therefore, the risk of hypertensive crises with concurrent use of 5-HT2 antagonists and
MAOIs is low.
Nefazodone is a potent inhibitor of the cytochrome P450 enzyme 3A3/4. As stated previously, this
enzyme is responsible for the metabolism of such common drugs as the triazolobenzodiazepines
alprazolam and triazolam, ketoconazole, erythromycin, and carbamazepine. The combination of
nefazodone and anti-arrhythmics, pimozide, or ziprasidone may enhance cardiac toxicity. Concurrent
use of nefazodone with these agents may raise serum levels, and clinicians should exercise caution in
combining these drugs.
Occasionally, switching from the SSRIs to 5-HT2 -antagonist drugs, particularly nefazodone, may be
problematic. One of the metabolites of nefazodone is m-CPP, which is metabolized via the cytochrome
P450 2D6 enzyme. Increased serum levels of m-CPP have been associated with dysphoric agitation.
Thus, simultaneous use of an SSRI and nefazodone, either current or recent (before the washout
period has ended), may be poorly tolerated in some patients. Fluoxetine can contribute to elevated
levels of m-CPP for 4–5 weeks after it is discontinued, and the other SSRIs may have this effect for 1–
2 weeks after they are discontinued. Therefore, it would be useful, ideally, to have a washout period
between stopping an SSRI and starting nefazodone. However, an alternative strategy is to allow no
washout period but start with smaller dosages of nefazodone (50–100 mg/day) and titrate upward
more gradually after discontinuing the SSRI.
Dosage and Administration
The manufacturer recommends starting trazodone at 150 mg/day and then increasing the dosage up to
600 mg/day (Table 3–5). Our experience has been that the drug is quite sedating, and we begin
patients at 50 mg/day and increase the dosage to 150 mg/day by day 7. Thereafter, each week, we
increase the daily dosage by 50–75 mg, up to 300 mg/day. In our experience, patients respond at a
modal dosage of 150–300 mg/day.
Because of trazodone’s short half-life, the optimal dosing for the treatment of depression is in two or
three divided doses a day. The bulk of the dose may be taken at bedtime to mitigate daytime
somnolence.
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http://www.psychiatryonline.com/popup.aspx?aID=231806&print=yes_chapterSome investigators have proposed that trazodone has a therapeutic window; as with nortriptyline, too
high plasma levels are associated with poor responses. Our experience suggests this may be so, and
several studies have supported a correlation between plasma levels and efficacy (Monteleone and
Gnocchi 1990; Spar 1987). Steady-state trazodone plasma levels above 650 ng/mL may be ideal for
antidepressant response. However, more study is needed to determine whether it is worthwhile to
obtain trazodone plasma levels routinely.
The manufacturer’s recommended starting dosage of nefazodone is 100 mg bid. However, we
recommend starting at 50 mg bid or lower and increasing the dose by 50 mg every 4 days to reach
200 mg/day. Thereafter, each week, the daily dosage may be increased by 100 mg until a therapeutic
dose is achieved. Minimal therapeutic antidepressant dosage is 300 mg/day, and most patients will
require at least 400 mg/day. Thus, it is reasonable to titrate the dosage to 400 mg/day and then
maintain this dosage for 3–4 weeks. If a response is not observed, the dosage may then be further
increased to a maximum of 600 mg/day. The initial dosage in elderly patients should be 50 mg/day.
Some patients may feel too sedated or activated at 100 mg bid, but they are often able to tolerate an
initial dosage of 50 mg bid. Therefore, we have recently come to start all patients routinely at 50–100
mg/day. The manufacturer recommends bid dosing, but some practitioners prescribe the drug to be
administered nightly, and this appears particularly feasible once patients have been on a steady
dosage for a few weeks. A slow-release formulation is being developed that would allow once-a-day
dosing. However, at the time of this writing, a once-a-day formulation is not available.
Discontinuation
Discontinuation syndromes appear uncommon for both trazodone and nefazodone but have been
reported. Some case reports suggested that the rapid discontinuation of trazodone may occasionally
lead to withdrawal symptoms, particularly rebound insomnia (Otani et al. 1994). As with the SSRIs,
there have been reports of paresthesias and dizziness associated with the sudden discontinuation of
nefazodone (Benazzi 1998; Kotlyar et al. 1999; Lauber 1999). Therefore, it is generally prudent to
taper these medications rather than to stop them suddenly. The total daily dose of nefazodone and
trazodone can be decreased by 50–100 mg each week.
SEROTONIN-NOREPINEPHRINE REUPTAKE INHIBITORS
(VENLAFAXINE AND DULOXETINE)
Venlafaxine (Effexor) (Figure 3–3) is a phenylethylamine that was released to the U.S. market in 1994.
In 1998, it became available in an extended-release form (Effexor XR), which is taken once a day.
Along with its FDA indication for the treatment of depression, Effexor XR became the first
antidepressant approved for the treatment of GAD and has also been approved for the treatment of
social anxiety disorder. In the past several years, venlafaxine has been growing in popularity as a drug
with an efficacy and mechanism of action that may be similar to those of TCA drugs without the safety
or side-effect liability of the TCAs.
Figure 3–3.
Chemical structures of the serotonin-norepinephrine reuptake inhibitors venlafaxine and duloxetine.
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http://www.psychiatryonline.com/popup.aspx?aID=231806&print=yes_chapterDuloxetine (Cymbalta) is an SNRI that was released in 2004 after a long delay. Like venlafaxine, it has
little affinity for other neurotransmitter receptors such as muscarinic or histaminic receptors. However,
it is a relatively more potent norepinephrine reuptake inhibitor (NRI) than is venlafaxine. Whether this
increased potency translates into improved efficacy is unclear. Initially, we see duloxetine as an
antidepressant that will be a first-line agent in depressed patients who have comorbidities such as pain
or stress incontinence. Duloxetine also makes sense as a first-line agent for patients with serious
depressions, including those with melancholic and psychotic subtypes. We suspect it will have an
important role to play in treating resistant depression. Over time, both venlafaxine and duloxetine may
become first-line agents for less severe depression as well.
A third SNRI, milnacipran, is under investigation in the United States for the treatment of fibromyalgia.
Studies overseas have documented the efficacy of milnacipran in depression. While other drugs are
under investigation for the treatment of fibromyalgia, milnacipran is farthest along in development and
most likely to secure the first FDA approval for this condition.
Pharmacological Effects
In contrast to the SSRIs, the potent 5-HT-blocking effects of venlafaxine are complemented by mild to
moderate effects on norepinephrine reuptake. In contrast, duloxetine is a potent 5-HT and
norepinephrine reuptake inhibitor. Several other pharmacological properties distinguish the SNRIs. For
example, the SNRIs promote a rapid downregulation of -adrenergic receptor–coupled cAMP (cyclic
adenosine monophosphate). This effect may correlate with an earlier onset of action for the SNRIs, as
some premarketing studies have suggested. In addition, venlafaxine is more weakly bound to protein
(27%) than are other antidepressants; this weaker binding may decrease the likelihood of displacing
tightly bound drugs, such as warfarin and phenytoin. Venlafaxine shares with citalopram and
escitalopram a very low potential for pharmacokinetic drug interactions because it is not a potent
inhibitor of any cytochrome P450 hepatic enzymes.
Indications
The SNRIs have proved useful in the treatment of both outpatients with major depression and
inpatients with melancholia. Given the ongoing debate about the utility of the SSRIs for more seriously
depressed inpatients, the SNRIs appear to provide a safe and effective alternative to the TCAs in
treating melancholic patients. In one study, venlafaxine appeared to be markedly more effective than
fluoxetine in the treatment of melancholic inpatients (Clerc et al. 1994). In addition, venlafaxine was
shown to be effective in some 35% of patients with treatment-refractory depression (Nierenberg et al.
1994).
Although it has generally been difficult to reliably demonstrate differences between SSRIs and
venlafaxine in overall response rates in individual studies, there may be some differences in overall
remission rates. Thus, a 50% reduction in score on a standard rating scale, such as the HDRS (a
standard measure of efficacy in antidepressant trials), may not reflect differences in remission rates
in a given 6- to 8-week antidepressant trial. A meta-analysis found that venlafaxine was more likely to
result in remission of symptoms than either TCAs or SSRIs (Einarson et al. 1999). In a meta-analysis
by Thase et al. (2001), it was concluded that venlafaxine was significantly more effective than SSRIs in
effecting remission. As indicated previously, a more recent meta-analysis indicated that venlafaxine
may be more effective than fluoxetine but not other SSRIs (Nemeroff et al. 2003).
Like venlafaxine, duloxetine appears to be an effective antidepressant and may be more efficacious on
some measures than are SSRIs. Several but not all double-blind studies have now demonstrated the
utility of duloxetine, particularly at achieving remission of depressive symptoms relative to placebo. In
a 9-week trial, duloxetine 60 mg administered once daily was compared with placebo in treating
patients with major depression. By the end of 9 weeks, 44% of 123 duloxetine-treated patients had
achieved remission, compared with only 16% of the 122 patients receiving placebo (Detke et al.
2002). In a second trial, 173 patients were randomized to treatment with duloxetine up to 120
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http://www.psychiatryonline.com/popup.aspx?aID=231806&print=yes_chaptermg/day, fluoxetine 20 mg/day, or placebo for 8 weeks. Duloxetine appeared to be more likely to
achieve response and remission than either fluoxetine or placebo (Goldstein et al. 2002).
A second FDA indication for Effexor XR is for the treatment of GAD. All five controlled trials of Effexor
XR in the treatment of GAD reported to date have shown superiority to placebo and sometimes to
comparison drugs such as buspirone (Davidson et al. 1999; Diaz-Martinez et al. 1998). Some studies
indicated that relatively low dosages of Effexor XR (75–150 mg/day) are useful in the treatment of
GAD, and most patients obtain some benefit within 2 weeks, with additional improvement often seen
over the next 6 weeks of treatment. Studies out to 6 months have reported significantly greater
efficacy for Effexor XR over placebo, with many patients continuing to improve beyond their acute
responses (Gelenberg et al. 2000). Venlafaxine is approved for the treatment of social anxiety
(Altamura et al. 1999; Lenderking et al. 1999). Likewise, venlafaxine has some demonstrated efficacy
in the treatment of PTSD, including PTSD that has failed to respond to an SSRI (Hamner and Frueh
1998). While the efficacy of duloxetine in the treatment of anxiety disorders is not fully established,
duloxetine would be expected to be of utility in treating the same types of anxiety disorders as is
venlafaxine. However, the noradrenergic effects of duloxetine may be difficult for some anxious
patients to tolerate.
Venlafaxine was approved for the treatment of social anxiety disorder in 2003. As with the SSRIs, the
effects of venlafaxine on social anxiety may be at least as large as its effects in depression and GAD.
Since the mechanism of action of the SNRIs is similar to that of the TCAs, the SNRIs also have utility in
treating some pain conditions. Venlafaxine has been studied in the treatment of neuropathic pain,
fibromyalgia, and other chronic pain conditions (Davis and Smith 1999; Kiayias et al. 2000; Pernia et
- 2000). Venlafaxine appears to be about as useful as the TCAs and superior to the SSRIs for chronic
pain. Dosages over 150 mg/day are often required. Duloxetine also appears to be useful in the
treatment of some somatic and pain symptoms. In a study by Detke and colleagues (2002),
duloxetine-treated patients had not only an improvement in their depression but a significant reduction
in shoulder pain, back pain, and pain that interfered with daily activities. It is likely that, as with the
TCAs, the improvement in pain was independent of the improvement in depression. Indeed, studies of
duloxetine in the treatment of diabetic neuropathy have shown clear benefit, and duloxetine was
approved for the treatment of neuropathy shortly after it was approved for the treatment of
depression. The drug has also been reported to be effective in treating fibromyalgia.
The SNRIs have been studied for use in other disorders. For example, a number of studies suggest that
venlafaxine may be effective in both childhood and adult attention-deficit/hyperactivity disorder
(ADHD) at dosages of 150–300 mg/day. Like other antidepressants that appear useful in ADHD,
including desipramine and bupropion, venlafaxine lacks disadvantages of drugs such as
methylphenidate that have some potential for abuse and require Drug Enforcement Administration
triplicate forms.
Another condition duloxetine may be valuable in treating is stress urinary incontinence. In fact,
duloxetine is approved outside the United States for treating stress urinary incontinence. In a large
trial involving 533 women, duloxetine at dosages of 20–80 mg/day was superior to placebo in reducing
the frequency of incontinence episodes. Duloxetine-treated patients had up to a 64% decrease in
incontinence episodes, while placebo-treated patients had a 41% decrease (Norton et al. 2002). The
differences from placebo were even greater in patients who had a high baseline frequency of
incontinence episodes.
Side Effects
The SNRIs share many of the side effects of the SSRIs. For example, GI side effects are common with
the SNRIs. In fact, duloxetine and venlafaxine may have a somewhat greater propensity for causing
nausea than do some of the SSRIs. As with the SSRIs, adaptation to this side effect occurs rapidly, in
the first 2–3 weeks of therapy. While some early work suggested a lower rate of sexual side effects
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http://www.psychiatryonline.com/popup.aspx?aID=231806&print=yes_chapterwith duloxetine than with the SSRIs, this seems doubtful to us. Any potent serotonin reuptake inhibitor
can cause sexual side effects, and both SNRIs are potently serotonergic. It is not likely that the
noradrenergic effects of the drug will mitigate the serotonin-dependent sexual side effects.
One side effect that differs from those of the SSRIs is treatment-emergent hypertension with
venlafaxine. This noradrenergically mediated side effect occurs in about 5% of patients at dosages of
venlafaxine (immediate release) less than 200 mg/day and in 13% of patients at dosages greater than
300 mg/day in venlafaxine-treated patients. The increase in blood pressure is usually modest, with an
an average increase in diastolic blood pressure of about 5–7 mm Hg with venlafaxine at high doses and
about 2 mm Hg with duloxetine. Nonetheless, it is important to monitor blood pressure, particularly in
the first 2 months of treatment at higher doses, particularly with the immediate-release venlafaxine.
We have seen some patients with a rise in blood pressure of 20–30 mm Hg. In general, there is little
evidence that preexisting hypertension predisposes a patient to greater increases in blood pressure
with the addition of venlafaxine (Thase 1998). Reducing the dose is often helpful. If it is not feasible to
do so, clinicians should consider adding a -blocker or an -blocker. The impression is that
hypertension has been less problematic with the extended-release formulation, perhaps reflecting
lower total daily doses or lack of peak effects.
An even less common side effect reported with venlafaxine is syncope. Syncope might reflect a Na
channel effect in genetically susceptible individuals. If syncope occurs, the patient’s medication should
be switched to one outside the class of SNRIs.
The more potent noradrenergic effects of duloxetine also result in a variety of anticholinergic-like side
effects, including dry mouth, constipation, and urinary retention. Elderly males might be particularly
susceptible to retaining urine and should be monitored.
Overdose
Fatal overdoses with venlafaxine, as with the SSRIs, are exceedingly rare but are occasionally
reported. As with the SSRIs, moderate overdoses of less than 30 times the daily dose tend to be more
associated with GI upset than with other symptoms. Gastric lavage is often helpful in these cases of
moderate overdose. More substantial overdoses involving 10 g or more have sometimes resulted in
seizures (Bhattacharjee et al. 2001; Gittelman and Kirby 1993; Mainie et al. 2001) and a serotonin
syndrome (Spiller et al. 1994). In the United Kingdom, there has been considerable concern about the
safety margin of venlafaxine in overdoses (Buckley and McManus 2002). Recently, a warning about risk
for lethality in overdose was added to venlafaxine’s package insert; the mechanism is unclear. There
have been no reported fatal overdoses of duloxetine thus far. Doses up to 1,200 mg have been treated
with lavage and supportive care.
Drug Interactions
The SNRIs can precipitate a serotonin syndrome when combined with the MAOIs, and this combination
is therefore contraindicated. Similarly, 2 weeks should elapse after stopping an MAOI before starting
an SNRI. Because venlafaxine has a short half-life (5 hours for venlafaxine and 11 hours for its major
metabolite, O-desmethylvenlafaxine), a 1-week washout is sufficient before starting an MAOI.
Venlafaxine and duloxetine are weak inhibitors of cytochrome 2D6. Like citalopram and escitalopram,
the SNRIs do not appear to be potent inhibitors of other hepatic enzymes. However, both duloxetine
and venlafaxine are metabolized by the 2D6 enzyme and, to some extent, the 1A2 enzyme as well.
Therefore, cimetidine, paroxetine, or other drugs that inhibit the metabolism of 2D6 could result in a
more pronounced increase in blood pressure or other side effects. Venlafaxine can increase haloperidol
blood levels, but this is not mediated by an effect on the 1A2 or 2D6 enzymes. Rather, it may be an
effect on excretion.
Dosage and Administration
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http://www.psychiatryonline.com/popup.aspx?aID=231806&print=yes_chapterThe manufacturer recommends that the extended-release formulation of venlafaxine (Effexor XR) be
initiated at 37.5 mg. Thereafter, doses can be increased by 37.5 mg every 3 days or 75 mg per week
until a dosage of 150 mg/day is reached. Beyond that, increases should be at a rate of 75 mg per
week. Although the manufacturer suggests that elderly patients do not require a lower starting dosage,
many geriatric psychiatrists have found that a starting dosage of 37.5 mg/day is better tolerated.
Increase of dosage should be gradual. For the extended-release formulation of venlafaxine, the
maximum recommended dosage is 225 mg/day; for the immediate-release form, it is 375 mg/day. We
recommend using the extended-release formulation. Most depressed outpatients appear to respond to
dosages in the range of 75 to 225 mg/day. Therefore, if no response is seen at the starting dosage for
2 weeks, the dosage may be titrated upward in 37.5-mg increments every 3 days or so, as tolerated.
In premarketing studies, the dosage was sometimes increased rapidly to the maximum dosage in the
first week of treatment. This rapid titration was sometimes associated with a more rapid onset of
action, but it also was poorly tolerated in many cases. Venlafaxine does have a linear dose-response
curve, and higher dosages are associated with greater response (as well as more prominent side
effects). Inpatients with melancholic depression and patients with depression refractory to other
treatments often require dosages closer to the maximum dosage of 375 mg/day (for the immediate
release form) administered in divided doses. On occasion we have used even higher dosages (450–600
mg/day) without problem.
We have tried a variety of doses of duloxetine in clinical trials. In general, starting the duloxetine at 30
mg in the morning with food is a reasonable approach. After 3–7 days, we increase the dosage to 60
mg/day. Some patients have less nausea at 30 mg bid, but most patients can manage 60 mg taken
once daily. It is reasonable to keep the dosage at 60 mg/day for 4 weeks before going up to
90 mg/day and then 120 mg/day in divided doses. However, dosages above 60 mg/day are not
necessarily more effective than 60 mg/day.
A recent trial compared venlafaxine (immediate release) and duloxetine in the treatment of major
depression. Starting dosages were 75 mg/day of venlafaxine and 60 mg/day of duloxetine. Duloxetine
was associated with twice as high a rate of dropout due to side effects as venlafaxine. These data
suggest that 30 mg/day of duloxetine is equivalent to 75 mg/day of venlafaxine. Unpublished data
from Lilly indicate that side effects of duloxetine are reduced dramatically by administering with food.
Discontinuation
The relatively short half-life of venlafaxine may predispose patients to an increased risk of
discontinuation symptoms when the drug is stopped suddenly (Boyd 1998; Dallal and Chouinard 1998;
Macbeth and Rajagopalan 1998). Significant dizziness has been reported with rapid discontinuation, as
have paresthesias and the typical SSRI withdrawal symptoms. Therefore, the manufacturer advises
tapering the dose for any patient who has been taking the drug for longer than 7 days. For patients
taking venlafaxine for more than 2 weeks, a gradual taper over at least a 2-week period is advised,
and some patients may require a 4-week taper or longer. Decreasing the dosage by 37.5 mg every 3
days or 75 mg per week circumvents withdrawal symptoms in many patients. Switching to sertraline
(Luckhaus and Jacob 2001) or supplementing the antiemetic ondansetron (Raby 1998) may also help.
In the double-blind studies of duloxetine, rapid discontinuation was associated with expected
symptoms. Thus a gradual taper schedule with this agent should be routinely instituted.
COMBINED NORADRENERGIC-DOPAMINERGIC ANTIDEPRESSANT
(BUPROPION)
Bupropion (Wellbutrin) is a unicyclic antidepressant (Figure 3–4) that was in the process of being
released in 1986, but its release was delayed pending an evaluation of its risk of inducing seizures. It
was not released until mid-1989, when it became clear that the increased seizure risk was dose related
and tended to occur in specific populations. In 1998, bupropion became available in a sustained
release formulation (Wellbutrin SR) that allows twice-a-day administration and also appears to
decrease the risk of seizures to about that associated with SSRIs. In 2003, bupropion became available
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http://www.psychiatryonline.com/popup.aspx?aID=231806&print=yes_chapterin an extended-release formulation (Wellbutrin XL) for once-a-day dosing. In 2003, a once-a-day
formulation (Wellbutrin XL) became available.
Pharmacological Effects
Bupropion is not a 5-HT reuptake blocker and does not inhibit monoamine oxidase. Its biochemical
mode of action is not completely clear. It was hypothesized to act via dopamine reuptake blockade;
however, its dopamine-potentiating effects in animals appear to occur at very high dosages and blood
levels, well beyond those routinely used in humans. The dopamine reuptake–blocking properties of
bupropion are an order of magnitude less than those of sertraline. When dopamine effects were
demonstrated in humans in one study, these effects appeared to be related to possible psychotic
reactions to the drug rather than to its antidepressant responses. Nonetheless, the dopaminergic
effects may be important, because the plasma levels of homovanillic acid, the primary metabolite of
dopamine, decrease in patients who respond to bupropion but not in patients who do not respond
(Golden et al. 1988).
In recent years, the noradrenergic effects of bupropion have become increasingly evident. The major
active metabolite of bupropion, hydroxybupropion, does appear to block the reuptake of
norepinephrine in rats. Earlier studies, involving mice, failed to show an effect on norepinephrine, but
this species metabolizes the drug differently. Indirect evidence for an effect on noradrenergic activity
also comes from data showing that the drug decreases 24-hour excretion of norepinephrine
metabolites.
Indications
Bupropion appears to be effective in many types of depression. It has demonstrated utility in
outpatients with mild to moderate depression as well as in inpatients with more severe depression. The
drug appears to be safe in depressed cardiac patients. There have been reports that the drug is less
likely to produce mania or rapid cycling, but episodes of mania on bupropion do occur. Conversely,
bupropion has been reported not to induce rapid cycling in patients with bipolar disorder. Since head
to-head comparisons of bupropion and other antidepressants are lacking in the treatment of bipolar
depression, it is difficult to fully assess bupropion’s proclivity for inducing mania relative to that of
other agents. Still, for the treatment of bipolar depression, bupropion is a reasonable first-line agent in
addition to mood stabilizers.
The second FDA indication for bupropion is in smoking cessation. Two controlled clinical trials indicate
that the sustained-release formulation of bupropion (which is also marketed under the trade name
Zyban) administered at 300 mg/day aids in smoking cessation (Goldstein 1998). More than 3,000
patients were studied in a clinical trial of the sustained-release formulation of bupropion in the
treatment of smoking cessation. As with the treatment of depression, the benefits of sustained-release
bupropion are not immediate and take several weeks or longer to be evident. After 7 weeks of
Figure 3–4.
Chemical structure of bupropion.
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http://www.psychiatryonline.com/popup.aspx?aID=231806&print=yes_chaptertreatment, more than twice as many patients on bupropion 300 mg/day (36%) were abstinent from
nicotine as patients administered placebo (17%). At 26-week follow-up, only 19% of bupropion-treated
patients and 11% of placebo-administered patients remained abstinent from smoking. These results
mirror those commonly seen in smoking cessation studies with nicotine preparations. In a recent trial,
we reported that bupropion was no better than placebo in achieving smoking abstinence in
adolescents. However, bupropion appeared to significantly decrease nicotine use (Killen et al. 2004).
The drug is being studied for appetite suppression.
The most recent indication for bupropion is in the treatment of seasonal affective disorder (SAD). SAD
has historically been treated with phototherapy, antidepressants, and mood stabilizers. However, there
had been no FDA-approved therapy for this disorder until the approval of bupropion XL. Studies
indicate that by starting treatment of bupropion while patients are well, the drug appeared to prevent
relapse and time to onset of new depressive symptoms when compared with placebo (Modell et al.
2005). Since some patients with SAD may have illness that falls in the bipolar spectrum, we have
found that a mood stabilizer such as lamotrigine or lithium can also be helpful, although there are few
empirical data for the use of a mood stabilizer.
Another fairly common use of bupropion is in the treatment of ADHD. Bupropion appears to be
effective in the treatment of ADHD in both adults and children (Cantwell 1998). Since bupropion is
metabolized to a number of amphetamine-like products, it appears to be a safe alternative to
stimulants in the treatment of ADHD. In adolescents who have comorbid substance abuse problems,
bupropion might be the first-line treatment (Riggs et al. 1998).
Two important uses of bupropion are as an adjunct to SSRI treatment to augment the antidepressant
effect and as an adjunct to counteract the sexual side effects of SSRIs. Bupropion does appear to
augment SSRI antidepressant effects and is generally less complicated to use than is either lithium or
thyroid supplements. The STAR*D study found that bupropion added to an SSRI was helpful but that it
was no more helpful than a parallel nonrandomized track in which buspirone was added (Trivedi et al.
2006). (Bupropion augmentation is discussed in greater detail in Chapter 9: “Augmentation Strategies
for Treatment-Resistant Disorders.”)
Bupropion is unique among the antidepressants in that it is probably not effective in the treatment of
anxiety disorders. One pilot study of bupropion in the treatment of panic disorder yielded negative
findings (Sheehan et al. 1983). To our knowledge, no recent studies have examined the efficacy of
bupropion in the treatment of panic disorder. Many anxious patients find bupropion too activating and
prefer other agents.
Bupropion’s metabolism is probably dependent on a number of hepatic enzymes; therefore,
interactions with the SSRIs may be less problematic than once thought. Still, there has been at least
one case report of a seizure being associated with the combination of fluoxetine and bupropion.
Side Effects
Bupropion has a favorable side-effect profile, in part because of its low affinity for muscarinic, –
adrenergic, and histaminic receptors. The only side effects of the sustained-release bupropion that
occurred reliably more commonly than with placebo in clinical trials of 100–300 mg/day were insomnia,
dry mouth, and tremor. The insomnia is best managed by moving the evening dose to earlier in the
afternoon. A separation of at least 8 hours between the morning and evening dose is advised.
Bupropion does not induce orthostatic hypotension or stimulate appetite. Some investigators have
argued that bupropion could be particularly useful in patients who gain weight while taking other
agents. There are reports that patients with sexual dysfunction who are taking other antidepressants
do better with bupropion, and, again, the drug has been reported to counteract SSRI-induced sexual
dysfunction.
Seizures for the immediate-release formulation of the drug have been reported at the rate of 4 per
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http://www.psychiatryonline.com/popup.aspx?aID=231806&print=yes_chapter1,000 at dosages less than 450 mg/day; this risk increased to 4 per 100 when the dosage was
increased above 450 mg/day. The sustained-release formulation, which has largely supplanted the
immediate-release formulation, appears to carry a seizure risk of about 1 per 1,000 patients at
dosages less than 400 mg/day. This risk is similar to the seizure risk associated with most
antidepressants. The risk of seizures appears to be enhanced in patients with a prior history of seizure
disorders, head injury, bulimia, and anorexia. Concurrent use of alcohol, stimulants, or cocaine also
enhances the risk of seizures in these patients. The manufacturer also cautions that single doses of the
drug should never exceed 150 mg for the immediate-release formulation and 200 mg for the
sustained-release preparation. The XL formulation may be taken as a single dose of up to 450 mg.
Overdose
Bupropion has proved relatively safe in overdose. However, there have been cases of completed
suicide with bupropion alone (Rohrig and Ray 1992). In some cases, patients who overdosed on
bupropion had significant neurological complications, including seizures and status epilepticus (Spiller
et al. 1994; Storrow 1994). Thus, some caution should be exercised in prescribing large supplies of
bupropion for suicidal patients.
Drug Interactions
Serious drug interactions are uncommon with bupropion. Bupropion is metabolized by the cytochrome
P450 2B6 enzyme, which is responsible for metabolizing very few drugs (orphenadrine and
cyclophosphamide). Thus, potential pharmacokinetic interactions with other antidepressants or general
medicines are unlikely.
Any drug that lowers the seizure threshold should be used cautiously with bupropion. Thus, drugs such
as clozapine, theophylline, and clomipramine should be used cautiously or avoided with bupropion.
Likewise, it may be prudent to avoid the use of bupropion in patients who are dependent on alcohol or
benzodiazepines, since sudden discontinuation of these drugs in the context of concurrent bupropion
use can increase seizure risk.
The use of an MAOI and bupropion is contraindicated. There appears to be an enhanced risk of general
toxicity with phenelzine and bupropion and a greater risk of hypertensive crises.
Dosage and Administration
Bupropion has a relatively wide usual dosage range (i.e., 200–450 mg/day). The modal optimum
dosage range in our experience has been 300 to 400 mg/day. Bupropion is available in an immediate
release formulation (75-mg and 100-mg tablets); in a sustained-release preparation (Wellbutrin SR)
(100-mg, 150-mg, and 200-mg tablets) given twice daily; and in an extended-release once-daily
formulation (150-mg and 300-mg tablets).
MIRTAZAPINE
Mirtazapine (Remeron), which was released in the United States in 1996, is chemically related to
mianserin, a drug that has been used for a number of years in Europe. Mirtazapine is FDA approved for
the treatment of depression but appears to be useful for a variety of other disorders. Although it did
not emerge as among the more popular antidepressants during the late 1990s, mirtazapine has
established important niches in clinical practice.
Pharmacological Effects
Mirtazapine has a tetracyclic chemical structure (Figure 3–5) but is unrelated to the TCAs. Its
mechanism of action is fairly unusual among the available antidepressants. It appears to be an
antagonist of central presynaptic 2 -adrenergic receptors. As an 2 -adrenergic receptor blocker,
mirtazapine acts to increase norepinephrine release. The increased noradrenergic tone results in a
rapid increase in synaptic 5-HT levels by mobilizing 5-HT release secondary to stimulation of 1 –
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Mirtazapine is not a specific reuptake blocker of any monoamine neurotransmitter. However, it does
appear to be a potent antagonist of H1 receptors—a feature that confers some of the drug’s more
problematic side effects. Mirtazapine does not have particularly strong anticholinergic effects and does
not significantly block postsynaptic -adrenergic receptors. As a result, postural hypotension is
generally not associated with mirtazapine use.
Mirtazapine is available in 7.5-mg, 15-mg, 30-mg, and 45-mg tablets. A quick-dissolving wafer
formulation (Remeron SolTabs) has been released.
Mirtazapine is well absorbed from the GI tract and extensively metabolized to at least four active
products. Each of these metabolites, including the most common, desmethylmirtazapine, is less active
than the parent drug. Mirtazapine is metabolized by cytochrome P450 2D6, 3A3/4, and 1A2 enzymes
but is neither an inducer nor an inhibitor of these hepatic enzymes (Fawcett and Barkin 1998). Thus, it
can be taken safely with other psychotropic agents.
Indications
In premarketing trials of mirtazapine, which involved several thousand patients, the drug appeared to
be as effective as the TCAs amitriptyline and clomipramine. Both outpatients with milder depression
and more severely depressed inpatients respond to mirtazapine. Compared with trazodone,
mirtazapine appears to be superior in the treatment of depressed inpatients (van Moffaert et al. 1995).
Mirtazapine has also been studied in treating brief recurrent depression, which meets all of the DSM-IV
(American Psychiatric Association 1994) criteria for major depression except for the time criterion.
Brief depression lasts less than 2 weeks but tends to recur many times in the course of a year.
Mirtazapine at low doses appears, on the basis of case reports, to effectively treat these depressive
episodes (Stamenkovic et al. 1998). Other subtypes of depression, including atypical depression and
seasonal depression, may also be responsive to mirtazapine (Falkai 1999).
More recent studies have directly compared mirtazapine with SSRIs in the treatment of depression
(Fava et al. 2001; Leiononen et al. 1999; Quitkin et al. 2001; Wheatley et al. 1998). Mirtazapine was
reported to be comparable in efficacy to fluoxetine, paroxetine, and citalopram and in each study was
slightly, though not significantly, more effective. Compared with the SSRIs, mirtazapine may have
more rapid anxiolytic and antidepressant effects (Thompson 1999). With mirtazapine, in contrast to
citalopram and paroxetine, the antidepressant and antianxiety effects are sometimes seen by the
second week. A meta-analysis by Thase (2003) found that mirtazapine was significantly more effective
than SSRIs.
Since mirtazapine, with its greater propensity for sedation and weight gain, is often used after SSRIs,
the STAR*D study evaluated the utility of mirtazapine for achieving remission after the failure of two
Figure 3–5.
Chemical structure of mirtazapine.
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remission after two failed antidepressant trials. The remission rate for mirtazapine on the HRSD at this
late stage of the study was only 8%.
Additionally, the dropout rate from adverse effects with mirtazapine appears to be usually similar to
that with the SSRIs.
We reported on a comparison of paroxetine and mirtazapine in elderly depressive patients (Schatzberg
et al. 2002). Mirtazapine was associated with significantly earlier response and fewer dropouts due to
adverse events than was paroxetine.
Preliminary data from open-label trials suggest that mirtazapine is useful for most of the anxiety
disorders that are responsive to SSRIs or venlafaxine. For example, mirtazapine may be useful in the
treatment of panic disorder, with or without concurrent depression (Carpenter et al. 1999b). Patients
with depression and comorbid GAD appear to do well when taking mirtazapine at dosages of 15–45
mg/day (Goodnick et al. 1999). Pilot studies of mirtazapine for PTSD also appear promising (Connor et
- 1999).
Another potential use for mirtazapine is in augmenting antidepressant effects. Because of its low risk of
pharmacokinetic interaction, mirtazapine should be relatively easy to combine with many
antidepressants. The drug, with its complex pharmacology, may complement antidepressants that act
more specifically. Preliminary data have shown that mirtazapine effectively augments SSRIs (Carpenter
et al. 1999a). In the STAR*D trial, the combination of mirtazapine (average dosage = 36 mg/day) with
venlafaxine (average dosage = 210 mg/day) resulted in remission-level responses in just 13% of
patients who had failed three consecutive antidepressant trials (McGrath et al. 2006). This result was
similar to the remission rate found for tranylcypromine in patients who had failed three trials. However,
the venlafaxine-mirtazapine combination was better tolerated than the tranylcypromine.
Mirtazapine had been reported to help reverse SSRI-induced sexual side effects (Farah 1999), but a
more recent double-blind trial failed to show benefits of mirtazapine in treating sexual side effects
(Michelson et al. 2000). In addition, the drug has been reported to help improve negative symptoms in
schizophrenia (Berk et al. 2001) and to ameliorate antipsychotic-induced extrapyramidal symptoms.
Side Effects
Mirtazapine has generally been well tolerated in clinical studies. The most common side effects are dry
mouth, sedation, somnolence, and weight gain. More than half of all patients treated with mirtazapine,
compared with less than 20% of patients treated with placebo, experienced somnolence. Somnolence
is more evident at lower doses than at higher doses because antihistaminic effects predominate
relative to noradrenergic or serotonergic effects at dosages below 15 mg/day. Thus, vis-à-vis sedation,
a starting dosage of 30 mg/day is often better and usually not more poorly tolerated than a dosage of
7.5 mg/day. A trial in Europe did compare mirtazapine at dosages of 15 mg/day and 30 mg/day and
found no differences in sedation between the two groups.
Weight gain and increased appetite are clear problems for some patients taking mirtazapine. In short
term trials of 6–12 weeks, about 20% of patients treated with mirtazapine reported increased appetite,
and 7.5% of patients had an increase in weight of at least 7%. In our clinical experience, at least 20%
of patients gain weight with long-term use of mirtazapine. The most reliable strategy for controlling
weight when taking mirtazapine is controlling appetite and exercise. The notion that higher doses of
mirtazapine may be less problematic for weight gain is less clear than the effects on somnolence.
Some clinicians anecdotally report that the use of H2 antagonists, such as ranitidine 150 mg bid,
mitigates the weight gain associated with mirtazapine, but this approach is untested. Likewise, some
clinicians use stimulants or sibutramine (Orlistat) to help control weight. However, sibutramine is a
serotonergic drug and may increase the risk of serotonergic side effects, while stimulants generally
require triplicate form prescriptions and have an established abuse potential. Weight gain in the elderly
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The effects of mirtazapine on cholesterol and triglycerides have become better recognized in recent
years. About 15% of patients demonstrate a significant (>20%) increase in cholesterol, and 6% of
patients experience a significant increase in triglycerides. It is thus worthwhile to obtain fasting
triglyceride and cholesterol levels at baseline and periodically with treatment, especially for patients
with known hypercholesterolemia or who have a history of high triglyceride levels. Concurrent use of
an HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase inhibitor such as atorvastatin
(Lipitor) has been anecdotally reported to reduce the cholesterol and lipid effects of mirtazapine at
dosages of 10–80 mg/day. Unless the benefits of mirtazapine are substantial, however, it may be
easier to switch to another agent if there are clinically significant increases in cholesterol or triglyceride
levels.
Along with bupropion and nefazodone, mirtazapine is one of the few antidepressants that have limited
sexual side effects. Switching from an SSRI to mirtazapine appears to resolve sexual dysfunction
associated with the use of an SSRI (Koutouvidis et al. 1999). There are case reports that indicate that
adding mirtazapine at dosages of 15–30 mg/day to an SSRI can mitigate SSRI-induced sexual side
effects (Koutouvidis et al. 1999). However, a more recent double-blind trial of mirtazapine in treating
SSRI-induced sexual side effects showed no benefit over placebo (Michelson et al. 2002).
Orthostatic hypotension, or conversely hypertension, is occasionally seen in patients treated with
mirtazapine. About 7% of patients experience significant dizziness, and some of this may be from
postural changes. It is worthwhile to occasionally monitor blood pressure in patients treated with
mirtazapine, particularly elderly patients. Other rare but significant side effects associated with
mirtazapine include elevations in hepatic transaminases in about 2% of patients—a rate similar to that
seen with SSRIs. Worries about agranulocytosis at the time of release of the drug to the market have
not been borne out.
Overdose
Mirtazapine appears to be fairly safe in overdose. We are unaware of fatal overdoses with mirtazapine
in doses of up to 2 g. The most common effect of overdose with mirtazapine is sedation. Gastric lavage
and supportive management have thus far been adequate in dealing with overdoses.
Drug Interactions
As indicated earlier, mirtazapine has a low risk of pharmacokinetic interactions. The most common
interaction is synergism with other CNS depressants. Concurrent benzodiazepines, barbiturates, or
alcohol increases the risk of significant somnolence and sedation. The combination of mirtazapine and
a CNS depressant also has an additive effect on motor impairment.
The proserotonergic effects of mirtazapine impart a potential risk of serotonin syndrome, although this
risk is largely obviated via its blocking 5-HT2 and 5-HT3 postsynaptic receptors. The 2 -noradrenergic
effects pose a risk of hypertensive crises when the drug is used in combination with an MAOI. As a
result, mirtazapine should be discontinued for at least 2 weeks before an MAOI is started and vice
versa.
Dosage and Administration
Although the recommended starting dosage is 15 mg/day, we now advise starting most patients at 30
mg/day. Geriatric patients and those with severe insomnia should be started at 15 mg/day.
Mirtazapine is administered once a day, about 1 hour before bedtime. The dose may then be increased
by 15 mg every 2 weeks to the maximum recommended dosage of 45 mg/day. In Europe, the
maximum dosage of the same drug is 60 mg/day, and we will sometimes push the dose to this level in
patients with treatment-resistant conditions.
NOREPINEPHRINE REUPTAKE INHIBITORS:REBOXETINE AND
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Reboxetine, a selective NRI antidepressant, has been in use for many years in Europe and South
America. Similarly, atomoxetine (Strattera) is an NRI approved for the treatment of ADHD. Neither of
the these agents is approved for the treatment of depression in the United States, but both have been
studied as potential antidepressants here. The American experience with both atomoxetine and
reboxetine as antidepressants or adjunctive treatments to serotonergic antidepressants has been
uneven. Monotherapy trials based in the United States have not been consistent in showing a benefit
for either NRI in the treatment of depression. For reboxetine, a U.S. trial with statistically significant
results was reported, but the effect size was small. Atomoxetine monotherapy trials have generally
failed. Likewise, although some small open-label studies have found benefit of atomoxetine or
reboxetine added to an SSRI in the treatment of resistant depression (Carpenter et al. 2005; Lucca et
- 2000; Papakostas et al. 2006), a recent study by Michelson et al. (2006) failed to demonstrate
efficacy for atomoxetine augmentation in patients who did not respond to sertraline.
Although neurotransmitter systems are clearly interconnected, it is equally evident that not everyone
who responds to one antidepressant will respond to another. The role of NRIs in the treatment of
depression remains unclear.
Pharmacological Effects
Reboxetine and atomoxetine enhance central norepinephrine neurotransmission by selectively blocking
the reuptake of norepinephrine. They are therefore selective NRIs. There is evidence that reboxetine
directly modulates the activity of the norepinephrine-rich locus coeruleus in the brain.
Alterations in the noradrenergic system have long been noted in depressed patients. For example,
levels of MHPG, the main metabolite of norepinephrine, are often increased in the urine, plasma, and
cerebrospinal fluid of depressed patients relative to control subjects. Abnormalities have been noted in
depressed patients in various norepinephrine receptors, including presynaptic 2 receptors and
postsynaptic 1 and receptors. Most antidepressants, even the SSRIs, are known to have specific
effects on norepinephrine receptors. For example, most antidepressants are known to downregulate
postsynaptic receptors with chronic administration. In fact, this reduction in receptors takes
several weeks and is correlated with the typical lag time of 3–6 weeks needed for antidepressants to
be effective.
Many symptoms of depression may be more closely related to norepinephrine function than to
serotonin function. For example, symptoms such as fatigue, hypersomnia, motoric retardation, and
anhedonia have been hypothesized to be more related to alterations in norepinephrine than to 5-HT,
although both are clearly important (Montgomery 1998). There is a strong interrelationship between
the noradrenergic and serotonergic systems.
Whether a selective NRI is more useful in treating some types of depression than other classes of
agents remains to be seen. However, the selectivity of reboxetine in norepinephrine reuptake makes it
unique among the antidepressants in the United States and Europe.
Indications
The only well-studied indication for reboxetine is for the treatment of major depression. European
studies have compared reboxetine with various antidepressants and placebo. For the treatment of
general depression, reboxetine appeared to be at least as effective as desipramine and fluoxetine
(Massana 1998; Massana et al. 1999). Reboxetine, however, appeared to be superior to fluoxetine in
improving social functioning. In addition, reboxetine was significantly better than fluoxetine in reducing
symptoms of severe depression and melancholic depression. As expected, 1-year data showed that
reboxetine is significantly more effective than placebo in preventing relapse and recurrence.
Although a noradrenergic agent would not necessarily be expected to be an effective treatment for
panic disorder, it is clear that noradrenergic agents such as nortriptyline and desipramine are effective
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http://www.psychiatryonline.com/popup.aspx?aID=231806&print=yes_chapterantipanic drugs. In double-blind studies comparing reboxetine with placebo in the treatment of panic
disorder, reboxetine appeared to be effective. However, the effects were not seen until after 5 weeks
of continuous treatment, and relatively higher doses of the drug may be required.
Two large-scale U.S. studies produced mixed results. In one, reboxetine had minimal, although
statistically significant, benefit over placebo. Paroxetine appeared to produce greater benefit. In the
other, no difference was seen between reboxetine and placebo. These studies held up expected FDA
approval for reboxetine.
Atomoxetine is approved only for the treatment of ADHD in both children and adults. The
manufacturer, Eli Lilly, studied atomoxetine as a potential antidepressant without demonstrating
consistent benefit. Atomoxetine has also been investigated in the treatment of pediatric enuresis
(Shatkin 2004), Tourette’s syndrome (Niederhofer 2006), and obesity (Gadde et al. 2006).
Side Effects
A specific norepinephrine reuptake blocker would be expected to have a side-effect profile that is
different from those of other classes of antidepressants. Compared with the SSRIs, reboxetine and
atomoxetine are less likely to produce nausea, diarrhea, somnolence, and sexual side effects (Mucci
1997). Unlike the TCAs, reboxetine does not have particularly strong anticholinergic effects. Thus,
relative to the TCAs, reboxetine and atomoxetine are less associated with typical antimuscarinic
effects. However, some common anticholinergic-like side effects, such as dry mouth, are also mediated
by the noradrenergic system. Among the side effects that have been reported more commonly with
reboxetine than with the SSRIs are dry mouth, constipation, urinary hesitancy, and hypotension.
Urinary hesitancy is much more common in males treated with the NRIs than in those treated with
fluoxetine, and caution should be taken in older men. Anecdotally, 1 antagonists such as prazosin and
tamsulosin may reverse the urinary hesitancy associated with the NRIs (Kasper and Wolf 2002). In
rare cases, reboxetine was associated with scrotal shrinkage, reflecting muscle contraction, though this
was not a serious issue with the drug.
The cardiovascular effects of the NRIs appear to be limited, with only 3% of patients reporting
hypertension versus 1% of subjects receiving placebo. Increased heart rate was no more common than
with placebo, but hypotension, although mild, was more common in patients treated with reboxetine
than in those treated with fluoxetine or placebo.
Overdose
Like many of the newer antidepressants, reboxetine and atomoxetine appear to be relatively safe in
overdose. There have been no fatal overdoses attributed to NRI overdose alone at the time of this
writing. However, NRI overdoses are associated with emesis, confusion, and tachycardia.
Dosage and Administration
The starting adult dosage is typically 4 mg bid. For most patients, the starting dose will be the
therapeutic dose. If no response is seen by 3–4 weeks, the dosage may be increased to the maximum
dosage of 10 mg/day. The half-life of the drug suggests bid dosing, although qd dosing can be tried. In
elderly patients, the typical starting dosage is 2 mg bid, with the maximum dosage of 6 mg/day.
Atomoxetine is typically started in adults at 40 mg/day, and the dosage is then increased to 80 mg/day
after at least 3 days at the lower dosage. The usual maximum dosage is 100 mg/day.
Drug Interactions
Because of the lack of significant cytochrome P450 enzyme effects, reboxetine has very little in the
way of pharmacokinetic interactions with other drugs. There may be a synergistic effect in the
combination of NRIs and other stimulating agents such as amphetamine or bupropion. In addition,
there can be synergistic effects of NRIs with a pressor agent or albuterol. The combination of NRIs and
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depression. At least one study of the combination of sertraline and reboxetine in rats indicated that the
combined drugs produced more rapid changes in serotonin and norepinephrine receptors than could be
produced by either drug alone (Harkin et al. 1999).
The use of an NRI with an MAOI is generally contraindicated. Although a serotonin syndrome is
unlikely, it is still possible that an NRI will interact with an MAOI in ways that might be problematic.
There is some speculation that reboxetine might mitigate the hypertensive effects of dietary tyramine
in patients taking MAOIs (Dostert et al. 1997).
Discontinuation
Because of its short half-life, reboxetine may pose a greater risk of causing discontinuation symptoms.
At this time, no specific syndrome has been associated with the abrupt discontinuation of an NRI.
However, given its pharmacokinetic profile, it would be prudent to discontinue the drug gradually. A
suggested taper schedule is to decrease the total daily dose by no more than 2–4 mg each week.
GEPIRONE
Gepirone is an older agent that has been studied in the treatment of anxiety disorders and, more
recently, in depression. Gepirone is in the same chemical class as buspirone but is a more potent 5-
HT1A agonist. An extended-release formulation of gepirone received a nonapprovable letter in 2004 but
could be approved in the future with additional studies. Buspirone, now available generically, was
never fully embraced by psychiatrists as an effective anxiolytic. Nonetheless, the drug was effective for
some patients and was particularly popular in primary care settings. The exact place for gepirone in
psychiatric practice remains to be seen.
In the more than 20 years that gepirone has been studied, its efficacy has been established in
generalized anxiety. More recent studies have suggested that gepirone, compared with placebo, is
effective in the treatment of major depression (Wilcox et al. 1996). It may be as effective as
imipramine in depressed patients (Feiger 1996). Some of the comparisons with placebo have been
significant but not robust. However, gepirone appears to have more robust separations from placebo in
the treatment of atypical depression. In one earlier trial, there was a 62% response rate in patients
with atypical depression treated for 8 weeks with up to 120 mg/day of gepirone versus only a 20%
response rate in placebo-treated patients (McGrath et al. 1994). More recently completed work also
supports the idea that gepirone may be selectively more effective in patients with atypical depression
(Quitkin and Gibertine 2001).
Gepirone has generally been well tolerated in clinical trials. The most common side effect was
dizziness, with some nausea, headache, and lightheadedness reported. Gepirone is probably weight
neutral. The most effective dosage range with the extended-release form for the treatment of
depression has been 40–80 mg/day.
We would consider gepirone as an alternative to bupropion or mirtazapine, in patients concerned about
sexual side effects. In addition, it might be a first-line alternative to the SSRIs in patients with atypical
depression. The role of gepirone as an augmenting agent to the SSRIs has not been assessed but
intuitively makes some sense.
TRICYCLIC AND TETRACYCLIC ANTIDEPRESSANTS
Structures
The chemical structures of TCAs and related compounds are remarkably similar (Figure 3–6).
Desipramine and nortriptyline are demethylated metabolites of imipramine and amitriptyline,
respectively. Amoxapine is a derivative of the antipsychotic loxapine and has an additional fourth ring
off a side chain. Maprotiline is a four-ring compound, with the fourth ring arising perpendicular to the
traditional three rings. Its side chain is identical to that of desipramine.
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Efficacy Second- or third-line agents for MDD (FDA approved for all)
Panic disorder
OCD (FDA approved for clomipramine)
Pain syndromes
Migraine prophylaxis
Enuresis (FDA approved for imipramine)
Side effects Dry mouth, constipation, urinary retention, blurred vision, confusion
Weight gain
Sedation
Sexual dysfunction
Orthostasis
Tachycardia
Cardiac conduction abnormalities
Dosage and
administration
Individualize with low hs dosing (25–50 mg) for imipramine and amitriptyline.
Increase by 25–50 mg every 3–7 days to target dosage of 150–300 mg/day.
(Nortriptyline should be started at 10–25 mg and increased, as needed, to a
maximum dosage of 150 mg/day.) Monitor levels and ECGs after dose stabilized.
Safety in
overdose
Lethal in overdose (induces arrhythmias).
Lavage and monitor on a cardiac bed for QRS widening.
Discontinuation Flulike and GI symptoms from cholinergic rebound. Reduce by 25–50 mg every 3
days.
Drug interactions CNS depressants: sedation, ataxia
Anticoagulants: warfarin levels
Antipsychotics: TCA and antipsychotic levels
Cimetidine: TCA levels
Clonidine: hypertensive crisis (avoid)
L-Dopa: TCAs absorption
MAOIs: serotonin syndrome (avoid clomipramine; imipramine and amitriptyline
may be used with close monitoring)
Stimulants: TCA levels
Oral contraceptives: TCA levels
Quinidine: arrhythmias (avoid)
SSRIs: TCA levels
Sympathomimetics: arrhythmias, hypertension, tachycardia
Note. CNS = central nervous system; ECG = electrocardiogram; FDA = U.S. Food and Drug
Administration; GI = gastrointestinal; MAOI = monoamine oxidase inhibitor; MDD = major depressive
disorder; OCD = obsessive-compulsive disorder; SSRI = selective serotonin reuptake inhibitor.
Figure 3–6.
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The pharmacological effects of the tricyclic and tetracyclic antidepressants are highly similar. Initially,
particular emphasis was placed on their relative effects in blocking the reuptake of norepinephrine or
5-HT. These differences came to underlie various theories on the biology of depression, particularly the
low-norepinephrine hypothesis versus the low-5-HT hypothesis. In recent years, theories have become
more complex as the pharmacological effects of these drugs have been shown to go beyond their mere
immediate reuptake-blocking effects to include later secondary effects on pre- and postsynaptic
receptors, on second-messenger systems, and on other neurotransmitter systems. Such effects may
account for differences among the various drugs in both their range of efficacy and their side effects.
At one time, the relative effects of norepinephrine reuptake–blocking versus 5-HT reuptake–blocking
were used to explain the relative sedative properties (5-HT) versus activating properties
(norepinephrine) of these drugs. Sedation, which early on was ascribed to serotonergic and
anticholinergic effects, has in part been ascribed to the antihistamine (H1 receptor) actions of TCAs.
Some investigators have argued that weight gain could also be due to H1 receptor–blocking effects.
Chemical structures of tricyclic and tetracyclic antidepressants.
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http://www.psychiatryonline.com/popup.aspx?aID=231806&print=yes_chapterAnticholinergic effects include dry mouth, constipation, urinary hesitancy, blurred vision, and
confusion. The H2 receptor–blocking effects may play a role in these drugs promoting healing of peptic
ulcers.
The relative norepinephrine reuptake–blocking effects, compared with 5-HT reuptake–blocking effects,
of the non-MAOI antidepressants are summarized in Table 3–7. The relative effects of these agents on
acetylcholine, 1 , H1 , 5-HT1 , and 5-HT2 receptors are summarized in Table 3–8. These potencies
represent best estimates based on receptor-binding and clinical studies. Note that the TCAs currently
available in the United States are relatively weak 5-HT reuptake blockers. Clomipramine is the one
exception to this rule. Indeed, in some in vivo models, TCAs—other than clomipramine—are devoid of
5-HT-blocking effects, as is trazodone. Moreover, recent research points to some of the
antidepressants as having 5-HT receptor–blocking effects, suggesting that some are 5-HT antagonists.
Taken together, laboratory data suggest that the tricyclics—other than clomipramine (see Chapter 6:
“Antianxiety Agents.”)—are weak serotonergic agents. In contrast, the SSRIs are relatively pure 5-HT
reuptake blockers, with little in the way of antagonist effects. Thus, these drugs offer an alternative for
the clinician. The tricyclic and tetracyclic antidepressants are virtually devoid of dopamine reuptake–
blocking effects. Of available antidepressants, only sertraline and bupropion have such effects, and the
effects are somewhat weak. Variations in biological effects help in drug selection, in terms of both
clinical efficacy and side effects. The types of side effects seen with tricyclic and tetracyclic compounds
are summarized in Table 3–9.
Table 3–7. Norepinephrine (NE) and serotonin (5-HT) reuptake–blocking effects of the non
MAOI antidepressants
Antidepressant
Ne 5-HT
amitriptyline
+ ++
amoxapine
++ +
bupropion
+/– 0
citalopram/escitalopram
0 +++
clomipramine
++ +++
desipramine
+++ +
doxepin
+ +
fluoxetine
0 +++
fluvoxamine
0 +++
imipramine
+ ++
maprotiline
++ 0
mirtazapine
+ –
nefazodone
0/+ +
nortriptyline
++ +
paroxetine
+ a
+++
protriptyline
+++ +
sertraline
0 +++
trazodone
0 +
trimipramine
0 0
venlafaxine
+ ++
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http://www.psychiatryonline.com/popup.aspx?aID=231806&print=yes_chapterNote. Data are approximations of relative activity from in vivo, in vitro, and clinical studies. Data on
clomipramine include results on desmethylclomipramine on both active metabolites with pronounced
effects on noradrenergic systems. In certain in vivo models, the tricyclic antidepressants (other than
clomipramine) and trazodone have been reported not to block 5-HT uptake. MAOI = monoamine
oxidase inhibitor. Strength of effect represented on a scale from 0 (no effect) to +++ (marked effect).
+/– indicates marginal effect.
aEffect at high doses.
Table 3–8. Relative receptor-blocking effects of antidepressants
Antidepressant Ach
1
H
1
5-HT
1
5-HT
2
amitriptyline +++ +++ ++ +/– +/–
amoxapine + ++ + +/– +++
bupropion 0 0 0 0 0
citalopram/escitalopram 0 0 0 0
clomipramine + ++ + 0 +
desipramine + + + 0 +/–
doxepin ++ +++ +++ +/– +/–
fluoxetine 0 0 0 0 +/–
fluvoxamine 0 0 0 0 0
imipramine ++ + + 0 +/–
maprotiline + + ++ 0 +/–
mirtazapine 0 0 +++ + +
nefazodone 0 + 0 + ++
nortriptyline + + + +/– +
paroxetine + 0 0 0 0
protriptyline +++ + + 0 +
sertraline 0 0 0 0 0
trazodone 0 ++ +/– + ++
trimipramine ++ ++ +++ 0 +/–
venlafaxine 0 0 0 0 0
Note. Data are approximations of relative activity from in vivo, in vitro, and clinical studies. ACh =
muscarinic acetylcholine receptor; 1 = 1 -adrenergic receptor; H1 = histamine1 receptor; 5-HT1 =
serotonin1 receptor; 5-HT2 = serotonin2 receptor. Strength of effect represented on scale from 0 (no
effect) to +++ (marked effect). +/– indicates marginal effect.
Table 3–9. Common or troublesome side effects of tricyclic and tetracyclic drugs
Anticholinergic Central nervous system
Dry mouth
Tremor
Constipation
Sedation
Blurred vision
Stimulation
Urinary hesitancy
Myoclonic twitches
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The principal indication for TCAs and related compounds approved by the FDA for marketing is major
depression. Other FDA-approved indications include anxiety (for doxepin) and childhood enuresis (for
imipramine as an adjunctive treatment). Nonapproved but common uses include insomnia (particularly
for amitriptyline and doxepin), headache (most commonly for amitriptyline, imipramine, and doxepin),
agoraphobia with panic attacks (for imipramine and clomipramine particularly), chronic pain syndromes
(most frequently for doxepin and maprotiline), and bulimia (for imipramine and desipramine).
Imipramine has also been reported to be effective in treating GAD, and trimipramine and doxepin were
once thought to be effective in treating peptic ulcers. The most recently released TCA, clomipramine,
has potent anti–obsessive-compulsive effects, as do the SSRIs, and is FDA approved for that use.
Obviously, these drugs exert rather wide pharmacological effects, which account for their potentially
broad range of actions. (For further discussion of the use of TCAs in the treatment of anxiety disorders,
see the section on antidepressants in Chapter 6: “Antianxiety Agents.”)
Currently, eight tricyclic and two tetracyclic antidepressants are available in the United States. One
tricyclic, clomipramine, is approved for the treatment of OCD but not for depression. It is used
worldwide, however, as a major antidepressant, particularly in cases of refractory depression. Generic
and brand names, formulations and strengths, and therapeutic dosage ranges of the tricyclic and
tetracyclic antidepressants are listed in Table 3–10.
Esophageal reflux
Seizure (maprotiline)
Cardiovascular
Extrapyramidal symptoms (amoxapine)
Orthostatic hypotension
Other
Palpitations
Perspiration
Conduction slowing
Weight gain
Hypertension
Sexual dysfunction
Impotence
Table 3–10. Tricyclic and tetracyclic antidepressants: names, formulations and strengths,
and dosages
Generic name
Brand namea Formulations and strengths Therapeutic dosage range
(mg/day)b
Tricyclics
amitriptyline Elavil Tablets: 10, 25, 50, 75, 100,
150 mg
150–300
clomipramine Anafranil Capsules: 25, 50, 75 mg 100–250
desipramine Norpramin Tablets: 10, 25, 50, 75, 100,
150 mg
150–300
doxepin Sinequan Capsules: 10, 25, 50, 75, 100,
150 mg
Oral solution: 10 mg/mL (120-
mL bottle)
150–300
imipramine Tofranil Tablets: 10, 25, 50 mg 150–300
imipramine
pamoate
Tofranil-PMc
Capsules: 75, 100, 125, 150 mg 150–300
nortriptyline Aventyl, Capsules: 10, 25, 50, 75 mg
50–150
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http://www.psychiatryonline.com/popup.aspx?aID=231806&print=yes_chapterThe original patents have expired on all of these drugs, and generic preparations are now available
(except for protriptyline). In the United States, use of generic compounds has not been without
controversy. Although generic drugs offered a savings for the consumer, some clinicians questioned
their pharmacological equivalence. One difficulty stemmed from the FDA definition of bioequivalence,
which relies heavily on the demonstration that an identical dosage of a generic preparation produces
blood levels within a specified range (20%–30%) above and below those produced by the original
compound. Even with approved generic preparations, some studies had suggested that they were not
truly equivalent to standard brands. Moreover, pharmaceutical companies were not required to prove
that their generic preparations had equivalence in clinical or biological potency. This area appears to be
less of a problem at present, since generic drug manufacturers have improved their production
methods.
Blood Levels
In past decades, considerable attention has been paid to the use of drug blood levels to monitor
treatment with various psychotropic agents. Currently, blood levels are most commonly used in
patients treated with TCAs, neuroleptics, clozapine, lithium carbonate, and anticonvulsants. Blood
levels have not proved to be useful with the SSRIs and most newer antidepressants. Likewise, blood
levels for benzodiazepines are neither widely available nor commonly used. Drug concentrations are
determined primarily in serum (e.g., for lithium carbonate and anticonvulsants) or plasma (e.g., for
TCAs). In addition to measuring the concentration of neuroleptics in blood, some laboratories measure
the relative binding to dopamine receptors (so-called radioreceptor assays). However, this practice has
not been widely adopted.
Generally, TCA serum levels are determined in blood drawn 8–12 hours after the patient’s last dose, in
an effort to avoid false peaks in blood levels that would occur if blood were drawn immediately after a
patient had taken the medication. Also, plasma levels are most accurate when the blood is drawn after
the patient has achieved steady state—the point at which a specific dose of drug given over a several
day period produces a consistent blood level. For most TCAs, this period is approximately 5–7 days.
Plasma levels can be particularly useful barometers of drug metabolism. There is approximately a 30-
fold difference among human subjects in plasma levels of TCAs produced by a single, fixed milligram
per-kilogram dose of a drug, reflecting the degree to which the slowest and fastest metabolizers differ
in drug absorption and metabolism. The TCAs are metabolized in part via the cytochrome P450 2D6
enzyme. Approximately 5%–7% of the Caucasian population is deficient in this enzyme. In addition,
metabolism of the TCAs is affected by age and by inhibition or activation by other drugs. Obviously,
slow metabolizers (such as elderly persons) are at a higher risk for attaining toxic levels of drugs; fast
Pamelor Oral solution: 10 mg/5 mL
(480-mL bottle)
protriptyline Vivactil Tablets: 5, 10 mg 15–60
trimipramine
maleate
Surmontil Capsules: 25, 50, 100 mg 150–300
Tetracyclics
amoxapine Asendin Tablets: 25, 50, 100, 150 mg 150–400
maprotiline Ludiomil Tablets: 25, 50, 75 mg 150–225
aExcept for imipramine pamoate and protriptyline, all the tricyclic and tetracyclic antidepressants
shown are available generically.
bDosage ranges are approximate. Many patients respond at relatively low dosages (even dosages
below those in the ranges given in table); others may require higher dosages.
cSustained release.
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http://www.psychiatryonline.com/popup.aspx?aID=231806&print=yes_chaptermetabolizers may have difficulty building drug levels. Most patients, however, fall in the middle range
of the normal bell-shaped curve distribution.
The clearest use of TCAs is for patients with more severe major depression. There is little or no
relationship between TCA level and clinical response in patients with nonendogenous depression or in
those with dysthymia. Two types of “positive” relationships between TCA level and clinical response in
endogenously depressed patients have been described in the literature. Glassman et al. (1977)
reported a sigmoidal relationship between response and imipramine plus desipramine levels; clinical
response increases with plasma level up to approximately 250 ng/mL and then levels off thereafter
(Figure 3–7). Glassman et al. reported rates of response of 30%, 67%, and 93% for patients with
plasma levels in the ranges of less than 150, 150–225, and greater than 225 ng/mL, respectively. For
nortriptyline, a curvilinear relationship has been described, as indicated in Figure 3–8. Response
increases with plasma level and then plateaus in the range of approximately 50–150 ng/mL, with a
decrease in response at plasma levels greater than 150 ng/mL. The critical range of 50–150 ng/mL has
been called the “therapeutic window.” Nonresponding patients with plasma levels of approximately 150
ng/mL may respond to a lowering of dosage and plasma level into the window. The decreased
responsivity at levels above the window is not due to side effects. Therapeutic windows have at times
been described for other drugs, but these windows are not as clear as that seen with nortriptyline.
Approximate therapeutic plasma levels for tricyclic and tetracyclic drugs are summarized in Table 3–
Figure 3–7.
Sigmoidal relationship between clinical response and imipramine plus desipramine plasma levels.
Figure 3–8.
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http://www.psychiatryonline.com/popup.aspx?aID=231806&print=yes_chapterA number of medications may increase or decrease plasma levels—generally by interfering with or
augmenting liver microsomal enzyme activity. For example, nicotine, barbiturates (including butalbital
[Fiorinal]), chloral hydrate, phenytoin, and carbamazepine induce breakdown of TCAs, and clinicians
should keep this in mind when prescribing TCAs for patients who are taking these compounds. In
contrast, antipsychotics (particularly phenothiazines), the SSRIs, methylphenidate, disulfiram, and
fenfluramine increase plasma levels by slowing drug metabolism in the liver. (Fenfluramine [Pondimin]
was withdrawn from the market in 1997, when “fen-phen” was found to be associated with heart valve
disease.) The SSRIs have become the agents one worries most about, because they are potent
competitive inhibitors of the cytochrome P450 2D6 enzyme and thus may substantially increase TCA
plasma levels. Conversely, TCAs increase phenothiazine plasma levels. Benzodiazepines and
antiparkinsonian medications have little or no effect on TCA levels.
A number of issues arise when one considers plasma level data. For one, studies generally use fixed
milligram-per-kilogram dosing, and consequently it is possible that a patient with a given TCA plasma
level (e.g., 250 ng/mL) taking the drug at a given dosage (e.g., 300 mg/day of imipramine) might well
have responded to a lower dosage and at a lower plasma level. In a sense, then, plasma levels can be
Curvilinear relationship between clinical response and nortriptyline plasma levels.
Table 3–11. Approximate therapeutic serum level ranges for tricyclic and tetracyclic drugs
Drug Serum level (ng/mL)
amitriptyline
100–250a
amoxapine Unknown
desipramine 150–300
doxepin
120–250a
imipramine
150–300a
maprotiline 150–250
nortriptylineb
50–150
protriptyline 75–250
trimipramine Unknown
aTotal concentration of drug and demethylated metabolite.
bHas a clear therapeutic window.
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http://www.psychiatryonline.com/popup.aspx?aID=231806&print=yes_chapterviewed as barometers of the adequacy of treatment. Patients who are not responding to a 4- to 6-week
trial of imipramine but who have attained a plasma level of 150 ng/mL or less may respond to an
increase in dosage and plasma level to greater than 200 ng/mL. On the other hand, other patients who
are responding at exactly the same dosage and plasma level do not need to have the dosage or plasma
level increased, even if the plasma level is below the therapeutic range. Some investigators have
advocated determining the plasma level for any patient who is responding to a TCA in order to record
that patient’s therapeutic plasma level while taking that drug. This could prove important if the patient
has a recurrence and requires retreatment.
Sometimes a routine check of a TCA blood level in a patient who is clinically much improved and has
only minor side effects reveals a plasma level of greater than 400 ng/mL, and the patient relapses
when the dose is decreased to bring down the plasma level. This result suggests that for that particular
patient, a very high plasma level is necessary for improvement. Indeed, there was a prospective report
that some patients require very high dosages and blood levels for an adequate response, although
there is an inherent risk with this approach.
So far, only amitriptyline shows clear toxicity related to plasma levels around 500 ng/mL. Obviously,
clinical judgment is necessary. An ECG is useful with patients who do well only at very high plasma
levels of the drug, to ensure that cardiac conduction is not seriously affected—that is, to ensure that no
intracardiac conduction slowing takes place.
Formerly, the variation in TCA assays among laboratories was of major importance, because clinicians
were unable to interpret a given value in their laboratories. Major national efforts to cross-validate
results from laboratories have helped, and this problem appears to have resolved.
In summary, plasma levels can provide useful clinical information if the clinician keeps these issues in
mind.
Side Effects
A review in the Physicians’ Desk Reference (PDR) of the package-insert information on each of the
TCAs and related agents indicates their myriad side effects. The side effects can be grouped broadly by
categories: anticholinergic, cardiovascular, and so forth (Table 3–9). This organization is somewhat
artificial, because a single side effect (e.g., sedation) may actually be due to any number of distinct
neurochemical effects (e.g., histamine blockade, increased 5-HT availability, 5-HT2 antagonism) or
combinations of effects. In addition, some side effects may reflect drug action either in the brain or at
the periphery or both (e.g., orthostatic hypotension).
How can clinicians help in the management of side effects? In some patients, particularly those with
complicating medical illness, side reactions may not be entirely controllable or manageable. There are,
however, some things that can be done, particularly for less severe reactions in medically healthy
patients.
One very important issue is attitude. Early on, some psychiatrists commonly had rather negative views
about medication, which were communicated indirectly or overtly to the patient, particularly if the
impetus to try medications had arisen from the patient and not the physician. In our experience, such
attitudes can be troubling to the patient, who must rely on the physician’s belief in the importance of
medication trials and in being able to deal with the side effects. The imperative for clinicians to develop
well-reasoned and balanced views about prescribing drugs has obviated this problem somewhat in
recent years.
A general principle of drug prescribing is that some side effects can be managed by reducing the
dosage or can be avoided by increasing the dosage slowly. In our experience, this is particularly true
for the early emergence of “spaciness,” depersonalization, confusion, orthostatic hypotension, or
marked sedation. If these reactions persist in the presence of more moderate dose escalation, a switch
to another TCA or another class of drug may be necessary. In dealing with anticholinergic side effects
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hypotension, nortriptyline is often a useful alternative, because it tends to produce orthostatic changes
at plasma levels above the so-called therapeutic window. Thus, nortriptyline is more easily tolerated
than imipramine, whose orthostatic effects are often produced at low plasma levels (see subsection on
TCA blood levels earlier in this section). Nortriptyline has been used successfully in several studies on
poststroke and geriatric depression.
Peripheral anticholinergic side effects have also been reported as being ameliorated by administering
bethanechol, a procholinergic drug, at dosages of 25–50 mg tid or qid, and generally continuing for as
long as the patient continues to take TCAs. This drug can be particularly helpful to patients with
urinary hesitancy. In cases of anticholinergic deliria, physostigmine (a centrally acting procholinergic
agent) may be administered either intravenously or intramuscularly to clarify the diagnosis.
Blurred vision as a result of TCAs can be treated with 4% pilocarpine drops or with oral bethanechol.
Patients otherwise doing well with maintenance TCA treatment, and therefore likely to be taking the
drug for some time, may require a change in their eyeglass prescription to correct the blurring of
vision.
For severe dry mouth, a 1% pilocarpine solution can be created by mixing the 4% solution available as
eyedrops with three parts water. This solution can be swished around the mouth for a few minutes,
30–60 minutes before an increase in salivation is needed. For example, patients may use this
mouthwash before having to give a lecture. Bethanechol in 5-mg or 10-mg tablets may be
administered sublingually for a similar effect. Although we know of no studies, anticholinergic effects
may be ameliorated with cholinesterase inhibitors.
An important, possibly antihistaminic, side effect of TCAs is weight gain—particularly seen with
amitriptyline and doxepin—which can be difficult to control pharmacologically. Often, patients who
demonstrate this side effect while taking one TCA will continue to gain weight when switched to
another, related drug. In some patients, switching to one of the newer antidepressants may be the
only way to maintain an antidepressant effect and promote weight reduction, because MAOIs also
cause weight gain. Unfortunately, some patients still continue to gain weight while receiving the drug
to which they are showing an antidepressant response. In such cases, support and advice regarding
dieting may be the only recourse. Addition of topiramate may facilitate weight loss.
The two tetracyclic agents, maprotiline and amoxapine, have been reported to produce troublesome
side effects—seizures and extrapyramidal symptoms—that have been less frequently reported with the
standard TCAs. Induced seizures have been reported in a number of single case reports of patients
taking maprotiline. Our group reported on a series of 11 patients with maprotiline-related seizures at
one hospital and a study of all U.S. maprotiline-related seizures (Dessain et al. 1986). In our series,
prolonged treatment (longer than 6 weeks) at high dosages (225–400 mg/day) appeared to be a major
factor. This was confirmed in the U.S. survey. In addition, rapid dose escalation—with the dosage
reaching 150 mg/day within 7 days—was a major factor in the general survey. When these two factors
were eliminated, the risk of seizures appeared to approximate that associated with classic
antidepressants (approximately 0.2%). The manufacturer of maprotiline altered its dosage guidelines,
recommending beginning treatment at 75 mg/day for 2 weeks, a maximum dosage of 225 mg/day for
up to 6 weeks, and maintenance at 175 mg/day or less. The previous dosage schedule was similar to
that of imipramine.
Amoxapine has been reported to produce a number of side effects associated with dopamine receptor
blockade. These side effects are similar to those more commonly found with the neuroleptic loxapine—
for example, galactorrhea, akathisia, and other extrapyramidal symptoms and even a few cases of
dyskinesia. Amoxapine is metabolized to a 7-OH metabolite. In some individuals, alternate
hydroxylation at the 8 position results in the accumulation of a neuroleptic metabolite. Generally
speaking, we recommend tapering or stopping medications if these symptoms occur (see subsection on
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Overdose
Overdoses can result in death. Tricyclics have narrow safety margins, and intracardiac slowing and
arrhythmias may result in death when overdoses are taken. In addition, patients taking overdoses can
demonstrate confusion, deliria, and loss of consciousness.
Dosage and Administration
Having evaluated a depressed patient, the clinician must determine whether TCAs are an appropriate
treatment. In the first edition of this manual, we subscribed to the approach of using a TCA first in the
treatment of endogenous or major depression. As a consequence of the superior safety and tolerability
of the newer agents, particularly the SSRIs, the TCAs were relegated to second-line status in the
second edition. However, some investigators continue to suspect that the TCAs are superior to the
newer agents in the treatment of more serious, melancholic depressive episodes. Although it has been
difficult to demonstrate greater efficacy for TCAs (see “Indications” subsection in section on SSRIs
earlier in this chapter), the jury is still out. Because the vast majority of studies on inpatients and
those with melancholic depression have employed TCAs, these agents still need to be considered early
in the treatment of more serious depression.
The choice of which TCA to use is somewhat a matter of personal preference. There is really
considerable overlap among these various drugs, although some are a bit more stimulating
(desipramine and protriptyline) and others are more sedating (amitriptyline and doxepin). Among the
secondary amines, desipramine and nortriptyline have become two of the most popular TCAs with
which to begin treatment. These two drugs have the most favorable side-effect profiles in the TCA
group. In addition, these two drugs have reliable plasma level data regarding clinical response. On the
other hand, amitriptyline has a very poor side-effect profile secondary to its anticholinergic and
antihistaminic side effects and may not be the best first choice for many patients, especially elderly
ones. With any of these drugs, the clinician is best advised to start with a relatively low dose, which
can then be increased slowly.
For imipramine, the starting doses and regimens vary. One common imipramine regimen is to
prescribe 75 mg/day during week 1 and to increase the dosage weekly, as needed, to 150 mg/day
during week 2, 225 mg/day during week 3, and 300 mg/day during week 4. Another approach is to
start at 50 mg/day, increasing the dosage by 25 mg every few days, as tolerated, to 150 mg/day; and
then, after about 2 weeks, to increase the dosage from 150 mg/day, at a rate of 50 mg every 3 days,
to 300 mg/day. (Similar dosage regimens are recommended for other uses of the drug, such as for
panic and pain.)
In prescribing imipramine for some patients, particularly elderly patients (who may be especially
intolerant or taking other medications), it seems reasonable to begin at 25 mg on day 1 and to
increase to 50 mg on day 2, allowing the patient to become acclimated to a single small dose. We also
advise a more conservative schedule of increases for elderly patients, keeping the dosage at 50
mg/day for 1 week and thereafter increasing it at a rate of 25 mg every 2 days to 150 mg/day. After 7
days at 150 mg/day, the dosage can be increased further as tolerated. Elderly patients present a
somewhat distinctive problem regarding drug-drug interactions (see Chapter 12, “Pharmacotherapy in
Special Situations”). The not uncommon medical problems of elderly persons and their relatively slow
drug metabolism usually dictate conservative management. However, clinicians must be careful: some
elderly patients are not slow metabolizers, but instead require reasonably high dosages and therefore
are at risk of being undertreated. The degree of side effects can be a useful barometer of the ability to
tolerate a given dosage, and plasma levels may aid in prescribing optimal doses (see subsections on
TCA blood levels and side effects earlier in this section).
For doxepin, amitriptyline, and trimipramine, dosage ranges similar to those for imipramine are
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in elderly patients and has a rapid effect on promoting sleep.
Protriptyline and nortriptyline are prescribed in rather different ways. For younger patients,
protriptyline is generally started at 15 mg/day (5 mg tid) in week 1, with an increase each week of 5–
10 mg in the daily dose, to a maximum dosage of 60 mg/day. For elderly patients, protriptyline is
generally begun at 10 mg/day, aiming for a maximum dosage of 30–40 mg/day. Nortriptyline, which is
the only TCA that clearly has a so-called therapeutic window, can be ineffective if plasma levels are
either too low or too high. The therapeutic dosage range for nortriptyline in adults is 50–150 mg/day.
We recommend starting at 50 mg/day and weekly increasing the daily dosage by 50 mg to 100
mg/day. (In elderly patients, begin at 25 mg/day and increase the dosage to 50 mg/day after 3–4
days.) After 3 weeks, a decrease in dosage may actually be helpful—a situation rather different from
that of the other TCAs (see subsection on TCA blood levels earlier in this section).
Amoxapine’s starting dosage in healthy adults is 150 mg/day, with a maximum dosage of 400 mg/day.
A few patients have been treated with up to 600 mg/day. However, this dosage increases the risk of
seizures. This drug may be particularly effective in treating psychotic depression (Anton and Sexauer
1983).
Maprotiline’s starting and maximum dosages are 75 and 225 mg/day, respectively. To avoid seizures,
the starting dose of maprotiline should be maintained for 2 weeks, and after 6 weeks of treatment, the
dosage should be reduced to a maximum of 175 mg/day (Dessain et al. 1986).
Discontinuation
In discontinuing or tapering TCAs, it is most prudent to do so at a maximum rate of 25–50 mg every
2–3 days. Many patients will demonstrate symptoms of cholinergic rebound if the TCA is discontinued
too abruptly. These symptoms include nausea, queasy stomach, cramping, sweating, headache, neck
pain, and vomiting. We have observed several patients who experienced intense GI symptoms during
and after TCA withdrawal. For these patients, propantheline bromide (15 mg tid prn) was extremely
helpful. Moreover, Nelson et al. (1983) reported that some patients demonstrate “rebound” hypomania
or mania with sudden cessation of TCAs, an observation confirmed by others.
When the issue of rebound symptoms versus a medical illness or recurrence of psychiatric symptoms is
in doubt, a single dose of the discontinued drug will often relieve the symptoms rapidly, confirming the
diagnosis of a withdrawal syndrome. There is one report in which withdrawal mania responded to
reinstitution of desipramine therapy (Nelson et al. 1983).
MONOAMINE OXIDASE INHIBITORS
Pharmacological Effects
The first-generation MAOIs—isocarboxazid, phenelzine, and tranylcypromine—have few direct effects
on reuptake or receptor blockade. Instead, they inhibit MAO in various organs, exerting greater effects
on monoamine oxidase A (MAO-A)—for which norepinephrine and 5-HT are primary substrates—than
on MAO-B, which acts primarily on other amines (e.g., phenylethylamine) and dopamine. Also, MAO-A
is found in the gut mucosa and is responsible for degrading various amines that can act as false
neurotransmitters and produce hypertensive crises (see later in this section). Isocarboxazid,
phenelzine, and tranylcypromine are so-called irreversible inhibitors. When the enzyme is inhibited by
these agents, protein regeneration is required before MAO enzymatic activity is restored. Selegiline
(Eldepryl), a selective irreversible MAO inhibitor used in the treatment of Parkinson’s disease, exerts its
effects on MAO-B and is generally thought to have a very low risk of producing hypertensive crises.
However, at the low dosages used in treating parkinsonian patients (5–10 mg/day), this drug is a weak
antidepressant, and data from Sunderland et al. (1989) suggested that at higher antidepressant
dosages, the drug affects both MAO-A and MAO-B and thus does not protect against hypertensive
crises. More information on selegiline is provided in the section “Selective and Reversible Monoamine
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Monoamine oxidase inhibitors (MAOIs): overview
Efficacy Third-line agents for
MDD (FDA approved for resistant depression)
Social anxiety
Panic disorder
Second-line agents for Parkinson’s disease (selegiline has FDA approval)
Side effects Weight gain
Orthostasis
Sexual dysfunction
Dry mouth
Insomnia/somnolence
Headache
Safety in overdose Can be lethal in overdose. Hypertensive crisis, stroke, and myocardial infarction
have been reported. Manage with lavage, emesis induction, and close
management of blood pressure and airway.
Dosage and
administration
Phenelzine: start at 15 mg bid or tid and increase by 15 mg per week to target
dosage of 60–90 mg/day.
Tranylcypromine: start at 10 mg bid or tid and increase by 10 mg per week to
target dosage of 40–60 mg/day.
Isocarboxazid: start at 10 mg bid and increase dosage, if the drug is tolerated, by
10 mg every 2–4 days to 40 mg/day by end of first week. Maximum
recommended dosage is 60 mg/day, administered in divided doses.
Selegiline transdermal system (Emsam): start with 6-mg patch daily for 4 weeks
and then increase to 9-mg patch for 2 weeks, and then 12-mg patch as needed.
No dietary restrictions at 6 mg/day.
Discontinuation Flulike symptoms, hallucinations, hypomania, and dysphoria reported with
sudden dis-continuation. Taper dose by 25% per week.
Drug interactions Foods containing high levels of tyramine (contraindicated) (see Table 3–14):
hypertensive crisis
-Blockers: hypotension, bradycardia
Oral hypoglycemics: hypoglycemic effects
Bupropion (contraindicated): hypertensive crisis, seizure
Carbamazepine (contraindicated): hypertensive crisis
Meperidine (contraindicated): serotonin syndrome
Nefazodone: possible serotonin syndrome
Sympathomimetics: hypertensive crisis
SSRIs (contraindicated): serotonin syndrome
TCAs: clomipramine contraindicated
Note. FDA = U.S. Food and Drug Administration; MDD = major depressive disorder; SSRI = selective
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http://www.psychiatryonline.com/popup.aspx?aID=231806&print=yes_chapterThere are two structural classes of MAOIs: the hydrazines (i.e., phenelzine) and the nonhydrazines
(tranylcypromine and selegiline) (Figure 3–9; Table 3–12).
Indications
The primary PDR clinical indication for MAOIs is for treatment of depression refractory to TCA therapy.
With so many other safer antidepressants currently available, MAOIs are now typically indicated when
several trials have failed. Still, some patients respond better to MAOIs than to any other class of
agents. Phenelzine has an FDA-approved indication for anxious depression. Although the British had
emphasized frequently that the MAOIs were not particularly helpful in treating the severe forms of
serotonin reuptake inhibitor; TCA = tricyclic antidepressant.
Figure 3–9.
Chemical structures of monoamine oxidase inhibitors (MAOIs).
Table 3–12. Monoamine oxidase inhibitors (MAOIs): names, formulations and strengths,
and dosages
Generic name Brand
name
Tablets and capsules Oral
concentrate
Usual therapeutic
dosage (mg/day)a
phenelzine Nardil Tablet: 15 mg None 45–90
selegiline Eldepryl
Carbex
Emsam
Capsule: 5 mg
Tablet: 5 mg
Patch: 6 mg/24 hr, 9
mg/24 hr, 12 mg/24 hr
None 20–50
tranylcypromine Parnate Tablet: 10 mg None 30–60
isocarboxazid Marplan Tablet: 10 mg None 30–60
aDosage ranges are approximate. Many patients respond at relatively low dosages (even dosages
below those in the ranges given in table).
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http://www.psychiatryonline.com/popup.aspx?aID=231806&print=yes_chaptermajor depression referred to in the past as endogenous, the American experience, including our own,
had been entirely different. These drugs were lifesavers for many severely depressed patients,
particularly those whose depression did not respond to TCAs.
Why the discrepancy? For one, there was little doubt that MAOIs were effective in patients with panic
attacks or with anxious or atypical depression. However, their effectiveness in patients with
melancholic or endogenous depression may require the prescription of considerably higher dosages
than those used in the early British trials, in which relatively low dosages were used. Another difficulty
with determining ranges of efficacy revolves around the occurrence of pronounced obsessionality,
agitation, and anxiety in many endogenously depressed patients, who may have, in the early studies,
been misdiagnosed as only anxiously depressed.
Investigators at Columbia University have attempted to define an atypical depressive syndrome that
preferentially responds to phenelzine and other MAOIs such as moclobemide. Their data suggest that
patients with atypical depression respond better to MAOIs than to TCAs. The SSRIs are also effective in
treating atypical depression. Because the SSRIs are considerably safer than the MAOIs, the use of
MAOIs in the treatment of atypical depression has dropped off considerably since the introduction of
fluoxetine. MAOIs are also effective in the treatment of social phobia.
Side Effects
Common side effects of MAOIs are listed in Table 3–13. Because MAOIs do not block acetylcholine
receptors, they produce less dry mouth, blurred vision, constipation, and urinary hesitancy than do
TCAs. However, we have seen patients who have developed urinary hesitancy, presumably as a result
of an increase in noradrenergic activity. When the problem occurs, a reduction in dosage may help. We
have been less impressed with the adjunctive use of bethanechol with MAOIs than with its use with
TCAs.
The most common side effect of MAOIs is dizziness, particularly of the orthostatic type. This side effect
appears to be somewhat more common with MAOIs than with TCAs. Dose reduction may help; but,
Table 3–13. Common or troublesome side effects of monoamine oxidase inhibitors (MAOIs)
Orthostatic hypotension
Hypertensive crises (interactions with foodstuffsa or medications)
Hyperpyrexic reactions
Anorgasmia or sexual impotence
Insomnia during night
Sedation (particularly in daytime; due to insomnia during night)
Stimulation during day
Muscle cramps and myositis-like reactions
Urinary hesitancyb
Constipationb
Dry mouthb
Weight gain
Myoclonic twitches
Skin irritation at patch site (Emsam)
aSee Table 3–14.
bLess than with tricyclic antidepressants.
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http://www.psychiatryonline.com/popup.aspx?aID=231806&print=yes_chapteragain, we have often found reduction in the dose to be problematic, because too great a reduction may
lead to reemergence of depressive symptoms. Alternative approaches include 1) maintenance of
adequate hydration—about eight glasses of fluid a day—and increased salt intake; 2) use of support
stockings, “bellybinders,” or corsets; and 3) addition of a mineralocorticoid (fludrocortisone [Florinef]).
Although this mineralocorticoid has been used in patients with orthostatic hypotension not induced by
medication, we have rarely found it to be helpful in the usual daily dose of 0.3 mg. We have been told
by colleagues that fludrocortisone can be effective at a total daily dose of 0.6–0.8 mg. An intriguing
report appeared before our second edition, pointing to the use of small amounts of cheese to help
maintain blood pressure—a counterintuitive but imaginative solution. However, most clinicians were
wary of the understandable risk of hypertensive crises with cheese, particularly when one did not really
know the tyramine content of the foodstuff. We are not aware of any recent reports on this. Similarly,
one would intuit that adding a stimulant (D-amphetamine or methylphenidate) to an MAOI would result
in marked surges of blood pressure. In fact, however, Feighner et al. (1985) reported that the addition
of stimulants for patients receiving MAOIs or MAOI-TCA combinations normalized blood pressure in
depressed patients with serious orthostatic hypotension or brought out a clinical response in patients
who had previously not had any response. There were no incidents of hypertensive crises; in fact,
several of the patients developed orthostatic hypotension. Daily dosages used were 5–20 mg of D
amphetamine and 10–15 mg of methylphenidate. These authors recommended beginning at a dosage
of 2.5 mg/day of either drug. We have heard of several clinicians in the community who have used
these approaches successfully, but we have also heard of occasional hypertensive crises when
stimulants were used in combination with MAOIs.
Sedation and activation are also potential problems, the latter being more common. Activation takes
two forms: stimulation during the day (particularly with tranylcypromine) and insomnia at night.
Tranylcypromine’s stimulatory effects have been related to its having a structure similar to that of
amphetamines, although this pharmacological link has not been clearly established. Overstimulation
can be ameliorated somewhat by dose reduction, although the side effect is not easily eliminated. If a
dose reduction does not result in a decrease in stimulation, patients may need to be switched to
another medication.
Phenelzine is, overall, far less stimulating and more sedating than tranylcypromine. As such it offers a
major alternative for daytime overstimulation. However, phenelzine may produce both insomnia and
secondary daytime sedation. Oddly, one often encounters insomnia in patients who are nevertheless
showing a good clinical response to the drug, making it a particularly difficult side effect to manage.
Changing the dosage regimen may be helpful. Patients who are not taking phenelzine in the evening
may benefit from switching drug taking to the evening hours. Conversely, patients who are taking
much of the drug in the evening may respond by taking it earlier in the day. These manipulations can
be helpful, although in our experience they are highly variable in their efficacy. Some patients may
ultimately require hypnotic agents to overcome persistent insomnia. By the second edition of this
manual, we had become very impressed with the addition of low doses of amitriptyline, trimipramine,
or trazodone (50–100 mg at bedtime) to counteract MAOI-induced sleep disturbances. Caution should
still be exercised in using trazodone or the TCAs with MAOIs because of the slight risk of developing a
serotonin syndrome. With trazodone, we recommend trying doses of 50–100 mg per night. An increase
to 150 mg hs can be tried if there has been no response at a lower dose and the medication has been
well tolerated.
As the dose of an MAOI is increased to high levels in an attempt to achieve a therapeutic effect,
patients occasionally become “intoxicated”—drunk, ataxic, confused, and sometimes euphoric. This is a
sign of overdose, and the dose should be reduced. Some patients develop muscle pains or
paresthesias—probably the result of the MAOIs interfering with pyridoxine (vitamin B6 ) metabolism.
Pyridoxine administered at dosages of approximately 100 mg/day can be helpful.
A particularly bothersome side effect is anorgasmia, which in some patients lessens over time. We
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cyproheptadine has been said to be helpful. Agents such as buspirone and bupropion are best avoided
in combination with MAOIs.
Overdose
Overdoses are not necessarily lethal. Patients will show sedation and orthostasis. However, overdoses
commonly involve other medications, resulting in serotonin syndromes or hypertensive reactions.
Drug Interactions
The greatest side-effect problems with MAOIs involve untoward interactions with certain foodstuffs or
cold remedies, which may produce hypertensive crises with violent cerebrovascular accidents, or
serotonin syndromes—consisting of hyperpyrexia, mental status changes, myoclonus, and delirium—
that can lead to coma and death. MAO in the intestinal tract degrades tyramine. When MAO is inhibited
by MAOIs, the individual is at risk for absorbing large amounts of tyramine and probably other
substances (e.g., phenylethylamine), which can act as false neurotransmitters or indirect agonists and
elevate blood pressure. Fortunately, dietary restrictions can markedly reduce the risk (Table 3–14).
Various prohibited foods are included in lists in the PDR. These lists have been reviewed by several
investigators, and relative risks have been attributed to many of the foods. As a general rule, we have
begun to specifically advise patients to avoid eating Chinese food because of the ingredients used
(e.g., soy sauce, sherry).
Table 3–14. Foods to be avoided with monoamine oxidase inhibitors (MAOIs)
Foods definitely to be avoided:
Beer, red wine
Aged cheeses (cottage and cream cheese are allowed)
Dry sausage
Fava or Italian green beans
Brewer’s yeast
Smoked fish
Liver (beef or chicken)
Foods that may cause problems in large amounts but are otherwise less problematic:
Alcohol
Ripe avocado
Yogurt
Bananas (ripe)
Soy sauce
Foods that were thought to be problems but are probably not problematic in usual quantities:
Chocolate
Figs
Meat tenderizers
Caffeine-containing beverages
Raisins
Source. Based on McCabe and Tsuang 1982.
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http://www.psychiatryonline.com/popup.aspx?aID=231806&print=yes_chapterThe serotonin syndrome is generally not due to interaction with foodstuffs. It represents increased
central 5-HT activity and may be particularly provoked by the addition of certain medications.
In some cases of either hypertensive or hyperpyrexic reactions, the exact cause is not clear. Of
particular importance regarding medication interactions is warning patients to check with their
physician before taking other medications along with the MAOIs. Meperidine (Demerol), epinephrine,
local anesthetics (containing sympathomimetic agents), and decongestants can be particularly
dangerous.
Frequently, we are asked which decongestant or antihistamine can be used with the MAOIs.
Unfortunately, there is little in the way of prospective data. Diphenhydramine is used by many
practitioners, with apparent success. One problem, however, with this approach is that some over-the
counter diphenhydramine elixirs contain pseudoephedrine, and at least one untoward interaction with
the latter agent has been seen by our group. Another option is nasal sprays, but with this form, too,
some patients may show increases in blood pressure.
Another issue has to do with general anesthesia—during ECT or surgery—in patients treated with
MAOIs. Although at first glance this seems a frightening prospect, there have been many patients who
have successfully undergone procedures requiring general anesthesia without consequence. Indeed,
Dr. George Murray informed us, for the second edition of this manual, that Massachusetts General
Hospital had collected reports on some 2,000 such cases. Obviously, anesthesiologists need to be
apprised of a patient’s medications in order to determine the safest approach. To this end, it is
probably wise to have patients taking MAOIs carry a MedAlert Card. Still, in many settings, surgeons
and anesthesiologists advise patients to stop taking MAOIs before undergoing surgery. Further study is
needed to determine the most prudent approach to this knotty problem.
If a patient develops a surge in blood pressure with violent headaches, he or she should be instructed
to go to a local emergency room. Phentolamine (Regitine), a central -blocker, can be administered
intravenously to reverse the acute rise in blood pressure. Years ago, some psychopharmacologists
recommended that patients take oral chlorpromazine when headache occurred. We have stopped this
practice unless patients have not had a documented increase in blood pressure, because some patients
will display marked headaches secondary to a lowering of blood pressure. Instead, we provide our
patients with nifedipine, a calcium channel blocker, in case they experience marked increases in blood
pressure; 10 mg per hour until relief occurs (generally one or two doses) appears to be very helpful.
To enhance absorption, patients should be instructed to bite into the capsule before swallowing. This
approach may prove problematic in elderly patients, because acute lowering of blood pressure and
myocardial infarction have been reported with this approach for these patients.
We advise patients with headaches to have their blood pressure checked. In addition, routine
monitoring of blood pressure with an MAOI, particularly during the first 6 weeks of treatment, seems
prudent (for both the hypotensive and the hypertensive effects of the drug).
Dosage and Administration
The traditional therapeutic dosage ranges of these three MAOIs are as follows: phenelzine, 45–90
mg/day; tranylcypromine, 30–60 mg/day; oral selegiline, 20–50 mg/day. Some patients require
treatment at the higher end of the dosage range. For example, 90 mg/day of phenelzine is commonly
required in a patient with severe depressive illness.
A patient treated with phenelzine should start taking the medication at 30 mg/day, and the dosage
should be increased to 45 mg/day after 3 days. Thereafter, the dosage can be increased at a rate of 15
mg per week to 90 mg/day. We have seen patients who require as much as 120 mg/day; however,
many patients cannot tolerate the orthostatic side effects of these drugs. Some investigators have
recommended a dosage of 1 mg/kg per day of the drug as a guideline for adequacy of treatment.
For tranylcypromine, a starting dosage of 20 mg/day for 3 days seems reasonable. The dosage can
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http://www.psychiatryonline.com/popup.aspx?aID=231806&print=yes_chapterthen be increased to 30 mg/day for 1 week, with increases of 10 mg per week to 50–60 mg/day. The
manufacturer’s current recommended maximum dosage of the drug is 40 mg/day. One investigator,
Dr. Jay Amsterdam, reported that extremely high dosages of the drug (110–130 mg/day) may help
patients with even the most refractory depression. There is some thought that at such high dosages
the drug is exerting alternative, additional effects—possibly acting as a reuptake blocker (Amsterdam
and Berwish 1989). Once a patient has responded, the medication should be maintained for a length of
time similar to that recommended for the TCAs.
Discontinuation
The currently available MAOIs irreversibly bind MAO to such a degree that it takes approximately 2
weeks after the MAOI is stopped for the enzyme to regenerate. During this time, tyramine and drug
interactions may occur. Thus, it is important to inform patients that they should maintain their dietary
and drug restrictions for 2 weeks after the MAOI is discontinued. In addition, these drugs should be
tapered to avoid rebound hypomania. Rarely, the withdrawal of an MAOI elicits a psychiatric
excitement or psychosis resembling a delirium more than mania. If the clinician wants to switch a
patient from one MAOI to another, care must be taken to avoid drug-drug interactions. The clinician
should taper the first MAOI and allow for a 10 to 14-day drug-free period before beginning another
MAOI. Some patients have experienced severe untoward reactions in switching from one MAOI to
another, particularly from phenelzine to tranylcypromine—perhaps reflecting the latter’s amphetamine
like properties. In general, a good reason to switch from one MAOI to another is intolerance to side
effects. If an adequate trial of an MAOI fails, there is little evidence that switching to another MAOI
helps.
When a transition between a TCA and an MAOI is being made, the PDR recommends that patients stop
taking all medications between trials for 10–14 days. Many clinicians, however, have reported that a
briefer drug-free period (i.e., 1–5 days) is sufficient for the transition from a TCA to an MAOI. For the
transition from an MAOI to a TCA, the 10- to 14-day period is generally recommended. The difference
in these strategies is probably due to the 10- to 14-day period needed to regenerate MAO.
However, patients taking MAOIs should wait 2 weeks before starting fluoxetine. For the transition from
fluoxetine to an MAOI, a 5-week period is recommended by the manufacturer because of the long half
life of the demethylated metabolite norfluoxetine. For the other SSRIs, a 2-week washout is adequate
before starting an MAOI. Likewise, a 1- to 2-week washout should ensue before switching to an MAOI
from venlafaxine and bupropion. The 5-HT2 antagonists nefazodone and trazodone appear to require
very short washouts; 1 week is quite enough.
SELECTIVE AND REVERSIBLE MONOAMINE OXIDASE INHIBITORS
As described earlier, all of the currently available MAOIs at antidepressant doses are nonselective and
irreversible inhibitors of MAO; that is, they irreversibly inhibit both MAO-A and MAO-B, and for enzyme
activity to commence, new MAO must be generated. Drugs that selectively block MAO-B, such as
selegiline, may substantially decrease the risk of hypertensive crises, because they do not substantially
affect MAO in the gut. Similarly, a reversible inhibitor of MAO-A would have a low affinity for MAO and
would be readily displaced by pressor amines, thus reducing the risk of a hypertensive crisis. Two
RIMAs, moclobemide and brofaromine, were under investigation, but interest in marketing these drugs
in the United States has waned considerably.
The FDA approved selegiline in 1991 for use in Parkinson’s disease under the trade name Eldepryl.
Much of the earlier clinical and scientific literature refers to selegiline by its earlier name, L-deprenyl.
Selegiline has proved a useful drug in Parkinson’s disease and may be the only antiparkinsonian drug
that has neuroprotective qualities and modestly affects the progression of the illness. At the dosages
used in Parkinson’s disease, 5–10 mg/day, the drug is a selective but irreversible inhibitor of MAO-B.
Unfortunately, currently available studies of the use of selegiline in depression suggest that dosages of
20–60 mg/day are required to relieve depression. At these higher dosages, both MAO-A and MAO-B
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http://www.psychiatryonline.com/popup.aspx?aID=231806&print=yes_chapterare inhibited and hypertensive crises following ingestion of tyramine in foods are possible. One such
case, albeit mild, has been reported in a patient treated with 20 mg/day of selegiline.
Over the past several years, a transdermal form of selegiline has also been studied for the treatment of
depression. A selegiline transdermal system, marketed under the brand name Emsam, was approved
by the FDA in February 2006.
There are numerous published clinical studies of the use of selegiline in depression (Agosti et al. 1991;
Mann et al. 1989; Sunderland et al. 1994). These studies can be interpreted as confirming the clear
therapeutic effect of selegiline in patients with atypical and chronic depression and more serious
depression. Furthermore, the Sunderland et al. study suggests that at a dosage of 60 mg/day,
selegiline is useful for and well tolerated by geriatric patients with treatment-resistant depression. The
drug is of substantial clinical interest because its pattern of side effects at dosages up to 40 mg/day
appears quite favorable compared with that of the older MAOIs. Selegiline does not seem to cause
clinically significant orthostatic hypotension or sexual dysfunction, and it may cause less insomnia than
the older drugs. Several patients who were unable to tolerate the side effects of older MAOIs have
tolerated selegiline quite well. It should be noted, however, that most published selegiline trials have
lasted only 4–6 weeks, and some patients treated with the older MAOIs develop clinically intolerable
side effects only after taking the drug for 2–3 months. Psychiatrists already experienced in the MAOI
management of patients may find selegiline worth trying in cases of treatment-resistant conditions.
Patients who have a good antidepressant response to MAOIs but who are experiencing intolerable side
effects may be the best candidates for selegiline.
Oral selegiline is currently not approved for use in depression. But transdermal selegiline is approved
for the treatment of depression. Because selegiline is metabolized to R isomers of amphetamine and
methamphetamine in the body and is a dopamine reuptake inhibitor, we strongly urge a 2-week
interval between stopping an older MAOI and starting selegiline. Patients treated with transdermal
selegiline at dosages higher than 6 mg/day should adhere to the usual restrictions of a low-tyramine
diet.
Three other comments are worth making. First, measuring platelet MAOI in patients who are taking
selegiline is probably not useful, because almost complete inhibition occurs after 1 week at a dosage of
10 mg/day. Second, the drug is very expensive: a local drugstore charges around $5 per 5-mg pill.
Finally, selegiline should not be stopped abruptly, because it is associated with a discontinuation
syndrome consisting of nausea, dizziness, and hallucinations.
At least two studies have demonstrated efficacy of transdermal selegiline against placebo in major
depression (Amsterdam 2003; Bodkin and Amsterdam 2002). Of interest is that in patch delivery,
selegiline in brain may be a far more potent MAO-A inhibitor, and this may confer greater efficacy. The
drug (in a patch) may earn FDA approval for acute and chronic major depression either with or without
atypical features. The transdermal formulation bypasses gut and liver and allows for higher plasma
levels with a low risk of foodstuff interactions. The drug is available in patches of 20, 30, and 40
mg/cm2 (6, 9, and 12 mg/24 hours, respectively) applied daily. In clinical trials, the starting daily dose
was typically 20 mg (6 mg/24 hours), and the daily dose was then increased by 10 mg (3 mg/24
hours) every 1–2 weeks to a maximum of 40 mg (12 mg/24 hours). The package insert indicates that
the 6- and 9-mg dose/24 hours may increase the risk for a tyramine interaction in some patients. This
observation is based on a study in healthy control subjects in which a high-tyramine diet was
associated with mild increases in blood pressure with the 9- and 12-mg patches. The risk of untoward
interactions is largely theoretical. We have done studies that used the 9- and 12-mg doses without a
restricted diet and have observed no increases in blood pressure.
Rash has been the primary side effect that was observed to be greater with transdermal selegiline than
with placebo. While most patients do not have substantial reactions to the patch, some skin reactions
can be quite intense. We have seen a few patients with erythema that extends far beyond the patch
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http://www.psychiatryonline.com/popup.aspx?aID=231806&print=yes_chaptersite, and pruritis is not uncommon. Oral diphenhydramine seems to help with the itching. After site
reactions, insomnia is the next most common side effect and is consistent with the amphetamine-like
effects of the drug. Standard sleep medications such as zolpidem or temazepam appear to be helpful
and are well tolerated. While sleep does seem to normalize after the patient has taken the drug for a
few weeks, just taking the patch off at night also seems to help. Unfortunately, taking half the dose
might also decrease the efficacy of the transdermal selegiline. The patch, designed for 24-hour
delivery, needs to be changed daily. Some patients have taken to cutting the 6 mg/24 hour patch in
half if they cannot tolerate a full dose. Although cutting the patch should reduce the daily dose in
proportion to the amount cut (since surface area of the patch is directly related to total drug dose), the
manufacturer recommends against cutting the patch because compromising the integrity of the patch
could affect reliability of transdermal drug delivery. The risk of a serotonin syndrome when transdermal
selegiline is used in combination with a serotonergic drug appears reduced but not eliminated. Thus,
the drug should not be combined with SSRIs, SNRIs, or most TCAs. However, orthostasis, weight gain,
and sexual dysfunction appear to be much less of a problem with transdermal selegiline than with oral
MAOIs.
Given the ease of use and better tolerability of transdermal selegiline versus oral MAOIs, we are
typically using it before considering other MAOIs. The patient profile that may best fit with transdermal
selegiline includes patients who have experienced failed trials with one or more classes of
antidepressants, depressed patients with prominent fatigue or cognitive deficits, and patients with
atypical depression.
Moclobemide is the best-studied RIMA. Its actions on MAO are easily reversed (i.e., do not require
regeneration of the enzyme). Moclobemide has a half-life of only 1–3 hours. It is available in Europe,
Canada, and other parts of the world, but not in the United States. Several thousand depressed
patients have been enrolled in moclobemide studies over the past 10 years, and it has been found to
be effective in a wide spectrum of depressive illnesses, including melancholic, endogenous, atypical,
psychotic (in combination with a neuroleptic), and bipolar subtypes (Fitton et al. 1992).
Moclobemide appears to be effective in elderly as well as younger patients and may be effective in the
treatment of social phobia. In unpublished South American trials, moclobemide appeared to be as
effective as—if not more effective than—imipramine and superior to placebo. However, one meta
analysis in Europe (Lotufo-Neto et al. 1999) suggested that moclobemide was not a particularly
effective antidepressant in comparison with imipramine and placebo. In another South American study,
moclobemide was significantly more effective than placebo in the treatment of social phobia.
The primary advantages of moclobemide over standard MAOIs are its tolerability and its safety. Nausea
is the only side effect reported more commonly for moclobemide than for placebo. Significant
orthostasis and other cardiovascular side effects are usually not seen. Furthermore, moclobemide has
proved safe in overdoses to 20 g.
Because moclobemide does not increase tyramine sensitivity (Cusson et al. 1991), the risk of dietary
interactions appears low. In Europe, the only significant dietary restriction is avoiding large amounts of
aged cheeses after taking a dose of the drug. Moclobemide is usually given after meals or at bedtime
to minimize dietary interactions.
The risk of serious drug interactions also appears to be lower with moclobemide. However, serious
interactions have been reported with meperidine, clomipramine, and possibly the SSRIs. There is one
report that moclobemide has been administered safely with fluvoxamine and fluoxetine (Dingemanse
1993). It is unlikely that moclobemide will be introduced soon in the United States because of a
number of failed trials, but it is available through pharmacies in Europe and Canada. Development of
another RIMA, brofaromine, has also been canceled because of an apparent lack of efficacy.
MELATONIN AGONIST–5-HT
2C ANTAGONIST
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http://www.psychiatryonline.com/popup.aspx?aID=231806&print=yes_chapterAgomelatine represents one of the more novel approaches to the pharmacotherapy of depression. The
drug’s 5-HT2C antagonist pharmacology provides both antidepressant and anxiolytic properties, while
the melatonin MT1 and MT2 agonist properties provide for sleep induction without much sedation. A
disturbance of circadian rhythms has long been recognized in mood disorders, most notably in sleep
and the diurnal variation common to melancholic depression. It remains to be seen whether a potent
melatonin agonist has other benefits in the treatment of depression.
Agomelatine has demonstrated anxiolytic and antidepressant properties in animal models (Papp et al.
2006). Preliminary clinical trials have demonstrated that dosages above 25 mg/day appear effective in
the treatment of depression (Loo et al. 2002a, 2002b). The first phase III trial to be completed was
very encouraging. Agomelatine 25–50 mg/day was superior to placebo in the treatment of depression
and was well tolerated (Kennedy and Emsley 2006). A analysis of more severely depressed patients
within the sample of 212 patients studied indicated that this subset also appeared to respond to
agomelatine. Thus, there is some hope that agomelatine may prove to be useful in severely depressed
and perhaps currently treatment-resistant patients.
Even if agomelatine proves no more efficacious than currently available treatments, its favorable side
effect profile may be a distinct advantage over that of many available antidepressants. Agomelatine’s
specific receptor effects are associated with fewer sexual side effects, less GI upset, and and less
daytime sedation than those of most serotonergic antidepressants (Dubocovich 2006). In addition,
there is no evidence of weight gain or of a discontinuation syndrome when the drug is stopped
abruptly.
It is anticipated that the target dosage of agomelatine will be 25 mg/day, with some patients
benefiting from a dosage of up to 50 mg/day. We can imagine the combination of agomelatine with
either SSRIs, bupropion, or SNRIs in the treatment of resistant depression, but no studies have yet
evaluated the augmenting benefit of agomelatine.
NOVEL ANTIDEPRESSANTS
Over the past several years, a variety of other novel approaches to the treatment of major depression
have been investigated. Whereas all marketed antidepressants appear to significantly impact
monoamines, these new agents appear to work by completely different mechanisms.
Among the more promising areas in antidepressant research is the use of agents that impact the
hypothalamic-adrenal axis in major depression. Since severe depression is often characterized by
hypercortisolemia, it has been speculated that some of the symptoms of a depressive episode might be
attributable to elevated cortisol levels. For example, there is some evidence that cognitive symptoms,
diurnal variation, and perhaps even psychotic symptoms in depression might be due, at least in part,
to elevated cortisol levels. Several types of anticortisol agents are under investigation. Corticotropin
releasing factor (CRF) antagonists have been synthesized by a number of pharmaceutical companies
and are being examined for anxiety disorders and depression (Mitchell 1998). One, R121919, has been
reported to produce significant antidepressant effects (Zobel et al. 2000), but its development was
canceled because of elevated liver enzymes. Likewise, glucocorticoid receptor antagonists that block
cortisol’s effects at the low-affinity receptor at the level of the cerebral cortex have shown promise as
antidepressants. Initial reports by our group suggested that mifepristone might have promise in the
treatment of psychotic depression (Belanoff et al. 2002). A biotechnology company that two of us
(A.F.S., C.D.) have an interest in has pursued more rigorous studies with mifepristone. Two double
blind trials of C-1073 600 mg/day for 7 days in the treatment of psychotic depression have yielded
surprising results. The first trial failed to show a benefit on its primary endpoint, a 30% reduction in
psychosis on the Brief Psychiatric Rating Scale (BPRS), but it did show differences when more rigorous
response, such as remission, was evaluated in post hoc analyses. The second trial demonstrated a
rapid and sustained effect on the psychosis in psychotic depression but insignificant separation from
placebo on measures of depression (DeBattista et al. 2006). We believe that the drug has more
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http://www.psychiatryonline.com/popup.aspx?aID=231806&print=yes_chapterimportant effects on psychosis than on depression. At the time of this writing, two phase III trials have
had inconclusive results. The response rate of the comparison groups (antidepressant plus placebo)
was as high as 95%, and the addition of mifepristone could not improve this response rate. Other
groups have demonstrated cognitive and mood improvements associated with mifepristone in the
treatment of bipolar depression (Young et al. 2004).
Corticotropin-releasing factor antagonists may also be useful in the treatment of anxiety and
depression. The first, uncontrolled human study of a CRF antagonist in the treatment of MDD
demonstrated that the drug appeared to alleviate depressive symptoms in a small number of patients
(Zobel et al. 2000). However, that CRF antagonist was subsequently shown to be hepatotoxic, and
thus its development was suspended. Nonetheless, a variety of CRF antagonists are in development,
with none past early Phase II trials.
Another line of antidepressant research has involved the use of peptide hormone antagonists, including
substance P antagonists, as antidepressants. In preliminary studies, two substance P antagonists
developed by Merck were found to be superior to placebo in the treatment of major depression
(Kramer et al. 1998, 2004). The drug also was well tolerated and had few side effects. However,
subsequent trials of MK-0869, unfortunately, failed in all five Phase III trials (Keller et al. 2006), and
the drug is no longer in development. Nonetheless, other pharmaceutical companies have developed
substance P antagonists that are currently being studied in major depression and social phobia. Our
hunch is that these drugs may prove to be more effective in treating anxiety disorders than treating
depression. Other peptide hormone neurotransmitters that are being investigated for developing
agents with antidepressant effects include somatostatin and cholecystokinin.
In addition to hormonal therapies, more conventional antidepressants are also under investigation. A
new type of 5-HT1A antagonist is under investigation. Buspirone-like compounds, such as gepirone and
ipsapirone, have proved disappointing as antidepressants. However, new compounds have shown early
evidence of being more potent in their monoamine effects than have their predecessors. Moreover,
gepirone has recently been resurrected and studied at higher doses in a long-acting formulation, with
mixed results. However, as noted previously, the drug did not receive approval, perhaps because of
limited efficacy data with the long-acting formulation.
Minaprine, which has been studied for many years, continues to be investigated. It is an atypical agent
with an affinity for serotonin, dopamine, and muscarinic receptors. Many double-blind studies have
attested to its efficacy and general tolerability. However, it is unclear whether it will ever be released
to the U.S. market.
In addition to reboxetine, other more selective NRIs, including lofepramine and viloxazine, also remain
in consideration. It remains to be seen what niche norepinephrine-specific agents will secure in the
armamentarium of antidepressants.
In the fourth edition of our manual, we wrote that “the next 10 years in antidepressant drug
development may be among the most promising since the development of the MAOIs and TCAs in the
1950s.” At this time, we are more skeptical as to whether the near future will yield any new
compounds with alternative mechanisms of action for the ambulatory depressed patient. What a
difference a few years make.
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Course Content
Introduction to Antidepressants: History and Context
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The Evolution of Antidepressants: A Historical Overview
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Understanding Depression: Why Antidepressants Matter
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Major Classes of Antidepressants: An Overview
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Quiz: Historical Milestones in Antidepressant Development
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Cultural and Social Perceptions of Antidepressants
Antidepressant Classes and Mechanisms of Action
Clinical Applications: Choosing the Right Antidepressant
Managing Side Effects and Drug Interactions
Future Trends and Developments in Antidepressant Therapy
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