Chapter 5 Mood Stabilizers

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Chapter 5. Mood Stabilizers

INTRODUCTION

The term mood stabilizer was first applied to the lithium salts when it became clear that they were effective not only in

alleviating mania but also as a prophylaxis against both manic and depressive cycles. Since the introduction of lithium to the

United States in 1969 there have been very few drugs approved as “mood stabilizers.” However, in recent years new drugs,

such as lamotrigine and aripiprazole, have been approved for the prevention of mania and depression in bipolar disorder. In

addition, a number of agents have been approved for the acute treatment of mania, and the first drugs for the acute

treatment of bipolar depression have now also been approved. It is somewhat less clear that any of the anticonvulsants

currently used in the treatment of bipolar affective disorder are as deserving of the term mood stabilizer as is lithium.

However, the atypical antipsychotics with clear benefits in the acute treatment and prevention of both mania and depression

do appear deserving of designation as mood stabilizers.

A derivative of valproic acid, divalproex sodium, was approved by the U.S. Food and Drug Administration (FDA) for the

treatment of acute mania in 1994. Since that time, it has surpassed lithium in the treatment of bipolar disorder in the United

States. Divalproex sodium offers the advantages over lithium of a superior therapeutic index and less toxicity. Although

divalproex sodium clearly alleviates manic symptoms, the efficacy in preventing manic episodes with this drug is less well

established than with lithium. Still, it appears to prevent them and depressive episodes in clinical practice. Valproate may

also have a wider range of efficacy in subtypes of bipolar disorder that are less responsive to lithium, including rapid cycling

and mixed states.

The anticonvulsant lamotrigine became only the second drug approved for use in the maintenance treatment of bipolar

disorder. While results from initial studies of lamotrigine in the treatment of acute mania were disappointing, findings from

subsequent studies of lamotrigine in delaying the time to onset of a new mood episode were quite convincing. Lithium is

more robust in preventing mania than in preventing depression, but the converse is true for lamotrigine. Since most patients

with bipolar disorder live in the depressed phase of the illness, lamotrigine is a welcome option for clinicians treating bipolar

patients.

Carbamazepine has been used for many years in the treatment of bipolar disorder, despite the lack of an FDA-approved

indication for this purpose. In recent years, it has become a third-line agent after lithium and valproate. The less preferred

status of carbamazepine has been due in part to its complex pharmacokinetic interactions and lower therapeutic index,

which make it somewhat more difficult to use in combination with many medications. In addition, the studies supporting its

utility in bipolar disorder had, until recently, been much smaller and less rigorous than the studies that were completed with

divalproex sodium and lithium. An extended-release form of carbamazepine (Carbatrol) has been more rigorously studied

and has been shown to be efficacious in the acute treatment of mania. This extended-release form received approval for the

treatment of bipolar disorder. A related, new compound, oxcarbazepine, does not appear to induce liver enzymes as much

and is generally better tolerated. As of this writing, it is not being actively studied in large-scale trials but is being used by

practitioners.

A variety of other anticonvulsants are being studied in bipolar disorder. These include gabapentin, pregabalin, topiramate,

tiagabine, ethosuximide, zonisamide, and levetiracetam. None of these drugs have convincing controlled data supporting

their use as a monotherapy in any phase of the bipolar disorder at the time of this writing. Nonetheless, drugs like

topiramate have shown benefits in counteracting weight gain associated with traditional mood stabilizers such as lithium or

divalproate.

Olanzapine, which had been approved for the treatment of acute mania in 2000, became the first antipsychotic also

approved in the maintenance treatment of bipolar I disorder. Like lithium, it probably does a better job preventing mania

than it does preventing depression. There are now double-blind studies supporting the use of all atypical antipsychotics

except clozapine in the treatment of acute mania. Quetiapine has been approved for the treatment of acute mania, as have

risperidone, ziprasidone, and aripiprazole.

While there have been literally thousands of controlled studies of antidepressant drugs in the treatment of unipolar

depression in the past 50 years, only a handful of studies have ever been completed on the treatment of bipolar depression.

The general assumption has been that an antidepressant should be effective whether treating bipolar or unipolar

depression. As we know from our clinical experience, however, this assumption may be wrong. Bipolar depressions may be

unresponsive, at times, to standard antidepressants. In 2004, the FDA approved the first drug for the acute treatment of

bipolar depression, an olanzapine-fluoxetine combination (OFC) capsule (Symbyax). In late 2006, quetiapine was approved

as a monotherapy for the treatment of bipolar depression.

In this chapter, we consider the range of potential mood stabilizers currently used in clinical practice. In addition, more

investigational agents, such as newer anticonvulsants, calcium channel blockers, and omega-3 fatty acids, are considered.

(See Table 5–1 for a listing of mood stabilizers and their formulations and strengths.)

Table 5–1. Mood stabilizers: names, formulations, and strengthsPrint: Chapter 5. Mood Stabilizers

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Generic name Brand name Formulations and strengths

lithium carbonatea Eskalith Capsule: 300 mg

Lithobid (slow release) Tablet: 300 mg

Eskalith-CR (controlled release)

Tablet: 450 mgb

lithium citrate

Genericc

Syrup: 8 mEq/5 mLd (480-mL bottle)

carbamazepinea

Tegretol Tablets: 100, 200, 300, 400 mg

Chewable tablet: 100 mg

Suspension: 100 mg/5 mL (450-mL bottle)

Tegretol-XR (sustained release) Tablets: 100, 200, 400 mg

Carbatrol (sustained release) Capsules: 100, 200, 300 mg

valproic acida

Depakene Capsule: 250 mg

Syrup: 250 mg/5 mL (480-mL bottle)

valproate sodium Depacon Injection: 100 mg/mL (5-mL vial)

divalproex sodium Depakote Enteric-coated tablets: 125, 250, 500 mg

Capsule, sprinkle: 125 mg

Depakote ER (sustained release) Tablets: 250, 500 mg

lamotrigine Lamictal Chewable tablets: 2, 5, 25 mg

Tablets: 25, 100, 150, 200 mg

gabapentina

Neurontin Capsules: 100, 300, 400 mg

Tablets: 100, 300, 400, 600, 800 mg

Oral solution: 250 mg/5 mL

oxcarbazepine Trileptal Tablets: 150, 300, 600 mg

Suspension: 300 mg/5 mL

topiramate Topamax Tablets: 25, 50, 100, 200 mg

Capsules, sprinkle: 15, 25 mg

tiagabine Gabitril Tablets: 2, 4, 12, 16 mg

aAvailable in generic form.

bScored tablets.

cCibalith-S: brand discontinued.

dEquivalent to 300 mg lithium carbonate.

LITHIUM

History and Indications

Lithium, usually as the carbonate and occasionally as the citrate salt, is still widely used in American psychiatry. However,

the use of valproate for the treatment of mood disorders now surpasses that of lithium. Lithium is approved by the FDA for

the treatment of acute mania and as maintenance therapy to prevent or diminish the intensity of “subsequent episodes in

those manic-depressive patients with a history of mania.” As discussed below, lithium is often used in patients with a

variety of recurrent episodic illnesses, with or without prominent affective features. It is also used adjunctively in patients

with mood lability, with impulsive or episodic violence or anger, or even with premenstrual dysphoria, alcoholism, borderline

personality disorder (BPD), or chronic schizophrenia. Further, it is used as a potentiating agent in a variety of

treatment-resistant disorders.

Lithium therapy: overview

Efficacy Bipolar mania and prophylaxis (FDA indicated)

Depression augmentation

Side effects Tremor

Polyuria

Polydipsia

Weight gain

Cognitive slowing

Hypothyroidism

Renal function

Dermatological side effects

Memory problems

Safety in overdose Frequently lethal in blood levels above 3.0 mEq/L and toxic above 1.5 mEq/L. Maintain fluid/electrolyte balance.

Gastric lavage; mannitol diuresis vs. hemodialysis for higher blood levels.

Dosage and

administration

Start at 300 mg bid or tid and increase total daily dose by up to 300 mg, as needed and tolerated, to blood level of

0.6–1.2 mEq/L for bipolar mania and 0.4–0.8 mEq/L for augmentation.Print: Chapter 5. Mood Stabilizers

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Lithium therapy: overview

Discontinuation Sudden discontinuation associated with risk of relapse. Taper over 3 months for bipolar mania if feasible.

Drug interactions Antipsychotics: may lithium toxicity

Bupropion: may seizure risk

Carbamazepine: neurotoxicity (rare)

Diuretics: lithium levels

Iodide salts: hypothyroidism

Neuromuscular blockers: respiratory depression

NSAIDs: lithium levels

SSRIs: serotonin syndrome (rare)

Theophylline: lithium levels

Urinary alkalinizers: lithium levels

Verapamil: or lithium levels

Note. FDA = U.S. Food and Drug Administration; NSAID = nonsteroidal anti-inflammatory drug; SSRI = selective serotonin reuptake

inhibitor.

The use of lithium salts in psychiatry was initiated by John Cade, an Australian state hospital superintendent, in 1949, and it

proved to be an effective, though somewhat toxic, treatment. The addition of serum level monitoring made the treatment

safe and provided the first general use of blood level monitoring for a psychiatric drug. The use of lithium in psychiatry

increased worldwide, although the United States was slow to participate because of an earlier disastrous experience in that

country with the unmonitored use of lithium chloride as a salt substitute, which had led to severe toxic reactions, some of

which were fatal. Schou (1978) was the first to report compelling evidence that lithium carbonate dramatically reduced the

incidence and duration of serious affective episodes in bipolar patients. Since that time, a large number of controlled,

double-blind studies have confirmed that lithium is clearly effective in reducing recurrences in both bipolar and unipolar

affective disorders, as well as being more effective than placebo in treating acute mania.

Pharmacological Effects

Much has been learned in the past 25 years about the possible mechanism of lithium in the treatment of bipolar disorder.

However, we are still some way from defining the key factors of lithium’s efficacy.

It has become clearer that the pharmacology of lithium is tremendously complex. Lithium may affect different parts of the

brain differently at different times. It is evident that lithium’s antibipolar effects are probably the result of complex actions

on at least three systems. Lithium appears to modulate the balance between excitatory and inhibitory effects of various

neurotransmitters such as serotonin (5-hydroxytryptamine; 5-HT), norepinephrine, glutamate, GABA ( -aminobutyric acid),

and dopamine. Lithium also effects neural plasticity through its effects on glycogen synthetase kinase–3 , cyclic

AMP–dependent kinase, and protein kinase C. Finally, lithium adjusts signaling activity via effects on second-messenger

activity (Jope 1999).

Lithium appears to enhance serotonergic transmission in a number of ways. For example, lithium appears to increase

synthesis of serotonin by increasing tryptophan reuptake in synaptosomes after even short-term use. With long-term use

(2–3 weeks), lithium appears to enhance the release of 5-HT from neurons in the parietal cortex and the hippocampus.

Furthermore, the chronic administration of lithium appears to cause a downregulation in serotonin 1A (5-HT1A), serotonin1B,

and serotonin2 (5 HT2) receptor subtypes (Massot et al. 1999).

Lithium also affects a number of other monoamine neurotransmitters. Initially, lithium appears to increase the rate of

synthesis of norepinephrine in some parts of the brain. It reduces the excretion of norepinephrine in patients with mania but

increases the excretion of norepinephrine metabolites in patients with depression. These effects are consistent with

lithium’s beneficial actions in both mania and depression. Likewise, lithium appears to block postsynaptic dopamine

receptors’ supersensitivity, in keeping with the clinical data that lithium is effective in controlling mania even when

psychotic features are present.

In recent years, the effect of lithium on second-messenger systems has been of particular interest. Because lithium affects a

variety of neurotransmitters, some investigators have speculated that the principal action of the drug may be on the

postsynaptic signal that a number of neurotransmitters generate. The so-called G proteins have been of particular interest in

lithium research because they function as signal transducers for a number of receptor types. G proteins appear to be quite

important in coordinating a balance among various neurotransmitters in the brain. Some preliminary evidence suggests that

lithium may have a direct or indirect effect on G proteins that mediates their actions.

The role of the phosphatidylinositol (PI) system, another second-messenger system, in the actions of lithium remains

unclear. Lithium appears to inhibit a number of enzymes in the PI system, including inositol monophosphatase. It is believed

that the PI system affects the receptor activity of many neurotransmitter systems, including the serotonergic, cholinergic,

and noradrenergic systems. The role of the PI second-messenger system in lithium’s actions is the subject of continued

investigation.

Clinical Indications

Lithium use can be divided into four main clinical areas:

1. To control rapidly acute, overt psychopathology as in mania or psychotic agitation.
2. To attempt to modify milder, ongoing or frequent but episodic clinical symptoms such as chronic depression or episodic irritability.Print: Chapter 5. Mood Stabilizers

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3. To establish a prophylactic maintenance regimen to avert future affective or psychotic episodes.
4. To enhance the effect of antidepressants in patients with major depressive episodes (see Chapters 3 and 9 in this manual).

Acute Mania

There is no final, conclusive statement possible about the use of lithium as a sole or primary drug treatment for acute mania.

The initial approval of lithium in the treatment of acute mania was based on three small double-blind studies completed

before 1971. A more recent study addressing the question of lithium for acute mania (Lambert and Venaud 1992) found that

half of 36 acutely manic patients who completed a 3-week trial responded to lithium and that this was about twice the rate

seen with placebo. These results were similar to those found in a larger, multicenter-based study comparing lithium,

valproate, and placebo in the treatment of acute mania (Bowden et al. 1994). In that study, both lithium and valproate were

twice as likely as placebo to produce a marked reduction in manic symptoms over a 3-week period.

Lithium alone is clearly more effective than placebo and is probably as effective as an antipsychotic in treating patients with

less severe excited mania. It is probably less effective and slower acting than an antipsychotic in disturbed, psychotic manic,

schizoaffective, or very hyperactive patients.

Given the delayed onset of action of lithium (7–14 days), most clinicians do not initiate treatment with lithium alone in acute

mania. It is common practice to begin by administering patients an antipsychotic, on the assumption that it will produce the

most rapid control of psychopathology or aid in patient management. Many clinicians then add lithium—either on the first

day of drug therapy or after the mania has begun to respond to antipsychotics—to stabilize the patient on both drugs. When

the patient is clearly much improved, some clinicians gradually taper the antipsychotic over several months so that the

patient will be taking lithium alone at the end of the episode. In patients whose hospitalizations are brief, both medications

will be in use at discharge, and the antipsychotic will be tapered when the patient is back in the community. Some early

studies on antipsychotic use indicated that more than 50% of the patients were still taking antipsychotics at 6-month

follow-up. Currently, most patients that have an atypical antipsychotic started for acute mania likely continue it as a

maintenance therapy.

An alternative strategy that has gained popularity is to initiate treatment of the acutely manic patient with both lithium and

a benzodiazepine such as lorazepam or clonazepam (Lenox et al. 1992). This strategy allows the clinician to immediately

address the insomnia and hyperactivity without the potentially toxic effects of an antipsychotic. However, using only a

benzodiazepine with lithium may not be ideal in the treatment of the acutely psychotic manic patient. In such patients, triple

therapy—a benzodiazepine, an antipsychotic, and lithium—allows smaller doses of the first two agents to be used for the

acute episode while lithium is initiated for long-term treatment.

The problem of severe neurotoxicity, reported mainly with the combined use of haloperidol or another high-potency

antipsychotic and lithium, deserves comment here. In the 1970s there was considerable concern about the possibility of

serious drug interactions between lithium and haloperidol, a concern based almost exclusively on anecdotal reports. When

the possible interaction was reviewed more recently, no significant interaction between lithium and neuroleptics was

detected beyond merely additive adverse effects (Kessel et al. 1992). Neurotoxicity, including delirium and other mental

status changes, may occur with lithium alone even at therapeutic dosages in elderly and organically compromised patients.

More recent experience suggests that patients who developed neurotoxicity on the combination either were lithium toxic

(often at toxic levels) or had a neuroleptic malignant syndrome. In general, the combination of antipsychotics and lithium

appears to be safe and efficacious.

Recurrent Bipolar Disorder

The evidence that lithium is effective in the prophylaxis of recurrent bipolar episodes is far more substantial than the

evidence of lithium’s efficacy in treating acute mania. Until olanzapine received a similar approval, lithium was the only drug

with an FDA-approved indication for the maintenance treatment of bipolar disorder. At least 10 double-blind studies suggest

that the relapse rate for bipolar patients is two to three times higher with placebo than with lithium. Among the best lithium

studies have been those completed recently using lithium as an active control in the lamotrigine maintenance studies

(Goodwin et al. 2004). These studies confirmed the utility of lithium in the maintenance treatment of bipolar disorder.

However, the rapid discontinuation of lithium in some of the earlier trials probably affected the relapse rates. The

prophylactic effects of lithium appear more pronounced in preventing manic than depressive recurrences, but both are

positively affected. However, only half, or perhaps fewer than half, of lithium-treated patients have complete suppression of

all episodes, even with excellent medication compliance. Furthermore, at least some of the patients who have manic

recurrences while taking maintenance lithium are blamed for noncompliance unjustifiably: the noncompliance is probably

secondary to a recurrence of mania rather than vice versa. In addition, some patients respond to lithium with suppression of

mania but with continuing episodes of depression; others show only a partial reduction in severity in both phases.

We have seen a number of patients who had been taking lithium for several years and had poor responses but who

continued to have episodes of mania and depression; they were judged to be lithium nonresponders, but their condition was

clearly even worse when lithium therapy was abandoned as ineffective. Patients with rapid-cycling and mixed-state types of

bipolar disorder generally do less well while taking lithium than do patients with less frequent or purely manic episodes.

However, even some of the former can have the severity of their episodes ameliorated. In addition, patients who tend to

develop severe stage III manic episodes with psychotic disorganization do more poorly with lithium treatment alone.

In initiating maintenance “prophylactic” lithium therapy, both the patient and (when available) a spouse or a significant

other need careful instruction about the purposes and requirements of lithium therapy, including its side effects and

complications. There is evidence that continuing involvement of bipolar patients and their spouses in couples groups, or of

single patients in lithium support groups, is helpful in maintaining drug compliance and in helping patients deal with past,Print: Chapter 5. Mood Stabilizers

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current, and future problems.

Many bipolar patients, when contemplating maintenance lithium therapy, ask, “Will I have to take lithium forever?” There

are two issues in this area. One is whether patients ever stop having recurrent manic and depressive episodes once several

episodes have occurred, and the other is whether abruptly stopping lithium will trigger an affective episode that might not

have otherwise occurred. The evidence from placebo substitution and lithium discontinuation studies involving patients

whose condition was already stabilized successfully with lithium maintenance is that relapses occur with considerable

frequency: about half the patients relapsed within 6 months. In other, uncontrolled studies, which involved small series of

patients, patients relapsed floridly within a few days. We suspect that the latter consequence is unusual but may actually

occur with some patients; it may account for some of the florid relapses seen in patients taking maintenance lithium who

experiment with stopping (or forget to take) their medication for a few days. In our experience, however, stopping lithium

abruptly for 2 or 3 days in patients who have developed uncomfortable symptoms of lithium toxicity has never led to a florid

relapse.

The area of lithium discontinuation is not well understood, but most clinicians assume that essentially all bipolar patients

whose condition is stable on lithium need to continue the medication indefinitely. Data confirm that abrupt discontinuation

of lithium after long-term treatment significantly increases the rate and speed of relapse (Faedda et al. 1993). More gradual

discontinuation of lithium in bipolar patients over several months appears to mitigate this risk substantially (Suppes et al.

1993). Discontinuation of lithium can be associated with increased risk for suicide (Tondo et al. 2001).

One wonders, however, whether withdrawal from lithium could be worth a trial for patients who have really stabilized both

their illness and their life circumstances for several years and in whom there is some evidence that prior episodes were

precipitated by stressors that are no longer present. Such trials of withdrawal from lithium need to be discussed in detail

with patients and their families, with all parties taking into account that about 90% of patients with mania will have a

recurrence at some time. Given the occasional rapid relapses observed with sudden discontinuation, slowly tapering the

drug in monthly 300-mg decrements would be indicated. Post and colleagues (1992) reported that some patients who

discontinued their lithium did not experience a response when readministered lithium for a recurrence of the disorder. These

data suggest that it may be prudent to err on the side of continuing lithium maintenance for longer rather than shorter

periods. However, a more recent prospective, naturalistic study demonstrated that patients with a recurrence of mania who

had previously had a response to lithium generally appear to have a response to rechallenge with the drug (Coryell et al.

1998).

Schizophrenia Spectrum Illnesses

There is reasonable evidence that lithium, at serum levels in the range of 0.8–1.1 mEq/L, is useful in combination with an

antipsychotic in treating patients with schizoaffective disorder. As many as 70% of these patients benefit from the addition

of lithium to a regimen of antipsychotics. In the few controlled studies in which lithium was added to an antipsychotic in

schizophrenic patients with or without manic symptoms, lithium was often more effective, on average, than placebo.

However, monotherapy with lithium appears much less efficacious than treatment with an antipsychotic alone in the

treatment of schizophrenia. In some chronically impaired schizophrenic patients with no more than the usual amount of

affective overlay, lithium produces useful but limited additional improvement when added to an antipsychotic regimen. This

effect occurs often enough to make a trial of lithium easily justifiable for any patient with treatment-resistant schizophrenia

or schizoaffective disorder, although perhaps only one in five will show clinical improvement. Also, for a subgroup of

chronically schizophrenic patients with brief, episodic angry outbursts, lithium appears to act by decreasing impulsive anger

rather than by reducing the level of psychosis. However, in patients with chronic, treatment-resistant psychotic illness, drug

treatments are often added and continued for months or years, even if no obvious clinical response or only a trivial

improvement has occurred, in the hope that the extra drugs might be helping. There seems little justification for continuing

such a use of lithium for longer than 6 months if no clinical benefit is apparent.

Depressive Disorders

Some depressive episodes improve with lithium alone. In fact, a number of controlled studies suggest that lithium may be as

effective as tricyclic antidepressants (TCAs) in the treatment of major depression. The response time, however, often lags

behind that of standard antidepressants. For recurrent unipolar depression, maintenance treatment with lithium appears to

be as effective as long-term treatment with imipramine in preventing recurrences (Prien et al. 1984). A number of studies

also suggest that adding lithium to a TCA, a selective serotonin reuptake inhibitor (SSRI), or a monoamine oxidase inhibitor

(MAOI) in a patient who has not responded to the antidepressant after 3–6 weeks may lead to a clear favorable response

(see Chapter 3: “Antidepressants” and Chapter 9: “Augmentation Strategies for Treatment-Resistant Disorders”).

In recurrent unipolar depression, the evidence from large-scale studies is mixed on the exact prophylactic potential of

lithium; some studies showed lithium and imipramine to be equally effective, whereas other studies showed imipramine to

be superior to lithium and both drugs to be superior to placebo. The combination of imipramine and lithium was not superior

to imipramine alone. Thus, clinicians may choose to use lithium alone to prevent recurrence of depression in bipolar

patients.

Lithium is among the best studied augmenters of antidepressant response. While most studies of lithium augmentation

involved augmentation of TCAs, lithium has proved useful in the augmentation of a variety of antidepressants (Bschor and

Bauer 2006). One of the larger randomized, albeit open, trials of lithium augmentation was in the STAR*D (Sequenced

Treatment Alternatives for Resistant Depression) trial. In that study, patients who had experienced two previous failed trials

were randomly assigned to lithium or triiodothyronine (T 3; Cytomel) augmentation. Approximately 16% of patients achieved

remission when lithium was added versus 25% of patients who were randomly assigned to T3 augmentation (Nierenberg et

3. 2006a). The difference was not statistically significant, but lithium was more poorly tolerated than the T3. While it isPrint: Chapter 5. Mood Stabilizers

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clear that lithium is an effective augmenter of antidepressants, there are far more choices for augmentation now than there

were 20 years ago, and lithium’s popularity in resistant depression has waned.

As a drug useful in episodic affective disorder, lithium has been tried in treating premenstrual dysphoria with some success,

but the vagueness of the condition and its alleged placebo responsivity make this potential indication a bit suspect. In

addition, the availability and success of SSRIs in the treatment of premenstrual dysphoria has rendered lithium all but

obsolete for this condition.

Rage and Irritability

There is a reasonable clinical literature, mainly but not exclusively uncontrolled, that supports the proposition that some

patients with episodic, uncontrolled outbursts of violent rage have a response to lithium. The drug certainly is not always

effective in such cases, but these predominantly nonpsychotic behavior disorders often present such appalling clinical

problems that any drug with a chance of helping substantially deserves a trial. We concur with Tupin’s (1975) general

position that in populations such as violent prisoners, lithium controls outbursts of rage that are nontriggered or are

triggered instantaneously by minor stimuli, but that lithium does not affect premeditated aggressive behavior. The drug is

helpful in some patients with organic disorders or mental retardation who display episodic angry outbursts. Lithium has also

shown some utility in the treatment of children with episodic aggressive outbursts and in mitigating the self-destructive

behavior of some patients with BPD. It should be noted that there have been a few case reports of lithium’s causing

increased aggressive behavior in patients with temporal lobe spike activity on the electroencephalogram (EEG). The use of

anticonvulsants and antipsychotics has largely supplanted lithium use in the management of hostility, impulse control, and

aggression in a variety of disorders (Goedhard et al. 2006).

Side Effects

Neuromuscular and Central Nervous System

Among the most common side effects in lithium therapy is tremor, principally noticed in the fingers (Table 5–2). It

resembles intentional, coffee-induced, or familial tremor in frequency, being faster than pseudoparkinsonian tremor. When

tremor is severe enough to affect handwriting, the writing is usually jagged and irregular, but not micrographic as in

parkinsonism. Tremor sometimes is worse at peak lithium blood level and can be ameliorated by dosage rearrangement.

Dosage reduction can often be used to bring the blood level low enough to make tremor either absent or mild and

inconspicuous. If there is good reason to maintain a serum lithium level that causes a disturbing degree of tremor,

propranolol at dosages ranging from 10 to 160 mg/day can be used to reduce the tremor.

Table 5–2. Toxicology of mood stabilizers

Drug

System lithium valproate CBZ gabapentin lamotrigine topiramate tiagabine

CNS Tremor

Ataxia

Cognitive

slowing

Sedation

Tremor

Ataxia

Sedation

Dizziness

Ataxia

Somnolence

Dizziness

Ataxia

Dizziness

Ataxia

Somnolence

Dizziness

Ataxia

Speech

problems

Cognitive

slowing

Dizziness

Somnolence

Difficulty

concentrating

GI Dyspepsia

Weight gain

Diarrhea

Dyspepsia

LFT increases

Weight gain

Hepatic failure

(rare)

Pancreatitis

Dyspepsia

LFT increases

Dyspepsia

(rare)

Nausea

Vomiting

Nausea

Dyspepsia

Abdominal pain

Nausea

Abdominal

pain

Dermatological Rash

Hair loss

Acne

Rash

Hair loss

Rash Pruritus

(rare)

Rash

Acne

Rash (rare)

Pruritis (rare)

Rash (rare)

Alopecia

Renal/Urogenital NDI

Nephropathy

Minimal SIADH None Vaginitis

Urinary tract

infection

Dysmenor-rhea

Metabolic

acidosisa

None

Cardiac T wave

changes

Sinoatrial block

Minimal Arrhythmia None Palpitations

(rare)

Hypotension

(rare)

BP changes

(rare)

Hypertension

Palpitations

Hematological Leukocytosis Thrombo-cytopenia

Coagulation defect

Thrombo-cytopenia

Aplastic anemia

(rare)

Leukopenia

(rare)

None Leukopenia None

Endocrine Hypothyroidism Minimal Lower levels of T3,

T4

None Hypothyroidism

(rare)

Weight

decrease

Goiter (rare)

Note. BP = blood pressure; CBZ = carbamazepine; CNS = central nervous system; GI = gastrointestinal; LFT = liver function test; NDI =Print: Chapter 5. Mood Stabilizers

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nephrogenic diabetes insipidus; SIADH = syndrome of inappropriate antidiuretic hormone; T3 = triiodothyronine; T4 = thyroxine.

aSecondary to hyperchloremia.

Some patients taking lithium also develop cogwheeling and mild signs of parkinsonism, and naturally occurring

parkinsonism can be aggravated. With toxic lithium levels, gross tremulousness and ataxia with dysarthria occur: the

patient appears to have gross neurological disorder and, often, to be confused or, less often, to be delirious at the same

time. Seizures occur rarely with severe lithium toxicity.

Some patients taking lithium complain of slowed mentation and forgetfulness and, on testing, show a memory deficit. In

fact, pooled data on side effects of lithium therapy suggest that memory problems are perhaps the leading cause of

noncompliance and the third most common side effect overall (Goodwin and Jamison 1990). Although such patients are

often suspected or accused of “using” such symptoms to avoid necessary lithium therapy, our impression is that these

complaints are real and constitute a basis for lowering the dosage or trying another therapy.

Some patients worry that they may become less creative while taking lithium. Schou (1979), however, has asserted that

75% of patients note no change or an improvement in their creativity with lithium therapy. The bipolar patients who have

the most prominent neuropsychological effects of lithium tend to be younger, depressed patients with higher lithium serum

levels (Kocsis et al. 1993). Thus, patients who complain that lithium is affecting their cognition or creativity might do well at

a somewhat lower dosage.

In addition, some patients may experience drowsiness and fatigue, which may further exacerbate the feeling of being

slowed down.

With all the above neurological symptoms, stopping lithium will lead to a disappearance of the side effects, but the

symptoms and signs may persist for 2–5 days, longer than one would expect it to take to clear the offending lithium from

the body.

Gastrointestinal

Chronic nausea and watery diarrhea can occur together or separately as signs of lithium toxicity. Episodic nausea occurring

only after each dose may be due to local gastric irritation and may be relieved by taking lithium with food. Shifting to a

different lithium preparation may also be helpful. For example, in cases of upper gastrointestinal (GI) distress,

sustained-release preparations may be beneficial. In contrast, patients with diarrhea who are on sustained-release

preparations may benefit from a switch to the shorter-release forms.

Weight Gain and Endocrine

Some patients gain weight progressively while taking lithium, and this side effect is second only to cognitive side effects as

a reason that patients stop taking the medication. The mechanisms underlying this side effect are unclear. However, lithium

appears to have an insulin-like action that may result in relative hypoglycemia (Jefferson et al. 1987). This hypoglycemia

may in turn promote eating and subsequent weight gain. A few patients have overt edema and/or lose several pounds

rapidly when lithium is stopped. More commonly, increased appetite with resulting weight gain is the problem, and

attempting to control weight with dietary regulation is often very difficult for the patient. Weight gain is greater in patients

who are overweight to begin with and is probably greater in patients with polydipsia, perhaps because they drink caloric

fluids.

Most patients show a transitory decrease in thyroid levels early in lithium therapy, and a very few show goiter with normal

thyroid studies except for elevated thyroid-stimulating hormone (TSH) levels. Some clinicians add thyroid supplements at

this point. However, we recommend using exogenous thyroid primarily in patients with marked goiter or in those with

associated anergia.

Up to 20% of patients, more commonly women, develop clinical hypothyroidism on lithium therapy, and 30% develop

elevated TSH levels (Jefferson et al. 1987).

In our clinic, we will typically obtain a TSH level before initiating lithium and then repeat it at 6 months and annually

thereafter.

Renal

Lithium causes polyuria with secondary polydipsia to a noticeable degree in some (perhaps roughly one out of five) patients.

In a few patients this effect may extend to severe renal diabetes insipidus, with urine volume up to 8 L/day and difficulty in

concentrating urine and maintaining adequate lithium serum levels. This range of renal effects is due to a decrease in the

resorption of fluid from the distal tubules of the kidney. It can be treated, obviously, by lowering the dose of lithium or

stopping the drug. In most, but not all, cases the renal effect wears off in days or weeks after lithium is stopped.

An alternative strategy with patients in whom lithium is clearly necessary and the polyuria is distressing is to add a loop or

thiazide diuretic. It is well documented that hydrochlorothiazide at a dosage of 50 mg/day decreases lithium clearance by

about 50% and therefore increases lithium plasma levels. Thus, one can rationally add 50 mg/day of hydrochlorothiazide

and then reduce the lithium dosage by 50% and carefully restabilize the desired lithium level. This maneuver is sometimes

effective, as it is in naturally occurring nephrogenic diabetes insipidus, and can be used in milder but troublesome cases of

polyuria. At the time of our first edition, amiloride (Midamor) had recently been reported to decrease lithium-induced

polyuria without, allegedly, affecting either potassium excretion or lithium serum levels. However, we had seen some

patients who showed increased lithium levels when amiloride was added. If this strategy is tried, one should check lithium

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The prohibition in the Physicians’ Desk Reference (PDR) against combining lithium with diuretics, particularly of the thiazide

type, is much overstated. It is true that harm can occur if a patient is stabilized on lithium at a clinically useful blood level

(e.g., 0.8 mEq/L) and a thiazide diuretic is added in ignorance: the lithium level can double and the patient may suddenly

develop signs of lithium toxicity. This increase can also occur with other drugs, most notably nonsteroidal anti-inflammatory

drugs such as ibuprofen, naproxen, and indomethacin. However, we see no problem in starting lithium therapy in a patient

already stabilized on a thiazide diuretic; even patients undergoing dialysis have been successfully treated with lithium.

Renal impairment before lithium therapy means the clinician should raise the dosage very slowly and cautiously, monitoring

serum levels carefully.

A different and potentially more serious renal problem is interstitial nephritis, first reported by Danish workers in 1977. It is

characterized by renal scarring and destruction. Currently, the problem no longer seems as threatening as it did initially.

Major renal impairment manifested by seriously decreased creatinine clearance appears to be quite rare. In a review, Gitlin

(1993) suggested that up to 5% of lithium-treated patients developed some renal insufficiency but that these changes were

generally not clinically significant ones. In a more recent review, polyuria secondary to lithium-induced decreases in renal

tubular function appeared to be progressive in many patients, whereas changes in glomerular function were not (Gitlin

1999). Patients exposed to multiple periods of lithium toxicity may be at greater risk for developing renal insufficiency.

Some patients with chronic affective disorders who have never taken lithium show renal pathology, and not all kidney

dysfunction in patients taking lithium is necessarily caused by this drug.

Still, it is worth checking kidney function every 6–12 months in patients on maintenance lithium. The “best” way would be to

measure creatinine clearance periodically, but logistic problems and doubts about patient reliability in 24-hour urine

collection have caused this procedure to be generally disfavored. Serum creatinine itself offers a reasonable indicator of

kidney function, because creatinine production is a function of muscle mass and is not affected by diet. We typically obtain a

serum creatinine level before initiating lithium and repeat it annually thereafter or as clinically indicated. Lithium serum

level at constant intake is also a function of glomerular filtration. Watching both measures periodically should allow

detection of early changes in glomerular function. Some practitioners check the patients’ reactive ability to concentrate their

urine. If the lithium dosage requirement gradually decreases and serum creatinine is persistently elevated (above 1.6

mg/100 mL), a nephrology consultation is indicated. Even if renal impairment appears to exist, the decision whether to stop

lithium therapy should be based on the total picture. Patients who obtain major benefits from maintenance lithium and have

either a mild renal deficit or a kidney problem that may not be lithium related can continue taking lithium, but more frequent

monitoring of kidney function is required.

Cardiovascular

Lithium can produce a variety of benign effects on the electrocardiogram (ECG), including T wave flattening and inversion. A

few cases have been reported in which a “sick sinus node” syndrome has been brought on by lithium. This complication is

very rare and probably not predictable unless the condition antedates the lithium therapy. Some patients have developed

problems with sinus node conduction after concurrent use of antiarrhythmic drugs (Jefferson et al. 1987). Baseline ECGs are

desirable in older patients or patients with a history of any cardiac dysfunction. Some caution should also be exercised in

using lithium in patients with particularly low heart rates at baseline.

Dermatological

A wide variety of diverse rashes from lithium have been described. Acne is perhaps the most common dermatological effect

of lithium use and has been reported to be helped by topical retinoic acid. Aggravation of preexisting or dormant psoriasis is

well documented, and a dry, noninflamed papular eruption is relatively common with maintenance lithium. Both zinc sulfate

and tetracycline have been tried as treatments for rashes, with variable success. Other rashes—of an itchy, presumably

allergic nature, less typical with lithium—can occur and often disappear if the specific lithium brand being used is changed.

Presumably these are allergic reactions to some ingredient in the capsule or tablet other than the lithium itself. Alopecia can

occur in patients taking lithium, but the hair often regrows, either with or without lithium.

Preparations

Lithium is available in the United States in several formulations (Table 5–1). The standard and least expensive form is the

carbonate in 300-mg capsules or scored tablets. Sustained-release preparations of the carbonate are also available, as is a

liquid preparation of lithium citrate; one teaspoonful of the last has the equivalent in ion content of 300 mg of the carbonate

(8 mEq). Other preparations, including the sulfate, and other dosage strengths are used in Europe. Despite more than 50

years of clinical experience with lithium, it is not entirely clear whether any of the formulations have definite superiority for

any purpose, aside from relieving GI side effects. Lithium citrate is obviously useful in patients who dislike or cannot

swallow pills.

The sustained-release preparations result in lower peak serum lithium levels after ingestion and probably result in the

release of less lithium ion in the stomach and more in the small intestine. If lithium irritation of the stomach mucosa is

causing nausea after each dose, the sustained-release preparation may reduce gastric irritation. If diarrhea is a problem

(and is not due to an elevated serum lithium level), the citrate may cause even faster absorption in the upper GI tract and

may reduce the diarrhea. However, we have seen patients who have diarrhea with standard lithium carbonate whose

diarrhea lessened when they took sustained-release lithium. The basic problem is that it is still unclear which lithium side

effects are related to peak serum level and which are related to steady-state serum level. Clinically, any side effect that

mainly occurs 1–2 hours after each oral dose of the standard preparation might be improved by the sustained-release form.

For example, nausea may be caused by gastric irritation from lithium or by an elevated serum level. The former causes

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There was a belief that sustained-release lithium would, in general, have fewer side effects and might, in particular, have

less effect on the concentrating ability of the renal tubules, leading to less polyuria and polydipsia. So far, this belief does

not seem to be the case, and it may even be that massing the total daily dose of lithium at bedtime may cause fewer renal

effects. One major European center (Copenhagen) has routinely been using once-a-day lithium dosing for many years,

suggesting that this dosage scheme is feasible and effective.

Dosage and Administration

Lithium dosage is titrated to achieve both therapeutic response and adequate plasma levels. The general presumption is that

levels of about 0.7–1.0 mEq/L are appropriate for maintenance therapy or the treatment of conditions other than manic or

psychotic excitement, whereas levels up to 1.5 mEq/L are sometimes needed in treating acute mania. Levels should be

obtained about 12 hours after the last dose, at which time the vagaries of absorption after drug ingestion are well past and a

relative steady state has been achieved (see the subsection on blood levels in the section “Tricyclic and Tetracyclic

Antidepressants” in Chapter 3: “Antidepressants”). These “ideal” levels are, of course, not carved in stone and must be

interpreted in the clinical context. Someone who has marked tremor, oversedation, vomiting, and ataxia at a level of 0.8

mEq/L either cannot tolerate that level or has some other medical condition causing the symptoms; lithium intolerance is

the more likely possibility. Other patients receiving maintenance therapy appear to have averted affective episodes for years

at levels as low as 0.4–0.6 mEq/L, and patients with daily symptoms such as irritability and anger report clinical

improvement at very low plasma levels. It is very hard to prove that these are or are not “real” drug responses. It is our

belief that many patients can be successfully maintained at relatively low plasma levels, particularly when the lithium is

combined with another agent. Occasionally, for a patient whose mania is still uncontrolled despite a level of 1.5 mEq/L for

several days and who has no side effects, a higher level can be cautiously tried.

Expedient establishment of high, adequate plasma levels of lithium (e.g., 0.8–1.2 mEq/L) is desired for acute mania. An

initial regimen of 300 mg bid to qid is indicated in healthy adolescent or adult patients; plasma levels should initially be

obtained every 3 or 4 days to ensure early detection of toxic lithium levels. The dosage should be titrated up (or down) as

necessary to achieve a level of approximately 1.0 mEq/L. In patients older than 60 or those with possible renal impairment,

the lower starting dose is indicated. In some elderly patients, we initiate lithium at 150 mg bid. Several articles have

described techniques for predicting the optimal dosage of lithium from a loading dose followed by several determinations of

levels over the next 24 hours. These techniques can be used, but they do not seem to us to offer benefit over clinical

titration. Response in acutely manic states may require 7–14 days, even with adequate plasma levels. As plasma levels

stabilize, the frequency of testing may be decreased—to two times a week initially, and eventually to once a week, as both

plasma levels and the clinical condition level out. If inadequate clinical response occurs within 4 weeks, it is safe to assume

that lithium monotherapy will not be effective for the acute episode. At this point, or earlier, adding a second mood stabilizer

should be considered.

With patients who are in remission and are being stabilized with lithium to avert future affective episodes, one can begin at

even lower dosages (one or two 300-mg doses per day); weekly plasma levels are often sufficient during dosage

adjustment. Again, the goal is to find a well-tolerated plasma level as close to 0.8 mEq/L as possible. It seems reasonable

that higher plasma levels should be associated with better prophylaxis. In one major collaborative study sponsored by the

National Institute of Mental Health (NIMH), patients whose lithium was maintained at 0.8 mEq/L and above had consistently

fewer recurrences than patients stabilized at lower levels (0.6 mEq/L or below) but had more side effects. The efficacy data

in this study generated considerable controversy, because when patients were initially randomized to low-plasma-level

groups, the dose may have been decreased so rapidly as to enhance the likelihood of relapse. Once a patient on maintenance

lithium is stabilized adequately with weekly plasma levels for a few weeks, monthly levels are sufficient, and after 6–12

months of stability, testing the levels every 6 months or as clinically indicated may suffice.

Once a patient has a stable daily dosage, it can be spread over the day in any suitable regimen. Usually, twice a

day—morning and bedtime—is convenient and well tolerated, and doses are less likely to be forgotten or overlooked. It has

been suggested, but not proved, that once-a-day dosing enhances compliance and may be associated with less polyuria. We

have found that once-a-day dosing at bedtime is often effective, but some patients feel drugged or dazed in the morning.

Gastric irritation after each dose is the major reason for use of divided doses. Smaller, more frequent doses are common

(and logistically easy) among hospitalized patients, but the patients are sometimes inadvertently discharged on these

regimens when a simpler regimen would suffice and might be taken more reliably after the patient returns home.

For other target symptoms, when the situation is less urgent, an initial dosage of 300 mg bid seems adequate. Some

patients who end up benefiting from lithium have presented with histories of marked lithium intolerance that appears to

have been caused by overaggressive initial dosing. In these less acute situations, a plasma level of 0.5–0.8 mEq/L is

probably adequate, and less frequent plasma level monitoring may be needed. It is also important to remember that one is

treating the patient, not the plasma level, and that both clinical status and adverse effects need frequent and careful

monitoring. Some patients report clear symptom relief at levels around 0.5 mEq/L; it seems unwarranted to push them to

higher levels unless they break through with symptoms at lower levels. Similarly, keeping a patient chronically nauseated,

mentally dulled, and grossly tremulous just to maintain an “adequate” plasma level is counterproductive in almost all

situations. In general, we advise aiming for lower levels (<0.6 mEq/L) in elderly patients.

For patients with chronic disorders manifesting overt, current target psychopathology—depression, schizophrenia, and

cyclothymia—a trial of about 4 weeks at adequate blood levels (or the highest tolerated levels) is usually sufficient to

determine whether lithium will be clinically useful.

If a patient has responded in the past to lithium but has stopped the drug for weeks or months, and if there is no reason to

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the drug at the prior dosage without retitrating. However, some patients require gradual dose escalation to allow optimal

dosing. Frequent blood level monitoring should be reinstituted.

Use in Pregnancy

Lithium is the only psychoactive, nonanticonvulsant drug that is thought to be associated with a specific birth defect,

Ebstein’s anomaly. This serious cardiac abnormality is not common in children born to mothers taking lithium (between

0.1% and 0.7%), but the defect is at least 20 times more common in these children than in the population at large. These

estimates are much lower than were earlier estimates, and some reviews have called into question whether there is a valid

association of Ebstein’s anomaly and lithium use (Giles and Bannigan 2006). The risk of a major birth defect needs to be

discussed with female patients taking lithium who either are planning to become pregnant or are already pregnant, because

the risk appears to exist primarily with first-trimester use (see Chapter 12: “Pharmacotherapy in Special Situations”). The

general risk of a major birth defect appears to be two to three times greater with lithium use than in the general population

(Cohen et al. 1994). Echocardiography and fetal ultrasound can be used after the sixteenth week of pregnancy to check for

the presence of cardiac abnormalities.

Another risk of lithium use, particularly in the third trimester, is large-gestational-weight infants. Higher birth weights have

been reported for some time in mothers exposed to lithium. The long-term significance of these higher birth weights in

infants is not established, but higher birth weight is not necessarily associated with poorer health outcomes.

Lithium Information Center

A lithium information center exists at the Madison Institute of Medicine in Madison, Wisconsin (telephone 608-827-2470;

fax 608-827-2479; www.miminc.org/aboutlithinfoctr.html). The staff is most helpful in conducting focused literature

searches for a small fee and can provide interested clinicians with answers to a wide variety of questions about lithium

problems encountered in their practice.

ANTICONVULSANTS

In the past two decades, increasing attention has been paid to the use of anticonvulsant medications in psychiatry, mainly to

promote mood stabilization (Table 5–3). The application of these agents stems from a number of observations on the

psychiatric sequelae of temporal lobe epilepsy, including hallucinations, angry outbursts, religiosity, and so forth. These

observations spurred on the use of phenytoin in the 1950s in psychiatric patients—with, at best, equivocal results (although

a controlled trial found phenytoin to be effective in the treatment of mania; Mishory et al. 2000). In more recent years,

several groups have further suggested that psychiatric symptoms could emanate from limbic seizures and that kindling

phenomena could play a major role in the development of psychoses and psychiatric disorders. Understandably, then, a

number of reports have emerged that other anticonvulsant agents (e.g., carbamazepine and valproic acid), which act

preferentially on temporal lobe or limbic systems, are effective in patients with bipolar disorder, particularly in acute mania.

Three compounds, valproic acid, carbamazepine, and lamotrigine, have received the lion’s share of attention (for chemical

structures of the thymoleptic anticonvulsants, see Figure 5–1), although many of the available anticonvulsants could

eventually prove useful in treating mood disorders.

Table 5–3. Anticonvulsant dosages in bipolar illness

Medication Usual dosage range Serum level ( g/mL)

valproate 15–60 mg/kg/day 50–125

carbamazepine 200–1,600 mg/day 6–10

lamotrigine 50–200 mg/day NA

gabapentin 900–3,600 mg/day NA

oxcarbazepine 600–2,400 mg/day NA

Note. NA = not applicable.

Figure 5–1.Print: Chapter 5. Mood Stabilizers

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Chemical structures of thymoleptic anticonvulsants.

Valproate

In contrast to almost all other drugs used in psychiatry, valproic acid has no rings. (Carbamazepine is tricyclic; valproic acid

could be said to be acyclic.) The drug is available in this country in the following forms: immediate-release valproic acid

(Depakene) and sodium valproate (Depakene syrup); delayed-release divalproex sodium (Depakote and Depakote Sprinkle),

containing equal molar of valproic acid and sodium valproate; an extended-release formulation of divalproex (Depakote-ER),

approved for migraines; and an injectable form (Depacon). The amide of valproic acid (valpromide [Dépamide]) is used in

Europe. All these preparations convert to valproic acid in the plasma.

Valproate therapy: overview

Efficacy Acute mania (FDA approved)

Bipolar prophylaxis (may be effective)

Mixed, rapid-cycling bipolar

Seizure disorders (FDA approved)Print: Chapter 5. Mood Stabilizers

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Valproate therapy: overview

Side effects Weight gain

Sedation

GI upset

Safety in overdose Serious effects notable mostly at 20 times normal serum level. Symptoms include nausea, vomiting, CNS

depression, and seizures. Manage with gastric lavage, forced emesis, and assisted ventilation.

Dosage and

administration

Start at 15 mg/kg in divided doses, up to a maximum of 60 mg/kg. Achieve serum levels of 50–100 g/mL.

Discontinuation Rapid discontinuation increases the risk of rapid relapse in bipolar disorder. Otherwise, discontinuation symptoms

are uncommon.

Drug interactions Drugs that valproate serum levels include:

cimetidine

erythromycin

phenothiazines

fluoxetine

aspirin

ibuprofen

Drugs that valproate serum levels include:

rifampin

carbamazepine

phenobarbital

ethosuximide

Note. CNS = central nervous system; FDA = U.S. Food and Drug Administration; GI = gastrointestinal.

Valproate may be the most convenient general term to encompass all these formulations. Valproate is FDA approved in

epilepsy for use in simple and complex absence attacks, partial seizures, and migraine prophylaxis. Valproate was given FDA

approval for the treatment of acute mania in 1994, followed by approval for Depakote ER in 2005. Valproate is still among

the most commonly used drugs in the treatment of bipolar disorder in American psychiatry. Valproate also continues to be

employed in treating many other kinds of symptoms, including aggression, agitation, and impulsivity in patients with a

variety of disorders.

Clinical Indications

Early work in the late 1960s by Lambert in France identified valproate as effective in a wide range of patients with mania

and schizoaffective mania when added to a wide variety of other drugs. Lambert’s group reported on more than 100 patients

but did not describe the patients in detail. In their study, which involved mainly patients with treatment-resistant

schizoaffective disorder with mania, moderate improvement was reported in more than half of the patients. In those

patients with acute mania without prior drug therapy, 10 of 14 improved. These results agree with the findings of a study of

valproate by Pope and colleagues (1991) at McLean Hospital and with other local clinical experience. In Pope et al.’s study,

there was a 54% improvement in a standard mania rating score in the valproate group, compared with only a 5%

improvement in this score in the placebo group. Interestingly, the antimanic effects of valproate were often observed in the

first few days of treatment.

Since the Pope study, a number of double-blind studies have been completed attesting to the efficacy of valproate in treating

acute mania. The largest, a double-blind, placebo-controlled study of 179 patients, found that lithium and valproate were

equivalent in effectiveness in treating acute mania and twice as effective as placebo (Bowden and McElroy 1995). In

addition, there is evidence that a loading dose strategy, typically using about 20 mg/kg/day of valproate, may reduce the

onset of action to 5 days or less (Keck et al. 1993a; McElroy et al. 1993). Using a 30 mg/kg loading dose to start, with a

reduction to 20 mg/kg after a few days, has also been suggested. The current data suggest that valproate is at least as well

studied and as effective as lithium in the treatment of acute mania. However, both lithium and valproate appear to be slower

acting than the atypical antipsychotics in the treatment of acute mania.

Valproate may be particularly useful in patients with mixed-state or rapid-cycling types of bipolar disorder. Freeman et al.

(1992) found that valproate showed good efficacy relative to lithium in the acute and long-term management of mixed

states. Bowden et al. (Bowden and Singh 2005; Bowden et al. 1994) noted that valproate was more effective than lithium in

treating bipolar patients with mixed states and irritable features and was also effective in treating bipolar patients with

rapid cycling. A number of other small open-label studies suggested that valproate may be quite useful in treating mixed and

manic states but somewhat less useful in preventing depressive episodes in bipolar patients with rapid cycling. Patients

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treatment. Other predictors of response to valproate include lack of psychotic episodes in patients with concurrent BPD

(Calabrese et al. 1993). A double-blind, placebo-controlled study has also reported significant effects for valproate in Cluster

B patients (Hollander et al. 2001).

A number of open-label studies have suggested that valproate is an effective prophylactic agent in the treatment of bipolar

disorder. Most of these studies suggested that valproate may be somewhat more effective in preventing manic than

depressive episodes. In a double-blind longitudinal study, Lambert and Venaud (1992) found that valproate was better

tolerated than, and as effective as, lithium in preventing subsequent bipolar episodes over a 2-year period. A large

multicenter study involving more than 300 patients failed, however, to demonstrate the efficacy of valproate over placebo in

the prevention of mania (Bowden et al. 2000). A priori selection of primary outcome measures appeared to interfere with

demonstrating the effectiveness of divalproex in the prophylaxis of mania. However, clinical experience with the drug still

suggests that it is effective in the maintenance treatment of bipolar disorder.

The efficacy of valproate in treating acute unipolar or bipolar depression is largely untested. As of this sixth edition, there

are still no controlled studies of valproate in treating unipolar depression. Several uncontrolled studies and case reports

suggested that valproate may have modest antidepressant efficacy in bipolar depression. We have reported that valproate

may be useful in the treatment of agitation associated with major depression (DeBattista et al. 2005). There are also case

reports suggesting that valproate may have a role in treating refractory major depression. Bowden, Calabrese, and

colleagues’ (2000) maintenance study suggested that divalproex prevented depressive episodes better than placebo in

bipolar patients even though it failed to show similar effects in mania. Low-dose valproate has been successfully used to

treat cyclothymia (Jacobsen 1993).

Some case reports and open-label studies have suggested that valproate may be useful in treating panic disorder,

particularly when the disorder is complicated by substance abuse and there is concern about using a benzodiazepine (Baetz

and Bowen 1998; Keck et al. 1993b; Ontiveros and Fontaine 1992; Woodman and Noyes 1994). We have generally not found

valproate to be that useful in treating anxiety disorders.

A study compared 4 weeks of valproate with placebo as an add-on to risperidone or olanzapine in decompensating

schizophrenic patients. Valproate add-on was significantly more effective than placebo in reducing positive symptoms

(Casey et al. 2001). There is also some evidence that valproate might speed response to antipsychotics in schizophrenia.

Valproate is increasingly being used in the treatment of agitation. A number of open-label trials have reported that valproic

acid is effective in treating agitation associated with dementia and brain injury (Herrmann 1998; Hilty et al. 1998; Kunik et

1. 1998; Lott et al. 1995). We have found that agitated dementia patients often respond to dosages as low as 125 mg/day,

although higher dosages are often tolerated and sometimes needed in these patients. Controlled trials have suggested that

low-dose valproate is often ineffective but that higher doses are often associated with high rates of discontinuation

secondary to side effects (Lonergan et al. 2004). Our group has also been interested in the use of divalproex sodium as an

adjunctive agent in the treatment of agitation associated with depression (DeBattista et al. 2005). In a 4-week open trial,

we found that an average dose of about 750 mg of divalproex significantly diminished agitation in depressed patients.

Valproate is also increasingly being used to control aggression, particularly in patients with brain injuries. Several open

studies reported that valproate helps control impulsivity, explosive outbursts, physical aggression, and self-destructiveness

in patients with brain injuries or mental retardation (Geracioti 1994; Ruedrich et al. 1999; Wroblewski et al. 1997). Some

evidence suggests that valproate may attenuate disruptive behavior in aggressive adolescents (Donovan et al. 1997). A

recent double-blind, placebo-controlled trial of valproate in patients with intermittent explosive personality failed to find

significant differences between drug and placebo, although both groups improved. However, in juvenile offenders, the drug

appeared to decrease aggressive outbursts (Steiner et al. 2003). In addition, adolescents who are at risk for developing

bipolar disorder and who also have problems with aggression tend to be less aggressive while taking valproate (Saxena et

1. 2006).

Valproate has been studied in the treatment of the impulsivity, affective instability, and self-destructiveness of BPD.

Borderline personality symptoms are sometimes thought to overlap with those of bipolar II disorder, and it makes some

sense to apply valproate to the treatment of BPD patients. Most studies have been small and uncontrolled (Hirschman et al.

1997; Stein et al. 1995; Wilcox 1995). However, in a more recent, larger trial, valproate did appear to be significantly more

effective than placebo in patients with Cluster B personality disorders. Valproate does appear to be an important adjunctive

agent for controlling some symptoms in many BPD patients. It has the advantage of being less toxic than lithium and most

other anticonvulsants in this population with self-destructive behavior. As indicated earlier, the drug appears to reduce

positive symptoms in relapsing patients with schizophrenia (Casey et al. 2001).

Dosage and Administration

The plasma half-life of valproate is on the order of 10–15 hours. A drug such as carbamazepine, phenobarbital, or phenytoin,

given concurrently, will induce hepatic enzymes and shorten valproate’s half-life by speeding its metabolism. In contrast to

carbamazepine, valproate is a modest hepatic enzyme inhibitor. Once an adequate blood level has been attained, it is likely

to remain adequate if intake remains constant. Blood levels should be taken about 12 hours after the last dose.

The usual starting dose of valproate is 15 mg/kg in two divided doses. Thus, the average 75-kg male might be started on

500 mg bid. In less acute settings, we tend to recommend a starting dose of 250–500 mg the first day, and that dose, if

tolerated, is titrated upward. Some clinicians employ once-a-day dosing of valproate in an effort to enhance compliance.

Given the pharmacokinetics of valproate, bid dosing is probably ideal. In addition, the large peaks in plasma levels with

once-a-day dosing often produce GI side effects, and this strategy tends to be poorly tolerated. Still, attaining high levels of

this highly bound, hydrophilic agent could allow more effective delivery into the central nervous system (CNS). ThePrint: Chapter 5. Mood Stabilizers

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sustained-release formula of divalproex sodium (Depakote ER) was approved for use in the treatment of acute mania or

mixed episodes in bipolar disorder. The ER form is not bioequivalent to the immediate-release form—it appears to produce a

serum level that is 10%–20% lower than with Depakote—which suggests some need for increasing the dose (by about

one-third) when converting patients to the ER formulation. The ER formulation may be somewhat less associated with side

effects such as weight gain. Preliminary studies have indicated that switching from the immediate-release Depakote to the

ER formulation of Depakote in bipolar patients was well tolerated and maintained stability. The dosage can be increased

each week by 10 mg/kg/day until an adequate therapeutic level is achieved, or to a maximum dosage of 60 mg/kg/day.

As described earlier, loading doses in the range of 20 mg/kg seem to speed the onset of action in treating acute mania.

Intravenous loading of divalproex sodium also appears to help stabilize mixed states and rapid cycling but may have little

effect on bipolar depression (Grunze et al. 1999a). Patients with mania tolerate medication side effects better than those

with depression. Thus, loading strategies are generally avoided in the latter.

In manic patients, levels greater than 45 g/mL seem to be required for antimanic effect, and levels up to 100 g/mL are

well tolerated. Sometimes, levels as high as 125 g/mL are required for optimal efficacy of valproate in the treatment of

acute mania. Most data suggest that blood levels should probably be between 85 g/ml and 125 g/ml in the treatment of

patients with mania or mixed states. Higher levels appear to be associated with side effects, including thrombocytopenia,

weight gain, and sedation (Bowden and Singh 2005). In beginning valproate therapy, the enteric-coated divalproex sodium

is generally less likely to cause GI distress than are the other formulations. Initial dosages of 250 mg bid are common; the

higher daily dosage should be reserved for actively manic patients. Valproic acid plasma levels should be obtained every few

days until a level greater than 50 g/mL is reached. There is some suggestion that clinicians should push the dose to

achieve levels greater than 75 g/mL in patients who are not responding. There is considerable variability in levels obtained

depending on the time since last dose. Over time blood levels should be collected in a similar relationship to last dose. As

with other drugs with which dosage is titrated to reach a specified blood level, the final daily dosage could vary widely,

anywhere from 750 to 3,000 mg/day. Some improvement may be evident within 4 days and should be seen within 2 weeks

of attaining a therapeutic blood level. If improvement has not occurred, higher doses and levels can be tried for another 2

weeks, but side effects may prove limiting. Sedation and GI distress are the likeliest limiting side effects early in therapy,

but only sedation is common, and valproate seems generally better tolerated than lithium carbonate.

When a patient acutely improves while taking valproate, one assumes that the drug can be continued as a maintenance

therapy at the same dosage and level, watching for any toxicity. This may, in fact, be a wise course. However, many patients

undergoing a trial of valproate are already taking various other drugs (e.g., lithium, a neuroleptic, carbamazepine,

antidepressants, clonazepam). Once valproate is working, the other drugs can be gradually withdrawn one at a time to

determine whether they are needed. Some may prove unnecessary, but tapering and stopping others may invite a relapse.

Only one-third of patients experience adequate response to monotherapy, so combination treatment is now the rule rather

than the exception. Valproic acid levels can be monitored weekly until stable and presumably adequate levels are achieved,

then monthly or less often during prolonged maintenance therapy. The level should be rechecked if new side effects occur or

if the clinical condition worsens.

Side Effects

A major concern with valproate has been the risk of severe, sometimes fatal, hepatotoxicity (Table 5–2). Fatal cases have all

been in neonates receiving multiple anticonvulsants, particularly barbiturates. Children younger than 2 years appear at

greatest risk for severe hepatotoxicity. The risk of hepatotoxicity makes the task of monitoring psychiatric patients taking

valproate a risk-benefit conundrum. One could order liver function tests every month or so because no one is sure whether

severe hepatocellular toxicity will occur. On the other hand, the available data could support the position that frequent liver

function tests are unnecessary and that patients and/or relatives should be told of the remote risk and informed about early

symptoms of liver disease (e.g., anorexia, jaundice, nausea, lethargy). We recommend liver function tests every 6–12

months. If liver function tests are done, minor elevations of hepatic enzyme levels up to three times the normal limit should

not necessarily lead to stopping the drug. Balancing the apparent clinical benefit to the patient with the abnormality of the

liver function tests is reasonable. The better the patient’s response, the more one persists in giving valproate in the face of

progressively abnormal liver function tests.

Pancreatitis can occur with Depakote after varying lengths of exposure. We have had one case of pancreatitis that occurred

after the patient had been taking the drug for more than 1 year. The patient presented with abdominal pain and had

elevated serum amylase levels. The reaction abated with drug cessation. The side effect is rare but does occur at a high

enough incidence for the clinician to consider.

Weight gain is the most common reason patients discontinue valproate. As many as half of the patients who use valproate

chronically experience significant weight gain. Maintaining an adequate diet and exercise regimen is clearly necessary for

patients taking valproate. Despite their best efforts, however, many patients find it difficult to control their weight. We have

found that the addition of topiramate at dosages of 50–200 mg/day has been an effective anorexiant for many patients and

may help with mood stabilization.

Thrombocytopenia and platelet dysfunction have been reported in patients taking valproate. Warning patients to report easy

bruising or bleeding is indicated. Platelet levels can be checked periodically.

Sedation is among the most common side effects of valproate therapy. As with other medications, shifting more of the dose

closer to bedtime will mitigate daytime sedation.

GI upset, the second most common side effect of valproate after weight gain, can take the form of nausea, cramps, emesis,

and diarrhea and is dose related. Enteric-coated tablets or divalproex sprinkle capsules help, as do histamine 2 blockersPrint: Chapter 5. Mood Stabilizers

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(e.g., famotidine [Pepcid] at 20 mg bid). Tremor and ataxia can also occur.

Another side effect, alopecia, is thought to be due to valproate’s interference with zinc and selenium deposition. Some

clinicians instruct patients to take multivitamins fortified with these two metals; Centrum Silver is a vitamin supplement

commonly used for this purpose. If significant alopecia occurs, the valproate should be discontinued. Hair regrowth may

take several months.

Coma and death are rare when valproate is taken with suicidal intent. The drug can be removed by hemodialysis. There is

also one report that valproate coma was reversed by naloxone.

Another, more recent concern has been the observation that valproic acid may be associated with the development of

polycystic ovaries in women. A study of 238 epileptic women found that 43% of patients taking valproic acid had polycystic

ovaries and 17% had elevated testosterone levels (Isojarvi et al. 1993). Among the women who started valproic acid before

age 20, 80% had polycystic ovaries. Since over 50% of women on valproic acid were also obese, and because obesity is

associated with polycystic ovaries, it is unclear whether valproic acid’s effects on the high rate of polycystic ovaries are a

direct result of the drug or an indirect effect of contributing to obesity. However, in the Systematic Treatment Enhancement

Program for Bipolar Disorder (STEP-BD), women with polycystic ovarian syndrome (PCOS) who discontinued their valproate

appeared to have significant improvement in PCOS symptoms despite the fact that there was no significant change in weight

(Joffe et al. 2006). This suggests that there may be a direct contribution of valproate to PCOS independent of obesity. In

addition, some forms of epilepsy appear to be associated with polycystic ovaries, independent of anticonvulsant use.

Independent replication of valproate as a cause of polycystic ovaries has not been reported despite hundreds of thousands

of patients treated. Two recent small surveys suggest rates of about 8%–10% in women treated with the drug, which are

slightly higher than the rates (4%–7%) in the general population (Joffe and Cohen 2004). Some child psychiatrists have

suggested caution in treating adolescent female bipolar patients with valproate, given the available data on polycystic

ovaries (Eberle 1998). More recent studies involving women with bipolar disorder who were taking divalproex also have not

shown an association with polycystic ovary disease (Rasgon et al. 2000). It is best to monitor females who are taking

valproate for the development of weight gain, hirsutism, menstrual irregularities, and acne.

Drug Interactions

Serious drug interactions are uncommon with valproate. However, the metabolism of valproate is approximately 25%

dependent on the cytochrome P450 system. A number of drugs that competitively inhibit various enzymes of the cytochrome

P450 system—including cimetidine, the SSRIs, and erythromycin—may be associated with an increase in valproate levels

(Table 5–4). Additionally, many nonsteroidal anti-inflammatory agents, including aspirin, may increase free valproate levels.

Other drugs, such as carbamazepine and rifampin, have been associated with reducing valproate levels.

Table 5–4. Drug interactions of anticonvulsant mood stabilizers

Anticonvulsant Drugs that may

anticonvulsant levels

Drugs that may

anticonvulsant levels

Drugs whose blood levels with concurrent

anticonvulsant use

valproate aspirin carbamazepine zonisamide

cimetidine ethosuximide Clinically significant metabolic induction by other

drugs with valproate not reported

clarithromycin oxcarbazepine

erythromycin phenobarbital

fluvoxamine phenytoin

fluoxetine primidone

ibuprofen rifampin

phenothiazines

topiramate

troleandomycin

carbamazepine cimetidine felbamate atypical antipsychotics

ciprofloxacin phenobarbital benzodiazepines

clarithromycin rifampin doxycycline

diltiazem

ethosuximide

doxycycline

fentanyl

erythromycin

glucocorticoids

fluconazole

methadone

fluoxetine

neuroleptics

fluvoxamine

oral contraceptives

grapefruit juice

phenytoin

isoniazid

protease inhibitors

itraconazole

TCAs (?)Print: Chapter 5. Mood Stabilizers

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Anticonvulsant Drugs that may

anticonvulsant levels

Drugs that may

anticonvulsant levels

Drugs whose blood levels with concurrent

anticonvulsant use

ketoconazole

theophylline

nefazodone

prednisolone

propoxyphene

protease inhibitors (e.g.,

ritonavir, indinavir)

TCAs

troleandomycin

valproate

verapamil

warfarin

lamotrigine valproate carbamazepine valproate

ethosuximide

oral contraceptives

oxcarbazepine

phenobarbital

phenytoin

primidone

oxcarbazepine

ethinyl estradiol

levonorgestrel

topiramate

oral contraceptives

Note. TCAs = tricyclic antidepressants; = increase; = decrease.

Valproate has been associated with an increase in the serum levels of a variety of drugs, including carbamazepine, warfarin,

and tolbutamide. These interactions are generally not clinically significant but may require reduced doses of the concurrent

medications. Valproate can double the levels of concurrent lamotrigine and increase the risk of rashes. When these two

agents are used together, lamotrigine doses are increased very gradually. In rare cases, valproate therapy has been

associated with hyperammonemia, with or without encephalopathy, which may occur despite normal hepatic function tests.

Concomitant administration of topiramate and valproate may raise this risk. In the package insert, a precaution is issued of

the associated risk of hyperammonemia with topiramate use. Moreover, valproate is contraindicated in patients with known

urea cycle disorder (e.g., ornithine transcarbamylase deficiency).

Use in Pregnancy

When valproate is taken during the first trimester of pregnancy, neural tube defects can occur (e.g., spina bifida,

anencephaly). Thus, valproate should generally be discontinued before anticipated pregnancies. However, if it is necessary

to continue valproate because of the significant risk of a disruptive relapse of bipolar illness during pregnancy, the patient

should be started on folate, 1 mg/day, early in the pregnancy and an ultrasound should be ordered at 18–20 weeks to

assess for fetal abnormalities. During the last 6 weeks of the pregnancy, vitamin K should also be prescribed to decrease the

risk of excessive bleeding. Given the risk of relapse in the postpartum period, valproate should generally be restarted after

delivery to reduce the risk of relapse.

Recent reports of lower IQ in children exposed in utero to valproate (Vinten et al. 2005) are very troubling, and we currently

recommend avoiding use of the drug during pregnancy whenever possible.

Carbamazepine therapy: overview

Efficacy Acute mania (FDA approved for Equetro only)

Mixed, rapid-cycling bipolar (not FDA approved)

Seizure disorders (FDA approved)

Side effects Sedation

Dizziness

Fatigue and nausea

Ataxia

Safety in

overdose

Serious symptoms may occur at 10–20 times normal serum levels. Symptoms include nausea, vomiting, CNS

depression, respiratory depression, and seizures. Management includes gastric lavage, forced emesis, assisted

ventilation.

Dosage and

administration

For the XR form: 200 mg bid, to therapeutic range of 800–1,200 mg/day. Follow serum levels to 6–10 g/mL.Print: Chapter 5. Mood Stabilizers

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Carbamazepine therapy: overview

Discontinuation Carbamazepine has not been associated with a withdrawal syndrome with rapid discontinuation. However, as with

other mood stabilizers, rapid discontinuation is associated with an increased risk of rapid relapse. In bipolar patients,

decrease dose over 6 months. In nonbipolar patients, dose may be decreased by 25% every 3 days.

Drug interactions Drugs that may carbamazepine levels include:cimetidine, ciprofloxacin, diltiazem, fluoxetine, fluvoxamine,

doxycycline, erythromycin, fluconazole, grapefruit juice, INH (isoniazid), ketoconazole, macrolide antibiotics

(erythromycin, clarithromycin, troleandomycin), nefazodone, norfloxacin, prednisolone, propoxyphene, protease

inhibitors (e.g., ritonavir), TCAs, valproate, verapamil, and warfarin

Drugs whose blood levels are by coadministration with carbamazepine include: atypical antipsychotics,

benzodiazepines, doxycycline, ethosuximide, fentanyl, glucocorticoids, haloperidol, methadone, oral contraceptives,

phenothiazines, phenytoin, sertraline, TCAs, and theophylline

Note. CNS = central nervous system; FDA = U.S. Food and Drug Administration; TCAs = tricyclic antidepressants; XR =

extended-release..

Carbamazepine

Carbamazepine was originally synthesized in 1957 and introduced into the European market in the early 1960s as a

treatment for epilepsy, particularly epilepsy involving the temporal lobes. Subsequently, it became widely used as a

treatment for “tic douloureux”—trigeminal neuralgia. Its use for bipolar disorder stems from the early 1970s when Japanese

researchers reported it was effective in many patients with manic-depressive illness, including patients whose condition

was refractory to lithium. In 1980, Ballenger and Post reported that carbamazepine was effective in a double-blind

crossover trial in patients with acute bipolar disorder. Since that time, many other controlled studies have documented the

utility of carbamazepine for acute mania. Kishimoto et al. (1983) reported that it was also effective in maintenance therapy,

and a number of controlled studies have subsequently confirmed this finding. However, carbamazepine had never been FDA

approved for the treatment of any aspect of bipolar disorder until an extended-release (ER) form of the drug (Equetro) was

approved in 2005 for the treatment of acute mania. We tend to regard carbamazepine as a less good initial choice than

either valproate, lithium, or an atypical in the treatment of bipolar disorder because of the propensity for pharmacokinetic

interactions with carbamazepine.

Carbamazepine has drug-interaction and side-effect profiles that make it more cumbersome to use, and, though well

studied, it is still less well studied than either lithium or valproate at this time. Still, there are many patients who do well

with carbamazepine who do not have an adequate response to valproate or lithium, and the combination of carbamazepine

and another mood stabilizer or atypical antipsychotic is often helpful.

Clinical Indications

There are now multiple controlled studies of carbamazepine in the treatment of acute mania and additional controlled

studies on its use as a mood stabilizer in the maintenance treatment of bipolar disorder. The FDA approval of Equetro for the

treatment of acute mania and mixed states was based on data from three controlled trials (Owen 2006; Weisler et al. 2006).

Many of the earlier studies have been compromised by concurrent neuroleptic or other drug use. Enough clinical evidence

exists to justify using carbamazepine in patients with bipolar disorder with a reasonable expectation that a proportion of

them—about 50%—will show clear clinical benefit. However, some patients who derive benefit from carbamazepine have

residual symptoms. The drug may work more rapidly than lithium but less rapidly than antipsychotics in acute mania.

Some patients who have a response to carbamazepine improve or stabilize with the drug alone; others do better with

carbamazepine plus another mood stabilizer or antipsychotic (see Chapter 9: “Augmentation Strategies for

Treatment-Resistant Disorders”). The major problem in assessing the clinical value of a drug like carbamazepine, which is

used mainly in treating seriously symptomatic psychiatric patients in whom more standard treatments have failed, is that all

other medications are rarely discontinued before the carbamazepine is added. Later, if the patient does well, other

preexisting drugs may or may not be tapered and stopped. Clinically, it is often hard to be sure when carbamazepine itself is

really working and when prior therapy may finally have begun to work.

Some evidence suggests that carbamazepine works better than lithium in producing stability in rapid-cycling bipolar

patients—those with four or more affective episodes a year. Even though there is some preliminary evidence of

carbamazepine’s superiority to lithium in rapid cycling, it is clear that this bipolar subtype is difficult to treat with any agent.

In one major study, patients without rapid-cycling bipolar illness were much more likely to respond to carbamazepine alone

than were patients with rapid-cycling bipolar illness (Okuma 1993). Likewise, carbamazepine may be more effective than

lithium in the maintenance treatment of patients with mixed episodes or rapid cycling (Greil et al. 1998). Some evidence

suggests that carbamazepine is preferentially effective in more severe, paranoid, and angry manic patients than in euphoric,

overactive, overtalkative, or overfriendly manic patients. Other potential indications for the drug include continuous-cycling

bipolar illness, in which there are no periods of euthymia between bipolar episodes. Overall, the data on predictors of

carbamazepine response have been mixed.

Carbamazepine has not been well studied in the treatment of major depression. Several small studies suggested that

carbamazepine may be useful in the treatment of bipolar depression, particularly when lithium is added to the regimen. In

general, carbamazepine does not appear to be nearly as effective in acute depression as in acute mania. Likewise, some case

reports suggest that carbamazepine is effective in the treatment of panic disorder, but there are much better antipanic drugs

than carbamazepine, and the only controlled trial yielded negative findings.

A complicating factor in adding carbamazepine to an antipsychotic is that carbamazepine induces liver enzymes and speedsPrint: Chapter 5. Mood Stabilizers

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metabolism of some other drugs. Haloperidol levels are clearly lowered substantially. Likewise, carbamazepine is known to

induce the metabolism of a number of atypical agents, including olanzapine, risperidone, and clozapine. Levels of other

antipsychotics can be checked before and 2–4 weeks after carbamazepine is added to see whether they have changed.

Worsening in some patients (and improvement in others) could be attributed to lowering of the neuroleptic blood level

rather than to the direct effects of carbamazepine. Similarly, carbamazepine may lower TCA and other antidepressant

plasma levels, making such combinations difficult.

Pilot studies of carbamazepine show some promise for this drug in treating violent nonpsychotic patients and patients

undergoing alcohol or benzodiazepine withdrawal.

An intriguing study by Cowdry and Gardner (1988) involved patients with BPD who had histories of frequent impulsive acts.

In this small but double-blind study, carbamazepine was notable for substantially decreasing impulsivity. The patients’

therapists all judged the patients to be much better. The patients, however, did not feel the drug was very effective. In the

same study, the patients felt better—but were much more impulsive—while taking alprazolam. Thus, there may be a role for

carbamazepine in treating patients with BPD. However, valproate also appears to be helpful in treating patients with BPD

and may be easier to use.

Other psychiatric disorders may also be characterized by impulsivity, aggressive outbursts, and affective instability. Patients

with posttraumatic stress disorder (PTSD) sometimes have these difficulties, and a number of open-label studies suggest

that carbamazepine is useful in treating some of these patients. Carbamazepine has demonstrated utility in the treatment of

agitation and violent outbursts associated with dementia. It is possible that carbamazepine is helpful in nephrogenic

diabetes insipidus, because it increases vasopressin release. Unfortunately, carbamazepine’s ability to effect such an

increase is blocked by lithium, making carbamazepine ineffective in lithium-induced polyuria and polydipsia. Carbamazepine

can, but rarely does, cause hyponatremia and water intoxication.

Dosage and Administration

Blood levels of carbamazepine should be monitored at least weekly throughout the first 8 weeks of treatment, because the

drug induces liver enzymes, which then speed the drug’s own metabolism. The blood level established at 3 weeks may

decrease by one-third at 6 weeks, even when the carbamazepine dosage is held constant. Starting with 100 mg (one-half

tablet) at bedtime is suggested to see whether the patient is oversedated. If the drug is well tolerated, it should be given at

a dosage of 100 mg bid on the second day, followed by 200 mg bid for the next few days. A sustained-release form of

carbamazepine, Tegretol-XR, is often taken once a day. Serum levels should be obtained twice a week in the first 2 weeks,

when possible—always about 12 hours after the last dose.

The dose should be adjusted to maintain a serum level of 4–12 g/mL. Higher levels are not generally more effective and are

often difficult to attain because of hepatic induction. We generally aim for levels in the range of 6–10 g/mL. Adjusting

levels upward means more risk of side effects. The most common signs of excessive carbamazepine blood levels are

diplopia, malcoordination, and sedation. Tolerance will also often develop. Moving all or most of the daily dose to bedtime

may help mitigate problems with sedation.

Carbamazepine ER (Equetro) is usually started at 400 mg/day in divided doses, and the dosage is then increased by 200

mg/day to a target dosage of around 600–1,200 mg/day. In the pooled bipolar trials, the mean dosage was 707 mg/day.

The maximum studied dosage is 1,600 mg/day.

Side Effects

The major concern with the clinical use of carbamazepine is the threat of agranulocytosis or aplastic anemia, both

potentially lethal conditions. As is usual with very rare, serious adverse drug reactions, estimates of incidence vary widely,

in this cases from 1 in 10,000 patients treated to a more recently estimated 1 in 125,000. There is a growing consensus that

frequent monitoring of blood counts is of limited value for patients on carbamazepine therapy. Aplastic anemia,

thrombocytopenia, and agranulocytosis occur so rapidly that a daily blood count would be required to detect them. More

recently, some experts have taken the position that regular blood counts are unnecessary and that warning the patient

and/or significant others to watch for overt symptoms of bone marrow suppression (e.g., fever, bruising, bleeding, sore

throat, petechiae) is more cost-effective.

Clinical practice with respect to chlorpromazine, with which agranulocytosis may be more frequent than with

carbamazepine, has long been to avoid regular blood counts. With clozapine, with which the rate of agranulocytosis is

perhaps 1%–2%, weekly counts have been demanded by the FDA. Obviously, no compelling recommendation is possible

with respect to carbamazepine. One compromise would be to get a complete blood count with every carbamazepine blood

level.

Once patients have started taking carbamazepine, a surprising number of them show a relative leukopenia, with or without

a drop in erythrocytes, during the first few weeks. Approximately 7% of adult patients and 12% of children develop

leukopenias while taking carbamazepine (Sobotka et al. 1990). Patients who run low white blood cell counts (WBCs) at

baseline appear to be at particular risk for developing significant leukopenias. Drops in WBC (in cells/mm 3 ) to the low

3,500s are not uncommon. If the differential is normal (more than 1,000 polymorphonuclear leukocytes) and the patient

seems to be benefiting from the treatment, carbamazepine can be continued. However, high-risk patients should be

monitored frequently in the first 3 months of therapy. After observing a WBC under 3,000 cells/mm 3 , the clinician will

almost certainly feel a need to get counts more frequently. The availability of consultation with a friendly, interested, helpful

hematologist is an asset to clinicians working with drugs such as carbamazepine and clozapine.

The most common side effects of carbamazepine are sedation, fatigue, nausea, and dizziness. At higher doses, ataxia,Print: Chapter 5. Mood Stabilizers

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diplopia, muscle incoordination, and nystagmus may be evident. Overdose of carbamazepine may result in stupor

progressing to coma and death.

Carbamazepine also can occasionally cause elevations in liver enzymes, but serious hepatotoxicity is quite rare. -Glutamyl

transferase (GGT), an index of hepatic activity, is frequently increased (up to 100%) and is typically not a cause for concern

unless the level is more than three times the normal level. Carbamazepine shares with TCAs the ability to slow cardiac

conduction. Rashes with carbamazepine are probably a bit more common than with other psychiatric drugs; one review

estimated a 5% incidence during the initiation of carbamazepine therapy.

Drug Interactions

Carbamazepine can influence the metabolism of a variety of drugs (Table 5–4), a feature that complicates its clinical use.

Quite frequently, it is difficult to assess the effect of carbamazepine on concurrent drug therapy.

Carbamazepine is metabolized mostly by the cytochrome P450 3A3/4 enzyme and can be increased by drugs that inhibit this

enzyme, including erythromycin, ketoconazole, fluvoxamine, fluoxetine, and calcium channel blockers. Serum

carbamazepine levels should be monitored closely with concurrent use of these medications.

In turn, carbamazepine induces the hepatic metabolism of many drugs that are metabolized via the cytochrome P450

enzyme 3A3/4, including steroids, oral contraceptives, TCAs, sertraline, benzodiazepines, and calcium channel blockers.

This interaction reduces the serum levels of these drugs and may decrease their efficacy. For some drugs, such as the TCAs,

blood levels can be monitored. For most other drugs, monitoring serum levels is not helpful. There is little information about

carbamazepine’s effects on SSRI levels. There have been cases of oral contraceptive failure with concurrent carbamazepine

use, and patients may need higher doses of benzodiazepines or antipsychotics if carbamazepine is used concurrently.

There have been some reports of CNS toxicity associated with the combination of carbamazepine and lamotrigine (Besag et

1. 1998). Symptoms have included dizziness and diplopia and appear to be related to changes in the serum level of

lamotrigine. Adding lamotrigine to carbamazepine appears to be more problematic than vice versa.

The use of clozapine in combination with carbamazepine is probably ill-advised. Although it is unclear whether the

combination substantially increases the risks of leukopenias, other options should be exercised before carbamazepine and

clozapine are used together.

Use in Pregnancy

In the past, carbamazepine was believed to be the safest of the anticonvulsants and the mood stabilizers for use during

pregnancy. However, it has become evident that carbamazepine is associated with the occurrence of fetal abnormalities of

the type seen with hydantoin: an increased incidence of craniofacial defects, fingernail hypoplasia, neural tube defects, and

developmental delay. Therefore, carbamazepine should be discontinued, if possible, during the first trimester of pregnancy.

As with divalproex sodium, folate supplements may reduce the risk of some of the neural tube effects of carbamazepine.

Carbamazepine does enter the breast milk, and the serum concentrations in the infant may be as high as 15% of the

maternal serum level (Brent and Wisner 1998). Although it is unclear what effect this serum level has on a developing

infant, breast-feeding should be discouraged unless no reasonable alternative exists.

Lamotrigine

Lamotrigine (Lamictal) had been used for a number of years in Europe before being introduced in the United States.

Lamotrigine has an FDA-approved indication for the treatment of partial complex and generalized seizures. In the early

1990s, lamotrigine began to be investigated as a treatment for bipolar disorder when epileptic patients reported an

improvement in their general sense of well-being independent of seizure control. While early controlled trials focusing on

acute mania failed to show benefit, subsequent trials in the maintenance treatment of bipolar disorder demonstrated that

lamotrigine delays the time to a next depressive or manic episode. These trials led to lamotrigine’s FDA approval in 2003 as

only the second drug, after lithium, indicated for the maintenance treatment of bipolar I disorder to delay the time to

occurrence of mood episodes.

Lamotrigine has a variety of pharmacodynamic effects that may explain its mood-stabilizing properties. For example, in

addition to decreasing glutamate release, lamotrigine also appears to modulate the reuptake of serotonin and generally

blocks the reuptake of monoamines, including dopamine (Xie and Hagan 1998). Despite the evidence that lamotrigine has a

profile that may confer antidepressant effects in addition to anticycling effects, the switch rate appears very low in bipolar

patients treated with lamotrigine. In fact, the pivotal maintenance trials of lamotrigine in bipolar disorder did not suggest

any higher rate of switching than with placebo.

Clinical Indications

Lamotrigine is indicated to delay the onset of new mood episodes in the maintenance treatment of bipolar disorder. Two

pivotal studies were completed, involving more that 500 bipolar I patients, that provided evidence of the efficacy of

lamotrigine in maintenance treatment. The first started with patients who were hypomanic or manic, whereas the second

started with patients in the depressed phase of the illness. Once the patients’ acute mood symptoms had resolved, they

were randomized to receive either lamotrigine or placebo for 12 months. What these studies demonstrated was that patients

receiving the lamotrigine did better longer than the patients receiving placebo. The time to a new episode of depression or

mania was delayed in the lamotrigine-treated patients—sometimes as much as twofold—relative to placebo, and this delay

was most pronounced for depressive episodes.

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lamotrigine is effective as an add-on or as monotherapy in patients who had no response to traditional trials of lithium, often

in combination with other mood stabilizers (Calabrese et al. 1999a, 1999b; Fogelson and Sternbach 1997; Koek and

Yerevanian 1998; Kotler and Matar 1998; Kusumakar and Yatham 1997a, 1997b). Case studies suggest that lamotrigine may

be effective in treating rapid cycling and mixed presentations of bipolar disorder (Fatemi et al. 1997; Kusumakar and

Yatham 1997a).

In a larger open trial (N = 75) involving bipolar patients, Calabrese and colleagues (1999b) found that 48% of patients in a

depressive episode had marked improvement in symptoms, while 20% had moderate improvement. In patients in a

hypomanic or manic state, 81% had marked improvement while taking lamotrigine. However, in controlled studies (whose

results are not yet published), lamotrigine has not proved effective for the treatment of mania.

There is some evidence that lamotrigine may also be effective in the treatment of bipolar depression. In a study by

Calabrese and colleagues (1999b), 175 patients with bipolar depression were randomized to either 200 mg of lamotrigine,

50 mg of lamotrigine, or placebo for 7 weeks. The authors found that lamotrigine was well tolerated and effective in 56% of

the high-dose and 48% of the lower-dose groups, resulting in a marked improvement in depressive symptoms, as measured

by Montgomery-Åsberg Depression Rating Scale scores. Only 29% of placebo-treated patients experienced the same marked

improvement. These improvements occurred in the first 3 weeks of treatment and continued for the length of the study (7

weeks). However, in a comparison with OFC (Symbyax), lamotrigine did not appear as effective in improving acute bipolar

depression (Brown et al. 2006). On the other hand, it was much better tolerated than OFC. In addition, augmenting mood

stabilizer–antidepressant combinations with lamotrigine also appeared to be of some benefit relative to adding either

risperidone or inositol in one STEP-BD analysis of refractory bipolar depression (Nierenberg et al. 2006b). Finally, as

reported earlier in this chapter, lamotrigine is also effective in delaying recurrence of depression and mania in bipolar

patients. Thus, lamotrigine became the second drug approved, in 2003, for the maintenance treatment of bipolar disorder.

In addition, lamotrigine is not associated with a significant switch to mania or hypomania.

In a crossover study of patients with refractory (mainly) rapid cycling, lamotrigine (52% response rate), but not gabapentin

(26% response rate), was more effective than placebo (23% response rate) in reducing symptoms (Frye et al. 2000).

Preliminary evidence suggests that, in addition to its potential use in treating bipolar disorder, lamotrigine may have a role

in treating related conditions. Case reports suggest that lamotrigine may be effective in cyclothymia, resistant unipolar

depression, schizoaffective disorder (Erfurth et al. 1998a, 1998b), and even BPD (Pinto and Akiskal 1998).

Side Effects

Lamotrigine, when dosed conservatively, appears to be generally well tolerated by most patients. In fact, compared with

other available approved maintenance treatments in bipolar disorder, lamotrigine is the least likely to be associated with

weight gain (Sachs et al. 2006) or cognitive side effects. However, a black box warning in the PDR indicates that lamotrigine

is associated with an increased risk of rash in up to 10% of patients. More concerning is the risk of serious skin reactions,

which occur in 1 in 1,000 adults and 1 in 100 children. These serious rashes, which include Stevens-Johnson syndrome, may

be fatal. Our general recommendation is that patients be well informed about the risk of rashes. We provide patients with a

list of antigen precautions. For example, in the first 3 months of treatment, we recommend avoiding new food or new

deodorants, detergents, cosmetics, fabric softeners, and so forth. Also, patients should be advised to avoid excessive sun

exposure early in treatment. Furthermore, anyone with a rash accompanied by systemic symptoms such as fever or

discomfort in the mouth, eye, or bladder should be instructed to discontinue the lamotrigine and go into the emergency

room for evaluation. Patients without systemic symptoms should be advised to see a dermatologist immediately. The risk of

rash appears to be increased when the dose of lamotrigine is titrated too rapidly or when lamotrigine is added to valproate,

which doubles the serum level of lamotrigine. In addition, patients who develop a rash while taking lamotrigine may well

have a recurrence of the rash when rechallenged with the drug (Buzan and Dubovsky 1998).

Common side effects include (in order of frequency) dizziness, headache, double vision, unsteadiness, sedation, and

uncomplicated rash. These symptoms occur in over 10% of treated patients, appear to be dose related, and may improve

over time. There have been reports that lamotrigine may, perhaps because of its serotonergic properties, decrease libido

and delay orgasm in both men and women. It is unclear if any of the antidotes regarding SSRIs reported in Chapter 3

(“Antidepressants”) will help with lamotrigine-induced sexual dysfunction. Weight gain appears less common with

lamotrigine than with lithium or valproate.

Overdoses can be serious and have been associated with the ingestion of 5 g or more of lamotrigine at one time. Symptoms

of overdose can include delirium, periorbital edema, generalized erythema, hepatitis, and renal failure (Briassoulis et al.

1998; Mylonakis et al. 1999). The management of overdose includes gastric lavage and supportive care.

Dosage and Administration

Lamotrigine is typically started at 25 mg/day for the first week, and the dosage is typically increased by 25–50 mg every 2

weeks. If the patient is currently taking valproate, the lamotrigine should be started at 12.5 mg/day and increased to 25

mg/day by the end of the third week. Thereafter, the dosage should be increased by no more than 12.5–25 mg every 2

weeks. Most of the bipolar disorder studies have had a target dosage of around 200 mg/day. We have certainly seen bipolar

and unipolar patients who appear to do well with dosages of 50–100 mg/day. However, maximum dosages for lamotrigine

may be as high as 500 mg/day.

No clear association between serum levels of lamotrigine and response exists. Thus, routine monitoring of serum levels is

not advised. However, in one small case series involving lamotrigine in treating schizoaffective disorder, serum levels

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Like all mood stabilizers, lamotrigine should be gradually tapered rather than abruptly discontinued if possible. Although no

discontinuation syndromes have been reported to date with lamotrigine, seizures are occasionally reported with the abrupt

discontinuation of any anticonvulsant.

Drug Interactions

As noted earlier, the primary interactions with lamotrigine are a doubling of serum levels with the addition of valproate and

a reduction of at least 25% of serum levels in conjunction with carbamazepine. Likewise, phenobarbital and primidone

decrease serum levels of lamotrigine by about 40%. Thus, higher doses of lamotrigine may be needed with carbamazepine,

primidone, and phenobarbital, while the dose of lamotrigine should be cut in half with concurrent valproate. In addition

lamotrigine appears to reduce serum levels of valproate by about 25%.

Valproate appears to increase lamotrigine levels; hence, the more conservative dosing strategy when a patient is taking it.

One report indicated that sertraline can substantially increase lamotrigine levels and lead to lamotrigine toxicity (Kaufman

and Gerner 1998). Sertraline’s inhibition of lamotrigine glucuronidation was suspected, and lamotrigine levels were

increased by 25% with just 25 mg of sertraline. At this time, it is advisable to adjust the starting and maintenance doses of

lamotrigine downward with concurrent use of sertraline.

Alcohol theoretically can exacerbate the sedation associated with lamotrigine. Interactions with over-the-counter drugs are

not known.

Use in Pregnancy

Lamotrigine is a category C teratogen. Animal studies suggest the possibility of fetal abnormalities, but human studies do

not exist. As with other agents, the known risks of discontinuing the drug for a pregnant patient should be assessed along

with the unknown risk of continuing taking it. At this time, most patients would be advised to discontinue the drug before

conception if possible.

Other Anticonvulsants

Several other anticonvulsants have become available in recent years that, as with valproate, carbamazepine, and

lamotrigine, are being explored in treating bipolar disorder and other psychiatric conditions (Table 5–5). Gabapentin has

been well studied in bipolar disorder and generally has been an ineffective albeit benign treatment. In addition, preliminary

studies have been done on oxcarbazepine, topiramate, and tiagabine in the treatment of bipolar disorder, with variable

results. In contrast, almost no data exist on the psychiatric benefits of anticonvulsants such as ethosuximide, levetiracetam,

and zonisamide at the time of this writing.

Table 5–5. New anticonvulsants

pregabalin

(Lyrica)

oxcarbazepine

(Trileptal)

gabapentin

(Neurontin)

lamotrigine

(Lamictal)

topiramate

(Topamax)

tiagabine (Gabitril)

Serum

plasma

level,

ng/mL

NA NA NA NA NA 1–234

Adult

dosage,

mg/day

150–600 600–2,400 900–2,400 (for

seizure

maintenance

treatment)

300–500 (for

seizure

maintenance

treatment)

200 (for bipolar

disorder

monotherapy)

100 (concurrently

with valproate for

bipolar disorder)

400 (concurrently

with

carbamazepine or

other

enzyme-inducing

drugs [and not

taking valproate]

for bipolar

disorder)

200–400(for

seizure

maintenance

treatment)

4–32

Protein

binding

— 40% bound Minimally

bound (<3%)

55% bound 20% bound 96% bound

Half-life,

hours

— 2–9 5–7 25–32 20–30 7–9Print: Chapter 5. Mood Stabilizers

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pregabalin

(Lyrica)

oxcarbazepine

(Trileptal)

gabapentin

(Neurontin)

lamotrigine

(Lamictal)

topiramate

(Topamax)

tiagabine (Gabitril)

Metabolic

pathway

— Hepatic CYP 3A

enzyme

Drug not

appreci-ably

metabolized

hepatically

Glucuronidation/

conjugation

20% metabolized

hepatically

Oxidation/glucuronidation

Routes of

elimination

— Renal (95%); fecal

(5%)

Renal Renal Renal Urinary (25%); fecal

(63%)

Common

drug

interactions

No significant

drug

interactions are

known; antacids

decrease

absorption and

bioavail-ability

of pregabalin

Induces metabolism

of CYP

3A3/4–dependent

drugs (weaker than

carbamazepine);

decreases levels of

phenobarbital,

phenytoin, sex

steroids, haloperidol,

valproic acid, calcium

channel blockers,

and others (see

Table 5–4)

No significant

drug

interactions are

known;

antacids

decrease

bioavailability of

gabapentin by

20%;

cimetidine

decreases renal

clearance by

13%

Valproate doubles

serum levels;

carbamazepine

decreases serum

levels by 50%;

phenytoin

decreases serum

levels by 50%

Phenobarbital

decreases serum

levels by 40%;

carbamazepine

decreases

topiramate levels

by 50%–60%;

valproate

decreases

topiramate levels

by 15%;phenytoin

decreases

topiramate levels

by 48%

Carbamazepine decreases

tiagabine levels; phenytoin

decreases tiagabine levels;

tiagabine decreases

valproate levels

Common

adverse

effects

Somnolence,

dizziness,

ataxia, fatigue

Dizziness,

drowsiness, ataxia,

weight gain

Somnolence,

dizziness,

fatigue, ataxia

Rash: 1 of

10(serious rashes,

such as

Stevens-Johnson

syndrome: 1 of

1,000), dizziness,

ataxia, nausea,

vomiting

Psychomotor

slowing,

decreased

concentration,

somnolence,

fatigue, anorexia,

kidney stone

formation

Dizziness, depression,

asthenia, nervousness,

tremors, somnolence,

cognitive deficits

Indication

(FDA

approved)

Partial seizures,

postherpetic

neuralgia

Partial complex

seizures

Partial seizures,

postherpetic

neuralgia

Partial seizures

Maintenance

treatment of

bipolar I disorder

Epilepsy Epilepsy

Note. CYP = cytochrome P450; FDA = U.S. Food and Drug Administration; NA = not applicable.

Source. Adapted for the most part from 2002 black book.

Gabapentin and Pregabalin

Gabapentin (Neurontin) was released in the United States in 1994 as an adjunctive treatment for focal seizures. In animal

models, gabapentin appeared to have anxiolytic properties and, as with other anticonvulsants, began to be examined in the

treatment of bipolar disorder. The mechanism of action for gabapentin appears to be via increasing GABA levels in the brain,

but the mode by which it accomplishes this increase is still not elucidated. Gabapentin, and its chemical cousin pregabalin,

have been more promising in the treatment of anxiety disorders than in the treatment of mood disorders. Both pregabalin

and gabapentin are known to bind to the 2- subunit of a voltage-gated calcium channel in the brain and spinal cord. The

result is to reduce the flow of calcium into the axon during depolarization and thus reduce neurotransmitter release from

that neuron. Pregabalin has been approved in the treatment of epilepsy and neuropathic pain and is under review for the

treatment of generalized anxiety disorder (GAD). The studies showing benefit of pregabalin in GAD appear compelling, and it

does not seem unlikely that pregabalin will ultimately be approved for this anxiety disorder.

Clinical indications

As with all the anticonvulsants used in psychiatry except divalproex sodium and lamotrigine, the only FDA-approved

indication for gabapentin and pregabalin had been adjunct treatment of patients with complex partial seizures. Both drugs

are approved for use in pain conditions.

Soon after its release, however, reports began to emerge that gabapentin might be useful for a variety of psychiatric and

nonpsychiatric conditions. Much of the psychiatric investigation of gabapentin over the past 7 years has focused on its role

in the treatment of bipolar disorder. The very benign side-effect and drug-interaction profiles of gabapentin made it a

potentially attractive alternative to other mood stabilizers. However, much of the data on gabapentin in bipolar disorder is

anecdotal, and more rigorous studies suggested that gabapentin has modest mood-stabilizing effects.

A number of open-label studies, most of which are small, suggest a modest role for gabapentin in bipolar disorder. These

studies suggest that gabapentin, typically in dosages of 900–2,700 mg/day, may help with bipolar depression, mixed states,

mania, and hypomania (Letterman and Markowitz 1999).

Data from double-blind studies are much more limited. One study at NIMH (Frye et al. 2000) examined the efficacy of

gabapentin in a small group of patients with treatment-resistant bipolar disorder; over 6 weeks, 26% of the patients takingPrint: Chapter 5. Mood Stabilizers

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gabapentin, compared with 23% of the patients receiving placebo, had a response. A more recent, unpublished multicenter

trial of gabapentin as an add-on to lithium or valproic acid done by Parke-Davis showed that gabapentin was no more

effective than placebo. Upward adjustment of the lithium dose in the placebo group may have obscured an effect for the

drug.

What one can draw from the gabapentin studies to date is that the mood-stabilizing effects of gabapentin are modest to

negligible. Gabapentin may help somewhat with the depressive and manic phases of bipolar disorder, and it tends to be well

tolerated. However, the use of gabapentin as a monotherapy for the treatment of mania or rapid cycling does not appear to

be justified.

The role of gabapentin in treating anxiety disorders may be greater than its role in treating bipolar disorder. Case reports

and double-blind studies support a possible role for gabapentin in anxiety disorders, particularly social phobia and panic

disorder. In a randomized, controlled trial, Pande and colleagues (1999) found that gabapentin, at dosages of 900–3,600

mg/day, was superior to placebo in the treatment of 69 patients with social phobia. However, the difference in response to

gabapentin relative to placebo, though statistically significant, was not dramatic. Still, gabapentin appears to be a

well-tolerated option for some patients with social anxiety disorder. Gabapentin may also prove to be a useful add-on for

patients getting only a partial response to antidepressants in the treatment of social phobia.

In contrast, pregabalin is fairly well studied in anxiety disorders but, on the basis of the experience of gabapentin, is not

being actively studied in bipolar disorder. Pregabalin at dosages ranging from 300 to 600 mg/day appear to be as effective

as a benzodiazepine in the treatment of GAD but without the risk of dependence (Frampton and Foster 2006). Pregabalin is

also being investigated in other anxiety disorders such as social anxiety disorder.

Another psychiatric use of gabapentin may be in the treatment of neuroleptic-induced movement disorders. Hardoy et al.

(1999) found that 14 of 16 patients with various mood disorders who had tardive dyskinesia improved with the addition of

gabapentin at dosages above 900 mg/day. Blepharospasms and oral mandibular dyskinesias appeared to improve with the

addition of gabapentin.

Finally, small case series suggest that gabapentin might help mitigate symptoms of withdrawal from cocaine and alcohol

(Chatterjee and Ringold 1999; Letterman and Markowitz 1999; Myrick et al. 1998).

Gabapentin is now commonly used in the treatment of neuropathic pain conditions. A number of studies, including several

double-blind studies, attest to the efficacy of gabapentin in improving pain associated with trigeminal neuralgia (Carrazana

and Schacter 1998), postherpetic neuralgia (Coleman and Stadel 1999; Rowbotham 1998), and diabetic neuropathy

(Backonja et al. 1998; Gorson et al. 1999; Morello et al. 1999). It has also been suggested that gabapentin is helpful in

migraine prophylaxis (D’Andrea et al. 1999; Lampl et al. 1999).

Side effects

Gabapentin and pregabalin are generally well tolerated. The most common side effects of both gabapentin and pregabalin

leading to discontinuation of the drug are somnolence and dizziness. The extent of these symptoms can be mitigated by

administering a larger percentage of the drug at night.

Other possible adverse effects associated with both gabapentin and pregabalin include ataxia, tremor, nausea, double

vision, and headache. Pregabalin may be associated with more weight gain than gabapentin. It is our experience that these

side effects tend to be dose related, mild, and manageable. If possible, a lower dose should be attempted before the drug is

discontinued. The headache often responds to nonsteroidal anti-inflammatory drugs and tends to improve with time.

Patients can gain weight while taking gabapentin, but, apparently, weight gain is much less than with most other potential

mood stabilizers. Sexual side effects appear to be uncommon.

Neither gabapentin nor pregabalin is appreciably metabolized by the liver, and both are excreted largely unchanged. Thus,

both drugs can be used by patients with advanced liver disease.

No completed suicides have been reported to date with gabapentin or pregabalin doses alone. Overdoses have not typically

been associated with significant adverse effects other than somnolence.

Drug interactions

No serious drug interactions have been reported with gabapentin or pregabalin. Neither gabapentin nor pregabalin appears

to inhibit cytochrome P450 enzymes to any degree and does not appear to alter the kinetics of lithium or additional

anticonvulsants. Antacids can reduce the bioavailability of gabapentin and pregabalin by 20%, so these agents should not be

taken simultaneously with gabapentin. Alcohol and other CNS depressants, theoretically, can increase the somnolence and

cognitive effects associated with gabapentin and pregabalin.

Use in pregnancy

Gabapentin and pregabalin are category C drugs, and their teratogenic effects in pregnancy have not been well studied. In

rats exposed to much higher relative doses than are typically used in patients, gabapentin appeared to inhibit bone

ossification in fetal pups. Neural tube defects do not appear to be common. As with all anticonvulsants, the risks of

discontinuing the gabapentin have to be weighed against the largely unknown risk of continuing to take the drug during

pregnancy. When possible, the gabapentin should be discontinued before conception or in the first trimester in most

patients until additional data are available on the safety of the drug in pregnancy.

Dosage and administration

Gabapentin is usually started at 300 mg at night. If tolerated, the dose can be increased to 300 mg bid the next day. ForPrint: Chapter 5. Mood Stabilizers

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some anxiety conditions, we start at 300 mg bid or tid. If the patient complains of excessive somnolence or dizziness, most

of the dose can be given at night to a maximum dose of 1,200 mg taken at one time. Doses higher than 1,200 mg at one time

are not well absorbed. To maximize compliance, we suggest sticking with bid dosing up to 1,200 mg bid. Thereafter, tid

dosing will be necessary up to dosages of 3,600 mg/day. Some patients do quite well at dosages in the range of 900 to

2,400 mg/day. For patients being treated for pain, the dosage is often titrated up to as high as 3,600 mg/day.

Pregabalin is usually started at a dosage of 100–150 mg/day in divided doses, and it is increased to a maximum dosage of

600 mg/day in divided doses (bid or tid regimen). The target dosage of 300–600 mg/day is the same for GAD as it is for

epilepsy. Patients with postherpetic neuralgia and neuropathic pain associated with diabetes often benefit from 150-300

mg/day.

Topiramate

Topiramate was FDA approved in 1998 and has the unique property among potential mood stabilizers of being associated

with weight loss rather than weight gain in 20%–50% of patients on the drug. A few preliminary reports suggest that

topiramate may have mood-stabilizing effects as an adjunctive therapy in bipolar disorder, cyclothymia, and schizoaffective

disorder (Gordon and Price 1999; Stephen et al. 1998). Unfortunately, none of the four double-blind trials conducted showed

any benefit of topiramate in the treatment of mania, mixed states, or any other aspect of bipolar disorder (Kushner et al.

2006). Open trials and case series have suggested that the addition of topiramate to a standard mood stabilizer might help

in the treatment of rapid cycling and comorbid alcohol abuse and comorbid aggression in bipolar patients. Topiramate may

also help with substance abuse problems independent of bipolar disorder.

Perhaps the most common use of topiramate in current clinical practice is as an anorexiant to mitigate weight gain

associated with other mood-stabilizing agents such as olanzapine. In one prospective study, the addition of topiramate to

olanzapine for 1 year seems to have mitigated the expected weight gain from olanzapine (Vieta et al. 2004). Another

controlled trial has suggested that patients with bipolar disorder and concurrent binge eating disorder benefit from the

addition of topiramate to lithium (Kotwal et al. 2006). Even in nonpsychiatric patients, topiramate seems to promote weight

loss in many patients. Weight loss of up to 25 kg in 6 months has been reported in patients who started topiramate in

addition to their mood stabilizer. In our experience, 50 mg/day is often an optimal dosage of topiramate to help with weight

loss.

The most common side effects of topiramate are somnolence, paresthesias, dizziness, vision problems, anorexia, and

cognitive problems. The cognitive side effects are the most troublesome, with some patients reporting dullness or memory

problems. These effects generally occur at dosages greater than 100 mg/day, but we have seen them persist in an older

patient even with dosage reduction to 25 mg/day. The side effects of the drug will remit in such cases with cessation.

Discontinuation of topiramate occurs most commonly secondary to psychomotor slowing, memory problems, fatigue, and

sedation. There is an increased risk of kidney stone formation with topiramate, particularly when the patient is on a

ketogenic diet and/or taking a carbonic anhydrase inhibitor. Patients should be instructed to drink plenty of water.

Hyperchloremic metabolic acidosis is also a theoretical side effect that we have not observed. The risk of developing this

condition may be enhanced by concomitant use of carbonic anhydrase inhibitors (e.g., acetazolamide), renal disease,

diarrhea, and so forth. Monitoring of serum bicarbonate during topiramate treatment is recommended.

Drugs with which topiramate interacts include carbamazepine and valproate, which reduce topiramate blood levels by 50%

and 15%, respectively. Conversely, topiramate can lower valproate levels by about 15%. Alcohol appears to potentiate the

somnolence and ataxia associated with topiramate.

Topiramate is usually initiated at a dosage of 12.5–25 mg/day, and the dosage is usually increased by 25 mg per week.

Dosages as low as 50 mg/day have anecdotally been added to standard mood stabilizers or olanzapine to counteract weight

gain associated with these agents. We have found this to be a helpful strategy at 50–150 mg/day. For mood effects, the

average dosages have been 100–200 mg/day given in divided doses. The usual maximum dosage of topiramate is 400

mg/day.

Tiagabine

Tiagabine was FDA approved for the treatment of epilepsy in 1998 and appears to work by increasing GABA levels. It

appears to have anxiolytic properties in animal models. In one small case series, the addition of tiagabine appeared to help

three patients with treatment-resistant bipolar disorder (Kaufman and Gerner 1998). In another open study of acute mania,

tiagabine was rapidly loaded and was found to be ineffective and poorly tolerated (Grunze et al. 1999b). In this small series,

one patient had a seizure that was probably related to the higher starting dose of tiagabine. Likewise, in an open case series

of tiagabine in refractory bipolar disorder, tiagabine was poorly tolerated and not particularly effective (Suppes et al. 2002).

At this time, there does not appear to be much evidence supporting the utility of tiagabine in either acute treatment of manic

symptoms or maintenance treatment of bipolar disorder (Young et al. 2006a, 2006b).

Common side effects of tiagabine include dose-related somnolence, dizziness, syncope, and nausea.

Tiagabine is usually started at a dosage of 4 mg/day, and the dosage is increased by 4–8 mg per week. The maximum

dosage of tiagabine is 56 mg/day given in two to four divided doses.

Oxcarbazepine

Another anticonvulsant, introduced to the United States in 2000, is oxcarbazepine (Trileptal). Oxcarbazepine has been used

in Europe for many years, and its use in treating bipolar disorder dates at least to the early 1980s. However, few studies

have examined the efficacy of oxcarbazepine in bipolar disorder. Controlled studies in pediatric bipolar populations have notPrint: Chapter 5. Mood Stabilizers

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found oxcarbazepine particularly efficacious (MacMillan et al. 2006; Wagner et al. 2006). The few small studies and case

reports available suggest that oxcarbazepine is effective as an add-on therapy in the treatment of acute mania and perhaps

other aspects of bipolar disorder (Emrich 1990; Pratoomsri et al. 2006). We have used oxcarbazepine in treating bipolar

patients who could not tolerate carbamazepine or with whom we were concerned about drug interactions. As with

carbamazepine, we have sometimes used oxcarbazepine to treat agitation.

The primary advantages of oxcarbazepine over its chemical analog, carbamazepine, are that it is better tolerated, does not

tend to autoinduce its own metabolism, and has somewhat less significant drug interactions. Importantly, oxcarbazepine

has not had the tendency to induce blood dyscrasias, such as aplastic anemia, that are occasionally reported with

carbamazepine.

Oxcarbazepine is often a milder inducer of the cytochrome 3A3/4 enzyme compared with carbamazepine. Still,

oxcarbazepine can render oral contraceptives less effective and reduce serum levels of valproate, phenytoin, and other

drugs. Thus, it is important to advise patients who are taking oral contraceptives that they may need to switch to a

higher-potency oral contraceptive or to supplement the pill with a barrier method.

The major disadvantage of oxcarbazepine is cost. Generic carbamazepine is inexpensive. Oxcarbazepine is not.

Oxcarbazepine is usually started at around 300 mg bid, and the dosage is increased gradually up to 2,400 mg/day. Our

experience is that the dosages of oxcarbazepine required to treat psychiatric symptoms are about 50% higher than those for

carbamazepine.

Levetiracetam, Zonisamide, and Ethosuximide

With the sudden availability of many anticonvulsants on the market, there has been an interest in the potential role of these

newer agents in bipolar and other psychiatric disorders. Levetiracetam is a rather benign anticonvulsant with a good

side-effect profile. At the highest doses, some patients experience somnolence and fatigue, but levetiracetam appears to be

fairly weight neutral and has not been associated with much in the way of cognitive or sexual side effects. Dosages of 500

mg bid to 1,500 mg bid have been said to be effective in a few case reports and a small open study in the treatment of mania

and depression with few side effects (Post et al. 2005). However, there is no convincing evidence of the drug’s utility in

bipolar disorder at this time, and our limited clinical experience with the drug has not been consistent with robust benefits.

Likewise, zonisamide at dosages of 100-600 mg/day has been reported to improve manic and depressive symptoms as an

adjunctive treatment (Ghaemi et al. 2006b). However, zonisamide has also been associated with worsening mood symptoms

in some some patients (McElroy et al. 2005). We have also found that zonisamide 200-400 mg/day, like topiramate, can

facilitate weight loss in bipolar patients. Ethosuximide might also have a role as an anorexiant, but its role in bipolar

disorder has not been evaluated. None of these anticonvulsants can be justified as a monotherapy in the treatment of any

phase of bipolar disorder at this time, but they may have a role as an adjunctive treatment in some bipolar patients.

ANTIPSYCHOTICS

Antipsychotic drugs have long been recognized as important agents in treating acute mania (see Chapter 4: “Antipsychotic

Drugs”). Chlorpromazine was the second drug approved for acute mania after lithium. Since all the standard mood

stabilizers (lithium, valproate, carbamazepine) require monitoring, have slow onsets of action, and are not as helpful during

the depressed phase of the illness, the atypical antipsychotics are becoming more commonly used as “mood stabilizers.” In

fact, much of the use of atypical antipsychotics is already in the treatment of mood disorders. Olanzapine has more FDA

indications in the treatment of bipolar disorder than does lithium. Olanzapine has long been approved for acute mania and

was more recently approved for use in the maintenance treatment of bipolar and the acute treatment of bipolar depression

(in combination with fluoxetine). Compared with lithium and carbamazepine, antipsychotics tend to work more rapidly in

controlling the excitement, agitation, thought disorder, and psychosis that may accompany acute mania. However, even in

contexts in which psychotic symptoms are not present, the antipsychotics work at least as well as lithium in acute mania

and perhaps even better. Like olanzapine, the other atypicals are also proving to be more versatile than agents such as

lithium and valproate in treating different aspects of bipolar disorder.

Olanzapine was FDA approved for the treatment of acute mania in 2000 and, in 2003, for maintenance therapy. For several

years, there were case reports suggesting that olanzapine is effective in mixed states (Ketter et al. 1998; Zullino and

Baumann 1999), bipolar depression (Weisler et al. 1997), and acute mania (Ravindran et al. 1997). A pivotal double-blind

study of 139 manic bipolar patients indicated that 48% of patients responded to olanzapine, whereas only half that number

responded to placebo (Tohen et al. 1999). Olanzapine was well tolerated in these patients. There are now multiple positive

trials of olanzapine in acute mania. There are two comparison trials with valproate in acute mania (Tohen et al. 2003a;

Zajecka et al. 2002). In both, olanzapine produced better efficacy, although in only the larger study (Tohen et al. 2003a) did

the difference reach statistical significance. Olanzapine appeared to produce more side effects. Sporadic reports suggest

that olanzapine may induce hypomania or mania in some patients (Lindenmayer and Klebanov 1998; Reeves et al. 1998).

However, it has become evident that olanzapine and other atypicals probably do not result in switching to mania commonly

and have a role to play in the long-term maintenance of bipolar disorder. Olanzapine alone also appears to do better than

placebo in treating bipolar depression, but the combination with fluoxetine is even more effective (Tohen et al. 2003b).

However, the combination of olanzapine and an SSRI is more effective than olanzapine alone (see Chapter 9, “Augmentation

Strategies for Treatment-Resistant Disorders”).

All of the current atypical antipsychotic agents except clozapine now have at least two double-blind studies (e.g., Keck et al.

2003a, 2003b) that indicate the drugs are effective in the treatment of acute mania. Quetiapine, ziprasidone, risperidone,

and aripiprazole are all approved for the treatment of acute mania. While olanzapine appears to be effective in delaying the

time to a new mood episode in bipolar I patients, some patients will not tolerate chronic treatment with olanzapine. WeightPrint: Chapter 5. Mood Stabilizers

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gain or metabolic concerns will be an issue for some patients. Aripiprazole has also demonstrated efficacy in the

maintenance treatment of bipolar disorder and is an alternative to olanzapine for some patients. In addition the atypicals

have proved helpful in the treatment of acute bipolar depression.

Olanzapine was first approved in combination with fluoxetine for the treatment of bipolar depression, and in 2006,

quetiapine also obtained approval as a monotherapy for the treatment of acute bipolar depression. Both ziprasidone and

aripiprazole continue to be explored in the treatment of bipolar depression, and it would not be particularly surprising if

both of these drugs prove equal to quetiapine and olanzapine in this regard. Likewise, virtually all of the atypicals are being

investigated in the maintenance treatment of bipolar disorder. It is evident that the atypical antipsychotics will play an

increasingly large role in the treatment of bipolar disorder relative to the anticonvulsants or other classes of agents.

Although clozapine is the only atypical without pivotal trials in bipolar disorder, it should be considered in the treatment of

some bipolar patients. Clozapine appears to be effective in the treatment of patients with more refractory bipolar disorder,

including the rapid-cycling subtype and bipolar disorder accompanied by psychosis (Green et al. 2000; Kimmel et al. 1994;

Suppes et al. 1994). The toxicity of clozapine relegates it to use as a third-line treatment when standard agents have failed.

BENZODIAZEPINES

Several benzodiazepines, chiefly clonazepam and lorazepam, have been reported to be useful in the treatment of acute

mania. It was initially believed that clonazepam might have antimanic properties unique among the benzodiazepines.

However, it has become increasingly clear that this is probably not the case. All the benzodiazepines appear to have a role in

treating the hyperkinesis, agitation, and insomnia associated with acute mania. Chouinard and associates in Montreal have

done much of the relevant work with clonazepam in mania (see, e.g., Chouinard et al. 1983). Reports suggested that

clonazepam might be useful as an adjunct to lithium or neuroleptics in the treatment of acute mania. However, Bradwejn

and colleagues (1990) found that clonazepam did not appear to be efficacious in the treatment of acute mania and was

inferior to lorazepam in this regard. Salzman and colleagues (1991) reported that lorazepam 2 mg im was as effective in

reducing aggression and agitation in psychotic patients as haloperidol 5 mg im. Lorazepam’s effects appeared to be

independent of its sedative properties. Lorazepam was better tolerated than was haloperidol. No evidence up to this time

has supported the use of a benzodiazepine alone for the maintenance treatment of bipolar disorder. The one study that used

clonazepam alone for prophylaxis was stopped early because all the enrolled subjects had relapsed within 3 months while

taking the medication.

Experience with clonazepam in the treatment of acute mania has been that it tends to lead to sedated manic patients whose

mania is unchanged when the sedation wears off. We have not been impressed with the antimanic versus sedating

properties of clonazepam. When a bipolar patient requires an agent for sleep, anxiety, or catatonia, clonazepam or the other

benzodiazepines should be considered. Clonazepam was among the most expensive benzodiazepines, and its only advantage

over agents like lorazepam may be its long half-life.

The dosages of clonazepam typically employed are 1–6 mg/day, although much higher dosages were used in the original

studies. Lorazepam dosages are similar, ranging from 1.5 to 8 mg/day.

The side effects of clonazepam and lorazepam are those of all current benzodiazepines: sedation, ataxia, and

malcoordination. With any sedative drug, in rare cases patients become disinhibited and agitated. Patients with a history of

attention-deficit/hyperactivity disorder in childhood may be at particular risk for sedative-induced angry agitation. We have

seen occasional bipolar patients who reported feeling more angry after taking clonazepam. No prospective data on this

potential side effect are available.

CALCIUM CHANNEL BLOCKERS

The calcium channel blockers, which include verapamil, nifedipine, diltiazem, and a number of newer agents, are used

primarily in the treatment of hypertension, angina, and supraventricular arrhythmias. Dysregulation of intracellular calcium

may be involved in some affective disorders, and this notion prompted Dubovsky and colleagues to begin studying the

efficacy of calcium channel blockers in treating bipolar patients (Dubovsky et al. 1982). Since then, a number of studies

have suggested that calcium channel blockers may have antimanic properties. Most of these studies were uncontrolled and

small, and interpretation of their findings was complicated by other drug use.

There is no evidence that patients whose condition is resistant to lithium or the anticonvulsants are any more likely to

respond to the calcium channel antagonists. On the contrary, patients who are unresponsive to the standard agents appear

likely to be unresponsive to calcium channel agents as well. There may, however, be instances in which the calcium channel

blockers are worth considering in the treatment of a bipolar patient. For example, bipolar patients with cardiovascular

problems (such as supraventricular arrhythmias and hypertension) that may be helped by a calcium channel blocker might

be assessed for antimanic effect while taking these drugs to determine whether they could be substituted for standard

mood-stabilizing agents. Likewise, a calcium channel blocker may be worth trying with a pregnant bipolar patient, because

the teratogenic risk of this category of drugs appears to be substantially lower than that of any of the standard agents. The

most common side effects of the calcium channel blockers are dizziness, headache, and nausea.

More serious side effects, which are rare, include malignant arrhythmias, hepatotoxicity, and severe hypotension and

syncope. The calcium channel blockers can produce orthostasis in elderly patients and may have an additive hypotensive

effect when used with other antihypertensive drugs. At high doses, anergy and somnolence are sometimes reported.

Dosing for the calcium channel blockers in treating bipolar illness is not well defined. Most investigators have used the

typical doses used for cardiovascular indications. Verapamil has been the most studied agent in its class. The usual starting

dosage in treating hypertension is 80 mg bid or tid, up to a maximum dosage of 480 mg/day. An alternative strategy is to

start with a half or a full 240-mg slow-release tablet and titrate the dosage upward to the maximum dosage as tolerated. ItPrint: Chapter 5. Mood Stabilizers

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is important to monitor blood pressure and pulse regularly as the dose is being titrated. Given the risk of arrhythmias, a

baseline ECG is also advised. Blood levels have never been correlated with efficacy or toxicity for any indication of a calcium

channel antagonist. Some investigators believe that the novel biochemical profile of nimodipine and other dihydropyridines

may confer greater brain penetrance and more efficacy in the treatment of bipolar disorder. Controlled trials are currently

under way.

Although combining the standard mood stabilizers is supported by the literature in difficult cases of bipolar illness, there is

no substantial evidence that adding a calcium channel blocker to lithium or other agents is advantageous. In fact, there are

reports of enhanced neurotoxicity when verapamil was added to lithium and carbamazepine. In general, it appears prudent

to avoid these combinations until we better understand the risks and benefits.

OMEGA-3 FATTY ACIDS

Omega-3 and omega-6 fatty acids are the building blocks of fats in the same way that amino acids are the building blocks of

proteins. A number of reports over the past 13 years suggest that affective illness may be associated with deficiencies of

some omega-3 fatty acids. For example, there appears to be some correlation between a higher ratio of arachidonic acid to

eicosapentaenoic acid (EPA) in more severely depressed patients than in less severely depressed patients. Other studies

have suggested that there may be lower levels of omega-3 fatty acids in the membranes of red blood cells in depressed

patients than in healthy control subjects. Furthermore, there is limited evidence suggesting that omega-3 fatty acids may

impact signal transduction in a manner analogous to the way lithium affects it. The lower rates of depression in some Asian

countries may be due to greater amounts of fish consumed in regular diets.

A double-blind study reported that adding supplemental omega-3 fatty acids to the drug regimens of bipolar patients

improved their outcomes (Stoll et al. 1999). In this study, 30 bipolar patients were randomized to either 9.6 g/day of

omega-3 supplements or olive oil (as a control) for 4 months. They continued taking standard mood stabilizers. The patients

treated with omega-3 experienced longer remission and more complete resolution of symptoms than the placebo-treated

patients.

Since the Stoll study, there have been several controlled trials of omega-3 fatty acids in the treatment of depression and

bipolar disorder. The data supporting the efficacy of omega-3 fatty acids in the treatment of bipolar disorder have been

mixed. For example, two other controlled trials of omega fatty acids (up to 6 g/day of EPA) in bipolar disorder failed to show

benefit (Keck et al. 2006; Post et al. 2003). Likewise, in unipolar depression, the data on omega-3 fatty acids are also

unclear. For example, some studies of omega-3 fatty acids in perinatal depression (Freeman et al. 2006) and pediatric

depression (Nemets et al. 2006) have suggested benefits, whereas other controlled studies have failed to show any

advantage of supplementing omega-3 fatty acids in adult depressed patients (Marangell et al. 2003). Most studies have used

1–6 mg/day of EPA, while others have used DHA. A few reports mentioned use of the combination of EPA and DHA.

The role of omega-3 fatty acid supplements in the treatment of affective illness remains uncertain. Studies thus far suggest

a more reliable effect of omega-3 fatty acids in some forms of unipolar depression than in bipolar maintenance. However,

the correct dose, duration of treatment, and form of omega-3 fatty acids remain to be established. Since these fatty acids are

fairly benign and may have other health benefits, some clinicians are supplementing the mood-stabilizing or antidepressant

regimens with omega-3 fatty acids. The most commonly reported side effects are belching and a fishy aftertaste. We do not

discourage patients from taking omega-3 fatty acids as we do many supplements. However, with the limited evidence

supporting their use, the routine prescription of any supplement does not appear warranted.

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