Chapter 9 Augmentation Strategies for Treatment-Resistant Disorders

Print: Chapter 9. Augmentation Strategies for Treatment-Resistant Dis… http://www.psychiatryonline.com/popup.aspx?aID=238341&print=yes…

1 of 29

31/01/2009 06:54

Print Close Window

DOI: 10.1176/appi.books.9781585622825.238338

Manual of Clinical Psychopharmacology >

Chapter 9. Augmentation Strategies for Treatment-Resistant Disorders

INTRODUCTION

It is the general hope of all clinicians that patients will respond to a single therapeutic agent.

However, such a response may be the exception rather than the rule. Although for a long time there

was much warranted consternation regarding polypharmacy (patients receiving too many different

types of medications), many patients do require simultaneous treatment with different classes of

drugs to achieve an adequate response. There are a number of reasons for combining medications.

Among the most common is to augment the effect of one agent—for example, lithium is combined

with an antidepressant to enhance antidepressant effect, or two mood stabilizers are combined to

reduce breakthrough mania. A second common reason for combining medications is to treat one

aspect of the illness—for example, an antidepressant is added to a mood stabilizer to treat a

depressive cycle of bipolar illness. Medications are also commonly combined to reduce side effects

of particular agents—for example, antiparkinsonian drugs are added to standard antipsychotics.

Finally, medications are combined to target specific symptoms, such as residual fatigue in a

depressed patient, or to bring out an expected response to an agent.

Unfortunately, research on combination treatments has lagged behind research on monotherapy.

For many years, neither the pharmaceutical industry nor the National Institute of Mental Health

(NIMH) had been particularly motivated to study the effects of medication combinations, except for

adverse effects. However, recently, pharmaceutical companies have pursued approval for

combination strategies. The NIMH has funded several large effectiveness trials, such as Sequenced

Treatment Alternatives for Resistant Depression (STAR*D) in major depression and the Systematic

Treatment Enhancement Program for Bipolar Disorder (STEP-BD), that have provided some

important information regarding optimal combination strategies. However, the conclusions that can

be drawn from these studies are limited by the lack of placebo arms and the tendency of open-label

(often nonrandomized) comparison studies to yield similar results across treatment groups. In

addition, these studies tend to not employ much clinical judgment; rather, they randomly assign

patients to different augmenting strategies regardless of symptom profile or other historical

diagnoses. Until more is learned about the biochemistry of various disorders and the range of

pharmacological effects of available and future medications, clinicians will constantly be faced with

using more than one agent to effect a positive response in individual patients.

Obviously, the number of potential combinations is vast, and consideration of all of them is beyond

the scope of our discussion in this chapter. Instead, we focus on combinations of agents used in

augmentation (Table 9–1) (medications used to counteract side effects have been discussed in the

previous chapters). We recommend that clinicians become familiar with a number of commonly

used combination drugs or combination regimens that have been reported in recent years to be

particularly effective in specific clinical situations. In addition, clinicians should become familiar

with combinations that can pose difficulties because of drug-drug interactions or additive side

effects.

Table 9–1. Potential augmenting agents for antidepressants

Antidepressant Augmenting agent

Tricyclics/tetracyclics lithium

thyroid supplements

amphetamines

SSRIsPrint: Chapter 9. Augmentation Strategies for Treatment-Resistant Dis… http://www.psychiatryonline.com/popup.aspx?aID=238341&print=yes…

2 of 29

31/01/2009 06:54

Antidepressant Augmenting agent

monoamine precursors

MAOIs

SSRIs lithium

thyroid supplements

TCAs

trazodone

buspirone

pindolol

modafinil

stimulants

atomoxetine/reboxetine

atypical antipsychotics

pramipexole/ropinirole

mirtazapine

bupropion

MAOIs lithium

thyroid supplements

TCAs

Note. SSRI = selective serotonin reuptake inhibitor; MAOI = monoamine oxidase inhibitor; TCA = tricyclic

antidepressant.

AUGMENTATION STRATEGIES FOR DEPRESSION

Lithium-Antidepressant Combinations

Lithium is the best-studied augmenter to antidepressants in patients with treatment-resistant

depression. However, this is different from saying lithium is the best augmenter or the strategy

that should be used before others are attempted. Lithium can be cumbersome to use, requiring

careful titration and serum level monitoring, and can be lethal in overdose. An ever-growing

number of augmentation strategies have been proposed, but lithium remains an important option

for treatment-resistant depression.

Lithium has been well studied in its own right as an antidepressant. Overall, the drug is effective in

some 50% of patients, with suggestions that it is best used in treating males with bipolar

depression (see Chapter 3: “Antidepressants,” and Chapter 5: “Mood Stabilizers”). de Montigny et

1. (1981) reported that the addition of lithium to a tricyclic antidepressant (TCA) trial resulted in

clinical improvement within 72 hours in patients who did not have a response to a TCA alone.

Before 1986, studies of lithium augmentation, which were typically open-label studies, suggested

that the response rate to lithium augmentation of TCAs was as high as 75%. More recent,

placebo-controlled studies have not typically confirmed this rapid clinical improvement or the more

robust response rate. They have, however, demonstrated that the addition of lithium is more

effective than is placebo. Although approximately one in four patients responds to lithium

augmentation within 1 week, the most robust responses have typically required 3 weeks or more.

Response often occurs at low dosages (600–1,200 mg/day) and at relatively low serum levels.

Current data suggest that serum levels in the range of 0.5 to 0.8 mEq/L are effective in lithium

augmentation of antidepressant effects (Bauer and Dopfmer 1999). The mechanism of action has

been hypothesized as a potentiation of serotonergic activity, via either increased biosynthesis or

receptor adaptation. Our experience with the combination has generally been favorable, and we

have been particularly impressed with results obtained in depressed patients with pronounced

obsessionality and agitation. However, there are no controlled trial data to support the clinical

impression. Price et al. (1983) reported that lithium also elicited a response in patients with

delusional depression who had not responded to the combination of amitriptyline and

perphenazine.Print: Chapter 9. Augmentation Strategies for Treatment-Resistant Dis… http://www.psychiatryonline.com/popup.aspx?aID=238341&print=yes…

3 of 29

31/01/2009 06:54

Lithium also appears to augment responses to other antidepressants. For example, patients with

bipolar depression with hypersomnia and hyperphagia (formerly termed “atypical”) may respond

dramatically to the combination of lithium and the monoamine oxidase inhibitor (MAOI)

tranylcypromine. In an open-label study, Price et al. (1985) found that 11 of 12 patients with

treatment-resistant depression responded to the combination of lithium and tranylcypromine. Many

of these patients had not had a response to lithium-TCA combinations. In a New Haven follow-up

study, patients with unipolar depression who were treated with desipramine plus lithium remained

euthymic in the community for much longer periods when not taking medication than did patients

who improved while taking desipramine plus placebo (Nierenberg et al. 1990).

A number of studies have confirmed the efficacy of lithium augmentation of selective serotonin

reuptake inhibitors (SSRIs). In an early report, Pope et al. (1988) found that lithium appeared to

augment the antidepressant effects of fluoxetine. More recent, double-blind studies have confirmed

this finding (Fava et al. 1994; Katona et al. 1995). Some evidence suggests that lithium may do a

better job augmenting SSRIs than augmenting TCAs. In a double-blind study, lithium more

effectively boosted the antidepressant actions of paroxetine than it did amitriptyline, and these

effects were seen as early as 2 weeks and continued for the 6 weeks of the study (Bauer et al.

1999). In the STAR*D trial, lithium augmentation was compared with addition of L-triiodothyronine

(T3) in patients who did not respond to two previous medication trials (Nierenberg et al. 2006a). At

this level (3) of the STAR*D protocol, patients received augmentation with a variety of

antidepressants that could include citalopram, venlafaxine, bupropion, and setraline. Both

augmenting strategies had modest, statistically equal efficacy, but lithium was much more poorly

tolerated than was T3. About 16% of the group receiving lithium augmentation achieved a

remission versus about 25% of the group receiving T3 augmentation. As with lithium augmentation

of TCA response, the maximum potentiation of SSRI response appears to require adequate lithium

serum levels and may require trials of 4 weeks or longer. (For further discussion of maintenance

treatment, see Chapter 3.) Overall, we would expect about 50% of patients who did not have a

response to a TCA or an SSRI to have a response after the addition of lithium.

There are probably certain characteristics in depressed patients that predict response to the

addition of lithium to their antidepressant regimen. Depressed patients may be more likely to

improve with lithium augmentation if they exhibit significant psychomotor retardation, have

significant anorexia and weight loss, and have low serum cortisol levels (Alvarez et al. 1997).

If lithium is to be added, it should be initiated at 300 mg bid for 2 days, and the dosage should be

increased to 900 mg/day for 3–4 days, with a further increase to 1,200 mg/day for 10–14 days. A

serum level of at least 0.5 mEq/L should be achieved. If there is no response, then the dose should

be gradually increased as tolerated to a serum level of 1.2 mEq/L. Given that there is probably a

bimodal distribution to response, with some patients responding within the first 2 weeks and

others requiring a month or more to achieve response (Thase et al. 1998), we tend to not regard a

lithium augmentation trial as failed until serum levels greater than 0.5 mEq/L are obtained for at

least 6 weeks, and we would prefer a level of 0.6 mEq/L or more.

Thyroid Supplement–Antidepressant Combinations

A number of years ago a debate emerged in the literature regarding whether thyroid preparations

(e.g., thyroxine [T4] and T3) prescribed with a TCA hastened the onset of the antidepressant effect.

Early studies in women suggested that it did, although subsequent studies in men, which also

employed higher dosages of TCAs, failed to substantiate the earlier finding. Then a fallow period

followed for this combination until 1982, when Goodwin et al. reported that the addition of 25–50

g/day of T3 (Cytomel) elicited within 7 days a clinical response in patients who had previously not

had a response to a seemingly adequate TCA trial. A number of subsequent clinical reports have

confirmed this observation, although some clinicians have reported responses requiring 14 days or

more of combined therapy. In a trial by R. T. Joffe et al. (1993), T3 augmentation of TCAs appeared

to be as effective as lithium, and both were significantly more effective than placebo. A subsequent

head-to-head crossover trial also suggested that patients receiving T3 augmentation were morePrint: Chapter 9. Augmentation Strategies for Treatment-Resistant Dis… http://www.psychiatryonline.com/popup.aspx?aID=238341&print=yes…

4 of 29

31/01/2009 06:54

likely to respond than were lithium-treated patients (Spoov and Lahdelma 1998). Statistical

equivalence of T3 augmentation to lithium augmentation was found in the STAR*D study reviewed

in the previous section (Nierenberg et al. 2006a). If thyroid and lithium augmentation are both

helpful in resistant depression, perhaps combining both lithium and thyroid with an antidepressant

would have additive effects. Unfortunately, a study by Joffe and colleagues (2006) did not find that

combining lithium with thyroid hormone had any advantages over either one alone.

Thyroid augmentation of MAOIs has been less well studied than that of TCAs. The response to

thyroid supplementation of MAOIs also appears to be somewhat less consistent than for other

antidepressants. Nonetheless, the combination of T3 and an MAOI appears to be well tolerated and

may be considered if lithium augmentation is not successful.

Several case reports have suggested that thyroid augmentation of the SSRIs may also be effective.

For example, R. T. Joffe (1992) found that Cytomel (T3) at 25–50 g/mL/day when added to

fluoxetine enhanced the antidepressant effects of the drug and was well tolerated. A number of

other case reports suggested that thyroid supplements may potentiate SSRI antidepressant effects

(Crowe et al. 1990; Gupta et al. 1991).

The data suggest that thyroid supplementation may be effective in combination with a wide

spectrum of antidepressants. However, good studies are lacking, and the available studies have

shown mixed results.

The mechanism of action of T3 potentiation of antidepressants is undetermined. Generally, theories

have revolved around the role of T3 in facilitating adrenergic receptor adaptation. However, Targum

et al. (1984) reported that patients who had a response to T3 demonstrated relatively enhanced

thyroid-stimulating hormone (TSH) responses to thyrotropin-releasing hormone (TRH) infusions,

suggesting that a subtle form of thyroid dysfunction might play a role in these patients’ condition.

Targum et al. suggested that patients with refractory depression who have a normal TSH but a

blunted response to the TRH stimulation test may be good candidates for thyroid augmentation.

Clinicians frequently ask whether T4 (Synthroid) is as effective as T3 in augmenting response to

TCAs. T4 is metabolized to T3 in humans. One double-blind study comparing 2-week treatments of

T4 and T3 indicated that T3 is significantly more effective. However, because T4 has a much longer

half-life, the patients may not have achieved steady state on T4, leaving the conclusions of the

study open to question (R. T. Joffe and Singer 1987). Possible explanations of the greater

effectiveness of T3 in some patients include difficulty in converting T4 to T3 or in transporting

thyroid into the brain. Recent data suggest that depressed patients may demonstrate decreased

cerebrospinal fluid levels of thyroid transport protein, which would limit the effect of T4 on the

brain. Clinically, we have seen a number of patients who did not respond to an antidepressant in

combination with T4 who did have a response when T3 was substituted. In addition, an occasional

patient benefits from high-dose T4 added to his or her antidepressant regimen. Arthur Prange’s

group (Bunevicius et al. 1999) has reported that in patients with thyroid disease who were treated

with T4, the addition of T3 improved both mood and cognition, suggesting that individuals could

have relative T3 deficiencies in brain. An open-label trial using T4 at an average of 482 g/day for 8

weeks found that more than 50% of the patients in a treatment-resistant population had a robust

response (Bauer et al. 1998). Although side effects were not common in this trial, the use of

supraphysiological doses of T4 for an extended time might be problematic for some patients.

Which patients appear to be the best candidates for thyroid augmentation? Clearly, patients who

have any evidence of thyroid abnormalities, including subclinical hypothyroidism, appear to be

good candidates. There is growing evidence that patients with mild thyroid abnormalities (slightly

elevated TSH, normal T3 and T4) are less likely to respond to antidepressants alone but respond to

the addition of a thyroid supplement (Sokolov et al. 1997). Women over the age of 50, perhaps

because they are most susceptible to hypothyroidism, also appear to have high responses to

thyroid augmentation. Overall, it is our impression that Cytomel (T3) is useful in patients with

pronounced psychomotor retardation. Cytomel may be experienced as energizing and may actually

help with weight loss in patients with atypical features. We have on occasion found that CytomelPrint: Chapter 9. Augmentation Strategies for Treatment-Resistant Dis… http://www.psychiatryonline.com/popup.aspx?aID=238341&print=yes…

5 of 29

31/01/2009 06:54

can also bring about a response in patients who have experienced a relapse while taking a TCA to

which they had previously responded.

Cytomel (T3) is typically started at 12.5–25 g/day, with dosage increases in 1-week increments to

50 g/day. Levothroid or Synthroid (T4) is typically initiated at 50 g/day and increased every

week or two, up to 200 g/day. Whereas an adequate trial of T3 may be 1–4 weeks, preparations of

T4 will probably require duration of 4–8 weeks because of its longer half-life. Thyroid preparations

tend to be well tolerated, but they should be used with caution in patients who have a history of

coronary artery disease, hypertension, or arrhythmia. If thyroid supplementation results in

significant suppression of TSH, it is thought that bone demineralization may occur during extended

treatment. However, Whybrow’s group (Whybrow 1994) has not observed demineralization in

bipolar patients with rapid cycling treated with high doses of T4. Overdoses occasionally result in

cardiac decompensation. If a patient responds positively, we recommend continuing the T3 for an

additional 60 days and then tapering by 12.5 g every 3 days. Some patients will demonstrate a

resumption of symptoms and will require resumption of the T3. One of our patients required

resumption of dose and maintenance for more than 1 year before T3 could finally be tapered off.

Results of thyroid function tests while the patient was taking T3 were essentially normal. After the

T3 was tapered, the patient’s T3 uptake, TSH, and T4 levels were all lower than normal but

normalized within 2–3 weeks. This patient demonstrated none of the stigmata of decreased thyroid

status immediately after discontinuation.

Estrogen, DHEA, and Testosterone Combinations With Antidepressants

For many years, estrogens have sometimes been used alone or in combination with antidepressants

to treat depression in women who are postmenopausal or postpartum whose conditions are

refractory to standard treatments. The results of using estrogens for depression have been uneven.

Some studies found estrogens to be useful in the treatment of depression in some women, and

others did not. The findings of an increased risk of breast cancer, heart attacks, and strokes in the

Women’s Health Initiative study in 2002 resulted in many women abandoning hormone

replacement therapy. However, estrogen does have some effects on mood, and some women

clearly have benefited from these effects. Coope (1981) found that estrogen had no significant

antidepressant effect when used alone for perimenopausal depression. On the other hand, studies

using higher doses of conjugated estrogens (5–25 mg/day) found some partial antidepressant

benefit in postmenopausal women. One published study in this area (Soares et al. 2001) found that

a transdermal patch of 17 estradiol was significantly more effective than placebo in reducing

depressive symptoms in perimenopausal women. This was a reasonably sized study (50 subjects)

with a sufficient duration of treatment. On the other hand, a study by Rasgon and colleagues

(2007) failed to show much benefit of adding transdermal estrogen to sertraline in depressed

postmenopausal women.

The utility of estrogens in postpartum depression is also uneven. Some studies failed to show any

benefit. However, a more recent study found estrogen to be an effective prophylaxis against

recurrent affective illness in the postpartum period (Sichel et al. 1995). Our experience with using

estrogens alone in women with refractory depression has not been particularly encouraging.

The combination of estrogens with antidepressants has yielded more consistent results. Several

studies before 1985 failed to show any additional benefit of combining estrogens with TCAs in

depressed women. However, there have been case reports of oral contraceptives augmenting the

effects of antidepressants in patients with refractory depression (Sherwin 1991). In addition,

postmenopausal women may respond better to fluoxetine if they are on hormone replacement

therapy than if they are not (Schneider et al. 1997, 2001). We studied premenopausal women who

were fluoxetine nonresponders and found that a high dosage of estrogen (10 mg/day of Estrace)

was no better than placebo in improving depressive symptoms.

Some cautions are worth considering when administering estrogens to women with mood

disorders. Estrogens appear to be capable of inducing rapid cycling in some women with bipolar

disorder, and progesterone may suppress rapid cycling. In addition, estrogen use carries the risk ofPrint: Chapter 9. Augmentation Strategies for Treatment-Resistant Dis… http://www.psychiatryonline.com/popup.aspx?aID=238341&print=yes…

6 of 29

31/01/2009 06:54

thrombophlebitis and an increased risk of breast, cervical, and uterine cancer. Unfortunately,

progesterone may induce depression in some women. Estrogens also appear to increase the

bioavailability and serum levels of TCAs. Thus, lower doses of TCAs are sometimes indicated when

an estrogen is added to the regimen.

At this time, the routine combination of estrogen with antidepressants is unwarranted. However,

some women with refractory depression in the postpartum or perimenopausal periods might

benefit from such a combination. Typical dosages of estrogens in successful studies ranged from 5

to 25 mg/day of conjugated estrogens. The risks of long-term use of high-dose, unopposed

estrogen, however, are probably too great to justify use of that approach for mild depression. It is

unclear whether specific estrogen receptor modulators (SERMs) such as raloxifene will have the

central nervous system (CNS) benefits of estrogen without the cancer risks.

Dehydroepiandrosterone (DHEA), a steroid precursor of both androgens and estrogens, has become

a very popular over-the-counter remedy for dysphoria (“Dehydroepiandrosterone” 1996). Some

controlled reports suggested that dosages of 50–100 mg/day result in increases in physical and

psychological well-being in women ages 40–70. An early study found that DHEA is more effective in

augmenting a standard antidepressant at dosages up to 90 mg/day than is placebo (Wolkowitz et

1. 1997). Likewise, there is some evidence that DHEA is significantly more effective than placebo

as a monotherapy for the treatment of dysthymia (Bloch et al. 1999). A number of studies have

also found DHEA to be effective in the treatment of depressive symptoms in midlife (Schmidt et al.

2005) and in patients with HIV-related illness (Rabkin et al. 2006) (see Chapter 3 and Chapter 13,

“Herbals and Dietary Supplements,” this volume).

The problem with DHEA, however, is that it is not a simple food supplement; it is a prohormone of

adrenal origin. Androgenic effects, including irreversible hair loss, hirsutism, and deepening of

voice, have occasionally been reported. In addition, there is some concern that DHEA could

accelerate tumor growth, because many malignancies, including those of the breast, endometrium,

and prostate, are hormone sensitive. It will be important to collect safety data concerning

long-term use of DHEA. Thus, we encourage prudence in using DHEA until further study is

completed.

Testosterone gel has been reported to be effective in a small double-blind, placebo-controlled trial

in men with refractory depression (Pope et al. 2003). This 8-week study was undertaken in men

with low or borderline low testosterone levels. In a previous trial, intramuscular testosterone had

failed to separate from placebo (Seidman et al. 2001). Likewise, a later study by Seidman and

colleagues (2005) in patients with SSRI-resistant depression did not show benefit to intramuscular

testosterone supplementation versus the injection of a placebo. Among the more significant risks of

testosterone supplementation is an increased risk of prostate cancer, although increased levels of

other androgens and estrogens may play more of a role than testosterone in enhancing the risk of

prostate cancer (Raynaud 2006). Regardless of the prostate risks, there may also be cardiovascular

risks and altered insulin resistance with testosterone supplements. Studies of testosterone

augmentation in depressed patients thus far suggest a potential role primarily in hypogonadal

depressed men. Given the unknown risks, testosterone therapy in depressed men with normal

testosterone levels does not appear warranted.

Dopamine Agonist–Antidepressant Combinations

In the early 1970s, Wharton and colleagues (1971) reported that the addition of methylphenidate

increased plasma levels of TCAs through inhibition of microsomal degradation of the TCA in the

liver (similar to the competitive inhibition observed with antipsychotic agents). This approach

offers a possible way of increasing TCA plasma levels without increasing TCA dose. In addition to

this effect, methylphenidate is a stimulant and may be useful in treating the anergia and

psychomotor retardation of endogenous depression. However, as described in Chapter 8, we do not

recommend adding methylphenidate to increase plasma levels, because higher TCA plasma levels

can be obtained by increasing the TCA doses. Rather, clinicians might want to use methylphenidate

for its energizing properties, but they should keep in mind that it may increase TCA plasma levelsPrint: Chapter 9. Augmentation Strategies for Treatment-Resistant Dis… http://www.psychiatryonline.com/popup.aspx?aID=238341&print=yes…

7 of 29

31/01/2009 06:54

and side effects. Fawcett et al. (1991) found that pemoline or dextroamphetamine was effective in

inducing improvement when added to an MAOI in patients with severe, treatment-refractory

depression. Although this combination was safe and no hypertensive crises were reported,

approximately one in five patients treated developed either hypomania or mania.

The traditional stimulants do appear to still have a role in patients with treatment-resistant

depression, those with concurrent attention-deficit disorders, and medically ill patients. Stimulants

can improve energy and concentration in medically ill patients and appear to be useful adjuvants to

most classes of antidepressants. Although less well studied in combination with newer

antidepressants, amphetamine-type drugs have been reported in case series to augment

venlafaxine and the SSRIs.

A number of new kinds of dopamine agonists have potential as augmenting agents in

treatment-resistant depression. For example, the D2, D3 agonist pramipexole (Mirapex), which has

an FDA-approved indication for the treatment of Parkinson’s disease, has also been evaluated as a

treatment for major depression. In one study, pramipexole separated from placebo to a comparable

degree as fluoxetine (Corrigan et al. 2000). We have found it useful as an adjunctive agent to

SSRIs in some patients with treatment-resistant depression at dosages up to 1 mg/day (DeBattista

1997). In addition, pramipexole appears to help with restless legs, including restless legs

exacerbated by the use of SSRIs (DeBattista et al. 2000). More recently, pramipexole was found to

improve depression in two small double-blind, placebo-controlled studies of bipolar depressed

patients (Goldberg et al. 2004; Zarate et al. 2004). We are currently studying ropinirole, with a

target dosage of 4–8 mg/day, as an augmenting strategy in treating resistant depression, and this

agent may also prove useful in some depressed patients.

Monoamine Precursor–Antidepressant Combinations

The addition of amino acids to antidepressants is based on the rationale that supplementing the

diet with precursors of monoamines may help correct a deficiency of the monoaminergic system.

Phenylalanine is a precursor of dopamine and norepinephrine; tryptophan is ultimately converted

into serotonin (5-HT). These amino acids have been combined with MAOIs, TCAs, and SSRIs in the

treatment of refractory depression, with varying degrees of success. The “Newcastle cocktail,”

which has been used for treatment-refractory depression, employed a combination of clomipramine

or phenelzine, lithium, and tryptophan (Montgomery 1991). This was said to be an effective

combination, but one that carried some risk of serotonin syndrome. Dosages of tryptophan used for

augmentation have ranged from 2 to 6 g/day. Tryptophan is not currently available in the United

States. Phenylalanine, which is available, has been used in dosages of 500 mg/day to 5 g/day as a

supplement. We have not been particularly impressed with phenylalanine augmentation. A related

strategy is the use of inositol, a precursor of an important intracellular second-messenger system:

the phosphatidylinositol (PI) system. The PI system may be important in mediating the effects of

lithium and various antidepressants. Levine et al. (1995) reported a small double-blind study

suggesting that inositol 6 g bid was useful and was more effective than placebo in treating patients

with major depression. However, in a follow-up study, no difference could be found between

placebo and inositol in the augmentation of SSRIs (Levine et al. 1999). In bipolar depression, the

addition of inositol 10–15 g was found to be as effective (or ineffective) as adding lamotrigine or

risperidone to lithium, valproate, or carbamazepine (Nierenberg et al. 2006b). Nonetheless, inositol

is a benign strategy that has a rationale for its use and will undoubtedly continue to be the subject

of studies.

SSRI Combinations

Since the SSRIs are now the most common agents used to treat depression, a number of potential

augmenting agents have been combined with the SSRIs in patients with treatment-resistant

depression. Lithium and thyroid augmentation are often used to enhance SSRI response, but a

number of other agents may also be useful (Table 9–1).

Among the most common augmenting agents currently used in clinical practice is bupropion. APrint: Chapter 9. Augmentation Strategies for Treatment-Resistant Dis… http://www.psychiatryonline.com/popup.aspx?aID=238341&print=yes…

8 of 29

31/01/2009 06:54

number of studies have suggested that bupropion, as a noradrenergic-dopaminergic agent, can

enhance the antidepressant effects of SSRIs and venlafaxine (Bodkin et al. 1997; Fatemi et al.

1999; Kirsch and Louie 1999). We have been studying the addition of sustained-release bupropion

(Wellbutrin SR) to SSRIs and believe it is a convenient and well-tolerated method of improving

antidepressant response (DeBattista et al. 2003). We start sustained-release bupropion at 150 mg

and then go to 150 mg bid by the end of the second week of treatment. Still, no good double-blind

studies are yet available to confirm the efficacy of this approach. The largest trial of bupropion

augmentation in the STAR*D trial found that augmenting citalopram with bupropion was about as

effective as augmenting with buspirone in producing a remission-level response (Trivedi et al.

2006; see also Chapter 3, this volume). Unfortunately, this trial was not a blinded, randomized

comparison. However, there was an advantage of bupropion over buspirone when focusing on

absolute change on one of the standard depression scales used in the study (QID-SR-16).

Improvement in the scale score was 25% with bupropion and only 17% with buspirone. The target

dosage for bupropion was 300–400 mg/day and 45–60 mg/day for buspirone.

We recently reported on a placebo-controlled study in which atomoxetine was added to sertraline

in patients who had not responded to monotherapy. Atomoxetine was not found to be superior to

placebo (Michelson et al. 2006).

Modafinil is a wake-promoting agent used in the treatment of narcolepsy (Ferraro et al. 1997). It

lacks the addictive potential and the hemodynamic side effects of stimulants. We have found that

100–200 mg of modafinil taken in the morning with an SSRI is well tolerated and helps with fatigue

and hypersomnia in depressed patients (DeBattista et al. 2003, 2004). The drug appears to work

quickly, within the first 2 weeks, if it is going to help. Modafinil is generally well tolerated in

combination with SSRIs. Side effects of modafinil such as headache, nausea, and anxiety are

usually mild and easy to manage.

In animal models, the combination of fluoxetine with desipramine produced marked and rapid

downregulation of postsynaptic -adrenergic receptors (Baron et al. 1988), suggesting that the

combination should be effective. Several reports have suggested this is the case (Nelson and Price

1995; Weilburg et al. 1989). However, the TCA dosing must be done very conservatively, because

the SSRIs slow the hepatic degradation of TCAs via competitive inhibition of cytochrome P450

(CYP) 2D6 and other CYP enzymes (see Chapter 3), resulting in potential elevation of TCA levels

and increased side effects (Aranow et al. 1989; Bell and Cole 1988). If a TCA is added in patients

already being treated with an SSRI, initiation of the TCA should be at low dosages: 25 mg/day of

nortriptyline or 50 mg/day of imipramine, with a further increase of 25 mg every 3 days as

tolerated to a target dosage of 75 mg/day of nortriptyline or 150–300 mg/day of imipramine.

Plasma levels of the TCA should be monitored closely, and electrocardiograms should be taken and

also monitored closely. When an SSRI is added to the TCA, we recommend first gradually reducing

the dosage of the TCA to 100 mg/day of nortriptyline or 150 mg/day of imipramine and monitoring

plasma levels. TCA levels should be obtained before and after dosage reduction as well as after

starting an SSRI.

Trazodone is often safe and useful as a hypnotic in patients who have insomnia as a result of taking

fluoxetine. In the course of such use, we found patients whose depressions cleared nicely after

trazodone was added to the fluoxetine. One study (Nierenberg et al. 1994) found that trazodone

100 mg at night counteracted fluoxetine- or bupropion-induced insomnia in 10 of 15 patients

treated. Doses of trazodone ranging from 25 to 300 mg are used for drug-induced insomnia. The

literature on trazodone augmentation of fluoxetine is more sparse; in one study (Nierenberg et al.

1992), trazodone seemed to potentiate the effects of fluoxetine in 3 of 8 patients treated. The

combination of trazodone and the SSRIs appears to be generally well tolerated and useful but

needs further study. The SSRIs have been combined with agents that act on the serotonin1A (5

HT1A) receptor to augment response and reduce side effects.

Buspirone, which is a 5-HT1A partial agonist, has been shown to potentiate the antidepressant

effects of fluoxetine in open-label studies, including the study by R. T. Joffe and Schuller (1993).Print: Chapter 9. Augmentation Strategies for Treatment-Resistant Dis… http://www.psychiatryonline.com/popup.aspx?aID=238341&print=yes…

9 of 29

31/01/2009 06:54

Dosages of buspirone as low as 5 mg/day and as high as 50 mg/day in these studies were enough

to effect a full response in the majority of patients who had not had a response or had only a partial

response. On the other hand, double-blind studies have failed to show any advantage to adding

buspirone to fluoxetine in the treatment of obsessive-compulsive disorder. Double-blind trials for

buspirone augmentation of SSRIs for treatment-resistant depression have yielded mixed results;

one study showed a benefit of buspirone over placebo (Bouwer and Stein 1997), and a more recent

study showed negative results (Landen et al. 1998). As reported earlier in this section, buspirone

was similar in efficacy to bupropion in augmenting SSRI response in the STAR*D trial (Trivedi et al.

2006). Because buspirone is such a relatively benign agent compared with other potential

augmenting agents, it is worth considering in treatment-resistant cases. A 4- to 6 week trial of

dosages of buspirone from 30 to 60 mg/day is probably adequate to determine whether

combination with an SSRI will be useful. In addition, buspirone may help attenuate SSRI-induced

sexual dysfunction, as reported in Chapter 3. However, we have not been impressed with buspirone

as an augmenting agent or in the treatment of SSRI-induced sexual dysfunction.

Another SSRI augmentation strategy is the use of pindolol, a blocker that also has 5-HT1A

antagonist properties. In two open-label studies (Artigas et al. 1994; Blier and Bergeson 1995), it

was found to potentiate antidepressant response. In both studies, pindolol 2.5 mg tid seemed to

speed the onset of action and lead to a response in the vast majority of patients who had not had a

response. A few patients did drop out of both studies because they became more irritable. Pindolol

may enhance serotonergic tone by acting on somatodendritic autoreceptors. We have attempted to

use pindolol to augment SSRI response, with mixed results. A controlled trial from Yale University

apparently found an increase in speed of onset. In a total of six controlled trials of pindolol

augmentation that had been completed to date, three had had positive results and three had had

negative results (McAskill et al. 1998). Still, pindolol may represent another fairly benign

augmentation strategy and should be considered when a patient fails to continue responding to an

SSRI after months of good response. There is a general impression that pindolol may hasten

antidepressant response but is relatively weak as an augmenter. The most common side effects of

pindolol include hypotension, dizziness, and fatigue, particularly at higher dosages. Some patients

report CNS activation—for example, insomnia, anxiety, and irritability. We recommend starting at

2.5 mg bid and increasing to 5 mg bid in the second week. Blood pressure should be monitored, and

if no response is seen in 3 weeks, the trial can be discontinued.

The use of mirtazapine to augment SSRIs in treating depression has proved very useful for some

patients. Some evidence suggests that the combination of venlafaxine or an SSRI plus mirtazapine,

although poorly studied, is efficacious and well tolerated in some patients with treatment-resistant

depression (Carpenter et al. 1999, 2002). In the STAR*D trial, the addition of mirtazapine to

venlafaxine in patients in whom three consecutive trials for depression had failed was at least as

effective as switching to an MAOI and was far better tolerated (McGrath et al. 2006).

Unfortunately, both treatments were only modestly beneficial in these patients with

treatment-resistant depression. Only 6.9% achieved remission when a switch was made to

tranylcypromine versus 13.7% when mirtazapine was added to venlafaxine. We have found that

mirtazapine 15–45 mg qhs is probably more effective than the addition of trazodone in helping with

sleep, anxiety, and depression. Clearly, more study is needed on the utility and tolerability of

mirtazapine augmentation.

Several reports indicate that adding clonazepam to an SSRI provides more rapid responses in

patients with panic disorder or major depression. In a study by Smith et al. (1998), clonazepam at

a dosage of 0.5–1.0 mg hs for the first 3 weeks of fluoxetine therapy appeared to have calming

effects and to accelerate overall antidepressant response. In another study (Goddard et al. 2001),

clonazepam at doses of up to 1.5 mg hs accelerated response to sertraline in panic disorder

patients.

Antipsychotic-Antidepressant Combinations

The combination of antidepressants and antipsychotics has been used in the treatment of bothPrint: Chapter 9. Augmentation Strategies for Treatment-Resistant Dis… http://www.psychiatryonline.com/popup.aspx?aID=238341&print=yes…

10 of 29

31/01/2009 06:54

psychotic and nonpsychotic depression. Psychotic depression occurs in up to 25% of inpatients

with major depression and tends to be less responsive to antidepressant therapy alone than are

nondelusional depressions. The data indicate that with the exception of amoxapine, which is

chemically related to the antipsychotic loxapine, an antipsychotic-antidepressant combination or

electroconvulsive therapy is probably required for effective treatment of this disorder. However,

some studies have suggested that monotherapy with SSRIs and newer agents may be effective in

the treatment of psychotic depression (Wijkstra et al. 2006; Zanardi et al. 2000). In addition,

patients with schizophrenia or schizoaffective disorder frequently develop depressive episodes that

may require the addition of an antidepressant to their antipsychotic regimen.

Most studies on psychotic depression have involved combining a TCA with a standard antipsychotic.

A prepackaged amitriptyline-perphenazine combination drug is available for use in psychotic and

anxious depression. This combination had appeared under two trade names (Triavil and Etrafon),

since discontinued. Various combinations of strengths are available, coded according to the dose of

each drug contained in the capsule (Table 9–2); the dose of perphenazine is given first. For

example, 2-25 contains 2 mg of perphenazine and 25 mg of amitriptyline. This neuroleptic-TCA

combination was widely used in the United States and was generally prescribed by primary care

practitioners. However, experienced psychopharmacologists advocate prescribing each drug

individually to allow for optional flexibility in dosing.

Table 9–2. Prepackaged combination antidepressants: names, formulations and strengths, and

dosages

Generic name Brand

name

Formulation and strengthsa

Dosageb

chlordiazepoxide–amitriptyline Limbitrol Tablets: 5-12.5, 10-25 3 tablets 10-25 to 6 tablets

10-25

perphenazine–amitriptyline

—c

Tablets: 2-10, 2-25, 4-10, 4-25,

4-50

2-25 tid to 4-50 qid

olanzapine–fluoxetine Symbyax Capsules: 6-25, 6-50, 12-25,

12-50

a Formulation strengths list amount (in milligrams) of first and second ingredients, respectively.

bAdult dosages; some patients may require lower dosages.

cAvailable in generic form only.

The newest antipsychotic-antidepressant combination pill is the combination of olanzapine and

fluoxetine (OFC, or Symbyax). Symbyax is the first drug approved for the treatment of bipolar

depression (see Chapter 5: “Mood Stabilizers”). In a controlled trial in 853 patients treated with

olanzapine alone, placebo, or OFC (6 mg/25 mg to 12 mg/50 mg), both OFC and olanzapine were

better than placebo. OFC was faster and more effective than olanzapine alone (Keck 2002). It is

also being studied in the treatment of resistant depression. An atypical antipsychotic, with its

serotonin2C receptor (5-HT2C) antagonism, would appear to be a useful adjunctive agent with an

SSRI. Research in the rat suggests that olanzapine in combination with an SSRI may increase

release of prefrontal dopamine. One study (Shelton et al. 2001) reported that the addition of

olanzapine to fluoxetine was rapidly effective in a population of patients with treatment-resistant

depression and more effective than continuing either fluoxetine or olanzapine alone. Several, as yet

unpublished, trials also support rapid improvement with OFC in treating resistant depression.

Lastly, OFC has been reported to be more effective than placebo in treating delusional depression

(Rothschild et al. 2004). However, an older combination pill, Triavil, never caught on with

psychiatrists because of the inability to individually titrate the antipsychotic and antidepressant.

OFC has not been fully embraced for the same reasons. Some patients do seem to like the

convenience of taking one capsule as opposed to two. In addition, having a single capsule may

reduce the number of co-pays, required by some insurance plans.Print: Chapter 9. Augmentation Strategies for Treatment-Resistant Dis… http://www.psychiatryonline.com/popup.aspx?aID=238341&print=yes…

11 of 29

31/01/2009 06:54

There is little doubt that the combination of an SSRI or serotonin-norepinephrine reuptake inhibitor

(SNRI) with other atypical antipsychotics is likely to be beneficial in many patients with

treatment-resistant unipolar, nonpsychotic depression as well. The atypical antipsychotics, with

their 5-HT2, and in some cases 5-HT1A, effects, can provide assistance in treating the insomnia,

anorexia, agitation, and anxiety that many depressed patients experience. Unfortunately, there

have been few double-blind studies published to date that have supported the use of atypicals in

nonpsychotic depression. However, many more studies have been completed but have not yet been

published. Shelton and colleagues (see Shelton 2003 for review) published the first report to

demonstrate the efficacy of adding an average dose of 12.5 mg of olanzapine to fluoxetine in

patients who had failed to respond to an SSRI alone. Superiority was demonstrated at 8 weeks over

continuing with fluoxetine alone. Generally, the addition of the atypical agent speeds up or adds to

the response, but continuing with the other agent alone often reaches a similar response by

conclusion of the study. Two subsequent, adequately powered, controlled trials of olanzapine

augmentation in resistant depression failed to show the same benefits. Smaller double-blind

studies and a number of open-label trials have suggested benefits of quetiapine and risperidone

augmentation of serotonergic antidepressants (McIntyre et al. 2006; Rapaport et al. 2006). More

definitive studies of antipsychotic augmentation using quetiapine, aripiprazole, and ziprasidone in

resistant depression are currently under way. The initial studies suggest a role for atypicals in the

augmentation of antidepressant response in resistant depression, but the findings are not

conclusive as of this writing.

Anecdotally, we have used all of the atypical agents as augmenters in nonpsychotic depression with

variable success. Anxious, agitated depressed patients often seem to benefit from the addition of

5–15 mg/day of olanzapine or 100–200 mg/day of quetiapine. More lethargic patients or those in

whom there is a greater concern about weight gain might benefit from augmentation with

aripiprazole 40–120 mg/day, risperidone 0.5–1 mg/day, or aripiprazole 10–15 mg/day. As with

any other strategy, the potential benefits of augmenting with an atypical antipsychotic must be

weighed against the potential mischief that an atypical antipsychotic might cause in metabolic

effects, extrapyramidal symptoms (EPS), and so forth.

Other TCA Combinations

One of the most controversial TCA combinations is that with MAOIs. Although proscribed in the

Physicians’ Desk Reference, the combination can be relatively safe and is occasionally effective in

patients who have failed to respond to treatment with an MAOI or a TCA alone. As indicated in

Chapter 3, combining MAOIs with sympathomimetic agents can result in acute hypertensive crises.

Because TCAs exert an effect on sympathetic systems, prudence is warranted. Early fears of the

combination came largely from a number of deaths that resulted from overdoses of the

combination. However, overdoses of either TCAs or MAOIs alone can be lethal.

In contrast to earlier reports, some clinicians have argued that the combination can be of unique

benefit. However, double-blind studies comparing a TCA, an MAOI, and their combination in

patients with non-treatment-resistant depression have failed to show that the combination is of

added benefit. The lack of superior efficacy for the MAOI-TCA combination could reflect the limited

doses of both drugs used (e.g., 45 mg of phenelzine and 150 mg of amitriptyline).

Some investigators have reported to us that combining higher doses of both is effective, and we

have noted positive results from this treatment with some patients. However, generally speaking, a

number of important caveats about the combination of an MAOI and a TCA should be noted:

It appears safest to start the two drugs together. Adding the TCA to the MAOI is far more dangerous

than adding the MAOI to the TCA.

1.  

Clomipramine combined with an MAOI (particularly tranylcypromine) is far more likely to produce

serotonin syndromes than are other TCAs. This combination is to be avoided. Lader, in the United

Kingdom (personal communication, 1988), recommended that when switching between an MAOI and

clomipramine in either direction, a 4-week interval be observed.

2.Print: Chapter 9. Augmentation Strategies for Treatment-Resistant Dis… http://www.psychiatryonline.com/popup.aspx?aID=238341&print=yes…

12 of 29

31/01/2009 06:54

Amitriptyline and trimipramine are believed to be the TCAs that best mix with an MAOI—that is, that

produce fewer hypertensive crises and, probably, serotonin syndromes. This is largely unproven,

although suggestive data do exist.

3.  

Phenelzine and isocarboxazid appear to be less problematic than does tranylcypromine, which may have

an amphetamine-like action.

4.  

An early TCA combination drug, Limbitrol (Table 9–2), available in the United States since 1980,

contains chlordiazepoxide. It carries an FDA-approved indication for the treatment of mixed anxiety

and depression. The numerical designation parallels that of Triavil. Limbitrol 10-25 contains 10 mg

of chlordiazepoxide and 25 mg of amitriptyline. It is also available in a 5-12.5 form (Table 9–2).

The recommended starting dosage in adults is three or four tablets a day of the 10-25 strength,

with a recommended maximum daily dosage of six tablets. In elderly patients, the recommended

starting dosage is one 5-12.5 tablet three or four times a day. Although data from previous studies

indicated that chlordiazepoxide alone was not an effective antidepressant, the combination was

shown to decrease anxiety, to aid sleep early in treatment (within the first 2 weeks), and to be

associated with better patient compliance. However, published studies have not indicated that

continued additional benefit can be obtained after the initial 4–6 weeks. Whenever possible,

clinicians who have used the combination for this initial period should consider switching to

prescribing these agents individually and eventually tapering the benzodiazepine. Limbitrol is used

quite rarely now, because the sedating effects of chlordiazepoxide are additive to those of

amitriptyline. Many patients taking amitriptyline do not require the addition of a benzodiazepine.

Thus, the advantages of Limbitrol in ease of use may be outweighed by the disadvantages of the

drug. Other benzodiazepines, such as lorazepam and alprazolam, are commonly added to TCAs to

treat concurrent agitation or panic in the weeks before the TCA begins working.

AUGMENTATION STRATEGIES FOR BIPOLAR DISORDER

Combinations of Two or More Mood Stabilizers

Lithium may be combined with anticonvulsants in the treatment of patients with refractory mania.

There are few prospective data using such combinations; however, a number of reports indicated

that lithium-carbamazepine combinations are effective with patients who have failed to respond to

these two agents given separately (see Chapter 5: “Mood Stabilizers”). Retrospective reviews have

generally found the combination of lithium and carbamazepine to be useful and synergistic

(Lipinski and Pope 1982; Peselow et al. 1994). However, at least one retrospective study (Fritze et

1. 1994) failed to find any benefit from combining lithium and carbamazepine in bipolar patients.

There is also evidence that the combination of lithium and carbamazepine may be particularly

useful in rapid-cycling bipolar disorder. The combination of lithium and carbamazepine appears to

be well tolerated. There is one report of increased risk of sinus node dysfunction with this

combination (Steckler 1994), but this effect appears to be rare. In addition, the combination of

lithium and carbamazepine may have a cumulative antithyroid effect (Kramlinger and Post 1990).

There is no evidence of increased neurotoxicity or blood dyscrasias with this combination. Dosing

schedules of the lithium and carbamazepine should parallel regimens used for prescribing each

drug alone. The therapeutic serum levels of both drugs should be monitored and maintained.

Lithium has also been combined with valproate with good results in patients with

treatment-refractory bipolar disorder. One study reported that patients who were older, whose

illness lasted longer, who were hospitalized more frequently, and who maintained higher valproate

levels might have a better response to the combination of valproate and lithium (McCoy et al.

1993). Few prospective studies are available to evaluate the combination of valproate and lithium

in the treatment of refractory bipolar disorder. One of the few prospective studies to date is an

open-label study by Sharma et al. (1993), who reported that eight of nine rapid-cycling patients

with bipolar disorder, most of whom failed to respond to the combination of lithium and

carbamazepine, responded when lithium was combined with valproate. In addition, combining the

two drugs also appeared to help the depressive phase of the illness in three of eight subjects. A

similar study found that the augmentation of lithium with valproate was successful in stabilizingPrint: Chapter 9. Augmentation Strategies for Treatment-Resistant Dis… http://www.psychiatryonline.com/popup.aspx?aID=238341&print=yes…

13 of 29

31/01/2009 06:54

rapid cycling in four geriatric patients (A. L. Schneider and Wilcox 1998). A number of small

prospective studies suggested that the combination of lithium and valproate may be more effective

in the prophylaxis of bipolar episodes than either one alone (Denicoff et al. 1997; Solomon et al.

1997, 1998). The combination of lithium and valproate seems to be well tolerated, and the dosing

should achieve adequate serum levels for both drugs. Occasionally, valproate has been combined

with carbamazepine when lithium is poorly tolerated or ineffective. There are anecdotal reports

that this combination is sometimes useful. However, valproate and carbamazepine compete for

hepatic metabolism, an effect that increases the risk of carbamazepine toxicity. For this reason,

some investigators have suggested that the combination of valproate and carbamazepine is

contraindicated. Our experience suggests that the combination may be used safely if serum levels

of both drugs are closely monitored and the doses are adjusted as necessary.

As reported in Chapter 5, newer anticonvulsants such as gabapentin, topiramate, and lamotrigine

have sometimes been combined with lithium and divalproex sodium in patients with

treatment-resistant bipolar disorder. As with most other combination treatments for bipolar

disorder, combining lithium or valproate with newer anticonvulsants is poorly studied. Gabapentin

has probably been best studied as an adjuvant to lithium in the treatment of bipolar disorder, and

the results have been mixed. Some evidence from open-label trials and case reports suggests that

gabapentin can help with both manic and depressive symptoms when added to an existing regimen

(Ghaemi et al. 1998; Perugi et al. 1999; Young et al. 1999). However, an unpublished double-blind

augmentation study found that gabapentin was not significantly more effective than placebo as an

add-on. Clearly, the combination of gabapentin with standard mood stabilizers is quite benign and

may help with anxiety and agitation even if it proves to be less robust as a mood stabilizer. We

typically use 900–2,700 mg/day as an adjuvant and do not recommend gabapentin as a

monotherapy for bipolar disorder.

Lamotrigine may prove to be a better mood stabilizer than gabapentin, and we have a number of

patients with treatment-resistant illnesses who have done well with the addition of lamotrigine.

There are very few data, other than case reports, on the utility of lamotrigine combinations. The

combination of lamotrigine with valproate or carbamazepine is more difficult to manage than the

combination with lithium. Valproate doubles the serum level of lamotrigine, increasing the risk of

rash, whereas carbamazepine cuts the lamotrigine serum levels in half. We have found lamotrigine

at dosages in the range of 50–200 mg/day particularly helpful in treating bipolar depression in

combination with lithium.

Topiramate may be more useful as an adjuvant than as an augmenting agent. The addition of

50–200 mg of topiramate to a standard mood-stabilizing regimen can help mitigate weight gain.

Whether topiramate also helps augment mood-stabilizing effects is less clear at this time.

Controlled monotherapy trials have been disappointing.

Mood Stabilizer–Antipsychotic Combinations

Mood stabilizers are frequently combined with antipsychotics in treating patients during acute

manic episodes. In fact, the vast majority of patients who are hospitalized with a manic episode

will be treated with an antipsychotic (Chou et al. 1996). As reported in Chapter 5 (“Mood

Stabilizers”), this combination is useful, but some interactions between neuroleptics and mood

stabilizers may occur. Lithium does have some antidopaminergic properties, and some patients may

have a greater proclivity for developing EPS when lithium is combined with neuroleptics. This

appears to be particularly true at higher or toxic lithium serum levels. Likewise, it has been

suggested that lithium increases the risk of tardive dyskinesia in patients also treated with typical

neuroleptics. However, whether lithium really adds to the risk of neuroleptic-induced tardive

dyskinesia in patients taking antipsychotics is still unanswered. As reported earlier, there does not

appear to be evidence of an increased risk of neurotoxicity when lithium is combined with

high-potency neuroleptics.

Both olanzapine and risperidone appear to be useful in combination with mood stabilizers for the

treatment of bipolar disorder. A few case reports suggested that adding olanzapine or risperidonePrint: Chapter 9. Augmentation Strategies for Treatment-Resistant Dis… http://www.psychiatryonline.com/popup.aspx?aID=238341&print=yes…

14 of 29

31/01/2009 06:54

to a mood stabilizer may rapidly boost antimanic effects (Ghaemi and Goodwin 1999; Ketter et al.

1998). A double-blind, placebo-controlled study comparing the addition of olanzapine to antimanic

therapy found that olanzapine augmentation was significantly more effective than placebo (Tohen

et al. 2002). There was a similar finding in a controlled trial of risperidone (Sachs et al. 2002).

More recently, Bowden and colleagues (2004) found that the addition of risperidone to a mood

stabilizer also enhanced efficacy during continuation treatment. As reported earlier, the addition of

risperidone to valproate, lithium, or carbamazepine in resistant bipolar depression was as effective

as the addition of inositol or lamotrigine (Nierenberg et al. 2006b). Weight gain is a particular

worry with such combinations, especially if the combinations are maintained over time. More

weight-neutral agents such as aripiprazole have been less well studied in combination with

standard mood stabilizers. The only study published to date of aripiprazole combination with a

mood stabilizer is an open study that indicates that the addition of aripiprazole might be effective

in some patients with treatment-resistant bipolar disorder (Ketter et al. 2006). There is evidence

that the atypical antipsychotics may be of benefit in the long-term maintenance of bipolar disorder

and that the combination of risperidone or olanzapine with a mood stabilizer may have a

synergistic effect in preventing subsequent episodes (Ghaemi et al. 1997). While the addition of

topiramate to a mood stabilizer may not help mood symptoms, topiramate clearly helps mitigate

weight gain (Vieta et al. 2004).

Clozapine tends to be at the bottom of the treatment algorithm for treatment-resistant bipolar

disorder because of its toxicity and complexity of use. As reported in Chapter 5, patients with

treatment-resistant bipolar disorder often respond to clozapine therapy. The combination of lithium

and clozapine may be synergistic—an effect that is a double-edged sword. On the one hand, some

patients with refractory illness have a response after addition of clozapine to their regimens. In

addition, lithium may mitigate the leukopenia associated with clozapine (Adityanjee 1995). On the

other hand, most of the known cases of neuroleptic malignant syndrome (NMS) associated with

clozapine have been associated with concurrent lithium use. Still, for the patient with

treatment-resistant bipolar disorder, the addition or substitution of clozapine in the regimen

remains an important option if other mood stabilizers and antipsychotics have failed.

Carbamazepine-antipsychotic combinations tend to be well tolerated. However, a larger dosage of

the antipsychotic is sometimes required because of carbamazepine’s tendency to induce hepatic

metabolism and reduce the serum levels of concurrent antipsychotics. Indeed, we have often found

it difficult to combine carbamazepine with an antipsychotic or an antidepressant for this reason.

This was particularly the case when carbamazepine was combined with TCAs. There is evidence

that rapid-cycling and refractory bipolar disorders are sometimes associated with subclinical

hypothyroidism, particularly in females (Whybrow et al. 1992). The use of lithium is sometimes the

culprit in producing this hypothyroidism, but the hypothyroidism may be independent of any use of

mood stabilizers. Adding T4 (Synthroid) to a mood stabilizer sometimes reduces cycling and

increases responsiveness to treatment.

Mood Stabilizer–Antidepressant Combinations

It is common practice to use an antidepressant with a mood stabilizer to treat the depressed phase

of bipolar illness. One potential drawback of this combination may be the induction of rapid cycling

(Wehr and Goodwin 1979; Wehr et al. 1988). The induction of rapid cycling has mostly been

observed with TCAs, but it may occur with MAOIs, SSRIs, and other classes of drugs. Thus, there

has been controversy in the field about whether it is better to add a second mood stabilizer or,

rather, an antidepressant to treat bipolar depression. A study by Young et al. (2000) attempted to

answer this question: 27 depressed bipolar patients were randomized to either paroxetine or an

additional mood stabilizer (either lithium or valproate). Over the 6-week trial, both strategies

improved the depression, but patients were more likely to benefit from the paroxetine than from

the mood stabilizer. Since this was a short trial, it is still conceivable that the addition of

antidepressant may be more problematic in the long run than the addition of another mood

stabilizer. We have little hesitation to add an antidepressant to a mood stabilizer for the average

patient with bipolar II disorder and find that the combination tends to be better tolerated and morePrint: Chapter 9. Augmentation Strategies for Treatment-Resistant Dis… http://www.psychiatryonline.com/popup.aspx?aID=238341&print=yes…

15 of 29

31/01/2009 06:54

effective than adding another mood stabilizer. However, for a patient with bipolar I disorder who

has a depressive episode while receiving monotherapy with a mood stabilizer, we might add a

second mood stabilizer first, because inducing a full-blown manic episode with an antidepressant is

more likely in a patient with bipolar I disorder than in a patient with bipolar II disorder.

Bupropion was initially thought to be less likely to induce rapid cycling or mixed states, but a few

cases of bupropion-induced mixed states and manic episodes have been reported. On the basis of

the limited data, we suggest trying bupropion or SSRIs before treating a depressed cycle of bipolar

illness with a noradrenergic antidepressant, including a TCA, duloxetine, reboxetine, or venlafaxine.

If rapid cycling is induced, the antidepressant should be discontinued if possible, and a combination

of mood stabilizers, with or without thyroid supplement, should be considered.

Mood Stabilizers and 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 since the early 1990s suggested that

affective illness may be associated with deficiencies of some omega-3 fatty acids. For example,

there appears to be a higher ratio of arachidonic acid to eicosapentaenoic acid in more severely

depressed patients compared with less severely depressed patients. Other studies have suggested

that there may be lower omega-3 fatty acids in the red blood cell membranes of depressed patients

compared with healthy control subjects. Furthermore, some limited evidence suggests that

omega-3 fatty acids may impact signal transduction in a manner analogous to lithium.

A preliminary 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. More recent studies of the adjunctive use of omega-3 fatty acids in both

bipolar disorder and unipolar depression have been inconclusive (see Chapters 5 and 13, this

volume).

The role of omega-3 fatty acid supplements in the treatment of affective illness remains uncertain.

Since these fatty acids are fairly benign and may have other health benefits, some clinicians are

supplementing the mood-stabilizing regimens of their bipolar patients with omega-3 fatty acids.

However, the benefits of this regimen are still largely unproven.

AUGMENTATION STRATEGIES FOR SCHIZOPHRENIA

Combinations of Two Antipsychotics

Combining two or more antipsychotics is generally frowned upon, since the utility of this approach

is not clear. However, an atypical antipsychotic can sometimes be augmented by a standard

antipsychotic drug. The most common example is the combination of clozapine, which has limited

D2 antagonism, and haloperidol or perphenazine. Although few data are available on the efficacy of

this approach, some patients appear to benefit. Risperidone combined with a standard

antipsychotic resulted in a modest but significant improvement in some patients with chronic

schizophrenia studied prospectively (Takahashi et al. 1999). The combination of other atypical

antipsychotics and standard antipsychotics may also be warranted if the maximum dosage of the

atypical agent has been achieved with less than satisfactory benefit. We tend to prefer the addition

of high-potency agents, because the weight gain, hypotensive, and sedation problems associated

with the atypical antipsychotics complicate the addition of low-potency agents. Since risperidone is

such a potent D2 antagonist by itself, we push the dosage of risperidone as tolerated by the patient

up to 12 mg/day rather than add a standard antipsychotic to it.

Does it make any sense to combine two atypical agents? Perhaps. A few case reports have

suggested that the addition of risperidone to clozapine might be helpful for some patients with

refractory schizophrenia (see Morera et al. 1999). However, the -adrenergic receptor–blockingPrint: Chapter 9. Augmentation Strategies for Treatment-Resistant Dis… http://www.psychiatryonline.com/popup.aspx?aID=238341&print=yes…

16 of 29

31/01/2009 06:54

properties of risperidone might be problematic in some patients being treated with clozapine, and

the addition of haloperidol might work just as well and with fewer complications. Likewise, the

combination of clozapine with aripiprazole (Ziegenbein et al. 2006) or ziprasidone (Ziegenbein and

Calliess 2006) has been anecdotally suggested to be beneficial and well tolerated in patients with

resistant schizophrenia. On the other hand, combining aripiprazole with other antipsychotics has

sometimes been associated with a worsening of symptoms (Chan and Sweeting 2006; Chan et al.

2006).

Combining two standard antipsychotics is sometimes done, but with unclear benefits. The most

common combination is a high-potency agent such a haloperidol and a low-potency agent such as

chlorpromazine. The rationale for using the low-potency agent is usually to help with sleep.

However, the clinician could obtain the same effect from adding higher doses of diphenhydramine

(50–100 mg qhs) to the antipsychotic, or better yet, a benzodiazepine. There is the rare patient

who clinically does better with two different standard antipsychotics, but there is rarely a time that

another class of agents (an atypical antipsychotic, a benzodiazepine, or a mood stabilizer) might

not work even better.

Combinations of Antidepressants and Antipsychotics

The SSRIs and other antidepressants have been combined with antipsychotics in the treatment of

negative symptoms and depression in schizophrenia, schizoaffective disorder, and psychotic

depression. Open-label studies have suggested that fluoxetine and fluvoxamine may help with

negative symptoms and mood problems in patients with schizophrenia (Goldman and Janecek

1990; Silver and Nassar 1992). One potential problem is that the SSRIs may raise the serum levels

of standard and atypical antipsychotics. In a double-blind trial of fluoxetine added to a depot

neuroleptic, negative symptoms were clearly improved with the fluoxetine treatment, but serum

levels of the antipsychotic were increased an average of 65% with fluphenazine and 20% with

haloperidol decanoate (Goff et al. 1995). Although EPS did not worsen in this study, some patients

clearly had a worsening of akathisia and other symptoms with the addition of fluoxetine or other

SSRIs to their antipsychotic regimen. Therefore, lower antipsychotic doses may be required when

antipsychotics are combined with the SSRIs. As indicated previously, SSRIs, particularly

fluvoxamine, can markedly elevate serum clozapine levels.

Other antidepressants may also benefit negative symptoms. Trazodone has shown modest benefits

in the treatment of negative symptoms, as has moclobemide. Trazodone produces significant but

modest improvements in negative symptoms compared with placebo when added to a standard

antipsychotic (Decina et al. 1994). Bodkin et al. (1996) found that selegiline 5 mg bid over 6 weeks

significantly improved negative symptoms and EPS in a group of 21 patients with schizophrenia or

schizoaffective disorder but had no effect on positive symptoms. At these low dosages, one would

not anticipate significant interactions with atypical, serotonergic antipsychotics, but caution should

be exercised. Transdermal selegiline at a dosage of 6 mg/day would be expected to be at least as

safe as low-dose oral selegiline. However, transdermal selegiline has not been evaluated in

schizophrenia as of this writing.

Nefazodone shares a more specific 5-HT2 antagonism with atypical antipsychotics. It would make

some sense, then, that nefazodone should help ameliorate negative symptoms in schizophrenia.

The only study to date that has tested this idea was an open-label trial of adding nefazodone to

standard antipsychotics over 26 weeks (G. Joffe et al. 1999). Three of eight patients ultimately

dropped out of the study, but those who remained experienced at least modest improvement in

both their EPS and their negative symptoms. Nefazodone is rarely used today. Another study

suggests that mirtazapine can also help with negative symptoms (Berk et al. 2001).

Finally, low doses of standard antipsychotics may actually increase the availability of dopamine

synaptically by stimulating presynaptic dopamine autoreceptors to release more dopamine. There

have been some anecdotal reports of both worsening of positive symptoms and improvement of

negative symptoms with low-dose antipsychotics. In a placebo-controlled study, amisulpride, a

dopamine-blocking benzamide antipsychotic not yet available in the United States, was found toPrint: Chapter 9. Augmentation Strategies for Treatment-Resistant Dis… http://www.psychiatryonline.com/popup.aspx?aID=238341&print=yes…

17 of 29

31/01/2009 06:54

significantly improve negative symptoms of schizophrenia at low doses (Boyer et al. 1995). At high

doses, amisulpride and standard antipsychotics may worsen negative symptoms by dampening

dopaminergic tone throughout the prefrontal cortex.

Combinations of Mood Stabilizers and Antipsychotics

As many as a third of schizophrenic patients do not respond adequately to an antipsychotic. One of

the earliest augmentation strategies for treatment-resistant schizophrenia was the addition of

lithium. Lithium augmentation of neuroleptics at relatively low dosages (300–900 mg/day) has

been said to be helpful in the treatment of schizophrenia (Johns and Thompson 1995). However,

most of the reports suggesting that lithium is a useful augmenting agent in treating schizophrenia

have been anecdotal. Several randomized, controlled studies have investigated the efficacy of

lithium when added to an antipsychotic. None has shown any benefit of adding lithium over adding

placebo in patients with well-characterized schizophrenia (Collins et al. 1991; Schulz et al. 1999;

Wilson 1993). It may be that earlier reports included patients with schizoaffective disorder or

psychotic mania, who may clearly benefit from lithium. Since lithium appears to increase the risk of

EPS and perhaps NMS with antipsychotics, we suggest using lithium augmentation primarily in

treating patients with suspected schizoaffective disorder. The dosage of the antipsychotic may

need to be lowered in some patients treated concurrently with lithium.

Valproate has been shown to be helpful as an adjunctive treatment in combination with

antipsychotics in the treatment of acute exacerbations of schizophrenia. Casey and colleagues

(2003) reported that adding 15–30 mg/kg/day of valproate resulted in earlier improvement in

psychotic symptoms in acutely ill schizophrenic patients. However, the effects of valproate as an

augmenter tend not to be evident at the endpoint of most trials (Basan et al. 2004). Thus,

valproate’s primary utility might be in speeding response, or perhaps as an adjunct in treating

agitation in some patients.

It has also been suggested that carbamazepine may boost antipsychotic effects. As with lithium,

many anecdotal and open-label studies have suggested a role for carbamazepine in

treatment-resistant schizophrenia. However, as with lithium, controlled trials have failed to show

much benefit of adding carbamazepine to an antipsychotic (Llorca et al. 1993; Martin Munoz et al.

1992). Since carbamazepine can substantially lower the serum levels of most concurrent

antipsychotics, we find it difficult to use carbamazepine as an augmenting agent in treating

schizophrenia.

An alternative to carbamazepine or valproate as an adjunctive agent in schizophrenia may be

topiramate. The addition of topiramate to antipsychotics has been reported to be beneficial in

resistant schizophrenia in a controlled trial (Tiihonen et al. 2005). Topiramate may also have the

advantage of mitigating antipsychotic-induced weight gain.

In general, mood stabilizers have been thought to have a limited role as augmenting agents in the

treatment of the core symptoms of schizophrenia. We have believed, on the other hand, that mood

stabilizers have a role as adjuvant agents in treating aggressive outbursts and agitation in patients

with schizophrenia. We have found gabapentin, at dosages up to 3,600 mg/day, and valproate, at

dosages of 750–2,000 mg/day, helpful in treating agitation and aggression in some patients with

schizophrenia. In addition, gabapentin may have the added benefit of helping with EPS in patients

treated with standard antipsychotics (see Chapter 5: “Mood Stabilizers”).

Other Augmentation Strategies

Abnormalities in glutamate transmission, particularly hypofunctioning of the N-methyl-D-aspartate

(NMDA) glutamate receptor, have been proposed in the etiology of deficit symptoms in

schizophrenia. To this end, a number of studies have examined the role of glycine and D-cycloserine

in augmenting the effects of antipsychotics. D-Cycloserine is an agonist of the NMDA receptor, and

a number of controlled trials have suggested that D-cycloserine improves negative symptoms and

neuropsychological functioning in patients taking standard antipsychotics (Goff et al. 1999b; RossePrint: Chapter 9. Augmentation Strategies for Treatment-Resistant Dis… http://www.psychiatryonline.com/popup.aspx?aID=238341&print=yes…

18 of 29

31/01/2009 06:54

et al. 1996; Tsai et al. 1998) but not in those taking clozapine (Goff et al. 1996, 1999a; Tsai et al.

1999). The dosage of D-cycloserine that was most effective was around 50 mg/day and tended to

be well tolerated. The effects of D-cycloserine on negative symptoms and cognitive functioning,

though significant, have not been particularly robust.

Glycine is an amino acid that is a co-agonist of the NMDA receptor. Early open trials suggested that

glycine helps some patients with schizophrenia and worsens symptoms in others (Rosse et al.

1989). A more recent crossover trial of high-dose glycine (0.8 g/kg) added to an antipsychotic

found that negative symptoms were significantly improved relative to placebo (Heresco-Levy et al.

1999). Glycine augmentation is a fairly benign strategy for improving negative symptoms.

However, it is unlikely that adding glycine to a standard antipsychotic is better in improving

negative symptoms than simply switching to an atypical agent. For patients who do not respond as

well to an atypical antipsychotic, the addition of glycine or D cycloserine may be an option.

Cyproheptadine (Periactin) is a general serotonin antagonist used primarily to treat migraines and

allergies. Its serotonin receptor antagonist properties have made it of interest to clinicians treating

negative symptoms in schizophrenia, since all atypical antipsychotics are also 5-HT2 antagonists. In

a controlled trial, cyproheptadine at a dosage of 24 mg/day significantly improved negative

symptoms and was well tolerated (Akhondzadeh et al. 1999). Cyproheptadine also has the

advantage of being anticholingergic and can help with EPS. The problem with cyproheptadine is

that most patients find it quite sedating, and 24 mg/day is a large dosage for many patients. It is

unclear whether smaller dosages might work just as well.

Finally, the serotonin3 (5-HT3) antagonist ondansetron has also been reported to be a useful

adjunctive or augmenting agent in resistant schizophrenia. Over the past 15 years, a number of

anecdotal reports have suggested that ondansetron, which is used primarily as an antinausea

medication, might help the cognitive and negative symptoms of schizophrenia. The first

double-blind study of ondansetron in resistant schizophrenia also seems to support the benefits of

this agent (Zhang et al. 2006). Patients with schizophrenia that is unresponsive to haloperidol were

more likely to see a 30% improvement in psychotic symptoms than were patients who had placebo

added to the haloperidol. Ondansetron is well tolerated but currently quite expensive. The dosage

of ondansetron used in Zhang et al.’s (2006) study was 8 mg/day administered for 12 weeks.

BIBLIOGRAPHY

Adityanjee: Modification of clozapine-induced leukopenia and neutropenia with lithium carbonate

(letter). Am J Psychiatry 152:648–649, 1995

Akhondzadeh S, Mohammadi MR, Amini-Nooshabadi H, et al: Cyproheptadine in treatment of

chronic schizophrenia: a double-blind, placebo-controlled study. J Clin Pharm Ther 24:49–52, 1999

[PubMed]

Alvarez E, Perez-Sola V, Perez-Blanco J, et al: Predicting outcome of lithium added to

antidepressants in resistant depression. J Affect Disord 42:179–186, 1997 [PubMed]

Aranow RB, Hudson JL, Pope HG Jr, et al: Elevated antidepressant plasma levels after addition of

fluoxetine. Am J Psychiatry 146:911–913, 1989 [PubMed]

Artigas F, Perez V, Alvarez E: Pindolol induces a rapid improvement of depressed patients treated

with serotonin reuptake inhibitors. Arch Gen Psychiatry 51:248–251, 1994 [PubMed]

Austin LS, Arana GW, Melvin JA: Toxicity resulting from lithium augmentation of antidepressant

treatment in elderly patients. J Clin Psychiatry 51: 344–345, 1990 [PubMed]

Bakish D, Hooper CL, Thornton MD, et al: Fast onset: an open study of the treatment of major

depressive disorder with nefazodone and pindolol combination therapy. Int Clin Psychopharmacol

12:91–97, 1997 [PubMed]

Baron BM, Ogden AM, Seigel BW, et al: Rapid down-regulation of beta-adrenoreceptors by

co-administration of desipramine and fluoxetine. Eur J Pharmacol 154:125–134, 1988 [PubMed]Print: Chapter 9. Augmentation Strategies for Treatment-Resistant Dis… http://www.psychiatryonline.com/popup.aspx?aID=238341&print=yes…

19 of 29

31/01/2009 06:54

Basan A, Kissling W, Leucht S: Valproate as an adjunct to antipsychotics for schizophrenia: a

systematic review of randomized trials. Schizophr Res 70:33–37, 2004 [PubMed]

Bauer M, Dopfmer S: Lithium augmentation in treatment-resistant depression: meta-analysis of

placebo-controlled studies. J Clin Psychopharmacol 19:427–434, 1999 [PubMed]

Bauer M, Hellweg R, Graf KJ, et al: Treatment of refractory depression with high-dose thyroxine.

Neuropsychopharmacology 18:444–455, 1998 [PubMed]

Bauer M, Zaninelli R, Muller-Oerlinghausen B, et al: Paroxetine and amitriptyline augmentation of

lithium in the treatment of major depression: a double-blind study. J Clin Psychopharmacol

19:164–171, 1999 [PubMed]

Bell IR, Cole JO: Fluoxetine induces elevation of desipramine levels and exacerbation of geriatric

nonpsychotic depression (letter). J Clin Psychopharmacol 8:447–448, 1988 [PubMed]

Berk M, Ichim C, Brook S: Efficacy of mirtazapine add-on therapy to haloperidol in the treatment of

the negative symptoms of schizophrenia: a double-blind, randomized, placebo-controlled study. Int

Clin Psychopharmacol 16(2):87–92, 2001 [PubMed]

Blier P, Bergeson R: Effectiveness of pindolol with selected antidepressant drugs in the treatment

of major depression. J Clin Psychopharmacol 15: 217–222, 1995 [PubMed]

Bloch M, Schmidt PJ, Danaceau MA, et al: Dehydroepiandrosterone treatment of midlife dysthymia.

Biol Psychiatry 45:1533–1544, 1999 [PubMed]

Bodkin JA, Cohen BM, Salomon MS, et al: Treatment of negative symptoms in schizophrenia and

schizoaffective disorder by selegiline augmentation of antipsychotic medication: a pilot study

examining the role of dopamine. J Nerv Ment Dis 184: 295–301, 1996 [PubMed]

Bodkin JA, Lasser RA, Wines JD Jr, et al: Combining serotonin reuptake inhibitors and bupropion in

partial responders to antidepressant monotherapy. J Clin Psychiatry 58:137–145, 1997 [PubMed]

Bommer M, Naber D: Subclinical hypothyroidism in recurrent mania. Biol Psychiatry 31:729–734,

1992 [also see comments]

Bouwer C, Stein DJ: Buspirone is an effective augmenting agent of serotonin selective reuptake

inhibitors in severe treatment-refractory depression. S Afr Med J 87 (4, suppl):534–537, 540, 1997

Bowden CL, Myers JE, Grossman F, et al: Risperidone in combination with mood stabilizers: a

10-week continuation phase study in bipolar I disorder. J Clin Psychiatry 65:707–714, 2004

[PubMed]

Boyer P, Lecrubier Y, Puech AJ, et al: Treatment of negative symptoms in schizophrenia with

amisulpride. Br J Psychiatry 166:68–72, 1995 [PubMed]

Bunevicius R, Kazanavicius G, Zalinkevicius R, et al: Effects of thyroxine as compared with

thyroxine plus triiodothyronine in patients with hypothyroidism. N Engl J Med 340:424–429, 1999

[PubMed]

Carpenter LL, Jocic Z, Hall JM, et al: Mirtazapine augmentation in the treatment of refractory

depression. J Clin Psychiatry 60:45–49, 1999 [PubMed]

Carpenter LL, Yasmin S, Price LH: A double-blind, placebo-controlled study of antidepressant

augmentation with mirtazapine. Biol Psychiatry 51:183–188, 2002 [PubMed]

Casey DE, Daniel DG, Wassef AA, et al: Effect of divalproex combined with olanzapine or risperidone

in patients with an acute exacerbation of schizophrenia. Neuropsychopharmacology 28:182–192,

2003 [PubMed]

Cattell DL, King EA: Estrogen for postnatal depression. J Fam Pract 43:22–23, 1996 [PubMed]

Chambers CD, Johnson KA, Dick LM, et al: Birth outcomes in pregnant women taking fluoxetine. NPrint: Chapter 9. Augmentation Strategies for Treatment-Resistant Dis… http://www.psychiatryonline.com/popup.aspx?aID=238341&print=yes…

20 of 29

31/01/2009 06:54

Engl J Med 335:1010–1015, 1996 [also see comments]

Chan J, Sweeting M: Combination therapy with non-clozapine atypical antipsychotic medication: a

review of current evidence. J Psychopharmacol November 8, 2006 [Epub ahead of print]

Chang JS, Ha KS, Young Lee K, et al: The effects of long-term clozapine add-on therapy on the

rehospitalization rate and the mood polarity patterns in bipolar disorders. J Clin Psychiatry

67:461–467, 2006 [PubMed]

Chou JC, Zito JM, Vitrai J, et al: Neuroleptics in acute mania: a pharmacoepidemiologic study. Ann

Pharmacother 30:1396–1398, 1996 [PubMed]

Collins PJ, Larkin EP, Shubsachs AP: Lithium carbonate in chronic schizophrenia—a brief trial of

lithium carbonate added to neuroleptics for treatment of resistant schizophrenic patients. Acta

Psychiatr Scand 84: 150–154, 1991 [PubMed]

Cooke RG, Joffe RT, Levitt AJ: T3 augmentation of antidepressant treatment in T4-replaced thyroid

patients. J Clin Psychiatry 53: 16–18, 1992 [also see comments]

Coope J: Is estrogen effective in the treatment of menopausal depression? J R Coll Gen Pract

31:134–180, 1981 [PubMed]

Corrigan MH, Denahan AQ, Wright CE, et al: Comparison of pramipexole, fluoxetine, and placebo in

patients with major depression. Depress Anxiety 11:58–65, 2000 [PubMed]

Crowe D, Collins JP, Rosse RB: Thyroid hormone supplementation of fluoxetine treatment (letter). J

Clin Psychopharmacol 10:150–151, 1990 [PubMed]

DeBattista C: Pramipexole in the treatment of resistant depression. Presentation at the annual

meeting of the New Clinical Drug Evaluation Unit (NCDEU), Boca Raton, FL, 1997

DeBattista C, Schatzberg AF: Estrogen modulation of monoamines, in Estrogen in Mental Health:

From the Bench to the Bedside. Edited by Liebenluft E. Washington, DC, American Psychiatric

Publishing, 1999

DeBattista C, Solvason HB, Breen JA, et al: Pramipexole augmentation of a selective serotonin

reuptake inhibitor in the treatment of depression. J Clin Psychopharmacol 20:274–275, 2000

[PubMed]

DeBattista C, Solvason HB, Poirer J, et al: A prospective trial of bupropion SR augmentation of

partial and nonresponders to serotonergic antidepressants. J Clin Psychopharmacol 23:27–30, 2003

[PubMed]

DeBattista C, Lembke A, Solvason HB, et al: A prospective trial of modafinil as an adjunctive

treatment of major depression. J Clin Psychopharmacol 24:87–90, 2004 [PubMed]

Decina P, Mukherjee S, Bocola V, et al: Adjunctive trazodone in the treatment of negative

symptoms of schizophrenia. Hosp Community Psychiatry 45:1220–1223, 1994 [PubMed]

Dehydroepiandrosterone (DHEA). Med Lett Drugs Ther 8 (985; October 11):91–92, 1996

de Montigny C, Grunberg F, Mayer A, et al: Lithium induces rapid relief of depression in tricyclic

antidepressant drug non-responders. Br J Psychiatry 138:252–255, 1981

de Montigny C, Cournoyer G, Morissette R, et al: Lithium carbonate addition in tricyclic

antidepressant–resistant unipolar depression. Arch Gen Psychiatry 40: 1327–1334, 1983

Denicoff KD, Smith-Jackson EE, Bryan AL, et al: Valproate prophylaxis in a prospective clinical trial

of refractory bipolar disorder. Am J Psychiatry 154:1456–1458, 1997 [also see comments]

Eden Evins A, Demopulos C, Nierenberg A, et al: A double-blind, placebo-controlled trial of

adjunctive donepezil in treatment-resistant mania. Bipolar Disord 8:75–80, 2006

Everett HC: The use of bethanechol chloride with tricyclic antidepressants. Am J PsychiatryPrint: Chapter 9. Augmentation Strategies for Treatment-Resistant Dis… http://www.psychiatryonline.com/popup.aspx?aID=238341&print=yes…

21 of 29

31/01/2009 06:54

132:1202–1206, 1976

Fatemi SH, Emamian ES, Kist DA: Venlafaxine and bupropion combination therapy in a case of

treatment-resistant depression. Ann Pharmacother 33:701–703, 1999 [PubMed]

Fava M, Rosenbaum JF, McGrath PJ, et al: Lithium and tricyclic augmentation of fluoxetine

treatment for resistant major depression: a double-blind, controlled study. Am J Psychiatry

151:1372–1374, 1994 [PubMed]

Fawcett J, Kravitz HM, Zajeda JM, et al: CNS stimulant potentiation of monoamine oxidase

inhibitors in treatment refractory depression. J Clin Psychopharmacol 11:127–132, 1991 [PubMed]

Feighner JP, Brauzer B, Gelenberg AJ, et al: A placebo-controlled multicenter trial of Limbitrol

versus its components (amitriptyline and chlordiazepoxide) in the symptomatic treatment of

depressive illness. Psychopharmacology (Berl) 61:217–225, 1979 [PubMed]

Ferraro L, Antonelli T, O’Connor WT, et al: Modafinil: an antinarcoleptic drug with a different

neurochemical profile to d-amphetamine and dopamine uptake blockers. Biol Psychiatry

42:1181–1183, 1997 [PubMed]

Flint AJ, Rifat SL: A prospective study of lithium augmentation in antidepressant-resistant geriatric

depression. J Clin Psychopharmacol 14:353–356, 1994 [PubMed]

Fontaine R, Ontiveros A, Elie R, et al: Lithium carbonate augmentation of desipramine and

fluoxetine in refractory depression. Biol Psychiatry 29: 946–948, 1991 [erratum: Biol Psychiatry

31:322, 1992; also see comments]

Fritze J, Beneke M, Lanczik M, et al: Carbamazepine as adjunct or alternative to lithium in the

prophylaxis of recurrent affective disorders. Pharmacopsychiatry 27:181–185, 1994 [PubMed]

Gerner RH, Stanton A: Algorithm for patient management of acute manic states: lithium, valproate,

or carbamazepine? J Clin Psychopharmacol 12 (1, suppl):57S–63S, 1992

Ghaemi SN, Goodwin FK: Use of atypical antipsychotic agents in bipolar and schizoaffective

disorders: review of the empirical literature. J Clin Psychopharmacol 19:354–361, 1999 [PubMed]

Ghaemi SN, Sachs GS, Baldassano CF, et al: Acute treatment of bipolar disorder with adjunctive

risperidone in outpatients. Can J Psychiatry 42: 196–199, 1997 [PubMed]

Ghaemi SN, Katzow JJ, Desai SP, et al: Gabapentin treatment of mood disorders: a preliminary

study. J Clin Psychiatry 59:426–429, 1998 [PubMed]

Ghaemi SN, Schrauwen E, Klugman J, et al: Long-term lamotrigine plus lithium for bipolar disorder:

one year outcome. J Psychiatr Pract 12:300–305, 2006 [PubMed]

Gitlin MJ, Weiner H, Fairbanks L, et al: Failure of T3 to potentiate tricyclic antidepressant response.

J Affect Disord 13:267–272, 1987 [PubMed]

Goddard AW, Brouette T, Almai A, et al: Early coadministration of clonazepam with sertraline for

panic disorder. Arch Gen Psychiatry 58:681–686, 2001 [PubMed]

Goff DC, Midha KK, Sarid-Segal O, et al: A placebo-controlled trial of fluoxetine added to neuroleptic

in patients with schizophrenia. Psychopharmacology (Berl) 117:417–423, 1995 [PubMed]

Goff DC, Tsai G, Manoach DS, et al: D-Cycloserine added to clozapine for patients with

schizophrenia. Am J Psychiatry 153:1628–1630, 1996 [PubMed]

Goff DC, Henderson DC, Evins AE, et al: A placebo-controlled crossover trial of D-cycloserine added

to clozapine in patients with schizophrenia. Biol Psychiatry 45:512–514, 1999a

Goff DC, Tsai G, Levitt J, et al: A placebo-controlled trial of D-cycloserine added to conventional

neuroleptics in patients with schizophrenia. Arch Gen Psychiatry 56:21–27, 1999b [also see

comments]Print: Chapter 9. Augmentation Strategies for Treatment-Resistant Dis… http://www.psychiatryonline.com/popup.aspx?aID=238341&print=yes…

22 of 29

31/01/2009 06:54

Goldberg JF, Burdick KE, Endick CJ: Preliminary randomized, double-blind, placebo-controlled trial

of pramipexole added to mood stabilizers for treatment-resistant bipolar depression. Am J

Psychiatry 161:564–566, 2004 [Full Text] [PubMed]

Goldman MB, Janecek HM: Adjunctive fluoxetine improves global functioning in chronic

schizophrenia. J Neuropsychiatry Clin Neurosci 2:429–431, 1990 [PubMed]

Goodwin FK, Prange A, Post RM, et al: Potentiation of antidepressant effects by L-triiodothyronine

in tricyclic nonresponders. Am J Psychiatry 139: 34–38, 1982 [PubMed]

Granacher RP, Baldessarini RJ: Physostigmine: its use in acute anticholinergic syndrome with

antidepressant and antiparkinson drugs. Arch Gen Psychiatry 23:375–380, 1978

Gupta S, Masand P, Tanquary JF: Thyroid hormone supplementation of fluoxetine in the treatment

of major depression. Br J Psychiatry 159:866–867, 1991 [PubMed]

Hayes SG: Barbiturate anticonvulsants in refractory affective disorders. Ann Clin Psychiatry

5:35–44, 1993 [PubMed]

Heninger GR, Charney DS, Sternberg DE: Lithium carbonate augmentation of antidepressant

treatment. Arch Gen Psychiatry 40:1335–1342, 1983 [PubMed]

Heresco-Levy U, Javitt DC, Ermilov M, et al: Efficacy of high-dose glycine in the treatment of

enduring negative symptoms of schizophrenia. Arch Gen Psychiatry 56:29–36, 1999 [also see

comments]

Hollander E, DeCaria CM, Schneier FR, et al: Fenfluramine augmentation of serotonin reuptake

blockade antiobsessional treatment. J Clin Psychiatry 51:119–123, 1990 [PubMed]

Holsboer F, Grasser A, Friess E, et al: Steroid effects on central neurons and implications for

psychiatric and neurological disorders. Ann N Y Acad Sci 746:345–359 [discussion 359–361], 1994

Hopwood SE, Bogle S, Wildgust HJ: The combination of fluoxetine and lithium in clinical practice.

Int Clin Psychopharmacol 8:325–327, 1993 [PubMed]

Howland RH: Lithium augmentation of fluoxetine in the treatment of OCD and major depression: a

case report (letter). Can J Psychiatry 36:154–155, 1991 [PubMed]

Howland RH: Thyroid dysfunction in refractory depression: implications for pathophysiology and

treatment. J Clin Psychiatry 54:47–54, 1993 [PubMed]

Joffe G, Appelberg B, Rimon R: Adjunctive nefazodone in neuroleptic-treated schizophrenic patients

with predominantly negative symptoms: an open prospective pilot study. Int Clin Psychopharmacol

14:233–238, 1999 [PubMed]

Joffe RT: Triiodothyronine potentiation of fluoxetine in depressed patients. Can J Psychiatry

37:48–50, 1992 [PubMed]

Joffe RT, Schuller DR: An open study of buspirone augmentation of serotonin reuptake inhibitors. J

Clin Psychiatry 54:269–271, 1993 [PubMed]

Joffe RT, Singer W: Thyroid hormone potentiation of antidepressants. Neuroendocrinology Letters

(St. Michael’s Hospital) 9:172, 1987

Joffe RT, Levitt AJ, Bagby RM, et al: Predictors of response to lithium and triiodothyronine:

augmentation of antidepressants in tricyclic nonresponders. Br J Psychiatry 163:574–578, 1993

[PubMed]

Joffe RT, Sokolov ST, Levitt AJ: Lithium and triiodothyronine augmentation of antidepressants. Can

J Psychiatry 51:791–793, 2006 [PubMed]

Johns CA, Thompson JW: Adjunctive treatments in schizophrenia: pharmacotherapies and

electroconvulsive therapy. Schizophr Bull 21:607–619, 1995 [PubMed]Print: Chapter 9. Augmentation Strategies for Treatment-Resistant Dis… http://www.psychiatryonline.com/popup.aspx?aID=238341&print=yes…

23 of 29

31/01/2009 06:54

Karunakaran K, Tungaraza TE, Harborne G: Is clozapine-aripiprazole combination a useful regime in

the management of treatment-resistant schizophrenia? J Psychopharmacol October 18, 2006 [Epub

ahead of print]

Katona CL, Robertson MM, Abou-Saleh MT, et al: Placebo-controlled trial of lithium augmentation of

fluoxetine and lofepramine. Int Clin Psychopharmacol 8:238, 1993

Katona CL, Abou-Saleh MT, Harrison DA, et al: Placebo-controlled trial of lithium augmentation of

fluoxetine and lofepramine. Br J Psychiatry 166: 80–86, 1995 [PubMed]

Keck PE: A randomized, placebo-controlled trial of olanzapine and olanzapine-fluoxetine

combination in the treatment of bipolar depression. Presentation at the 155th annual meeting of

the American Psychiatric Association, Philadelphia, PA, May 2002

Keck PE Jr, McElroy SL, Vuckovic A, et al: Combined valproate and carbamazepine treatment of

bipolar disorder. J Neuropsychiatry Clin Neurosci 4: 319–322, 1992 [PubMed]

Ketter TA, Winsberg ME, DeGolia SG, et al: Rapid efficacy of olanzapine augmentation in

nonpsychotic bipolar mixed states (letter). J Clin Psychiatry 59:83–85, 1998 [also see comments]

Ketter TA, Wang PW, Chandler RA, et al: Adjunctive aripiprazole in treatment-resistant bipolar

depression. Ann Clin Psychiatry 18:169–172, 2006 [PubMed]

Kirsch MA, Louie AK: Combination treatment with venlafaxine and bupropion (letter). Am J

Psychiatry 156:494, 1999 [Full Text] [PubMed]

Kishimoto A: The treatment of affective disorder with carbamazepine: prophylactic synergism of

lithium and carbamazepine combination. Prog Neuropsychopharmacol Biol Psychiatry 16:483–493,

1992 [PubMed]

Kline NS, Pare M, Hallstrom C, et al: Amitriptyline protects patients on MAOIs from tyramine

reactions. J Clin Psychopharmacol 2:434–435, 1982 [PubMed]

Kramlinger KG, Post RM: Addition of lithium carbonate to carbamazepine: hematological and

thyroid effects. Am J Psychiatry 147:615–620, 1990 [also see comments]

Kusalic M: Grade II and grade III hypothyroidism in rapid-cycling bipolar patients.

Neuropsychobiology 25:177–181, 1992 [PubMed]

Landen M, Bjorling G, Agren H, et al: A randomized, double-blind, placebo-controlled trial of

buspirone in combination with an SSRI in patients with treatment-refractory depression. J Clin

Psychiatry 59:664–668, 1998 [PubMed]

Lemberger L, Rowe H, Bosomworth J, et al: The effect of fluoxetine on the pharmacokinetics and

psychomotor responses of diazepam. Clin Pharmacol Ther 43: 412–419, 1988 [PubMed]

Levine J, Brak Y, Gonzalves M, et al: Double-blind controlled trial of inositol treatment of major

depression. Am J Psychiatry 152:792–794, 1995 [PubMed]

Levine J, Mishori A, Susnosky M, et al: Combination of inositol and serotonin reuptake inhibitors in

the treatment of depression. Biol Psychiatry 45: 270–273, 1999 [PubMed]

Lipinski JF, Pope HG Jr: Possible synergistic action between carbamazepine and lithium carbonate

in the treatment of three acutely manic patients. Am J Psychiatry 139: 948–949, 1982 [PubMed]

Llorca PM, Wolf MA, Lancon C, et al: Comparative efficacy of bromocriptine, carbamazepine and

cyproheptadine with neuroleptics in 24 refractory chronic schizophrenic patients [in French].

Encephale 19:565–571, 1993 [PubMed]

Martin Munoz JC, Morinigo Dominguez AV, Mateo Martin I, et al: Carbamazepine: an efficient

adjuvant treatment in schizophrenian [in Spanish]. Actas Luso-Esp Neurol Psiquiatr y Cienc Afines

20: 11–16, 1992Print: Chapter 9. Augmentation Strategies for Treatment-Resistant Dis… http://www.psychiatryonline.com/popup.aspx?aID=238341&print=yes…

24 of 29

31/01/2009 06:54

McAskill R, Mir S, Taylor D: Pindolol augmentation of antidepressant therapy. Br J Psychiatry

173:203–208, 1998 [also see comments] [erratum: Br J Psychiatry 173:443, 1998]

McCoy L, Votolato NA, Schwarzkopf SB, et al: Clinical correlates of valproate augmentation in

refractory bipolar disorder. Ann Clin Psychiatry 5:29–33, 1993 [PubMed]

McElroy SL, Pope HG Jr (eds): Use of Anticonvulsants in Psychiatry: Recent Advances. Clifton, NJ,

Oxford Health Care, 1988

McGinness J, Kishimoto A, Hollister LE: Avoiding neurotoxicity with lithium-carbamazepine

combinations. Psychopharmacol Bull 26:181–184, 1990 [PubMed]

McGrath PJ, Stewart JW, Fava M, et al: Tranylcypromine versus venlafaxine plus mirtazapine

following three failed antidepressant medication trials for depression: a STAR*D report. Am J

Psychiatry 163:1531–1541 [quiz 1666], 2006

McIntyre A, Gendron A, McIntyre A: Quetiapine adjunct to selective serotonin reuptake inhibitors or

venlafaxine in patients with major depression, comorbid anxiety, and residual depressive

symptoms: a randomized, placebo-controlled pilot study. Depress Anxiety December 18, 2006

[Epub ahead of print]

Michelson D, Aller AA, Amsterdam JD, et al: Addition of atomoxetine for depression incompletely

responsive to sertraline: a randomized, double-blind, placebo-controlled study, in Syllabus and

Proceedings Summary, American Psychiatric Association Annual Meeting, Toronto, ON, Canada, May

20–25, 2006, p 74

Mitchell P, Withers K, Jacobs G, et al: Combining lithium and sodium valproate for bipolar disorder.

Aust N Z J Psychiatry 28:141–143, 1994 [PubMed]

Montgomery SA: Selectivity of antidepressants and resistant depression, in Advances in

Neuropsychiatry and Psychopharmacology, Vol 2: Refractory Depression. Edited by Amsterdam JD.

New York, Raven, 1991, pp 93–104

Morera AL, Barreiro P, Cano-Munoz JL: Risperidone and clozapine combination for the treatment of

refractory schizophrenia. Acta Psychiatr Scand 99:305–306 [discussion: 306–307], 1999

Mouaffak F, Tranulis C, Gourevitch R, et al: Augmentation strategies of clozapine with

antipsychotics in the treatment of ultraresistant schizophrenia. Clin Neuropharmacol 29:28–33,

2006 [PubMed]

Muly EC, McDonald W, Steffens D, et al: Serotonin syndrome produced by a combination of

fluoxetine and lithium (letter). Am J Psychiatry 150:1565, 1993 [PubMed]

Nelson JC, Price LH: Lithium or desipramine augmentation of fluoxetine treatment (letter). Am J

Psychiatry 152:1538–1539, 1995 [PubMed]

Nierenberg AA, Keck PE: Management of monoamine oxidase inhibitor–associated insomnia with

trazodone. J Clin Psychopharmacol 9:45–54, 1989

Nierenberg AA, Price CH, Charney DS, et al: After lithium augmentation: a retrospective follow-up

of patients with antidepressant-refractory depression. J Affect Disord 18:67–75, 1990

Nierenberg AA, Cole JO, Glass L: Possible trazodone potentiation of fluoxetine: a case series. J Clin

Psychiatry 53:83–85, 1992 [PubMed]

Nierenberg AA, Adler LA, Pelow E, et al: Trazodone for antidepressant associated insomnia. Am J

Psychiatry 151:1069–1072, 1994 [PubMed]

Nierenberg AA, Fava M, Trivedi MH, et al: A comparison of lithium and T3 augmentation following

two failed medication treatments for depression: a STAR*D report. Am J Psychiatry 163:1519–1530

[quiz 1665], 2006a

Nierenberg AA, Ostacher MJ, Calabrese JR, et al: Treatment-resistant bipolar depression: a STEP-BDPrint: Chapter 9. Augmentation Strategies for Treatment-Resistant Dis… http://www.psychiatryonline.com/popup.aspx?aID=238341&print=yes…

25 of 29

31/01/2009 06:54

equipoise randomized effectiveness trial of antidepressant augmentation with lamotrigine, inositol,

or risperidone. Am J Psychiatry 163:210–216, 2006b

Okuma T: Effects of carbamazepine and lithium on affective disorders. Neuropsychobiology

27:138–145, 1993 [PubMed]

Ontiveros A, Fontaine R, Elie R: Refractory depression: the addition of lithium to fluoxetine or

desipramine. Acta Psychiatr Scand 83:188–192, 1991 [PubMed]

Palinkas LA, Barrett-Connor E: Estrogen use and depressive symptoms in postmenopausal women.

Obstet Gynecol 80:30–36, 1992 [PubMed]

Pare CMB, Kline N, Hallstrom C, et al: Will amitriptyline prevent the “cheese” reaction of

monoamine oxidase inhibitors? Lancet 2:183–186, 1982 [PubMed]

Perugi G, Toni C, Ruffolo G, et al: Clinical experience using adjunctive gabapentin in

treatment-resistant bipolar mixed states. Pharmacopsychiatry 32:136–141, 1999 [PubMed]

Peselow ED, Fieve RR, Difiglia C, et al: Lithium prophylaxis of bipolar illness: the value of

combination treatment. Br J Psychiatry 164:208–214, 1994 [PubMed]

Pope HG Jr, McElroy SL, Nixon RA: Possible synergism between fluoxetine and lithium in refractory

depression. Am J Psychiatry 145:1292–1294, 1988 [PubMed]

Pope HG Jr, Cohane GH, Kanayama G, et al: Testosterone gel supplementation for men with

refractory depression: a randomized, placebo-controlled trial. Am J Psychiatry 160:105–111, 2003

[Full Text] [PubMed]

Price LH, Conwell Y, Nelson JC: Lithium augmentation of combined neuroleptic-tricyclic treatment

in delusional depression. Am J Psychiatry 140: 318–322, 1983 [PubMed]

Price LH, Charry DS, Heninger GR: Efficacy of lithium-tranylcypromine treatment in refractory

depression. Am J Psychiatry 142:619–623, 1985 [PubMed]

Rabkin JG, McElhiney MC, Rabkin R, et al: Placebo-controlled trial of dehydroepiandrosterone

(DHEA) for treatment of nonmajor depression in patients with HIV/AIDS. Am J Psychiatry

163:59–66, 2006 [Full Text] [PubMed]

Rapaport MH, Gharabawi GM, Canuso CM, et al: Effects of risperidone augmentation in patients with

treatment-resistant depression: results of open-label treatment followed by double-blind

continuation. Neuropsychopharmacology 31:2505–2513, 2006 [erratum:

Neuropsychopharmacology 31:2514, 2006)]

Rasgon NL, Dunkin J, Fairbanks L, et al: Estrogen and response to sertraline in postmenopausal

women with major depressive disorder: a pilot study. J Psychiatr Res 41:338–343, 2007 [PubMed]

Raynaud JP: Prostate cancer risk in testosterone-treated men. J Steroid Biochem Mol Biol

102:261–266, 2006 [PubMed]

Remington G, Saha A, Chong SA, et al: Augmentation strategies in clozapine-resistant

schizophrenia. CNS Drugs 19:843–872, 2005 [PubMed]

Rosse RB, Theut SK, Banay-Schwartz M, et al: Glycine adjuvant therapy to conventional neuroleptic

treatment in schizophrenia: an open-label, pilot study. Clin Neuropharmacol 12:416–424, 1989

[PubMed]

Rosse RB, Fay-McCarthy M, Kendrick K, et al: D-Cycloserine adjuvant therapy to molindone in the

treatment of schizophrenia. Clin Neuropharmacol 19: 444–450, 1996 [PubMed]

Rothschild AJ, Samson JA, Besset MP, et al: Efficacy of the combination of fluoxetine and

perphenazine in the treatment of psychotic depression. J Clin Psychiatry 54: 338–342, 1993

[PubMed]Print: Chapter 9. Augmentation Strategies for Treatment-Resistant Dis… http://www.psychiatryonline.com/popup.aspx?aID=238341&print=yes…

26 of 29

31/01/2009 06:54

Rothschild AJ, Williamson DJ, Tohen MF, et al: A double-blind, randomized study of olanzapine and

olanzapine/fluoxetine combination for major depression with psychotic features. J Clin

Psychopharmacol 24:365–373, 2004 [PubMed]

Sachs GS, Weilburg JB, Rosenbaum JF: Clonazepam vs. neuroleptics as adjuncts to lithium

maintenance. Psychopharmacol Bull 26:137–143, 1990 [PubMed]

Sachs GS, Grossman F, Ghaemi SN, et al: Combination of a mood stabilizer with risperidone or

haloperidol for treatment of acute mania: a double-blind, placebo-controlled comparison of efficacy

and safety. Am J Psychiatry 159:1146–1154, 2002 [Full Text] [PubMed]

Schatzberg AF, DeBattista CB, DeGolia S: Valproate in the treatment of agitation associated with

depression. Psychiatr Ann 26:1–4, 1996

Schmidt PJ, Daly RC, Bloch M, et al: Dehydroepiandrosterone monotherapy in midlife-onset major

and minor depression. Arch Gen Psychiatry 62:154–162, 2005 [PubMed]

Schneider AL, Wilcox CS: Divalproate augmentation in lithium-resistant rapid cycling mania in four

geriatric patients. J Affect Disord 47:201–205, 1998 [PubMed]

Schneider LS, Small GW, Hamilton SH, et al: Estrogen replacement and response to fluoxetine in a

multicenter geriatric depression trial. Fluoxetine Collaborative Study Group. Am J Geriatr

Psychiatry 5:97–106, 1997 [PubMed]

Schneider LS, Small GW, Clary CM: Estrogen replacement therapy and antidepressant response to

sertraline in older depressed women. Am J Geriatr Psychiatry 9:393–399, 2001 [PubMed]

Schulz SC, Thompson PA, Jacobs M, et al: Lithium augmentation fails to reduce symptoms in poorly

responsive schizophrenic outpatients. J Clin Psychiatry 60: 366–372, 1999 [PubMed]

Seidman SN, Spatz E, Rizzo C, et al: Testosterone replacement therapy for hypogonadal men with

major depressive disorder: a randomized, placebo-controlled clinical trial. J Clin Psychiatry

62:406–412, 2001 [PubMed]

Seidman SN, Miyazaki M, Roose SP: Intramuscular testosterone supplementation to selective

serotonin reuptake inhibitor in treatment-resistant depressed men: randomized placebo-controlled

clinical trial. J Clin Psychopharmacol 25:584–588, 2005 [PubMed]

Sharma V, Persad E: Augmentation of valproate with lithium in a case of rapid cycling affective

disorder. Can J Psychiatry 37:584–585, 1992 [PubMed]

Sharma V, Persad E, Mazmanian D, et al: Treatment of rapid cycling bipolar disorder with

combination therapy of valproate and lithium. Can J Psychiatry 38:137–139, 1993 [PubMed]

Shelton RC: The combination of olanzapine and fluoxetine in mood disorders. Expert Opin

Pharmacother 4(7):1175–1183, 2003 [PubMed]

Shelton RC, Tollefson GD, Tohen M, et al: A novel augmentation strategy for treating resistant

major depression. Am J Psychiatry 158:131–134, 2001 [Full Text] [PubMed]

Shelton RC, Williamson DJ, Corya SA, et al: Olanzapine/fluoxetine combination for

treatment-resistant depression: a controlled study of SSRI and nortriptyline resistance. J Clin

Psychiatry 66:1289–1297, 2005 [PubMed]

Sherwin BB: Estrogen in refractory depression, in Advances in Neuropsychiatry and

Psychopharmacology, Vol 2: Refractory Depression. Edited by Amsterdam JD. New York, Raven,

1991, pp 209–218

Sichel DA, Cohen LS, Robertson LM, et al: Prophylactic estrogen in recurrent postpartum affective

disorder. Biol Psychiatry 38:814–818, 1995 [PubMed]

Silver H, Nassar A: Fluvoxamine improves negative symptoms in treated chronic schizophrenia. Biol

Psychiatry 31:698–704, 1992 [PubMed]Print: Chapter 9. Augmentation Strategies for Treatment-Resistant Dis… http://www.psychiatryonline.com/popup.aspx?aID=238341&print=yes…

27 of 29

31/01/2009 06:54

Simhandl C, Denk E, Thau K: The comparative efficacy of carbamazepine low and high serum level

and lithium carbonate in the prophylaxis of affective disorders. J Affect Disord 28:221–231, 1993

[PubMed]

Smith WT, Londborg PD, Glaudin V, et al: Short-term augmentation of fluoxetine with clonazepam

in the treatment of depression: a double-blind study. Am J Psychiatry 155:1339–1345, 1998 [Full

Text] [PubMed]

Soares CN, Almeida OP, Joffe H, et al: Efficacy of estradiol for the treatment of depressive disorders

in perimenopausal women. Arch Gen Psychiatry 58:529–534, 2001 [PubMed]

Sokolov ST, Levitt AJ, Joffe RT: Thyroid hormone levels before unsuccessful antidepressant therapy

are associated with later response to T3 augmentation. Psychiatry Res 69:203–206, 1997 [PubMed]

Solomon DA, Ryan CE, Keitner GI, et al: A pilot study of lithium carbonate plus divalproex sodium

for the continuation and maintenance treatment of patients with bipolar I disorder. J Clin

Psychiatry 58:95–99, 1997 [PubMed]

Solomon DA, Keitner GI, Ryan CE, et al: Lithium plus valproate as maintenance polypharmacy for

patients with bipolar I disorder: a review. J Clin Psychopharmacol 18:38–49, 1998 [PubMed]

Spiker DG, Weiss JC, Dealy RS: The pharmacological treatment of delusional depression. Am J

Psychiatry 142:430–436, 1985 [PubMed]

Spoov J, Lahdelma L: Should thyroid augmentation precede lithium augmentation? A pilot study. J

Affect Disord 49:235–239, 1998 [PubMed]

Steckler TL: Lithium- and carbamazepine-associated sinus node dysfunction: nine-year experience

in a psychiatric hospital. J Clin Psychopharmacol 14:336–339, 1994 [PubMed]

Stein G, Bernadt M: Lithium augmentation therapy in tricyclic resistant depression: a controlled

trial using lithium in low and normal doses. Br J Psychiatry 162:639–640, 1993

Stoll AL, Locke CA, Marangell LB, et al: Omega-3 fatty acids and bipolar disorder: a review.

Prostaglandins Leukot Essent Fatty Acids 60:329–337, 1999 [PubMed]

Stromgren LS: The combination of lithium and carbamazepine in treatment and prevention of

manic-depressive disorder: a review and a case report. Compr Psychiatry 31:261–265, 1990

[PubMed]

Takahashi N, Terao T, Oga T, et al: Comparison of risperidone and mosapramine addition to

neuroleptic treatment in chronic schizophrenia. Neuropsychobiology 39:81–85, 1999 [PubMed]

Targum SD, Grengberg RD, Harmon RL, et al: Thyroid hormone and the TRH stimulation test in

refractory depression. J Clin Psychiatry 45:345–346, 1984 [PubMed]

Thase ME, Kupfer DJ, Frank E, et al: Treatment of imipramine-resistant recurrent depression: an

open clinical trial of lithium augmentation. J Clin Psychiatry 50: 385–388, 1989 [PubMed]

Thase ME, Howland RH, Friedman ES: Treating antidepressant nonresponders with augmentation

strategies: an overview. J Clin Psychiatry 59 (5, suppl):5-12 [discussion: 13–15], 1998

Tiihonen J, Halonen P, Wahlbeck K, et al: Topiramate add-on in treatment-resistant schizophrenia:

a randomized, double-blind, placebo-controlled, crossover trial. J Clin Psychiatry 66:1012–1015,

2005 [PubMed]

Tohen M, Chengappa KN, Suppes T, et al: Efficacy of olanzapine in combination with valproate or

lithium in the treatment of mania in patients partially nonresponsive to valproate or lithium

monotherapy. Arch Gen Psychiatry 59:62–69, 2002 [PubMed]

Tollefson GD, Sanger TM, Anderson SW: The use of an olanzapine:fluoxetine combination in the

treatment of major depression with psychotic features: results from a large, prospective

double-blind trial, in Abstracts of the 40th Annual Meeting of the American College ofPrint: Chapter 9. Augmentation Strategies for Treatment-Resistant Dis… http://www.psychiatryonline.com/popup.aspx?aID=238341&print=yes…

28 of 29

31/01/2009 06:54

Neuropsychopharmacology, Waikoloa, HI, 2001, p 58

Trivedi MH, Fava M, Wisniewski SR, et al, and STAR*D Study Team: Medication augmentation after

the failure of SSRIs for depression. N Engl J Med 354:1243–1252, 2006 [PubMed]

Tsai G, Yang P, Chung LC, et al: D-Serine added to antipsychotics for the treatment of

schizophrenia. Biol Psychiatry 44:1081–1089, 1998 [also see comments]

Tsai GE, Yang P, Chung LC, et al: D-Serine added to clozapine for the treatment of schizophrenia.

Am J Psychiatry 156:1822–1825, 1999 [Full Text] [PubMed]

The Upjohn Company: Technical Report Synopsis: A Multicenter Study to Evaluate the

Pharmacokinetic and Clinical Interactions Between Alprazolam and Imipramine. Kalamazoo, MI,

The Upjohn Company, 1986

The Upjohn Company: Technical Report Synopsis: A Pharmacokinetic/Pharmacodynamic Evaluation

of the Combined Administration of Alprazolam and Fluoxetine. Kalamazoo, MI, The Upjohn

Company, 1990

Vieta E, Sanchez-Moreno J, Martinez-Aran A, et al: Effects on weight and outcome of long-term

olanzapine-topiramate combination treatment in bipolar disorder. J Clin Psychopharmacol

24:374–378, 2004 [PubMed]

Vieweg V, Shutty M, Hundley P, et al: Combined treatment with lithium and carbamazepine (letter).

Am J Psychiatry 148:398–399, 1991 [also see comments]

Wehr TA, Goodwin FK: Rapid cycling in manic-depressives induced by tricyclic antidepressants.

Arch Gen Psychiatry 36:555–559, 1979 [PubMed]

Wehr TA, Sack DA, Rosenthal NE, et al: Rapid cycling affective disorder: contributing factors and

treatment responses in 51 patients. Am J Psychiatry 145:179–184, 1988 [PubMed]

Weilburg JB, Rosenbaum JF, Biederman J, et al: Fluoxetine added to non-MAOI antidepressants

converts nonresponders to responders: a preliminary report. J Clin Psychiatry 50:447–449, 1989

[PubMed]

Wharton RN, Perel JM, Dayton PG, et al: A potential clinical use for methylphenidate with tricyclic

antidepressants. Am J Psychiatry 127:1619–1625, 1971 [PubMed]

Wheatley D: Potentiation of amitriptyline by thyroid hormone. Arch Gen Psychiatry 26:229–233,

1972 [PubMed]

White K, Simpson G: Combined MAOI–tricyclic antidepressant treatment: a reevaluation. J Clin

Psychopharmacol 1:264–282, 1981 [PubMed]

Whybrow PC: The therapeutic use of triiodothyronine and high dose thyroxine in psychiatric

disorders. Acta Med Austriaca 21:47–52, 1994 [PubMed]

Whybrow PC, Bauer MS, Gyulai L: Thyroid axis considerations in patients with rapid cycling

affective disorder. Clin Neuropharmacol 15:391A–392A, 1992

Wijkstra J, Lijmer J, Balk FJ, et al: Pharmacological treatment for unipolar psychotic depression:

systematic review and meta analysis. Br J Psychiatry 188:410–415, 2006 [PubMed]

Wilson WH: Addition of lithium to haloperidol in non-affective, antipsychotic non-responsive

schizophrenia: a double blind, placebo controlled, parallel design clinical trial. Psychopharmacology

(Berl) 111:359–366, 1993 [PubMed]

Wolkowitz OM, Reus VI, Roberts E, et al: Antidepressant and cognition-enhancing effects of DHEA

in major depression. Ann N Y Acad Sci 774: 337–339, 1993

Wolkowitz OM, Reus VI, Roberts E, et al: Dehydroepiandrosterone (DHEA) treatment of depression.

Biol Psychiatry 41:311–318, 1997 [PubMed]Print: Chapter 9. Augmentation Strategies for Treatment-Resistant Dis… http://www.psychiatryonline.com/popup.aspx?aID=238341&print=yes…

29 of 29

31/01/2009 06:54

Young LT, Robb JC, Hasey GM, et al: Gabapentin as an adjunctive treatment in bipolar disorder. J

Affect Disord 55:73–77, 1999 [PubMed]

Young LT, Joffe RT, Robb JC, et al: Double-blind comparison of addition of a second mood stabilizer

versus an antidepressant to an initial mood stabilizer for treatment of patients with bipolar

depression. Am J Psychiatry 157:124–126, 2000 [Full Text] [PubMed]

Zanardi R, Franchini L, Serretti A, et al: Venlafaxine versus fluvoxamine in the treatment of

delusional depression: a pilot double-blind controlled study. J Clin Psychiatry 61:26–29, 2000

[PubMed]

Zarate CA, Payne JL, Singh J, et al: Pramipexole for bipolar II depression: a placebo-controlled

proof of concept study. Biol Psychiatry 56:54–60, 2004 [PubMed]

Zhang ZJ, Kang WH, Li Q, et al: Beneficial effects of ondansetron as an adjunct to haloperidol for

chronic, treatment-resistant schizophrenia: A double-blind, randomized, placebo-controlled study.

Schizophr Res 88:102–110, 2006 [PubMed]

Ziegenbein M, Calliess IT: Clozapine and ziprasidone: a useful combination in patients with

treatment-resistant schizophrenia. J Neuropsychiatry Clin Neurosci 18:246–247, 2006 [Full Text]

[PubMed]

Ziegenbein M, Wittmann G, Kropp S: Aripiprazole augmentation of clozapine in treatment-resistant

schizophrenia: a clinical observation. Clin Drug Investig 26:117–124, 2006 [PubMed]

Copyright © 2009 American Psychiatric Publishing, Inc. All Rights Reserved.