Richard C. Shelton, MD

Side effects to discontinuing serotonin reuptake inhibitor (SRI) treatment are common and may be severe.¹ Patients who are not prepared for these reactions may attribute symptoms to other causes such as a medical illness. Educate your patient about potential side effects to mitigate problems such as relapse or patient distress.

1 Warn your patient

Alert patients to potential discontinuation reactions when prescribing any antidepressant, particularly SRIs because they seem to cause more discontinuation problems than other classes of drugs. Although reactions appear to be more common and severe with short-acting drugs such as venlafaxine and paroxetine, they can occur with longer half-life agents such as fluoxetine and sertraline.

Warn patients about discontinuation effects when starting treatment and before the planned drug taper. In particular, caution them against missing doses or stopping a drug without informing you.

2 Know the symptoms

Common discontinuation symptoms can be grouped into six areas:

• Neurosensory—vertigo, paresthesias, shock-like reactions, myalgia
  
• Neuromotor—tremor, myoclonus, ataxia, visual changes, piloerection
  
• Gastrointestinal—nausea, vomiting, diarrhea
  
• Psychiatric—anxiety, depressed mood, suicidal ideation, irritability
  
• Vasomotor—flushing, diaphoresis
  
• Other neuropsychiatric—anorexia, insomnia, vivid dreams, asthenia, chills.²
  

3 Distinguish discontinuation reactions from relapse

Although depressed mood and anxiety may occur during taper, these symptoms tend to be transient in most patients. Severe or persistent symptoms—including emerging suicidal ideation—may indicate a relapse.

4 Reduce medication slowly

Tapering is recommended for all antidepressants but should be particularly slow for certain drugs—including venlafaxine, paroxetine, and clomipramine—which can cause significant discontinuation effects. For example, venlafaxine at 225 mg/d could be reduced by 75 mg/d every 1 to 2 weeks, with a final step at 37.5 mg/d for at least 1 week.

If discontinuation reactions are a problem, ultimate discontinuation may require substituting a longer-acting medication such as fluoxetine during the tapering period. For example, add fluoxetine, 10 to 20 mg/d, for 1 week, then stop both antidepressants or discontinue the first medication and continue fluoxetine for 2 to 3 weeks until the risk of reactions passes.

Clinicians often are concerned about serotonin syndrome caused by combining SRIs. Isolated cases have been reported, but the small, finite chance of serotonin syndrome is much lower than the risk of severe discontinuation reactions.

5 Titrate up and taper down

When switching to another SRI, titrate the second drug upward while tapering off the first. Remember that changing to a drug that does not act on serotonin, such as bupropion, can protect against discontinuation effects.

6 Allow for pregnancy

Infants born to mothers taking antidepressants can exhibit discontinuation symptoms,² particularly with shorter-acting drugs such as paroxetine or venlafaxine. Consider tapering the antidepressant early in the patient’s third trimester, then re-institute treatment after delivery. If an antidepressant is required during pregnancy, try using one with a longer half-life such as fluoxetine.

Drug brand names

• Bupropion • Wellbutrin
  
• Clomipramine • Anafranil
  
• Fluoxetine • Prozac
  
• Paroxetine • Paxil
  
• Sertraline • Zoloft
  
• Venlafaxine • Effexor
  

Side effects to discontinuing serotonin reuptake inhibitor (SRI) treatment are common and may be severe.¹ Patients who are not prepared for these reactions may attribute symptoms to other causes such as a medical illness. Educate your patient about potential side effects to mitigate problems such as relapse or patient distress.

1 Warn your patient

Alert patients to potential discontinuation reactions when prescribing any antidepressant, particularly SRIs because they seem to cause more discontinuation problems than other classes of drugs. Although reactions appear to be more common and severe with short-acting drugs such as venlafaxine and paroxetine, they can occur with longer half-life agents such as fluoxetine and sertraline.

Warn patients about discontinuation effects when starting treatment and before the planned drug taper. In particular, caution them against missing doses or stopping a drug without informing you.

2 Know the symptoms

Common discontinuation symptoms can be grouped into six areas:

• Neurosensory—vertigo, paresthesias, shock-like reactions, myalgia
  
• Neuromotor—tremor, myoclonus, ataxia, visual changes, piloerection
  
• Gastrointestinal—nausea, vomiting, diarrhea
  
• Psychiatric—anxiety, depressed mood, suicidal ideation, irritability
  
• Vasomotor—flushing, diaphoresis
  
• Other neuropsychiatric—anorexia, insomnia, vivid dreams, asthenia, chills.²
  

3 Distinguish discontinuation reactions from relapse

Although depressed mood and anxiety may occur during taper, these symptoms tend to be transient in most patients. Severe or persistent symptoms—including emerging suicidal ideation—may indicate a relapse.

4 Reduce medication slowly

Tapering is recommended for all antidepressants but should be particularly slow for certain drugs—including venlafaxine, paroxetine, and clomipramine—which can cause significant discontinuation effects. For example, venlafaxine at 225 mg/d could be reduced by 75 mg/d every 1 to 2 weeks, with a final step at 37.5 mg/d for at least 1 week.

If discontinuation reactions are a problem, ultimate discontinuation may require substituting a longer-acting medication such as fluoxetine during the tapering period. For example, add fluoxetine, 10 to 20 mg/d, for 1 week, then stop both antidepressants or discontinue the first medication and continue fluoxetine for 2 to 3 weeks until the risk of reactions passes.

Clinicians often are concerned about serotonin syndrome caused by combining SRIs. Isolated cases have been reported, but the small, finite chance of serotonin syndrome is much lower than the risk of severe discontinuation reactions.

5 Titrate up and taper down

When switching to another SRI, titrate the second drug upward while tapering off the first. Remember that changing to a drug that does not act on serotonin, such as bupropion, can protect against discontinuation effects.

6 Allow for pregnancy

Infants born to mothers taking antidepressants can exhibit discontinuation symptoms,² particularly with shorter-acting drugs such as paroxetine or venlafaxine. Consider tapering the antidepressant early in the patient’s third trimester, then re-institute treatment after delivery. If an antidepressant is required during pregnancy, try using one with a longer half-life such as fluoxetine.

Drug brand names

• Bupropion • Wellbutrin
  
• Clomipramine • Anafranil
  
• Fluoxetine • Prozac
  
• Paroxetine • Paxil
  
• Sertraline • Zoloft
  
• Venlafaxine • Effexor
  

Side effects to discontinuing serotonin reuptake inhibitor (SRI) treatment are common and may be severe.¹ Patients who are not prepared for these reactions may attribute symptoms to other causes such as a medical illness. Educate your patient about potential side effects to mitigate problems such as relapse or patient distress.

1 Warn your patient

Alert patients to potential discontinuation reactions when prescribing any antidepressant, particularly SRIs because they seem to cause more discontinuation problems than other classes of drugs. Although reactions appear to be more common and severe with short-acting drugs such as venlafaxine and paroxetine, they can occur with longer half-life agents such as fluoxetine and sertraline.

Warn patients about discontinuation effects when starting treatment and before the planned drug taper. In particular, caution them against missing doses or stopping a drug without informing you.

2 Know the symptoms

Common discontinuation symptoms can be grouped into six areas:

• Neurosensory—vertigo, paresthesias, shock-like reactions, myalgia
  
• Neuromotor—tremor, myoclonus, ataxia, visual changes, piloerection
  
• Gastrointestinal—nausea, vomiting, diarrhea
  
• Psychiatric—anxiety, depressed mood, suicidal ideation, irritability
  
• Vasomotor—flushing, diaphoresis
  
• Other neuropsychiatric—anorexia, insomnia, vivid dreams, asthenia, chills.²
  

3 Distinguish discontinuation reactions from relapse

Although depressed mood and anxiety may occur during taper, these symptoms tend to be transient in most patients. Severe or persistent symptoms—including emerging suicidal ideation—may indicate a relapse.

4 Reduce medication slowly

Tapering is recommended for all antidepressants but should be particularly slow for certain drugs—including venlafaxine, paroxetine, and clomipramine—which can cause significant discontinuation effects. For example, venlafaxine at 225 mg/d could be reduced by 75 mg/d every 1 to 2 weeks, with a final step at 37.5 mg/d for at least 1 week.

If discontinuation reactions are a problem, ultimate discontinuation may require substituting a longer-acting medication such as fluoxetine during the tapering period. For example, add fluoxetine, 10 to 20 mg/d, for 1 week, then stop both antidepressants or discontinue the first medication and continue fluoxetine for 2 to 3 weeks until the risk of reactions passes.

Clinicians often are concerned about serotonin syndrome caused by combining SRIs. Isolated cases have been reported, but the small, finite chance of serotonin syndrome is much lower than the risk of severe discontinuation reactions.

5 Titrate up and taper down

When switching to another SRI, titrate the second drug upward while tapering off the first. Remember that changing to a drug that does not act on serotonin, such as bupropion, can protect against discontinuation effects.

6 Allow for pregnancy

Infants born to mothers taking antidepressants can exhibit discontinuation symptoms,² particularly with shorter-acting drugs such as paroxetine or venlafaxine. Consider tapering the antidepressant early in the patient’s third trimester, then re-institute treatment after delivery. If an antidepressant is required during pregnancy, try using one with a longer half-life such as fluoxetine.

Drug brand names

• Bupropion • Wellbutrin
  
• Clomipramine • Anafranil
  
• Fluoxetine • Prozac
  
• Paroxetine • Paxil
  
• Sertraline • Zoloft
  
• Venlafaxine • Effexor
  

Adding second-generation antipsychotics (SGAs) may boost the effectiveness of antidepressants in treatment-resistant unipolar major depression. Exactly when to try SGAs remains unclear, however, given their potential for adverse effects.

Major depression often is severe and chronic, and many patients remain ill even after multiple rounds of treatment. For patients without psychosis, where do SGAs fit into an algorithm for treatment-resistant depression?

This article examines the evidence on antipsychotic augmentation and discusses issues to consider—effectiveness, adverse effects, therapeutic dosages, and the patient’s quality of life—in making your clinical decisions.

Antidepressants alone

An optimal trial. Most depressed patients do not experience full response after initial antidepressant treatment, even with optimal therapeutic trials. An optimal trial means maintaining the maximum tolerated dosage within the antidepressant’s typical therapeutic range for at least 3 weeks.¹ Reported remission rates from initial and second-line treatments include:

• one-third of patients after a vigorous initial trial of citalopram in a National Institute of Mental Health study²
  
• 20% to 30% of patients given citalopram plus bupropion or buspirone³ or switched to bupropion, sertraline, or venlafaxine⁴
  
• 50% of patients treated for depression in a primary care practice during the first 2 years after an initial antidepressant prescription.⁵
  

Subsequent options. In addition to various monotherapies and combinations, many options have been proposed for managing nonresponse to initial antidepressant therapy (Table 1). These include:

• augmenting with lithium, thyroid hormone, pindolol, or estrogen
  
• switching to a drug in another therapeutic class, such as a tricyclic antidepressant or monoamine oxidase inhibitor
  
• adding cognitive-behavioral therapy.⁷
  

Box 1

Therapeutic suggestions when an SSRI does not lead to remission*

Atypicals for unipolar depression

Why atypicals? Researchers are investigating the use of SGAs in treatment-resistant mood disorders because of these drugs’ unique psychopharmacologic properties (Box 2).^9-11

Except for clozapine, all available SGAs—aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone—are FDA-approved for acute bipolar mania. Evidence also strongly supports the benefits of quetiapine¹² and the fixed-dose olanzapine/ fluoxetine combination¹³ for bipolar depression. Olanzapine/fluoxetine—originally studied for use in treatment-resistant unipolar depression—is approved for bipolar depression.¹⁴

Robust response. An uncontrolled case series first suggested that an SGA might help treat unipolar depression after initial selective serotonin reuptake inhibitors (SSRIs) fail to achieve remission. Ostroff and Nelson¹⁵ enrolled 8 outpatients (5 men, 3 women, ages 36 to 75) with nonpsychotic unipolar major depression that did not respond to initial fluoxetine or paroxetine. Patients had been taking fluoxetine, 20 to 40 mg/d, for 6 weeks to 4 months or paroxetine, 10 to 30 mg/d, for 2 to 8 weeks.

Patients reported a robust clinical effect within days after risperidone, 0.5 to 1.0 mg/d, was added to the SSRIs. Depression symptoms dropped to remission levels within 1 week, as measured by baseline and follow-up Hamilton Rating Scale for Depression (HAM-D) scores.

Olanzapine/fluoxetine. Our group subsequently enrolled 28 nonpsychotic patients with unipolar depression in a double-blind, placebo-controlled trial.¹⁴ We first treated these patients—who had not responded adequately to an SSRI or an antidepressant from another class—with open-label fluoxetine, up to 60 mg/d. Those whose scores on depression rating scales improved by ≥30% were excluded from the double-blind phase, when we randomly assigned the remaining patients to:

• olanzapine, mean 12.5 mg/d, plus placebo (n=8)
  
• a continuation of fluoxetine, mean 52 mg/d, plus placebo (n=10)
  
• or olanzapine/fluoxetine, mean 13.5/52 mg/d (n=10).
  

Final depression remission rates (HAM-D score ≤8 for 2 weeks) were:

• 60% with olanzapine/fluoxetine
  
• 25% with olanzapine alone
  
• 20% with continuation fluoxetine.
  

Until recently, researchers had been unable to replicate these results or extend this study in larger populations because of high response rates in the monotherapy treatment groups.^16,17 In May 2006, however, Thase et al¹⁸ presented data from a large-scale replication trial that confirmed the finding of a more robust effect with fixed-dose olanzapine/fluoxetine in unipolar major depression, compared with olanzapine or fluoxetine monotherapy.

Box 2

• sertraline, 100 to 200 mg/d
  
• sertraline plus ziprasidone, 80 mg/d
  
• or sertraline plus ziprasidone, 160 mg/d.
  

Risperidone. One three-phase study²¹ evaluated the long-term efficacy of adding risperidone to citalopram in 489 patients with treatment-resistant depression. The design was:

• phase 1: 4 to 6 weeks of open-label citalopram, 20 to 60 mg/d (N=489)
  
• phase 2: 4 to 6 weeks of citalopram plus open-label risperidone, 0.25 to 2 mg/d (N=386)
  
• phase 3: 24 weeks of citalopram plus double-blind risperidone or placebo (N=241).
  

Median time to relapse in phase 3 was 102 days with risperidone augmentation and 85 days with placebo—not a statistically significant difference. Relapse rates were 53.3% with risperidone and 54.6% in the control group. These results suggest that risperidone had an initial acute effect that was not sustained.

In another study,²² 463 depressed patients received an optimized antidepressant trial. The 274 who did not respond sufficiently were randomly assigned to risperidone, 1 to 2 mg/d, or placebo for 6 weeks. Mean HAM-D scores fell from 24.2 to 15.2 in the risperidone group and from 24.6 to 17.5 in the control group—a modest but statistically significant difference in favor of risperidone. The baseline-toendpoint change in this study is similar to that reported in a trial of risperidone, 1 to 4 mg/d, plus paroxetine, 20 to 40 mg/d, in bipolar depression.²³

Shelton²⁴ compared the effectiveness of adding risperidone or bupropion to SSRIs and serotonin norepinephrine reuptake inhibitors (SNRIs) for 6 weeks. Risperidone and bupropion were similarly effective as augmentation, but risperidone had a more rapid effect—producing statistically significant greater benefits within the first week of treatment.

Aripiprazole. Two open-label trials showed that aripiprazole combined with SSRIs exerts generally beneficial effects in treatment-resistant depression.^25,26 Simon and Nemeroff²⁵ began by adding aripiprazole at 10 mg/d, but emerging akathisia prompted them to reduce the starting dosage to 2.5 mg/d.

Barbee et al²⁷ reported the results of a retrospective case series of aripiprazole augmentation in depressed patients who had not responded adequately to multiple medication trials, including SGAs. Fourteen of 30 patients (46.7%) were rated “much improved” or “very improved” with added aripiprazole, based on Prospective Global Assessment of Functioning and Clinical Global Impressions- Improvement scores. But 9 patients (30%) did not complete the full course of therapy, and 6 of the 14 responders (42.9%) relapsed while taking aripiprazole. The net response rate across 6 weeks was 27%.

Although this study involved only aripiprazole, the results suggest that trying a second SGA may not be more effective after a first SGA fails to improve treatment-resistant depression.

Quetiapine. A 9-week, open-label, variable-dose study of 11 patients²⁸ first suggested that augmenting SSRIs with quetiapine could improve residual anxiety in resistant depression. Subsequently, 112 patients with major depression and anxiety were randomly assigned to single-blind treatment with paroxetine, ≥60 mg/d, with or without quetiapine, ≥200 mg/d. After 8 weeks, the 58 patients receiving quetiapine augmentation showed greater improvement than the 54 receiving SSRI monotherapy, based on Hamilton Anxiety Scale (HAM-A) and HAM-D scores.²⁹

Adding quetiapine to antidepressant therapy was then examined in a randomized, placebo-controlled trial by McIntyre et al.³⁰ Fifty-eight patients with unipolar depression who had not responded adequately after 6 weeks of SSRI or SNRI therapy were randomly assigned to quetiapine, 50 to 600 mg/d (mean dose 202±93 mg/d) or placebo for 8 weeks. Adjunctive quetiapine was significantly more effective than placebo, as measured by HAM-D scores. Patients receiving quetiapine also showed significantly better HAM-A scores at all points except week 8.

The dropout rate was relatively high for both groups—11 of 29 (38%) receiving quetiapine and 13 of 29 (45%) receiving placebo. The main reasons for discontinuation were side effects with quetiapine (sedation, dry mouth, and weight gain) and lack of effect with placebo.

These results are similar to those of another double-blind, placebo-controlled trial,³¹ in which 32 patients with SSRI/SNRI-resistant depression received adjunctive quetiapine, 200 to 400 mg/d (mean 268 mg/d) or placebo for 8 weeks.

Though small, these studies indicate that quetiapine may be effective as augmentation for treatment-resistant unipolar depression. Controlled data from a larger study are needed.

Discussion. Because of insufficient data, we do not know if SGAs are equivalent when used to augment antidepressant therapy in unipolar major depression. Olanzapine has been studied more than other SGAs in treatmentresistant depression and has shown efficacy in several—but not all—short- and long-term augmentation trials. Evidence on other SGAs is limited, and no head-to-head comparisons have been reported.

Adverse effects

Some SGAs may be effective in treatment-resistant depression, but any discussion of using them must also include their potential for adverse effects.

Weight gain and subsequent metabolic syndrome have been associated with olanzapine and—to a lesser degree—with quetiapine and risperidone. Ziprasidone and aripiprazole have relatively little effect on patients’ weight.

Extrapyramidal symptoms. All SGAs carry a risk of tardive dyskinesia. The risk is lower with SGAs than with first-generation antipsychotics (FGAs) but is an important clinical consideration.³²

Hyperprolactinemia. Risperidone has been associated with an elevated risk of hyperprolactinemia, although less than that associated with FGAs.³³ This risk does not appear to be a problem with quetiapine³⁴ and aripiprazole;³⁵ it is low with olanzapine (except at higher dosages);³⁶ and the prolactin increase associated with ziprasidone may resolve within the first month of treatment.³⁷

Prescribing rationale

‘Overcautious’ treatment. Even with careful management of side effects, SGAs are not preferred to strategies such as switching antidepressants or adding bupropion for treatment-resistant unipolar depression. But do not exclude SGAs solely because of their potential for adverse effects.

I am concerned about anecdotal reports of overcautious clinicians basing medication choices largely on safety—and, by extension, legal—considerations rather than on effectiveness. Certainly, safety concerns should prevail when two options are equally effective. But we do our patients no service by selecting ineffective drugs just because they have a low potential for adverse effects or by dosing effective drugs below the therapeutic range (Table 2).

When a drug is effective and may be the best choice for the patient, the question becomes, “Can I manage the potential for adverse effects?” When prescribing SGAs, it is important to monitor patients’ weight and serum lipid and glucose levels and regularly to look for abnormal involuntary movements.

An important question remains: Where do SGAs belong in the hierarchy of treatment options? Unfortunately, treatment guidelines for depression do not typically mention antipsychotics. Because of relative safety issues, two trials of monotherapies of different classes and, perhaps, combination therapy with bupropion would come before SGAs. However, it remains unclear exactly where.

SGAs probably belong ahead of electroconvulsive therapy or vagal nerve stimulation. But should they come before augmentation with lithium or thyroid hormone? Or, for that matter, trials of tricyclics or monoamine oxidase inhibitors?

Unfortunately, the available evidence provides little guidance. For a list of therapeutic algorithms developed for treatment-resistant depression, see Related resources.

Table 2

Recommended dosing of SGAs to augment antidepressant therapy

Algorithms for treatment-resistant depression

• Trivedi MH, Kern JK, Grannemann BD, et al. A computerized clinical decision support system as a means of implementing depression guidelines. Psychiatr Serv 2004;55(8);879-85.
  
• Rush AJ, Crismon ML, Kashner TM, et al. Texas Medication Algorithm Project, phase 3 (TMAP-3): rationale and study design. J Clin Psychiatry 2003;64(4);357-69.
  
• Trivedi M. Algorithms in clinical psychiatry: a stepped approach toward the path to recovery. Psychopharmacol Bull 2002;36(suppl 2);142-9.
  
• Trivedi MH, Kleiber BA. Algorithm for the treatment of chronic depression. J Clin Psychiatry 2001;62(suppl 6);22-9.
  
• Crismon ML, Trivedi M, Pigott TA, et al. The Texas Medication Algorithm Project: report of the Texas Consensus Conference Panel on Medication Treatment of Major Depressive Disorder. J Clin Psychiatry 1999;60(3);142-56.
  

• Aripiprazole • Abilify
  
• Bupropion • Wellbutrin
  
• Buspirone • BuSpar
  
• Citalopram • Celexa
  
• Clozapine • Clozaril
  
• Desipramine • Norpramin
  
• Duloxetine • Cymbalta
  
• Imipramine • Tofranil
  
• Lithium • various
  
• Nortriptyline • Pamelor
  
• Olanzapine • Zyprexa
  
• Olanzapine/fluoxetine • Symbyax
  
• Phenelzine • Nardil
  
• Pindolol • Visken
  
• Quetiapine • Seroquel
  
• Risperidone • Risperdal
  
• Selegiline (patch) • EMSAM
  
• Sertraline • Zoloft
  
• Tranylcypromine • Parnate
  
• Venlafaxine • Effexor
  
• Ziprasidone • Geodon
  

Dr. Shelton receives grant/research support from Eli Lilly and Co., GlaxoSmithKline, Pfizer, Janssen Pharmaceutica, sanofi-aventis, Wyeth Pharmaceuticals, AstraZeneca Pharmaceuticals, and Abbott Laboratories. He is a consultant to Pfizer and Janssen Pharmaceutica and a speaker for Bristol-Myers Squibb Co., Eli Lilly and Co., Janssen Pharmaceutica, Pfizer, GlaxoSmithKline, Solvay Pharmaceuticals, Wyeth Pharmaceuticals, and Abbott Laboratories.

Adding second-generation antipsychotics (SGAs) may boost the effectiveness of antidepressants in treatment-resistant unipolar major depression. Exactly when to try SGAs remains unclear, however, given their potential for adverse effects.

Major depression often is severe and chronic, and many patients remain ill even after multiple rounds of treatment. For patients without psychosis, where do SGAs fit into an algorithm for treatment-resistant depression?

This article examines the evidence on antipsychotic augmentation and discusses issues to consider—effectiveness, adverse effects, therapeutic dosages, and the patient’s quality of life—in making your clinical decisions.

Antidepressants alone

An optimal trial. Most depressed patients do not experience full response after initial antidepressant treatment, even with optimal therapeutic trials. An optimal trial means maintaining the maximum tolerated dosage within the antidepressant’s typical therapeutic range for at least 3 weeks.¹ Reported remission rates from initial and second-line treatments include:

• one-third of patients after a vigorous initial trial of citalopram in a National Institute of Mental Health study²
  
• 20% to 30% of patients given citalopram plus bupropion or buspirone³ or switched to bupropion, sertraline, or venlafaxine⁴
  
• 50% of patients treated for depression in a primary care practice during the first 2 years after an initial antidepressant prescription.⁵
  

Subsequent options. In addition to various monotherapies and combinations, many options have been proposed for managing nonresponse to initial antidepressant therapy (Table 1). These include:

• augmenting with lithium, thyroid hormone, pindolol, or estrogen
  
• switching to a drug in another therapeutic class, such as a tricyclic antidepressant or monoamine oxidase inhibitor
  
• adding cognitive-behavioral therapy.⁷
  

Box 1

Therapeutic suggestions when an SSRI does not lead to remission*

Atypicals for unipolar depression

Why atypicals? Researchers are investigating the use of SGAs in treatment-resistant mood disorders because of these drugs’ unique psychopharmacologic properties (Box 2).^9-11

Except for clozapine, all available SGAs—aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone—are FDA-approved for acute bipolar mania. Evidence also strongly supports the benefits of quetiapine¹² and the fixed-dose olanzapine/ fluoxetine combination¹³ for bipolar depression. Olanzapine/fluoxetine—originally studied for use in treatment-resistant unipolar depression—is approved for bipolar depression.¹⁴

Robust response. An uncontrolled case series first suggested that an SGA might help treat unipolar depression after initial selective serotonin reuptake inhibitors (SSRIs) fail to achieve remission. Ostroff and Nelson¹⁵ enrolled 8 outpatients (5 men, 3 women, ages 36 to 75) with nonpsychotic unipolar major depression that did not respond to initial fluoxetine or paroxetine. Patients had been taking fluoxetine, 20 to 40 mg/d, for 6 weeks to 4 months or paroxetine, 10 to 30 mg/d, for 2 to 8 weeks.

Patients reported a robust clinical effect within days after risperidone, 0.5 to 1.0 mg/d, was added to the SSRIs. Depression symptoms dropped to remission levels within 1 week, as measured by baseline and follow-up Hamilton Rating Scale for Depression (HAM-D) scores.

Olanzapine/fluoxetine. Our group subsequently enrolled 28 nonpsychotic patients with unipolar depression in a double-blind, placebo-controlled trial.¹⁴ We first treated these patients—who had not responded adequately to an SSRI or an antidepressant from another class—with open-label fluoxetine, up to 60 mg/d. Those whose scores on depression rating scales improved by ≥30% were excluded from the double-blind phase, when we randomly assigned the remaining patients to:

• olanzapine, mean 12.5 mg/d, plus placebo (n=8)
  
• a continuation of fluoxetine, mean 52 mg/d, plus placebo (n=10)
  
• or olanzapine/fluoxetine, mean 13.5/52 mg/d (n=10).
  

Final depression remission rates (HAM-D score ≤8 for 2 weeks) were:

• 60% with olanzapine/fluoxetine
  
• 25% with olanzapine alone
  
• 20% with continuation fluoxetine.
  

Until recently, researchers had been unable to replicate these results or extend this study in larger populations because of high response rates in the monotherapy treatment groups.^16,17 In May 2006, however, Thase et al¹⁸ presented data from a large-scale replication trial that confirmed the finding of a more robust effect with fixed-dose olanzapine/fluoxetine in unipolar major depression, compared with olanzapine or fluoxetine monotherapy.

Box 2

• sertraline, 100 to 200 mg/d
  
• sertraline plus ziprasidone, 80 mg/d
  
• or sertraline plus ziprasidone, 160 mg/d.
  

Risperidone. One three-phase study²¹ evaluated the long-term efficacy of adding risperidone to citalopram in 489 patients with treatment-resistant depression. The design was:

• phase 1: 4 to 6 weeks of open-label citalopram, 20 to 60 mg/d (N=489)
  
• phase 2: 4 to 6 weeks of citalopram plus open-label risperidone, 0.25 to 2 mg/d (N=386)
  
• phase 3: 24 weeks of citalopram plus double-blind risperidone or placebo (N=241).
  

Median time to relapse in phase 3 was 102 days with risperidone augmentation and 85 days with placebo—not a statistically significant difference. Relapse rates were 53.3% with risperidone and 54.6% in the control group. These results suggest that risperidone had an initial acute effect that was not sustained.

In another study,²² 463 depressed patients received an optimized antidepressant trial. The 274 who did not respond sufficiently were randomly assigned to risperidone, 1 to 2 mg/d, or placebo for 6 weeks. Mean HAM-D scores fell from 24.2 to 15.2 in the risperidone group and from 24.6 to 17.5 in the control group—a modest but statistically significant difference in favor of risperidone. The baseline-toendpoint change in this study is similar to that reported in a trial of risperidone, 1 to 4 mg/d, plus paroxetine, 20 to 40 mg/d, in bipolar depression.²³

Shelton²⁴ compared the effectiveness of adding risperidone or bupropion to SSRIs and serotonin norepinephrine reuptake inhibitors (SNRIs) for 6 weeks. Risperidone and bupropion were similarly effective as augmentation, but risperidone had a more rapid effect—producing statistically significant greater benefits within the first week of treatment.

Aripiprazole. Two open-label trials showed that aripiprazole combined with SSRIs exerts generally beneficial effects in treatment-resistant depression.^25,26 Simon and Nemeroff²⁵ began by adding aripiprazole at 10 mg/d, but emerging akathisia prompted them to reduce the starting dosage to 2.5 mg/d.

Barbee et al²⁷ reported the results of a retrospective case series of aripiprazole augmentation in depressed patients who had not responded adequately to multiple medication trials, including SGAs. Fourteen of 30 patients (46.7%) were rated “much improved” or “very improved” with added aripiprazole, based on Prospective Global Assessment of Functioning and Clinical Global Impressions- Improvement scores. But 9 patients (30%) did not complete the full course of therapy, and 6 of the 14 responders (42.9%) relapsed while taking aripiprazole. The net response rate across 6 weeks was 27%.

Although this study involved only aripiprazole, the results suggest that trying a second SGA may not be more effective after a first SGA fails to improve treatment-resistant depression.

Quetiapine. A 9-week, open-label, variable-dose study of 11 patients²⁸ first suggested that augmenting SSRIs with quetiapine could improve residual anxiety in resistant depression. Subsequently, 112 patients with major depression and anxiety were randomly assigned to single-blind treatment with paroxetine, ≥60 mg/d, with or without quetiapine, ≥200 mg/d. After 8 weeks, the 58 patients receiving quetiapine augmentation showed greater improvement than the 54 receiving SSRI monotherapy, based on Hamilton Anxiety Scale (HAM-A) and HAM-D scores.²⁹

Adding quetiapine to antidepressant therapy was then examined in a randomized, placebo-controlled trial by McIntyre et al.³⁰ Fifty-eight patients with unipolar depression who had not responded adequately after 6 weeks of SSRI or SNRI therapy were randomly assigned to quetiapine, 50 to 600 mg/d (mean dose 202±93 mg/d) or placebo for 8 weeks. Adjunctive quetiapine was significantly more effective than placebo, as measured by HAM-D scores. Patients receiving quetiapine also showed significantly better HAM-A scores at all points except week 8.

The dropout rate was relatively high for both groups—11 of 29 (38%) receiving quetiapine and 13 of 29 (45%) receiving placebo. The main reasons for discontinuation were side effects with quetiapine (sedation, dry mouth, and weight gain) and lack of effect with placebo.

These results are similar to those of another double-blind, placebo-controlled trial,³¹ in which 32 patients with SSRI/SNRI-resistant depression received adjunctive quetiapine, 200 to 400 mg/d (mean 268 mg/d) or placebo for 8 weeks.

Though small, these studies indicate that quetiapine may be effective as augmentation for treatment-resistant unipolar depression. Controlled data from a larger study are needed.

Discussion. Because of insufficient data, we do not know if SGAs are equivalent when used to augment antidepressant therapy in unipolar major depression. Olanzapine has been studied more than other SGAs in treatmentresistant depression and has shown efficacy in several—but not all—short- and long-term augmentation trials. Evidence on other SGAs is limited, and no head-to-head comparisons have been reported.

Adverse effects

Some SGAs may be effective in treatment-resistant depression, but any discussion of using them must also include their potential for adverse effects.

Weight gain and subsequent metabolic syndrome have been associated with olanzapine and—to a lesser degree—with quetiapine and risperidone. Ziprasidone and aripiprazole have relatively little effect on patients’ weight.

Extrapyramidal symptoms. All SGAs carry a risk of tardive dyskinesia. The risk is lower with SGAs than with first-generation antipsychotics (FGAs) but is an important clinical consideration.³²

Hyperprolactinemia. Risperidone has been associated with an elevated risk of hyperprolactinemia, although less than that associated with FGAs.³³ This risk does not appear to be a problem with quetiapine³⁴ and aripiprazole;³⁵ it is low with olanzapine (except at higher dosages);³⁶ and the prolactin increase associated with ziprasidone may resolve within the first month of treatment.³⁷

Prescribing rationale

‘Overcautious’ treatment. Even with careful management of side effects, SGAs are not preferred to strategies such as switching antidepressants or adding bupropion for treatment-resistant unipolar depression. But do not exclude SGAs solely because of their potential for adverse effects.

I am concerned about anecdotal reports of overcautious clinicians basing medication choices largely on safety—and, by extension, legal—considerations rather than on effectiveness. Certainly, safety concerns should prevail when two options are equally effective. But we do our patients no service by selecting ineffective drugs just because they have a low potential for adverse effects or by dosing effective drugs below the therapeutic range (Table 2).

When a drug is effective and may be the best choice for the patient, the question becomes, “Can I manage the potential for adverse effects?” When prescribing SGAs, it is important to monitor patients’ weight and serum lipid and glucose levels and regularly to look for abnormal involuntary movements.

An important question remains: Where do SGAs belong in the hierarchy of treatment options? Unfortunately, treatment guidelines for depression do not typically mention antipsychotics. Because of relative safety issues, two trials of monotherapies of different classes and, perhaps, combination therapy with bupropion would come before SGAs. However, it remains unclear exactly where.

SGAs probably belong ahead of electroconvulsive therapy or vagal nerve stimulation. But should they come before augmentation with lithium or thyroid hormone? Or, for that matter, trials of tricyclics or monoamine oxidase inhibitors?

Unfortunately, the available evidence provides little guidance. For a list of therapeutic algorithms developed for treatment-resistant depression, see Related resources.

Table 2

Recommended dosing of SGAs to augment antidepressant therapy

Algorithms for treatment-resistant depression

• Trivedi MH, Kern JK, Grannemann BD, et al. A computerized clinical decision support system as a means of implementing depression guidelines. Psychiatr Serv 2004;55(8);879-85.
  
• Rush AJ, Crismon ML, Kashner TM, et al. Texas Medication Algorithm Project, phase 3 (TMAP-3): rationale and study design. J Clin Psychiatry 2003;64(4);357-69.
  
• Trivedi M. Algorithms in clinical psychiatry: a stepped approach toward the path to recovery. Psychopharmacol Bull 2002;36(suppl 2);142-9.
  
• Trivedi MH, Kleiber BA. Algorithm for the treatment of chronic depression. J Clin Psychiatry 2001;62(suppl 6);22-9.
  
• Crismon ML, Trivedi M, Pigott TA, et al. The Texas Medication Algorithm Project: report of the Texas Consensus Conference Panel on Medication Treatment of Major Depressive Disorder. J Clin Psychiatry 1999;60(3);142-56.
  

• Aripiprazole • Abilify
  
• Bupropion • Wellbutrin
  
• Buspirone • BuSpar
  
• Citalopram • Celexa
  
• Clozapine • Clozaril
  
• Desipramine • Norpramin
  
• Duloxetine • Cymbalta
  
• Imipramine • Tofranil
  
• Lithium • various
  
• Nortriptyline • Pamelor
  
• Olanzapine • Zyprexa
  
• Olanzapine/fluoxetine • Symbyax
  
• Phenelzine • Nardil
  
• Pindolol • Visken
  
• Quetiapine • Seroquel
  
• Risperidone • Risperdal
  
• Selegiline (patch) • EMSAM
  
• Sertraline • Zoloft
  
• Tranylcypromine • Parnate
  
• Venlafaxine • Effexor
  
• Ziprasidone • Geodon
  

Dr. Shelton receives grant/research support from Eli Lilly and Co., GlaxoSmithKline, Pfizer, Janssen Pharmaceutica, sanofi-aventis, Wyeth Pharmaceuticals, AstraZeneca Pharmaceuticals, and Abbott Laboratories. He is a consultant to Pfizer and Janssen Pharmaceutica and a speaker for Bristol-Myers Squibb Co., Eli Lilly and Co., Janssen Pharmaceutica, Pfizer, GlaxoSmithKline, Solvay Pharmaceuticals, Wyeth Pharmaceuticals, and Abbott Laboratories.

Adding second-generation antipsychotics (SGAs) may boost the effectiveness of antidepressants in treatment-resistant unipolar major depression. Exactly when to try SGAs remains unclear, however, given their potential for adverse effects.

Major depression often is severe and chronic, and many patients remain ill even after multiple rounds of treatment. For patients without psychosis, where do SGAs fit into an algorithm for treatment-resistant depression?

This article examines the evidence on antipsychotic augmentation and discusses issues to consider—effectiveness, adverse effects, therapeutic dosages, and the patient’s quality of life—in making your clinical decisions.

Antidepressants alone

An optimal trial. Most depressed patients do not experience full response after initial antidepressant treatment, even with optimal therapeutic trials. An optimal trial means maintaining the maximum tolerated dosage within the antidepressant’s typical therapeutic range for at least 3 weeks.¹ Reported remission rates from initial and second-line treatments include:

• one-third of patients after a vigorous initial trial of citalopram in a National Institute of Mental Health study²
  
• 20% to 30% of patients given citalopram plus bupropion or buspirone³ or switched to bupropion, sertraline, or venlafaxine⁴
  
• 50% of patients treated for depression in a primary care practice during the first 2 years after an initial antidepressant prescription.⁵
  

Subsequent options. In addition to various monotherapies and combinations, many options have been proposed for managing nonresponse to initial antidepressant therapy (Table 1). These include:

• augmenting with lithium, thyroid hormone, pindolol, or estrogen
  
• switching to a drug in another therapeutic class, such as a tricyclic antidepressant or monoamine oxidase inhibitor
  
• adding cognitive-behavioral therapy.⁷
  

Box 1

Therapeutic suggestions when an SSRI does not lead to remission*

Atypicals for unipolar depression

Why atypicals? Researchers are investigating the use of SGAs in treatment-resistant mood disorders because of these drugs’ unique psychopharmacologic properties (Box 2).^9-11

Except for clozapine, all available SGAs—aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone—are FDA-approved for acute bipolar mania. Evidence also strongly supports the benefits of quetiapine¹² and the fixed-dose olanzapine/ fluoxetine combination¹³ for bipolar depression. Olanzapine/fluoxetine—originally studied for use in treatment-resistant unipolar depression—is approved for bipolar depression.¹⁴

Robust response. An uncontrolled case series first suggested that an SGA might help treat unipolar depression after initial selective serotonin reuptake inhibitors (SSRIs) fail to achieve remission. Ostroff and Nelson¹⁵ enrolled 8 outpatients (5 men, 3 women, ages 36 to 75) with nonpsychotic unipolar major depression that did not respond to initial fluoxetine or paroxetine. Patients had been taking fluoxetine, 20 to 40 mg/d, for 6 weeks to 4 months or paroxetine, 10 to 30 mg/d, for 2 to 8 weeks.

Patients reported a robust clinical effect within days after risperidone, 0.5 to 1.0 mg/d, was added to the SSRIs. Depression symptoms dropped to remission levels within 1 week, as measured by baseline and follow-up Hamilton Rating Scale for Depression (HAM-D) scores.

Olanzapine/fluoxetine. Our group subsequently enrolled 28 nonpsychotic patients with unipolar depression in a double-blind, placebo-controlled trial.¹⁴ We first treated these patients—who had not responded adequately to an SSRI or an antidepressant from another class—with open-label fluoxetine, up to 60 mg/d. Those whose scores on depression rating scales improved by ≥30% were excluded from the double-blind phase, when we randomly assigned the remaining patients to:

• olanzapine, mean 12.5 mg/d, plus placebo (n=8)
  
• a continuation of fluoxetine, mean 52 mg/d, plus placebo (n=10)
  
• or olanzapine/fluoxetine, mean 13.5/52 mg/d (n=10).
  

Final depression remission rates (HAM-D score ≤8 for 2 weeks) were:

• 60% with olanzapine/fluoxetine
  
• 25% with olanzapine alone
  
• 20% with continuation fluoxetine.
  

Until recently, researchers had been unable to replicate these results or extend this study in larger populations because of high response rates in the monotherapy treatment groups.^16,17 In May 2006, however, Thase et al¹⁸ presented data from a large-scale replication trial that confirmed the finding of a more robust effect with fixed-dose olanzapine/fluoxetine in unipolar major depression, compared with olanzapine or fluoxetine monotherapy.

Box 2

• sertraline, 100 to 200 mg/d
  
• sertraline plus ziprasidone, 80 mg/d
  
• or sertraline plus ziprasidone, 160 mg/d.
  

Risperidone. One three-phase study²¹ evaluated the long-term efficacy of adding risperidone to citalopram in 489 patients with treatment-resistant depression. The design was:

• phase 1: 4 to 6 weeks of open-label citalopram, 20 to 60 mg/d (N=489)
  
• phase 2: 4 to 6 weeks of citalopram plus open-label risperidone, 0.25 to 2 mg/d (N=386)
  
• phase 3: 24 weeks of citalopram plus double-blind risperidone or placebo (N=241).
  

Median time to relapse in phase 3 was 102 days with risperidone augmentation and 85 days with placebo—not a statistically significant difference. Relapse rates were 53.3% with risperidone and 54.6% in the control group. These results suggest that risperidone had an initial acute effect that was not sustained.

In another study,²² 463 depressed patients received an optimized antidepressant trial. The 274 who did not respond sufficiently were randomly assigned to risperidone, 1 to 2 mg/d, or placebo for 6 weeks. Mean HAM-D scores fell from 24.2 to 15.2 in the risperidone group and from 24.6 to 17.5 in the control group—a modest but statistically significant difference in favor of risperidone. The baseline-toendpoint change in this study is similar to that reported in a trial of risperidone, 1 to 4 mg/d, plus paroxetine, 20 to 40 mg/d, in bipolar depression.²³

Shelton²⁴ compared the effectiveness of adding risperidone or bupropion to SSRIs and serotonin norepinephrine reuptake inhibitors (SNRIs) for 6 weeks. Risperidone and bupropion were similarly effective as augmentation, but risperidone had a more rapid effect—producing statistically significant greater benefits within the first week of treatment.

Aripiprazole. Two open-label trials showed that aripiprazole combined with SSRIs exerts generally beneficial effects in treatment-resistant depression.^25,26 Simon and Nemeroff²⁵ began by adding aripiprazole at 10 mg/d, but emerging akathisia prompted them to reduce the starting dosage to 2.5 mg/d.

Barbee et al²⁷ reported the results of a retrospective case series of aripiprazole augmentation in depressed patients who had not responded adequately to multiple medication trials, including SGAs. Fourteen of 30 patients (46.7%) were rated “much improved” or “very improved” with added aripiprazole, based on Prospective Global Assessment of Functioning and Clinical Global Impressions- Improvement scores. But 9 patients (30%) did not complete the full course of therapy, and 6 of the 14 responders (42.9%) relapsed while taking aripiprazole. The net response rate across 6 weeks was 27%.

Although this study involved only aripiprazole, the results suggest that trying a second SGA may not be more effective after a first SGA fails to improve treatment-resistant depression.

Quetiapine. A 9-week, open-label, variable-dose study of 11 patients²⁸ first suggested that augmenting SSRIs with quetiapine could improve residual anxiety in resistant depression. Subsequently, 112 patients with major depression and anxiety were randomly assigned to single-blind treatment with paroxetine, ≥60 mg/d, with or without quetiapine, ≥200 mg/d. After 8 weeks, the 58 patients receiving quetiapine augmentation showed greater improvement than the 54 receiving SSRI monotherapy, based on Hamilton Anxiety Scale (HAM-A) and HAM-D scores.²⁹

Adding quetiapine to antidepressant therapy was then examined in a randomized, placebo-controlled trial by McIntyre et al.³⁰ Fifty-eight patients with unipolar depression who had not responded adequately after 6 weeks of SSRI or SNRI therapy were randomly assigned to quetiapine, 50 to 600 mg/d (mean dose 202±93 mg/d) or placebo for 8 weeks. Adjunctive quetiapine was significantly more effective than placebo, as measured by HAM-D scores. Patients receiving quetiapine also showed significantly better HAM-A scores at all points except week 8.

The dropout rate was relatively high for both groups—11 of 29 (38%) receiving quetiapine and 13 of 29 (45%) receiving placebo. The main reasons for discontinuation were side effects with quetiapine (sedation, dry mouth, and weight gain) and lack of effect with placebo.

These results are similar to those of another double-blind, placebo-controlled trial,³¹ in which 32 patients with SSRI/SNRI-resistant depression received adjunctive quetiapine, 200 to 400 mg/d (mean 268 mg/d) or placebo for 8 weeks.

Though small, these studies indicate that quetiapine may be effective as augmentation for treatment-resistant unipolar depression. Controlled data from a larger study are needed.

Discussion. Because of insufficient data, we do not know if SGAs are equivalent when used to augment antidepressant therapy in unipolar major depression. Olanzapine has been studied more than other SGAs in treatmentresistant depression and has shown efficacy in several—but not all—short- and long-term augmentation trials. Evidence on other SGAs is limited, and no head-to-head comparisons have been reported.

Adverse effects

Some SGAs may be effective in treatment-resistant depression, but any discussion of using them must also include their potential for adverse effects.

Weight gain and subsequent metabolic syndrome have been associated with olanzapine and—to a lesser degree—with quetiapine and risperidone. Ziprasidone and aripiprazole have relatively little effect on patients’ weight.

Extrapyramidal symptoms. All SGAs carry a risk of tardive dyskinesia. The risk is lower with SGAs than with first-generation antipsychotics (FGAs) but is an important clinical consideration.³²

Hyperprolactinemia. Risperidone has been associated with an elevated risk of hyperprolactinemia, although less than that associated with FGAs.³³ This risk does not appear to be a problem with quetiapine³⁴ and aripiprazole;³⁵ it is low with olanzapine (except at higher dosages);³⁶ and the prolactin increase associated with ziprasidone may resolve within the first month of treatment.³⁷

Prescribing rationale

‘Overcautious’ treatment. Even with careful management of side effects, SGAs are not preferred to strategies such as switching antidepressants or adding bupropion for treatment-resistant unipolar depression. But do not exclude SGAs solely because of their potential for adverse effects.

I am concerned about anecdotal reports of overcautious clinicians basing medication choices largely on safety—and, by extension, legal—considerations rather than on effectiveness. Certainly, safety concerns should prevail when two options are equally effective. But we do our patients no service by selecting ineffective drugs just because they have a low potential for adverse effects or by dosing effective drugs below the therapeutic range (Table 2).

When a drug is effective and may be the best choice for the patient, the question becomes, “Can I manage the potential for adverse effects?” When prescribing SGAs, it is important to monitor patients’ weight and serum lipid and glucose levels and regularly to look for abnormal involuntary movements.

An important question remains: Where do SGAs belong in the hierarchy of treatment options? Unfortunately, treatment guidelines for depression do not typically mention antipsychotics. Because of relative safety issues, two trials of monotherapies of different classes and, perhaps, combination therapy with bupropion would come before SGAs. However, it remains unclear exactly where.

SGAs probably belong ahead of electroconvulsive therapy or vagal nerve stimulation. But should they come before augmentation with lithium or thyroid hormone? Or, for that matter, trials of tricyclics or monoamine oxidase inhibitors?

Unfortunately, the available evidence provides little guidance. For a list of therapeutic algorithms developed for treatment-resistant depression, see Related resources.

Table 2

Recommended dosing of SGAs to augment antidepressant therapy

Algorithms for treatment-resistant depression

• Trivedi MH, Kern JK, Grannemann BD, et al. A computerized clinical decision support system as a means of implementing depression guidelines. Psychiatr Serv 2004;55(8);879-85.
  
• Rush AJ, Crismon ML, Kashner TM, et al. Texas Medication Algorithm Project, phase 3 (TMAP-3): rationale and study design. J Clin Psychiatry 2003;64(4);357-69.
  
• Trivedi M. Algorithms in clinical psychiatry: a stepped approach toward the path to recovery. Psychopharmacol Bull 2002;36(suppl 2);142-9.
  
• Trivedi MH, Kleiber BA. Algorithm for the treatment of chronic depression. J Clin Psychiatry 2001;62(suppl 6);22-9.
  
• Crismon ML, Trivedi M, Pigott TA, et al. The Texas Medication Algorithm Project: report of the Texas Consensus Conference Panel on Medication Treatment of Major Depressive Disorder. J Clin Psychiatry 1999;60(3);142-56.
  

• Aripiprazole • Abilify
  
• Bupropion • Wellbutrin
  
• Buspirone • BuSpar
  
• Citalopram • Celexa
  
• Clozapine • Clozaril
  
• Desipramine • Norpramin
  
• Duloxetine • Cymbalta
  
• Imipramine • Tofranil
  
• Lithium • various
  
• Nortriptyline • Pamelor
  
• Olanzapine • Zyprexa
  
• Olanzapine/fluoxetine • Symbyax
  
• Phenelzine • Nardil
  
• Pindolol • Visken
  
• Quetiapine • Seroquel
  
• Risperidone • Risperdal
  
• Selegiline (patch) • EMSAM
  
• Sertraline • Zoloft
  
• Tranylcypromine • Parnate
  
• Venlafaxine • Effexor
  
• Ziprasidone • Geodon
  

Dr. Shelton receives grant/research support from Eli Lilly and Co., GlaxoSmithKline, Pfizer, Janssen Pharmaceutica, sanofi-aventis, Wyeth Pharmaceuticals, AstraZeneca Pharmaceuticals, and Abbott Laboratories. He is a consultant to Pfizer and Janssen Pharmaceutica and a speaker for Bristol-Myers Squibb Co., Eli Lilly and Co., Janssen Pharmaceutica, Pfizer, GlaxoSmithKline, Solvay Pharmaceuticals, Wyeth Pharmaceuticals, and Abbott Laboratories.

Patients with bipolar disorder spend half their lives significantly symptomatic, mainly in the depressive phase.¹ Treating bipolar depression poses a clinical challenge, although new research is starting to uncover some answers. Antidepressant drugs are commonly used, but recent data question the effectiveness of this practice.²

An olanzapine-fluoxetine combination (OFC), FDA-approved for treating bipolar type I depression, has demonstrated efficacy in clinical trials.

How it works

Most atypical antipsychotics—including olanzapine—are potent 5-HT_2A (serotonin) receptor antagonists. This effect is similar to that of some antidepressants and may mediate some antidepressant and antianxiety effects of these drugs.³

Like most atypicals, olanzapine is also a potent 5-HT_2C blocker. While binding to this receptor, serotonin inhibits dopamine release in the nucleus accumbens and frontal cortex.⁴ Thus, serotonin blockade would increase dopamine release in these areas. One study showed that olanzapine and fluoxetine together increased dopamine and norepinephrine in the frontal cortex of rats, compared with either drug given individually.⁵ Dopamine is critical to regulating motivation, defined as the ability to exert energy to obtain rewards.⁶ Olanzapine also interacts with dopaminergic (D_1-5), muscarinic (M_1-5), alpha₁ adrenergic, histamine₁, serotonin (5-HT_2B,2C,3,6), and glutamate and other receptors.

Pharmacokinetics

Combining olanzapine and fluoxetine in one capsule raises potential kinetic problems. Olanzapine’s mean half-life is 30 hours,⁷ but fluoxetine’s is 24 to 72 hours and its principal active metabolite, norfluoxetine, has a half-life of 4 to 16 hours.⁷ Because fluoxetine and norfluoxetine inhibit the cytochrome P (CYP)-450 2D6 enzyme—which is involved in their metabolism—autoinhibition of degradation occurs with chronic dosing, thereby increasing the relative half-life of fluoxetine and norfluoxetine. Therefore, maximum steady-state plasma levels will be achieved with olanzapine and fluoxetine at very different rates, although this has not posed a problem in clinical trials. Still, consider this disparity when evaluating potential side effects or drug-drug interactions.

Table 1

Drugs that may interact with OFC

Both compounds reach maximum concentration in 4 to 6 hours.⁷ Although food’s effect on OFC’s absorption has not been tested, a clinically important effect is unlikely. Food does not significantly alter absorption kinetics of olanzapine or fluoxetine.⁷

Avoid giving OFC concomitantly with drugs metabolized by CYP 2D6 and 2C (Table 1), because fluoxetine is a potent inhibitor of these isoenzymes. The resulting altered plasma concentrations could lead to drug-drug interactions.⁸

Efficacy

In an 8-week, double-blind, multinational trial,⁹ 833 patients with bipolar I disorder in the depressive phase randomly received placebo, olanzapine alone (5 to 20 mg/d), or OFC in several fixed combinations (all shown as olanzapine/fluoxetine): 6/25 mg/d, 6/50 mg/d, or 12/50 mg/d. Dosage titration was allowed.

The researchers found that:

• OFC was significantly more effective than placebo. A mean 18.5-point improvement in Montgomery-Asberg Depression Rating Scale (MADRS) scores was reported in the OFC group, compared with a mean 11.9-point improvement in the placebo group.
• Olanzapine alone produced a mean 15-point MADRS score reduction. Remission criteria were achieved in 24.5%, 32.8%, and 48.8% of patients treated with placebo, olanzapine, and OFC, respectively.
• Both OFC and olanzapine alone produced greater MADRS score reductions than did placebo at every follow-up week. Mania induction rates were low in the olanzapine and OFC treatment groups (5.7% and 6.4%, respectively) as measured with the Young Mania Rating Scale.

Shelton et al³ also compared OFC to olanzapine and fluoxetine alone in treatment-resistant unipolar depression. Thirty-two patients with major depression who responded inadequately to two types of antidepressants were treated with fluoxetine, up to 60 mg/d. After 7 weeks, 28 patients who did not respond to fluoxetine then received fluoxetine alone (mean modal dose: 52 mg/d), olanzapine alone (12.5 mg/d), or OFC (13.5 mg/52 mg/d) for another 8 weeks.

Olanzapine alone produced a transient effect at week 3 with relapse thereafter, possibly because of interactions between olanzapine and falling fluoxetine plasma concentrations over the first 3 weeks. Fluoxetine monotherapy produced minimal results across the 8-week random phase.

The OFC group, however, achieved significant improvement in MADRS scores compared with the placebo group after week one. The effect continued throughout the trial and during a subsequent 8-week open-label phase.³

Recent data suggest continued benefit in treatment- and nontreatment-resistant depressed patients for up to 1 year.¹⁰ Two follow-up trials—one using a lead-in with venlafaxine, the second with nortriptyline—produced negative results. In both studies, however, patients achieved a robust effect while continuing the same drug during the double-blind phase, suggesting that initial trials were inadequate.^11,12 OFC showed early onset of effect in both studies. Other large-scale attempts at replication are anticipated.

Tolerability

Common side effects of OFC include increased appetite, weight gain, somnolence, fatigue, nausea, diarrhea, and dry mouth—the same effects associated with olanzapine or fluoxetine.

Combining the agents does not lessen the side effects, particularly olanzapine-induced weight gain. Simple, assertive dietary and exercise counseling can counteract olanzapine-induced weight gain.¹³ Sexual dysfunction was reported infrequently in clinical trials but is possible with exposure to fluoxetine.

Extrapyramidal side effects, including akathisia, appear to be relatively infrequent. Tardive dyskinesia (TD) is unlikely, although cases putatively associated with olanzapine have been reported.⁵ Many patients with TD have taken conventional antipsychotics, however, so the causal link with olanzapine is obscure. Still, alert patients and families to the possibility of TD and its emerging features.

Table 2

Olanzapine-fluoxetine: Fast facts

Although considered rare, isolated cases of neuroleptic malignant syndrome have been attributed to olanzapine.¹⁴ Cycle induction has not been reported in clinical trials, but be mindful of this possibility with long-term treatment.

Clinical implications

Taking olanzapine and fluoxetine as a single capsule could save the patient substantial cost. OFC comes in four dosing forms (Table 2), allowing for some flexibility.

It is unclear whether clinicians will prefer the single combination capsule or prescribe each drug separately to increase flexibility. Starting treatment with olanzapine and fluoxetine individually allows the psychiatrist to change the dosages independently and in smaller increments. Taken as separate agents, however, the two products are more expensive than the combined formula. OFC costs about the same as olanzapine alone. On the other hand, if the clinician begins the compounds individually, converting to the dosages in the combined product probably will not be exactly 1:1.

Tolerability is another major advantage of OFC; the combined agent exhibited a 10% dropout rate because of adverse effects compared with 4.6% for placebo.⁷ Moreover, some patients will prefer the convenience of using a single capsule instead of two medications.

Related resources

• Tollefson GD, Sanger TM. Anxious-depressive symptoms in schizophrenia: a new treatment target for pharmacotherapy? Schizophr Res 1999;35(suppl):S13-S21.
• Symbyax Web site. www.symbyax.com

Drug brand names

• Citalopram • Celexa
• Clomipramine • Anafranil
• Diazepam • Valium
• Fluoxetine • Prozac
• Haloperidol • Haldol
• Imipramine • Tofranil
• Metoprolol succinate • Toprol
• Nortriptyline • Aventyl
• Olanzapine • Zyprexa
• Omeprazole • Prilosec
• Phenytoin • Dilantin
• Proguanil • Malarone
• Propafenone • Rythmol
• Propranolol • Inderal
• Risperidone • Risperdal
• Tolbutamide • Orinase
• Venlafaxine • Effexor
• Warfarin • Coumadin

Disclosure

Dr. Shelton receives research grants from Abbott Laboratories, Eli Lilly and Co., GlaxoSmithKline, Janssen Pharmaceutica, Pfizer Inc., and Wyeth Pharmaceuticals; is a consultant to Janssen Pharmaceutica, Pfizer Inc., and Wyeth Pharmaceuticals; and is a speaker for Abbott Laboratories, Eli Lilly and Co., Forest Pharmaceuticals, GlaxoSmithKline, Janssen Pharmaceutica, Pfizer Inc., and Wyeth Pharmaceuticals

Patients with bipolar disorder spend half their lives significantly symptomatic, mainly in the depressive phase.¹ Treating bipolar depression poses a clinical challenge, although new research is starting to uncover some answers. Antidepressant drugs are commonly used, but recent data question the effectiveness of this practice.²

An olanzapine-fluoxetine combination (OFC), FDA-approved for treating bipolar type I depression, has demonstrated efficacy in clinical trials.

How it works

Most atypical antipsychotics—including olanzapine—are potent 5-HT_2A (serotonin) receptor antagonists. This effect is similar to that of some antidepressants and may mediate some antidepressant and antianxiety effects of these drugs.³

Like most atypicals, olanzapine is also a potent 5-HT_2C blocker. While binding to this receptor, serotonin inhibits dopamine release in the nucleus accumbens and frontal cortex.⁴ Thus, serotonin blockade would increase dopamine release in these areas. One study showed that olanzapine and fluoxetine together increased dopamine and norepinephrine in the frontal cortex of rats, compared with either drug given individually.⁵ Dopamine is critical to regulating motivation, defined as the ability to exert energy to obtain rewards.⁶ Olanzapine also interacts with dopaminergic (D_1-5), muscarinic (M_1-5), alpha₁ adrenergic, histamine₁, serotonin (5-HT_2B,2C,3,6), and glutamate and other receptors.

Pharmacokinetics

Combining olanzapine and fluoxetine in one capsule raises potential kinetic problems. Olanzapine’s mean half-life is 30 hours,⁷ but fluoxetine’s is 24 to 72 hours and its principal active metabolite, norfluoxetine, has a half-life of 4 to 16 hours.⁷ Because fluoxetine and norfluoxetine inhibit the cytochrome P (CYP)-450 2D6 enzyme—which is involved in their metabolism—autoinhibition of degradation occurs with chronic dosing, thereby increasing the relative half-life of fluoxetine and norfluoxetine. Therefore, maximum steady-state plasma levels will be achieved with olanzapine and fluoxetine at very different rates, although this has not posed a problem in clinical trials. Still, consider this disparity when evaluating potential side effects or drug-drug interactions.

Table 1

Drugs that may interact with OFC

Both compounds reach maximum concentration in 4 to 6 hours.⁷ Although food’s effect on OFC’s absorption has not been tested, a clinically important effect is unlikely. Food does not significantly alter absorption kinetics of olanzapine or fluoxetine.⁷

Avoid giving OFC concomitantly with drugs metabolized by CYP 2D6 and 2C (Table 1), because fluoxetine is a potent inhibitor of these isoenzymes. The resulting altered plasma concentrations could lead to drug-drug interactions.⁸

Efficacy

In an 8-week, double-blind, multinational trial,⁹ 833 patients with bipolar I disorder in the depressive phase randomly received placebo, olanzapine alone (5 to 20 mg/d), or OFC in several fixed combinations (all shown as olanzapine/fluoxetine): 6/25 mg/d, 6/50 mg/d, or 12/50 mg/d. Dosage titration was allowed.

The researchers found that:

• OFC was significantly more effective than placebo. A mean 18.5-point improvement in Montgomery-Asberg Depression Rating Scale (MADRS) scores was reported in the OFC group, compared with a mean 11.9-point improvement in the placebo group.
• Olanzapine alone produced a mean 15-point MADRS score reduction. Remission criteria were achieved in 24.5%, 32.8%, and 48.8% of patients treated with placebo, olanzapine, and OFC, respectively.
• Both OFC and olanzapine alone produced greater MADRS score reductions than did placebo at every follow-up week. Mania induction rates were low in the olanzapine and OFC treatment groups (5.7% and 6.4%, respectively) as measured with the Young Mania Rating Scale.

Shelton et al³ also compared OFC to olanzapine and fluoxetine alone in treatment-resistant unipolar depression. Thirty-two patients with major depression who responded inadequately to two types of antidepressants were treated with fluoxetine, up to 60 mg/d. After 7 weeks, 28 patients who did not respond to fluoxetine then received fluoxetine alone (mean modal dose: 52 mg/d), olanzapine alone (12.5 mg/d), or OFC (13.5 mg/52 mg/d) for another 8 weeks.

Olanzapine alone produced a transient effect at week 3 with relapse thereafter, possibly because of interactions between olanzapine and falling fluoxetine plasma concentrations over the first 3 weeks. Fluoxetine monotherapy produced minimal results across the 8-week random phase.

The OFC group, however, achieved significant improvement in MADRS scores compared with the placebo group after week one. The effect continued throughout the trial and during a subsequent 8-week open-label phase.³

Recent data suggest continued benefit in treatment- and nontreatment-resistant depressed patients for up to 1 year.¹⁰ Two follow-up trials—one using a lead-in with venlafaxine, the second with nortriptyline—produced negative results. In both studies, however, patients achieved a robust effect while continuing the same drug during the double-blind phase, suggesting that initial trials were inadequate.^11,12 OFC showed early onset of effect in both studies. Other large-scale attempts at replication are anticipated.

Tolerability

Common side effects of OFC include increased appetite, weight gain, somnolence, fatigue, nausea, diarrhea, and dry mouth—the same effects associated with olanzapine or fluoxetine.

Combining the agents does not lessen the side effects, particularly olanzapine-induced weight gain. Simple, assertive dietary and exercise counseling can counteract olanzapine-induced weight gain.¹³ Sexual dysfunction was reported infrequently in clinical trials but is possible with exposure to fluoxetine.

Extrapyramidal side effects, including akathisia, appear to be relatively infrequent. Tardive dyskinesia (TD) is unlikely, although cases putatively associated with olanzapine have been reported.⁵ Many patients with TD have taken conventional antipsychotics, however, so the causal link with olanzapine is obscure. Still, alert patients and families to the possibility of TD and its emerging features.

Table 2

Olanzapine-fluoxetine: Fast facts

Although considered rare, isolated cases of neuroleptic malignant syndrome have been attributed to olanzapine.¹⁴ Cycle induction has not been reported in clinical trials, but be mindful of this possibility with long-term treatment.

Clinical implications

Taking olanzapine and fluoxetine as a single capsule could save the patient substantial cost. OFC comes in four dosing forms (Table 2), allowing for some flexibility.

It is unclear whether clinicians will prefer the single combination capsule or prescribe each drug separately to increase flexibility. Starting treatment with olanzapine and fluoxetine individually allows the psychiatrist to change the dosages independently and in smaller increments. Taken as separate agents, however, the two products are more expensive than the combined formula. OFC costs about the same as olanzapine alone. On the other hand, if the clinician begins the compounds individually, converting to the dosages in the combined product probably will not be exactly 1:1.

Tolerability is another major advantage of OFC; the combined agent exhibited a 10% dropout rate because of adverse effects compared with 4.6% for placebo.⁷ Moreover, some patients will prefer the convenience of using a single capsule instead of two medications.

Related resources

• Tollefson GD, Sanger TM. Anxious-depressive symptoms in schizophrenia: a new treatment target for pharmacotherapy? Schizophr Res 1999;35(suppl):S13-S21.
• Symbyax Web site. www.symbyax.com

Drug brand names

• Citalopram • Celexa
• Clomipramine • Anafranil
• Diazepam • Valium
• Fluoxetine • Prozac
• Haloperidol • Haldol
• Imipramine • Tofranil
• Metoprolol succinate • Toprol
• Nortriptyline • Aventyl
• Olanzapine • Zyprexa
• Omeprazole • Prilosec
• Phenytoin • Dilantin
• Proguanil • Malarone
• Propafenone • Rythmol
• Propranolol • Inderal
• Risperidone • Risperdal
• Tolbutamide • Orinase
• Venlafaxine • Effexor
• Warfarin • Coumadin

Disclosure

Dr. Shelton receives research grants from Abbott Laboratories, Eli Lilly and Co., GlaxoSmithKline, Janssen Pharmaceutica, Pfizer Inc., and Wyeth Pharmaceuticals; is a consultant to Janssen Pharmaceutica, Pfizer Inc., and Wyeth Pharmaceuticals; and is a speaker for Abbott Laboratories, Eli Lilly and Co., Forest Pharmaceuticals, GlaxoSmithKline, Janssen Pharmaceutica, Pfizer Inc., and Wyeth Pharmaceuticals

Patients with bipolar disorder spend half their lives significantly symptomatic, mainly in the depressive phase.¹ Treating bipolar depression poses a clinical challenge, although new research is starting to uncover some answers. Antidepressant drugs are commonly used, but recent data question the effectiveness of this practice.²

An olanzapine-fluoxetine combination (OFC), FDA-approved for treating bipolar type I depression, has demonstrated efficacy in clinical trials.

How it works

Most atypical antipsychotics—including olanzapine—are potent 5-HT_2A (serotonin) receptor antagonists. This effect is similar to that of some antidepressants and may mediate some antidepressant and antianxiety effects of these drugs.³

Like most atypicals, olanzapine is also a potent 5-HT_2C blocker. While binding to this receptor, serotonin inhibits dopamine release in the nucleus accumbens and frontal cortex.⁴ Thus, serotonin blockade would increase dopamine release in these areas. One study showed that olanzapine and fluoxetine together increased dopamine and norepinephrine in the frontal cortex of rats, compared with either drug given individually.⁵ Dopamine is critical to regulating motivation, defined as the ability to exert energy to obtain rewards.⁶ Olanzapine also interacts with dopaminergic (D_1-5), muscarinic (M_1-5), alpha₁ adrenergic, histamine₁, serotonin (5-HT_2B,2C,3,6), and glutamate and other receptors.

Pharmacokinetics

Combining olanzapine and fluoxetine in one capsule raises potential kinetic problems. Olanzapine’s mean half-life is 30 hours,⁷ but fluoxetine’s is 24 to 72 hours and its principal active metabolite, norfluoxetine, has a half-life of 4 to 16 hours.⁷ Because fluoxetine and norfluoxetine inhibit the cytochrome P (CYP)-450 2D6 enzyme—which is involved in their metabolism—autoinhibition of degradation occurs with chronic dosing, thereby increasing the relative half-life of fluoxetine and norfluoxetine. Therefore, maximum steady-state plasma levels will be achieved with olanzapine and fluoxetine at very different rates, although this has not posed a problem in clinical trials. Still, consider this disparity when evaluating potential side effects or drug-drug interactions.

Table 1

Drugs that may interact with OFC

Both compounds reach maximum concentration in 4 to 6 hours.⁷ Although food’s effect on OFC’s absorption has not been tested, a clinically important effect is unlikely. Food does not significantly alter absorption kinetics of olanzapine or fluoxetine.⁷

Avoid giving OFC concomitantly with drugs metabolized by CYP 2D6 and 2C (Table 1), because fluoxetine is a potent inhibitor of these isoenzymes. The resulting altered plasma concentrations could lead to drug-drug interactions.⁸

Efficacy

In an 8-week, double-blind, multinational trial,⁹ 833 patients with bipolar I disorder in the depressive phase randomly received placebo, olanzapine alone (5 to 20 mg/d), or OFC in several fixed combinations (all shown as olanzapine/fluoxetine): 6/25 mg/d, 6/50 mg/d, or 12/50 mg/d. Dosage titration was allowed.

The researchers found that:

• OFC was significantly more effective than placebo. A mean 18.5-point improvement in Montgomery-Asberg Depression Rating Scale (MADRS) scores was reported in the OFC group, compared with a mean 11.9-point improvement in the placebo group.
• Olanzapine alone produced a mean 15-point MADRS score reduction. Remission criteria were achieved in 24.5%, 32.8%, and 48.8% of patients treated with placebo, olanzapine, and OFC, respectively.
• Both OFC and olanzapine alone produced greater MADRS score reductions than did placebo at every follow-up week. Mania induction rates were low in the olanzapine and OFC treatment groups (5.7% and 6.4%, respectively) as measured with the Young Mania Rating Scale.

Shelton et al³ also compared OFC to olanzapine and fluoxetine alone in treatment-resistant unipolar depression. Thirty-two patients with major depression who responded inadequately to two types of antidepressants were treated with fluoxetine, up to 60 mg/d. After 7 weeks, 28 patients who did not respond to fluoxetine then received fluoxetine alone (mean modal dose: 52 mg/d), olanzapine alone (12.5 mg/d), or OFC (13.5 mg/52 mg/d) for another 8 weeks.

Olanzapine alone produced a transient effect at week 3 with relapse thereafter, possibly because of interactions between olanzapine and falling fluoxetine plasma concentrations over the first 3 weeks. Fluoxetine monotherapy produced minimal results across the 8-week random phase.

The OFC group, however, achieved significant improvement in MADRS scores compared with the placebo group after week one. The effect continued throughout the trial and during a subsequent 8-week open-label phase.³

Recent data suggest continued benefit in treatment- and nontreatment-resistant depressed patients for up to 1 year.¹⁰ Two follow-up trials—one using a lead-in with venlafaxine, the second with nortriptyline—produced negative results. In both studies, however, patients achieved a robust effect while continuing the same drug during the double-blind phase, suggesting that initial trials were inadequate.^11,12 OFC showed early onset of effect in both studies. Other large-scale attempts at replication are anticipated.

Tolerability

Common side effects of OFC include increased appetite, weight gain, somnolence, fatigue, nausea, diarrhea, and dry mouth—the same effects associated with olanzapine or fluoxetine.

Combining the agents does not lessen the side effects, particularly olanzapine-induced weight gain. Simple, assertive dietary and exercise counseling can counteract olanzapine-induced weight gain.¹³ Sexual dysfunction was reported infrequently in clinical trials but is possible with exposure to fluoxetine.

Extrapyramidal side effects, including akathisia, appear to be relatively infrequent. Tardive dyskinesia (TD) is unlikely, although cases putatively associated with olanzapine have been reported.⁵ Many patients with TD have taken conventional antipsychotics, however, so the causal link with olanzapine is obscure. Still, alert patients and families to the possibility of TD and its emerging features.

Table 2

Olanzapine-fluoxetine: Fast facts

Although considered rare, isolated cases of neuroleptic malignant syndrome have been attributed to olanzapine.¹⁴ Cycle induction has not been reported in clinical trials, but be mindful of this possibility with long-term treatment.

Clinical implications

Taking olanzapine and fluoxetine as a single capsule could save the patient substantial cost. OFC comes in four dosing forms (Table 2), allowing for some flexibility.

It is unclear whether clinicians will prefer the single combination capsule or prescribe each drug separately to increase flexibility. Starting treatment with olanzapine and fluoxetine individually allows the psychiatrist to change the dosages independently and in smaller increments. Taken as separate agents, however, the two products are more expensive than the combined formula. OFC costs about the same as olanzapine alone. On the other hand, if the clinician begins the compounds individually, converting to the dosages in the combined product probably will not be exactly 1:1.

Tolerability is another major advantage of OFC; the combined agent exhibited a 10% dropout rate because of adverse effects compared with 4.6% for placebo.⁷ Moreover, some patients will prefer the convenience of using a single capsule instead of two medications.

Related resources

• Tollefson GD, Sanger TM. Anxious-depressive symptoms in schizophrenia: a new treatment target for pharmacotherapy? Schizophr Res 1999;35(suppl):S13-S21.
• Symbyax Web site. www.symbyax.com

Drug brand names

• Citalopram • Celexa
• Clomipramine • Anafranil
• Diazepam • Valium
• Fluoxetine • Prozac
• Haloperidol • Haldol
• Imipramine • Tofranil
• Metoprolol succinate • Toprol
• Nortriptyline • Aventyl
• Olanzapine • Zyprexa
• Omeprazole • Prilosec
• Phenytoin • Dilantin
• Proguanil • Malarone
• Propafenone • Rythmol
• Propranolol • Inderal
• Risperidone • Risperdal
• Tolbutamide • Orinase
• Venlafaxine • Effexor
• Warfarin • Coumadin

Disclosure

Dr. Shelton receives research grants from Abbott Laboratories, Eli Lilly and Co., GlaxoSmithKline, Janssen Pharmaceutica, Pfizer Inc., and Wyeth Pharmaceuticals; is a consultant to Janssen Pharmaceutica, Pfizer Inc., and Wyeth Pharmaceuticals; and is a speaker for Abbott Laboratories, Eli Lilly and Co., Forest Pharmaceuticals, GlaxoSmithKline, Janssen Pharmaceutica, Pfizer Inc., and Wyeth Pharmaceuticals