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
Remission: Why it’s the goal of antidepressant therapy
Table 1Depression is often chronic and disabling. Selective serotonin reuptake inhibitors (SSRIs) are the mainstay of treatment, but recent data suggest that:
- few patients achieve therapeutic remission with initial SSRIs
- relapse or recurrence after remission is common.6
Clinically, this means psychiatrists contend with treatment resistance in nearly all patients with major depression.
Chronic, inadequately treated depression has a pervasive, adverse effect on patients’ quality of life, impairing the ability to work and perform social roles such as parenting. Even when an antidepressant produces partial response, considerable impairment remains. Depressed patients who do not achieve full therapeutic remission remain in this partially remitted, disabled state throughout treatment.8
Aggressive and persistent management is the key to effectively treating major depression.
Therapeutic suggestions when an SSRI does not lead to remission*
| Pharmacotherapy | Example | Recommended dosing |
|---|---|---|
| Monotherapy | An SNRI such as: | |
| Duloxetine | 30 to 120 mg/d | |
| Venlafaxine XR | 150 to 375 mg/d | |
| Combination therapies with SSRIs | Bupropion | 200 to 400 mg/d |
| Buspirone | 30 to 60 mg/d | |
| Augmentation | Lithium | 900 to 1,200 mg/d |
| Thyroid hormone | 25 mcg/d | |
| Pindolol | 5 to 30 mg bid | |
| Estrogen (such as 17a-estradiol) | 100 mcg/d | |
| Switch to another Tricyclic antidepressant class | Tricyclic | |
| Imipramine | 150 to 250 mg/d* | |
| Nortriptyline | 75 to 200 mg/d* | |
| Desipramine | 150 to 250 mg/d* | |
| MAOI | ||
| Phenelzine | 30 to 60 mg/d | |
| Tranylcypromine | 20 to 60 mg/d | |
| Selegiline (patch) | 9 to 12 mg/patch/day | |
| * Suggestions are not listed in stepwise order | ||
| MAOI: monoamine oxidase inhibitor | ||
| SNRI: serotonin-norepinephrine reuptake inhibitor | ||
| SSRI: selective serotonin reuptake inhibitor | ||
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: