Atypical Neuroleptics

It has been suggested that typical antipsychotics increase the severity of depression or the number of depressive episodes in long-term maintenance treatment of bipolar patients (Keck et al. 1998; Kukopulos et al. 1980), although older literature from the 1950s and the 1960s suggested they may have antidepressive effects (Barsa and Kline 1957). Typical an-tipsychotics are also characterized by distressing side effects, including extrapyramidal side effects and tardive dyskinesia (Kane 1988).

A variety of atypical antipsychotics have repeatedly demonstrated beneficial effects in treatment-resistant depression, mainly as augmentation strategies (Barbee et al. 2004; Kennedy and Lam 2003; Masan 2004). Because treatments for unipolar depression are usually effective in bipolar depression, atypical antipsychotics are of increasing interest to those studying bipolar depression. Since the 1990s, preliminary data have suggested a role for atypical neuroleptics in the treatment of dys-phoric mania or mixed mania: clozapine (McElroy et al. 1991), risperidone (Vieta et al. 1998), and olanzapine (Zullino and Baumann 1999) were reported in open studies to have some beneficial effects in dyspho-ric mania (see Chapter 8, "Antipsychotics in Bipolar Depression").

Clozapine

Clozapine was reported to have some effects on the dysphoric components of mania (Suppes et al. 1992). However, its antidepressant efficacy is not clear. The use of clozapine demands weekly monitoring, due to the 1%-2% incidence of agranulocytosis, and its use is reserved for patients with treatment-resistant conditions.

Risperidone

In open trials on patients with bipolar mania, risperidone therapy has led to significant reductions in depression scores compared with baseline. Four open-label studies of risperidone in bipolar subjects exhibiting mania, mixed state, or bipolar depression, were done in 2001-2003 (McIntyre and Katzman 2003; Vieta et al. 2001a, 2001b; Yatham et al. 2003). The Hamilton Rating Scale for Depression (Ham-D) or Mont gomery-Asberg Depression Rating Scale (MADRS) served as rating scales and risperidone was added to ongoing mood-stabilizing treatment. These studies examined the efficacy of risperidone for 3-6 months, demonstrating reduction of Ham-D or MADRS scores from baseline in patients with bipolar mania by 5-12 points.

Olanzapine

Vieta et al. (2001c) conducted an open study with olanzapine in a group of 23 bipolar type I and type II patients experiencing frequent relapses, residual subsyndromal symptoms, and inadequate responses to mood stabilizers, such as lithium, valproate, or carbamazepine. Treatment was maintained throughout the study. Last-observation-carried-for-ward analysis showed that after the introduction of olanzapine, there was a significant reduction of Clinical Global Impression (CGI) scores for both manic and depressive symptoms.

Reductions in depression scores in patients with bipolar mania have been significantly greater with olanzapine compared with placebo when olanzapine was administered as a monotherapy or as an add-on treatment to mood stabilizers (Tohen et al. 2002, 2003). Sanger et al. (2001) followed 113 bipolar patients previously participating in doubleblind studies in a 49-week open-label extension phase. These patients demonstrated significant improvement in 21-item Ham-D scores along with antimanic effects. Baker et al. (2003) analyzed data from two similar placebo-controlled studies (N=246) of olanzapine in mania, focusing on depression scores in acutely ill manic patients with significant depressive symptoms (n=86). Olanzapine demonstrated a broad spectrum of efficacy, effectively treating both manic and depressive symptoms during mania. However, it is important to remember that depression during mania may be the same as isolated bipolar depression. It is important to specifically investigate the efficacy of treatment modalities in depressed, nonmanic, patients.

Olanzapine and Olanzapine-Fluoxetine Combination in the Treatment of Bipolar I Depression

Tohen et al. (2003) conducted a double-blind, 8-week, randomized, multisite, controlled trial of 833 adults with bipolar I depression with a MADRS score of at least 20 points. Patients were randomly assigned to receive placebo (n = 377); 5-20 mg/day of olanzapine (n = 370); or olanza-pine-fluoxetine combination (OFC) 6 and 25 mg/day, 6 and 50 mg/day, or 12 and 50 mg/day (n =86). Olanzapine was found to be more effec tive than placebo but with a small, clinically insignificant effect size. OFC was found to be more effective than olanzapine and placebo in the treatment of bipolar I depression without increased risk of developing manic symptoms over the brief duration of the study. Shi et al. (2004) analyzed the above study for health-related, quality-of-life effects of these treatments and found that patients with bipolar depression receiving olanzapine or OFC for 8 weeks had greater improvement in health-related quality of life than those receiving placebo. OFC treatment was associated with greater improvement in health-related quality of life than olanzapine alone.

Comparing Risperidone and Olanzapine

McIntre et al. (2002) compared olanzapine with risperidone as an addon to lithium or valproate for 6 months in 21 type I and II bipolar subjects in an open design. Ham-D scores served as a measure of depressive symptoms and significant reduction of Ham-D was noticed in both groups with no significant difference between them.

Quetiapine

Calabrese et al. (2005) reported on a study of 360 type I and 182 type II bipolar depressed patients receiving quetiapine monotherapy or placebo in a double-blind fashion for 8 weeks. Response rates for patients receiving 300 mg/day or 600 mg/day of quetiapine were 57.6% and 58.2%, respectively, significantly higher than 36.1% for placebo and only minimally smaller than the effect of antidepressants in unipolar depressive illness. Similarly, the remission rate (defined as MADRS<12) was significantly higher in the quetiapine-treated patients (52.9%) compared with placebo (28.4%). Separation from placebo was seen as early as the first week and remained significantly higher for the entire duration of the 8-week study (Calabrese et al. 2005).

An open-label, 12-week prospective study was conducted to assess the efficacy and tolerability of quetiapine in the treatment of patients with bipolar and schizoaffective disorder who were suboptimally responsive to mood stabilizers alone. The authors reported an overall improvement in these patients including a significant improvement in depressive symptoms (Sajatovic et al. 2001).

Altamura et al. (2003) reported on an open study of quetiapine in 28 bipolar patients. These patients received quetiapine or classical mood stabilizers at flexible doses for 12 months. Patients treated with both showed improvement of manic and depressive symptoms. Sokol-ski and Denson (2003) added quetiapine to bipolar patients who were partially responsive to lithium or valproate and found that quetiapine augmentation resulted in significant improvements in clinician-rated bipolar severity scores (CGI-BP) for both manic and depressive symptoms.

Ziprasidone

No controlled research data have been published on ziprasidone, an atypical drug also reported to inhibit reuptake of norepinephrine and serotonin (Schmidt et al. 2001). However, Papakostas et al. (2004) reported that ziprasidone can augment selective serotonin reuptake inhibitors (SSRIs) in SSRI-resistant major depressive disorder.

Summary

Preliminary studies suggest that atypical neuroleptics may exhibit some beneficial effects in bipolar depression. Most studies were uncontrolled or studied the effects of atypical neuroleptics on depressive symptoms in mixed bipolar patients. However, given the clear efficacy of typical antipsychotics in depression (whose clinical use was prevented mostly by extrapyramidal symptoms and tardive dyskinesia) it is likely that atypical antipsychotics will be increasingly useful in depression. If so, this may blur the traditional diagnostic boundaries between schizophrenia and affective disorder. It might also make the continuum between mania, mixed states, and depression less relevant to treatment.

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