Olanzapine alone (n=3) or combined with an antidepressant (n=12) has also been reported to improve both depression and psychosis.3 In a double-blind, amitriptyline-controlled trial, Svestka and Synek4 found that olanzapine demonstrated antidepressant efficacy in 33 unipolar and seven bipolar depressed patients. Thirteen of these patients also had psychotic symptoms.
Shelton et al5 reported the results of a two-center, 8-week, double-blind comparison of olanzapine alone, fluoxetine alone, or their combination in 28 patients suffering from treatment-resistant, non-bipolar disorder without psychosis. They found that the combination was superior to either drug alone based on improvement in the Hamilton Depression Rating Scale (HDRS) total score. From their preliminary data, it also appears that the doses required were relatively low, reducing the risk of side effects.
Their findings, however, need to be replicated in more controlled studies with combinations, addressing possible adverse effects, the potential for clinically relevant drug interactions, decreased compliance rates, and increased cost of treatment. Earlier reports raised concern about the potential of these agents to increase switching to hypomania or mania. But in more recent reports, this has not emerged as a significant problem.7
Finally, several case reports and case series indicate that agents such as clozapine and risperidone may augment ECT in particularly severe, treatment-resistant depressive episodes.7
Management of bipolar and schizoaffective depressed episodes
Neuroleptics Antipsychotics are frequently used to manage more severe, usually psychotic episodes of bipolar and schizoaffective depression. Reports indicate that affectively ill patients receiving neuroleptics may be more prone to develop neuromotor adverse effects than are those suffering from schizophrenia. Thus, their use for such patients must be well justified, limited in dosage and duration, and carefully monitored for the emergence of acute and tardive neurological events.
Novel antipsychotics Novel antipsychotics have demonstrated fewer propensities than have neuroleptics in worsening depression or negative symptoms in schizophrenic patients, and have possible antidepressant effects. In support of this hypothesis, and reminiscent of data from earlier risperidone and olanzapine trials, ziprasidone was observed to improve the Montgomery Asberg Rating Scale (MADRS) and Brief Psychotic Rating Scale (BPRS) depressive cluster scores in three clinical trials with schizophrenic and schizoaffective patients.8,9
Vieta et al reported the efficacy and safety of risperidone add-on therapy for treating various episodes of bipolar (n=358) and schizoaffective (n=183) disorders.6 In this multicenter, open study, 33 patients (6.1%) suffered a depressed episode and received a mean risperidone dose of 1.6 (± 2.3) mg/d added to their ongoing but ineffective drug regimen. Mean HDRS declined significantly over the 6-month course. Further, switch rates were low and in the expected range for spontaneous fluctuations seen in these disorders.
The results of a 6-week, double-blind, controlled trial of risperidone versus haloperidol in 62 patients with schizoaffective disorder, bipolar or depressed subtype, were published.10 Risperidone (average dose of 5.5 mg/d) was comparable to haloperidol (average dose of 10.8 mg/d) in reducing the mean in the Positive and Negative Syndrome Scale and Clinician-Administered Rating Scale for Mania change scores.
In those patients with baseline HDRS scores ≥ 20, risperidone produced a significantly greater reduction in mean change scores than did haloperidol. In addition, patients had no mood switches with risperidone or haloperidol; there was a significantly higher incidence of patients who had extra-pyramidal symptoms with haloperidol than among those taking risperidone; and six patients in the group taking haloperidol dropped out after experiencing adverse effects. None of the patients taking risperidone dropped out.
Table 2
Lithium versus antipsychotics for acute mania
| Lithium | Antipsychotics | ||||
|---|---|---|---|---|---|
| Responders (%) (n=64) | Nonresponders (%) (n=10) | Responders (%) (n=38) | Nonresponders (%) (n=33) | Difference | |
| 5 studies | 89% | 11% | 54% | 46% | 35% |
| Adapted from Janicak PG, Newman RH, Davis JM. Advances in the treatment of mania and related disorders: a reappraisal. Psychiatric Ann. 1992;22(2):94. | |||||
Management of bipolar manic or mixed episodes
Up to 80% of all bipolar patients receive an antipsychotic drug during the acute and/or maintenance phase of their illness, even though loading doses of valproate and benzodiazepines may also be used during an exacerbation and pose much less risk, especially in terms of adverse neurological effects.
Neuroleptics Shortly after their introduction, neuroleptics were found to reduce mortality secondary to dehydration and exhaustion in many highly agitated patients during an acute manic episode such as lethal catatonia.7
While earlier controlled studies found these agents to be effective in the treatment of acute mania, they are clearly less efficacious than lithium for core manic symptoms.11Table 2 demonstrates a meta-analysis of five well-controlled, double-blind studies documenting the statistical superiority of lithium over neuroleptics. These agents, however, offer the advantage of a more rapid onset of action, particularly when given in the acute parenteral formulation, and are superior to lithium in the initial control of agitation. Further, long-acting depot formulations of neuroleptics may be the only viable strategy for chronic, recurrent, noncompliant patients.