Major mood disorders are challenging to diagnose and often difficult to treat. They entail unipolar depression; bipolar disorder, which includes manic, depressed, or mixed episodes; and schizoaffective disorder, which includes both depressed and bipolar subtypes. Antidepressants and mood stabilizers are the primary pharmacological treatments. They may be insufficient, however, for patients with more severe episodes, often characterized by psychosis and treatment resistance.
In these patients, antipsychotics have played an important but controversial part in management, primarily as oral or parenteral adjuncts. Literature and clinical experience now support another, unique role for the current generation of novel agents.
Compared to earlier antipsychotics, these agents produce substantially fewer neurological adverse effects, including acute extrapyramidal and tardive syndromes, and can augment antidepressants and mood stabilizers. In addition, they may:
- Possess a better antipsychotic profile, with enhanced therapeutic effects on positive, negative, cognitive, and mood symptoms
- Have a role in the acute and long-term management of these disorders when anticipated parenteral formulations become available (e.g., acute intramuscular olanzapine and ziprasidone—and long-acting intramuscular risperidone)
- Possess inherent thymoleptic properties (see “Unresolved issues with antipsychotics,” below).
UNRESOLVED ISSUES WITH ANTIPSYCHOTICS
- Defining what constitutes a mood stabilizer.1 Proposed definitions suggest that the drug must entail the following:
- Clarifying the mechanisms underlying the apparent mood-regulating effects of novel agents
- Ascertaining both acute and maintenance efficacy
- Clarifying the propensity of some agents to switch depressed patients into mania
- Increasing the number of well-designed studies with sufficient sample sizes, including comparison trials assessing the relative efficacy of different novel agents
- Reducing the tendency to publish only positive reports when new drugs are first available
- Introducing parenteral formulations of novel agents
- Resolving concerns about weight gain, new-onset diabetes, QT c prolongation, and sedation
- Rectifying the current level of substantially greater costs
Management of unipolar depression
Neuroleptics Delusions and hallucinations indicate a more severe form of depressive disorder, with poor short- and long-term outcomes in comparison to those without psychosis. To illustrate, Table 1 lists a summary of response rates in psychotic and nonpsychotic depressed patients given a tricyclic antidepressant (TCA). The data indicate that patients suffering from psychotic depression typically do not benefit from antidepressant monotherapy and usually require a combination of antidepressant and antipsychotic or, alternatively, electroconvulsive therapy (ECT).
There is, however, some limited clinical and neuroimaging evidence that amoxapine can be used as an effective monotherapy in this group. Amoxapine is an antidepressant whose primary active metabolite, 8-hydroxy amoxapine, may have antipsychotic properties.1 With the possible exception of amoxapine, combined antipsychotic-antidepressant treatment is the rule.
Table 1
Psychotic and nonpsychotic depressed patients’ response to monotherapy with a tricyclic antidepressant
| Psychotic | Nonpsychotic | ||||
|---|---|---|---|---|---|
| Responders (%) (n=127) | Nonresponders (%) (n=236) | Responders (%) (n=464) | Nonresponders (%) (n=227) | Difference | |
| 13 studies | 35% | 65% | 67% | 33% | 32% |
| Adapted from Chan CH, Janicak PG, Davis JM, et al. Response of psychotic and nonpsychotic depressed patients to tricyclic antidepressants. J Clin Psychiatry. 1987;48:197-200. | |||||
Historically, studies have also evaluated neuroleptic monotherapy for depressed patients. While some reported superiority over a placebo, none found conventional antipsychotics superior to imipramine. Indeed, patients with schizophrenia who are treated with a neuroleptic often develop symptoms that are difficult to distinguish from depression (e.g., secondary negative symptoms). These often improve when the neuroleptic is discontinued or the patients are switched to a novel antipsychotic such as risperidone, olanzapine, or ziprasidone, all of which have putative antidepressant effects.
When employing an antipsychotic in depressed patients, the dosage and duration of treatment are two critical considerations. To minimize neuromotor adverse effects, use low doses of a neuroleptic (e.g., haloperidol, 1 to 5 mg/d) in conjunction with the primary antidepressant therapy. The neuroleptic should then be tapered gradually after psychotic symptoms have been controlled, usually during the acute phase of treatment. Ideally, patients would then take antidepressant monotherapy through the continuation phase and, if necessary, the maintenance phase of treatment. If psychosis recurs, re-introduce the antipsychotic intermittently.
Novel antipsychotics In contrast to neuroleptics, novel antipsychotics have been reported to improve depression in various psychotic and mood disorders.
For example, ziprasidone has serotonin and noradrenergic reuptake blocking effects comparable to such classic TCAs as imipramine and amitriptyline, as well as high binding affinity at the 5-HT1A, 5-HT1D, and 5-HT2C receptors. This neuroreceptor profile indicates possible antidepressant effects.
While randomized, controlled trials with mood-disordered patients are few, there have been promising preliminary reports of augmentation of antidepressants with risperidone and olanzapine in both psychotic and nonpsychotic depressed patients.
Ostroff and Nelson2 reported the results of an open-label study of eight SSRI-nonresponsive patients (mean treatment 7.3 weeks). These patients had no psychotic features and had a dramatic reduction in depressive symptoms, as well as some improvement in sexual dysfunction, with the addition of 0.5 mg to 1.0 mg risperidone. The clinicians suggested that risperidone’s 5-HT2A antagonism might explain its augmentation of the partial SSRI response.