Management of major depressive disorder with psychotic features

Pharmacotherapy for the treatment of MDD with psychotic features should consist of a combination of an antidepressant and antipsychotic medication. This combination has been shown to be more effective than either agent alone. Some combinations have been studied specifically for MDD with psychosis. The Study of the Pharmacotherapy of Psychotic Depression (STOP-PD), a 12-week, double-blind, randomized controlled trial, found that the combination of sertraline and olanzapine was efficacious and superior to monotherapy with olanzapine in an acute setting.⁶ In another study, the combination of olanzapine and fluoxetine was also found to be superior to olanzapine monotherapy in reducing Hamilton Depression Rating Scale (HAM-D) scores.⁷Quetiapine, when used in combination with venlafaxine, was found to be superior to venlafaxine monotherapy in response.⁸ Lastly, amitriptyline in combination with either haloperidol or perphenazine has been shown to be superior to monotherapy.^9,10 However, no medications are specifically FDA-approved for the indication of depression with psychotic features. Because none of these agents have been compared in head-to-head trials, any combination of antidepressant and antipsychotic medication can be used. Due to the greater risk of adverse effects with first-generation antipsychotics (FGAs), such as extrapyramidal symptoms (EPS), second-generation antipsychotics (SGAs) should be trialed first.

How long should treatment last?

The optimal timeline for treating patients with MDD with psychotic features is unknown. According to the TMAP algorithm and expert opinion, the continuation phase of pharmacotherapy should include treatment for at least 4 months with an antipsychotic medication and at least 2 years to lifetime treatment with an antidepressant.⁵ The STOP-PD II study, which was a continuation of the 12-week STOP-PD study, examined antipsychotic duration to determine the effects of continuing olanzapine once an episode of psychotic depression had responded to olanzapine and sertraline.¹¹ Patients who had achieved remission after receiving olanzapine and sertraline were randomized to continue to receive this combination or to receive sertraline plus placebo for 36 weeks. The primary outcome was relapse, which was broadly defined as 1 of the following¹¹:

• a Structured Clinical Interview for the DSM (SCID)-rated assessment that revealed the patient had enough symptoms to meet criteria for a DSM-IV major depressive episode
• a 17-item HAM-D scoren of ≥18
• SCID-rated psychosis
• other significant clinical worsening, defined as having a suicide plan or attempting suicide, developing SCID-rated symptoms of mania or hypomania, or being hospitalized in a psychiatric unit.

Compared with sertraline plus placebo, continuing sertraline plus olanzapine reduced the risk of relapse over 36 weeks (hazard ratio, 0.25; 95% confidence interval, 0.13 to 0.48; P < .001).¹¹ However, as expected, the incidence of adverse effects such as weight gain and parkinsonism was higher in the olanzapine group. Therefore, it is important to consider the potential long-term adverse effects of continuing antipsychotic medications. The STOP-PD II trial showed benefit in continuing antipsychotic therapy over 36 weeks, but did not answer the question of how long to continue antipsychotic therapy.

Weighing the evidence

Electroconvulsive therapy is considered a first-line treatment option for MDD with psychotic features; however, because of limitations associated with this approach, antidepressants plus antipsychotics are often utilized as an initial treatment. Essentially, any antipsychotic agent can be prescribed in conjunction with an antidepressant, but due to the greater risk of adverse effects associated with FGAs, SGAs should be trialed first. The results of the STOP-PD⁶ and STOP-PD II¹¹ studies have shown that once a patient responds to an antidepressant and antipsychotic, combination therapy needs to continue for at least 9 months to reduce the risk of relapse. Thereafter, reducing the dose of the antipsychotic can be considered after 1 year of treatment; however, no data exist about which agent and tapering schedule to consider. Because no optimal duration has been fully established, consider a slow and gradual taper when stopping antipsychotic therapy to allow for assessment of recurring symptoms.

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