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Novel Antipsychotics for Treatment-Resistant Depression

(PSYCHIATRIC TIMES) - Currently available antidepressant medications are effective for a large segment of the population with depression. However, recent data suggest that a sizable portion of patients with unipolar depression do not experience full therapeutic recovery. For example, Simon et al. (1999) found that only about half of depressed patients treated with antidepressants in a primary care setting achieve recovery over a two-year period. Since lack of full response is common, management strategies need to be established and implemented. Current approaches include: the use of combination antidepressant treatments (e.g., selective serotonin reuptake inhibitor and bupropion [Wellbutrin]), augmentation (e.g., the addition of lithium [Eskalith, Lithobid] or thyroid hormone to an antidepressant), the addition of psychotherapy or electroconvulsive therapy (Shelton, 2003, 1999). However, even with these approaches, a significant minority of patients do not experience a full therapeutic effect.

Recently, novel antipsychotics have shown some promise for the management of depressive disorders. From a mechanistic standpoint, the pharmacological properties of at least some of these drugs predict antidepressant properties. Novel antipsychotics act, to varying degrees, on a variety of dopamine, serotonin (5HT), glutamate and other receptors. The antagonism of 5HT2A receptors is common among these drugs, and blockade of this subtype is seen with other antidepressant agents such as mirtazapine (Remeron) and nefazodone (Serzone). Blocking of 5HT2C receptors has also been shown to enhance release of frontal dopamine and norepinephrine, which is thought to be a key antidepressant property (Shelton, 2003; Zhang et al., 2000).

Further, several lines of clinical evidence support the usefulness of novel agents for the management of depression. These include the use of novel antipsychotics for the mood symptoms of schizophrenia (Tollefson and Sanger, 1999) and both mixed and depressive states in bipolar disorder (Tohen et al., 2003). In fact, evidence supporting the effectiveness of novel antipsychotics in depressive disorders is not new. For example, clozapine (Clozaril) has been shown effective for the management of mood symptoms in schizophrenia, dysphoric mania and psychotic depression (Shelton, 2003).

A key question, however, is whether certain of these drugs are producing direct antidepressant effects or are augmenting actions when combined with antidepressants, or alternatively, whether the actions are related to the antipsychotic effects alone. Tohen et al. (2003) reported that olanzapine (Zyprexa) given alone or in combination with fluoxetine (Prozac) produced a greater antidepressant response than placebo in patients with bipolar I disorder depression. Both olanzapine and combined olanzapine and fluoxetine (Symbyax) produced beneficial effects on core symptoms of depression, including sadness, pessimistic thoughts, suicidal ideation, fatigue and poor concentration (Tohen et al., 2003). This suggests that the actions are not mediated via the impact of the antipsychotic drug on psychotic symptoms alone.

Based on this line of reasoning, olanzapine was tested in an augmentation trial with fluoxetine in 28 patients with treatment-resistant, nonpsychotic unipolar depression (Shelton et al., 2001). Treatment resistance was demonstrated retrospectively by a failure of a previous adequate trial of two different antidepressants and a prospective run-in of six weeks of fluoxetine up to 60 mg/day.

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