Antipsychotics in the Treatment of Depressive Disorders: A Focus on Atypical Antipsychotics

Antipsychotics in the Treatment of Depressive Disorders: A Focus on Atypical Antipsychotics


Depression remains a significant challenge in the medical community. Despite advances in treatment, many patients do not respond positively to conventional treatments. Atypical antipsychotics have emerged as a potential solution, especially for those resistant to standard treatments.

What Are Atypical Antipsychotics?

Often termed as second-generation antipsychotics, atypical antipsychotics differ from their typical counterparts primarily in their interaction with serotonin receptors. They are considered “atypical” due to their distinct clinical profile and tend to have fewer side effects, including extrapyramidal symptoms which involve tremors and involuntary movements12.

Historical Perspective

Antipsychotics have a long history in treating depressive disorders. The treatment effect of phenothiazines was found comparable to tricyclic antidepressants. However, side effects like extrapyramidal symptoms reduced their popularity for depression monotherapy. Over time, atypical antipsychotics, with fewer side effects, replaced typical ones, especially for patients with severe or psychotic symptoms1.

Mechanism of Action

The antidepressant effects of atypical antipsychotics involve:

  • Rapid disengagement and decreased activation of dopamine receptors.
  • Blockage of the norepinephrine transporter.
  • Reduced cortisol levels.
  • Increase in Brain-derived neurotrophic factor levels.
  • Regulation of monoamine, glutamate, gamma-aminobutyric acid (GABA), and other neurotrophic factors12.

FDA Approvals and Commonly Prescribed Atypical Antipsychotics

The United States Food and Drug Administration (USFDA) has approved:

  • Aripiprazole as an adjunctive treatment for depressive disorders.
  • Combination of olanzapine and fluoxetine for treatment-resistant depression.
  • Slow-release quetiapine as an adjunctive treatment for depressive disorders1.

Other commonly prescribed atypical antipsychotics for depression include:

  • Olanzapine
  • Risperidone2

Benefits and Risks

While atypical antipsychotics have shown promise in treating depression, they come with potential risks. Some studies indicate an increased mortality risk for elderly patients with dementia when treated with atypical antipsychotics. Other side effects include weight gain, diabetes, and dyslipidemia2.


Atypical antipsychotics offer a new avenue for treating depression, especially for those resistant to standard treatments. However, like all medications, they come with benefits and risks. It’s essential for clinicians to monitor patients closely and for patients to be informed about potential side effects.

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