Atypicals: Do They Work for Depression?

Atypicals: Do They Work for Depression?In the beginning of modern psychiatry, there was only one medication— Thorazine (Chlorpromazine). Thorazine was originally classified as an antihistamine, and was used to treat everything thrown in the path of psychiatrists: psychosis, mania, depression, and anxiety. Between 1960 and 1976, fully 17 double blind trials of Thorazine and Mellaril (thioridazine) for depression were published, and most were successful (1).

With the advent of the atypicals, it seems that we have come full circle. They are great for treating psychosis, of course. We now know that they are also robustly effective for mania (Zyprexa is FDA approved, and Risperdal, Seroquel, Geodon, and Abilify all have high quality controlled data for effectiveness). We use them for non-psychotic anxiety, especially in substance abusers, without batting an eye. Now, it appears that atypicals are effective antidepressants as well!

While the published evidence for atypicals for depression is scant, it is gaining momentum. The first widely read article appeared in Journal of Clinical Psychiatry in 1999 (2). Ostroff and Nelson at Yale reported on a case series of 8 patients who had failed trials of SSRIs (either Prozac or Paxil). Each patient was started on low dose Risperdal as an augmentor of the antidepressant. Dosages were from 0.5 mg to 1 mg, generally at night. Lo and behold, the recoveries were immediate and dramatic. Hamilton depression scale scores plummeted overnight in some cases, generally from the high teens or low 20s to below 6. One grateful patient sent the authors a letter thanking them for a “miraculous” cure.

The first thought in your mind may very well be: Were these patients actually suffering from occult psychotic depression? Not really. While the authors report than some of them were highly anxious and ruminative, others were simply anergic and sad.

This study is intriguing, but we’ve all seen promising case reports in psychiatry yielding treatments eventually proven ineffective in rigorous trials. The only published double-blinded controlled trial that TCR was able to locate in Medline was a study by Shelton and colleagues in the American Journal of Psychiatry (3). The study was funded by Eli Lilly, but was fairly designed, if rather small. A total of 28 patients with treatment-resistant non-psychotic depression (defined here as failure of two antidepressant trials, not necessarily from different classes) were randomly assigned to three groups: Prozac alone (n=10, average dose 52 mg); Zyprexa alone (n=8, dose 12.5 mg); and Prozac/Zyprexa combination (n=10, dose 52/13.5 mg).

The Prozac/Zyprexa combination was dramatically more effective than either Prozac or Zyprexa alone, as measured by the MADRS depression scale. As was true in the Ostroff case series, depressive symptoms decreased very quickly, with responses by week 1. The downside? You may have already guessed: Zyprexa-treated patients gained 13 to 14 pounds over the course of this 4 month study.

The bottom line is that atypicals appear to enhance response to antidepressants, and work very quickly in select patients. Why atypicals should ease depression is anybody’s guess at this point, but most authors focus on the 5HT 2A blocking properties, a quality shared by two bonafide antidepressants— Remeron and Serzone. The theory is that blocking 5HT 2A receptors enhances serotonergic transmission at the 5HT 1A receptor, which is thought to be where most antidepressant and antianxiety action occurs.

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But whatever the reasons, atypicals appear to work for depression. There is a problem here, however. Makers of atypicals are touting their anti-manic properties heavily, and one might argue that they can’t have it both ways. Can a powerful anti-manic agent also be an antidepressant? If so, they are the first true “mood stabilizers.”

TCR VERDICT: Give them a try!


1. Robertson MM, Trimble MR. Major tranquilizers used as antidepressants: a review. J Affect Disord 1982;4:173-193.

2. Ostroff RB, Nelson JC. Risperidone augmentation of selective serotonin reuptake inhibitors in major depression. J Clin Psychiatry 1999;60: 256-259.

3. Shelton RC, Tollefson GD, Tohen M et. al. A novel augmentation strategy for treatment resistant major depression. Am J Psychiatry 2001;158:131-134.

Atypicals: Do They Work for Depression?

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APA Reference
Psychiatry Report, T. (2013). Atypicals: Do They Work for Depression?. Psych Central. Retrieved on October 27, 2020, from


Scientifically Reviewed
Last updated: 27 Apr 2013
Last reviewed: By John M. Grohol, Psy.D. on 27 Apr 2013
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