Treatment for severe recurring disorders like psychotic depression often proves ineffective and facilitates side effects bad enough to nearly match those of the disorder itself, with extreme weight gain, lethargy, and dangerously high blood pressure most notable among them. Psychotic depression resembles schizophrenia in that affected subjects experience paranoia and hallucinations, may lash out at caregivers, and often prove unable to care for themselves.

Since most medications are not strong enough to combat these conditions, the disorder's most common treatment models involve electro-convulsive therapy (ECT) and the use of powerful atypical antipsychotic drugs, such as Seroquel and Zyprexa, that lead to the negative side-effects listed above. In what might seem like a counter-intuitive conclusion, researchers now propose adding traditional SSRI antidepressant meds (Prozac, Zoloft) to these treatment regimens in order to counteract the negative side effects of the powerful therapies and create a more balanced patient. This treatment model received attention from the academic community in the past, but recent research on the topic presents the most compelling evidence of its effectiveness to date.

The most recent study centered on a 12-week trial performed at Cornell University that involved 259 subjects, previously diagnosed with psychotic depression, who displayed at least one symptom of delusions or irrational behaviors. Researchers gave Zyprexa to all subjects but split them into two groups, one of which received Zoloft throughout the study and one of which received a placebo in its place. Researchers also categorized results by age, comparing outcomes for subjects under 60 to those over 60. They found that members of the SSRI group were nearly twice as likely (42% to 24%) to move into a stage of remittance characterized by a significant decrease in related symptoms.

Unfortunately, side effects remained severe for all subjects, and this may have facilitated the study's abnormally high 45% dropout rate.  Side-effects, especially those related to weight gain, were less troublesome for those in the older group, and this finding is consistent with the results of previous related research revealing that senior subjects have fewer problems with the meds. So the consequences of atypical antipsychotic treatment remain extreme, but the fact that SSRI combination therapy produced significantly more cases of remission is encouraging.