SSRI augmentation of antipsychotics for negative symptoms of schizophrenia

While antipsychotics do produce some reduction of negative symptoms in people with schizophrenia, the improvement is somewhat less than in other symptoms of the condition.

Negative symptoms reflect a deficit in two clusters of symptoms:

An expressive deficit (affective flattening, poverty of speech)
Amotivational state (asociality, amotivational and apathy)

Persistent negative symptoms are a clinically important problem for a subgroup of otherwise stable individuals despite adequate antipsychotic drug treatment, and, are correlated with social and clinical long term morbidity and poor functioning in many areas of life.

There is a body of evidence that antidepressants help individuals who are in an acute episode of a major depressive disorder comorbid with their schizophrenic illness or when used to prevent another episode (Janicak PG, et al, 1993). Some controlled studies find antidepressants have a beneficial effect for negative symptoms, but many do not. It is therefore important to explore the direct effect of antidepressants on negative symptoms that is not explained by comorbid major depressive disorder.

The recently published ACTIONS trial explores one antidepressant (Citalopram) versus placebo for the long term treatment of selected people with schizophrenia who have persistent negative symptoms, but who do not have a comorbid acute major depressive illness.


The results fail to find evidence not only in quality of life and negative symptoms, but also in both clusters of negative symptoms, nor in a wide variety of other symptoms. Since negative symptoms produce considerable morbidity, the failure of benefit seen long term and the effect on health economic outcome is consistent with the clinical outcome.

A recent comprehensive meta-analysis (Helfer B. et al. 2016) found evidence for an overall small benefit, but this could result from a small effect in all patients or a larger effect in some studies, and, no difference in others. Some individual studies find antidepressant augmentation produced benefits in people with schizophrenia, while others do not. The latter could occur because of four possibilities:

Bias in a few studies can be carried through to the final meta-analysis result. There are many possibilities for bias to creep into studies, despite the best efforts of investigators. Individual investigators seek verification of their hypotheses, with positive results useful in seeking public grants. Industry sponsors seek positive results, and such bias could exist for several trials of that specific drug. Publication bias is a result that positive studies are more likely to be published than negative studies, and this is particularly so for small studies
It is possible that only a subtype of patients respond. For example, some of these might be people with schizophrenia who also have comorbid major depressive disorders.
It is possible there could be differences in the mechanisms of action of different subtypes of antidepressants
It is possible the beneficial effect could develop slowly so that a longer term study is necessary to demonstrate efficacy.