Augmentation Strategies for Negative Symptoms of Schizophrenia

December 13, 2017 · Posted in Potential Treatments 


In a 2017 article in the journal JAMA Psychiatry, Christoph U. Correll and colleagues reviewed 42 secondary strategies to treat schizophrenia when the primary antipsychotic treatment has an incomplete effect. Many people with schizophrenia show only a limited response to antipsychotic drugs, so additional treatments are often necessary, but currently there are no US Food and Drug Administration guidelines for combination treatment.

Correll and colleagues compiled data from 29 meta-analyses covering 381 individual trials. They found that while the meta-analyses were well done, the quality of the data in the original studies was lacking.

Focusing on Negative Symptoms

However, since the negative symptoms of the illness such as apathy, withdrawal, and blunted emotional response are the hardest to treat, any amount of improvement in this area could be particularly helpful. Large to moderate effect sizes were reported for the effectiveness of the following medications in reducing negative symptoms (in decreasing order): serotonin and norepinephrine reuptake inhibitor (SNRI) antidepressants, serotonin type 3 receptor active drugs (such as ondansetron), lamotrigine, acetylcholine esterase inhibitors, testosterone, the antibiotic minocycline, the anticonvulsant topiramate, antipsychotics, estrogen active compounds, any antidepressant, and modafinil.

The review did not include the positive findings on the antioxidant n-acetylcysteine (NAC). Researcher Michael Berk and colleagues reported in the journal Biological Psychiatry in 2008 that patients who received NAC in addition to maintenance treatment for schizophrenia saw more improvement in 24 weeks than those who received a placebo in addition to their normal treatment.

Clozapine, the most effective antipsychotic drug for patients with treatment-resistant schizophrenia, was not successfully augmented by any of the strategies in this review article. However, a few studies have found that adding the antipsychotic aripiprazole to clozapine treatment helps improve symptoms of schizophrenia and allows for a reduction in clozapine dosage, which improves tolerability. Studies have also shown that electroconvulsive therapy (ECT) can augment clozapine in people with treatment-resistant schizophrenia.

Editor’s Note: Given the serious impairment faced by people with schizophrenia, which is often driven by negative symptoms, some of these augmentation strategies deserve careful trials in individual patients. This is especially true of approaches that also work on positive symptoms (such as lamotrigine) or ones that pose little risk of side effects, such as NAC and minocycline.  


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