Review of: Lang X et al, J Transl Med 2023(1),21:432

Study Type: Randomized controlled open-label study

Antipsychotics clearly work well for positive symptoms in schizophrenia, but they are less effective for negative symptoms. This study from China tested whether adding a selective serotonin reuptake inhibitor (SSRI) could improve negative symptoms and allow lower dosing of an antipsychotic in schizophrenia.

The study enrolled 230 treatment-naive patients who were within the first five years of a schizophrenia diagnosis. All patients were between 18 and 45 years old. Substance use disorders and significant medical problems were exclusions. Over 24 weeks, patients were randomized to receive either (a) risperidone 2–3.5 mg/day with sertraline 50–100 mg/day or (b) risperidone 4–6 mg/day alone. Clonazepam was permitted for insomnia and anxiety.

The main outcome measure was change in the Positive and Negative Syndrome Scale (PANSS), supplemented by the Hamilton Depression Rating Scale (HAM-D), the Personal and Social Performance Scale (PSP), and a side effects scale. Blind raters assessed the patients with these scales at baseline and after months one, two, three, and six. Prolactin levels were also measured. At baseline, the subjects were markedly to severely impaired.

Over the course of the study, the risperidone-sertraline group showed more improvement than the risperidone-alone group. With more time, these differences grew, but both groups benefited from treatment. PANSS, HAM-D, and PSP scores were all superior with the sertraline combination (p<0.03 or better), indicating functional and symptomatic improvement. Side effects and prolactin levels were also lower in the combined treatment group. 

The dropout rate was 14%, with more dropouts in the risperidone-only group (26 patients) than the combination group (six patients). Most dropouts were due to side effects. 

Unfortunately, the study design makes it impossible to tell whether the superior outcomes were due to the lower risperidone dosage or the addition of sertraline in the combination group. Also, it is possible that the observed benefits were due to treatment of an undiagnosed depressive episode, as the average baseline HAM-D score was an elevated 24. 

CARLAT TAKE

Although imperfect in design, this study builds on prior evidence that SSRIs improve negative symptoms in schizophrenia. In choosing an SSRI, note that sertraline, citalopram, and escitalopram rarely cause drug interactions, whereas fluoxetine, paroxetine, fluvoxamine, and high-dose sertraline (above 150 mg) raise serum levels of many antipsychotics.