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Antidepressants may be best add-on to antipsychotics in schizophrenia

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Time for closer look at adjunctive antidepressants

Much of the research into adjunctive therapy in schizophrenia is of poor quality, and other hurdles make it difficult to understand the best treatment approach. The new study links the addition of an antidepressant to a substantial lowering of psychiatric hospitalization risk, compared with initiating another antipsychotic, wrote Donald C. Goff, MD. Previous randomized controlled trials (RCTs) have suggested that adding on antidepressants can moderately reduce symptoms – mainly negative ones – in schizophrenia. The study findings are preliminary and suggest that an RCT is in order.

Dr. Goff disclosed grants from Avanir.

These statements are based on an accompanying editorial by Dr. Goff of New York University (JAMA Psychiatry. 2019 Feb 20. doi: 10.1001/jamapsychiatry.2018.4318).



Antidepressants could be the best adjunctive treatment for adult outpatients with schizophrenia who are taking a second-generation antipsychotic and need a change in medication, results of an observational study suggest. Patients who added antidepressants to their treatment had a lower risk of psychiatric hospitalization and emergency room visits than did those who tried an alternative antipsychotic, and those who took mood stabilizers and benzodiazepines were significantly more likely to die over 365 days.

Specifically, “the possibility that adjunctive use of gabapentin is associated with increased risk of death raises a serious concern,” wrote T. Scott Stroup, MD, MPH, of the department of psychiatry at Columbia University, New York, and his associates in JAMA Psychiatry.

Often, Dr. Stroup and his associates noted, second-generation antipsychotics often are insufficient to alleviate symptoms and leave patients with functional limitations. Still, there’s “little high-quality evidence” regarding the best treatments for schizophrenia, said Dr. Stroup, who is also affiliated with the New York State Psychiatric Institute, and his associates.

Using a Medicaid database, the researchers retrospectively tracked 81,921 outpatients with schizophrenia (aged 18-64 years; mean age, 41 years; 46% women) who were treated with a single antipsychotic from 2001-2010. Each patient added an antidepressant (31,117), a benzodiazepine (11,941), a mood stabilizer (12,849), or another second-generation antipsychotic (26,014).

The researchers examined treatment outcomes over a yearlong period after patients began their new treatment and compared the various groups to the reference group (those who began taking an additional antipsychotic medication).

Compared with the reference group, patients who took an antidepressant had a lower risk of psychiatric hospitalization (hazard ratio, 0.84; 95% confidence interval, 0.80-0.88), while the benzodiazepine group had a higher risk (HR, 1.08; 95% CI, 1.02-1.15), and the mood stabilizer group saw no major difference (HR, 0.98; 95% CI, 0.94-1.03). Similar results were found for the risk of psychiatric emergency department visits, compared with the reference group: The HR with the addition of an antidepressant was 0.92 (95% CI, 0.88-0.96), 1.12 with a benzodiazepine (95% CI, 1.07-1.19), and 0.99 with a mood stabilizer (95% CI, 0.94-1.04).

In regard to mortality, the researchers found that mood stabilizers and benzodiazepines stood apart on the risk front with HRs of 1.31 (95% CI, 1.04-1.66) and 1.22 (95% CI, 0.98-1.52), respectively. Among mood stabilizer use, Gabapentin accounted for 1,755 initiations (13.7%) and was associated with 45 deaths (28.0%), the researchers reported. “No other mood stabilizer appeared to be associated with a higher rate of death than the others.”

Dr. Stroup and his associates cited several limitations. One is that the results might not be generalizable because the investigators looked only at patients who were enrolled in the Medicaid program. Nevertheless, “improved pharmacologic treatment of schizophrenia and consequent reduced need for hospitalization and ED visits associated with more antidepressant and less benzodiazepine use would represent a significant benefit for individuals and for public health,” they wrote.

The study authors reported various relationships with drugmakers, including Auspex, Intra-Cellular Therapies, Eli Lilly, Bristol-Myers Squibb, and Merck. The study was funded by a Patient-Centered Outcomes Research Institute award.

SOURCE: Stroup TS et al. JAMA Psychiatry. 2019 Feb 20. doi: 10.1001/jamapsychiatry.2018.4489.

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