Summary: A new study indicates that certain medication combinations may lead to better outcomes for people with schizophrenia. Researchers reported that patients who added an antidepressant to their ongoing antipsychotic treatment were less likely to require hospitalization or emergency care for psychiatric reasons than those who began another antipsychotic or a benzodiazepine.
Source: Columbia University.
Some combinations of psychiatric medications appear to work better than others for patients with schizophrenia, according to new research.
The findings were published in JAMA Psychiatry.
Antipsychotic medications are the primary treatment for schizophrenia, targeting psychotic symptoms such as delusions and hallucinations. However, many patients continue to experience additional symptoms—depression, anxiety, agitation, and mood instability—that antipsychotics alone may not fully address. To manage these broader symptom profiles, clinicians commonly add other psychiatric drugs such as antidepressants, benzodiazepines, mood stabilizers, or even a second antipsychotic.
“Antipsychotic medications are used to treat psychotic symptoms such as delusions and hallucinations, but there is little guidance on what to do for other types of symptoms like depression, anxiety, or excitement,” explains T. Scott Stroup, MD, MPH, professor of psychiatry at Columbia University Vagelos College of Physicians and Surgeons and the paper’s lead author. “Additional medications are often prescribed, but we know little about how different psychiatric drug combinations affect people with schizophrenia. Until now we have known virtually nothing about how these strategies compare to each other.”
To compare real-world outcomes across common adjunctive strategies, the research team analyzed national Medicaid records for 81,921 adults diagnosed with schizophrenia. All participants had been stably treated with a single antipsychotic for at least three months before initiating one of four adjunctive approaches: an antidepressant, a benzodiazepine, a mood stabilizer, or a second antipsychotic.
Using statistical methods to balance patient characteristics across the four treatment groups, the investigators compared outcomes during the first year after adding the adjunctive medication. The primary outcome was psychiatric hospitalization; secondary outcomes included psychiatric emergency department visits and overall mortality.
Key findings showed that adding an antidepressant to ongoing antipsychotic therapy was associated with a meaningful reduction in acute psychiatric events compared with initiating a different antipsychotic. Specifically, antidepressant add-on therapy was linked with a 16% lower risk of psychiatric hospitalization compared with starting another antipsychotic and a 22% lower risk compared with beginning a benzodiazepine. For psychiatric emergency visits, antidepressants were associated with an 8% lower risk versus another antipsychotic and an 18% lower risk versus benzodiazepines.
By contrast, initiating a benzodiazepine in addition to an antipsychotic was associated with worse short-term outcomes: higher rates of psychiatric hospitalization and emergency visits compared with switching to another antipsychotic. Mood stabilizers showed outcomes similar to switching antipsychotics for hospitalization and emergency visits, but the study observed an increased risk of all-cause mortality associated with initiating a mood stabilizer—an association that the authors note warrants careful attention and further study.
“Our study adds more evidence that benzodiazepine use should be limited and that combining antidepressants with antipsychotic drugs for individuals with schizophrenia may have benefits,” says Stroup. He emphasizes that more work is needed to define when antidepressants are most helpful and which symptom profiles benefit most from their addition, since antidepressants may be used for conditions beyond depression.
The practice of prescribing multiple psychiatric medications—often called polypharmacy—is common in schizophrenia care. The investigators suggest their results support a more measured, evidence-informed approach to polypharmacy that prioritizes combinations shown to reduce acute psychiatric crises and avoids combinations associated with poorer outcomes.
The study team included T. Scott Stroup, MD, MPH; Tobias Gerhard, PhD; Stephen Crystal, PhD; Cecilia Huang, PhD; Zhiqiang Tan, PhD; Melanie M. Wall, PhD; Chacku Mathai, AAS; and Mark Olfson, MD, MPH. The research was supported by a Patient-Centered Outcomes Research Institute award (CER-1310-06750).
Conflicts of interest disclosed by the authors include prior industry-sponsored activities and consultancy for some investigators; details were reported in the original publication. The authors reported no additional financial or other conflicts of interest beyond those disclosed.
Abstract (condensed)
This comparative effectiveness study used U.S. national Medicaid data from 2001 to 2010 to examine outcomes among 81,921 adult outpatients with schizophrenia who were stably treated with a single antipsychotic and then initiated an antidepressant, benzodiazepine, mood stabilizer, or another antipsychotic. Propensity scores and weighted Cox proportional hazards models were used to account for differences across groups and to compare outcomes over 365 days on an intention-to-treat basis. Initiating an antidepressant was associated with reduced risk of psychiatric hospitalization and emergency department visits compared with starting another antipsychotic. Initiating a benzodiazepine was associated with increased risk of psychiatric hospitalization and emergency visits. Initiating a mood stabilizer showed no significant difference for hospitalizations or emergency visits compared with another antipsychotic but was associated with an increased risk of mortality, a finding that requires further investigation. The authors conclude that, in this large real-world dataset, adjunctive antidepressant treatment appeared beneficial for reducing acute psychiatric care needs, while benzodiazepines and mood stabilizers were associated with less favorable outcomes and should be used with caution.
This report summarizes findings from a peer-reviewed study. For clinicians and patients, the results highlight the importance of weighing potential benefits and risks when adding medications to antipsychotic treatment in schizophrenia and support careful, evidence-based choices about adjunctive therapy.