A study recently published in BMC Psychiatry found that antipsychotic dosage reduction in patients with bipolar and major depressive disorders was associated with an increase in all-cause and mental health-related hospitalizations. Below, lead author Stanley N. Caroff, MD, of the University of Pennsylvania in Philadelphia explains the findings and their ramifications.
The study was funded by Teva Pharmaceuticals, Petach Tikva, Israel, which was involved in the design of the study and the collection, analysis, and interpretation of data.
Q: What led you and your colleagues to conduct research on this topic?
A: Traditionally, antipsychotics have been used in acute mania or depression for agitation or psychotic symptoms until remission was achieved with antidepressants, mood stabilizers, or electroconvulsive therapy. After remission, tapering off antipsychotics was advised to reduce chances of adverse effects associated with long-term treatment, particularly tardive dyskinesia (TD). Unfortunately, today many mood disorder patients remain on antipsychotics chronically with limited evidence on proper maintenance dosing, long-term effectiveness, and safety in these episodic and remitting disorders.
Secondly, apart from prescription of recently approved vesicular monoamine transporter-2 inhibitors (deutetrabenazine, valbenazine), recommendations for treating TD include modification of antipsychotic dosing. Although often recommended in treatment guidelines, there are few data examining the effect of antipsychotic dose reduction on TD or on the course of bipolar and major depressive disorders.
Q: Please briefly describe your study and its findings.
A: To address the gap in knowledge on the risks of dose reduction as a recommended treatment for TD, we conducted a retrospective matched cohort study to analyze the utilization of hospital resources resulting from ≥ 10% and ≥ 30% reductions in antipsychotic doses for patients with bipolar and major depressive disorders. Medical claims from 6 US states over a 6-year period were analyzed for patients with ≥10% or ≥30% reductions in antipsychotic dose (cases) and compared using survival analyses with matched controls receiving a stable dosage. Outcomes included hospitalizations for disease-specific mood disorders or other psychiatric disorders, all-cause hospitalizations, emergency room visits, and claims for TD.
A total of 23,992 patients with bipolar disorder and 17,766 with major depressive disorder had a ≥ 10% dose reduction, while 19,308 and 14,728, respectively, had a ≥ 30% dose reduction. In multivariate analyses, cases with a ≥ 10% dose reduction had a statistically significant increased risk of disease-specific admission, other psychiatric admission, all-cause admission, and all-cause emergency room visits. Similar results were observed following an ≥ 30% dose reduction. Dose reduction was not associated with decreased claims for new or persistent TD.
These results show small but statistically significant effects of antipsychotic dose reductions on increasing all-cause and mental health-related hospitalizations which may lead to increased health care costs, especially for patients with bipolar disorder.
Q: Were any of the outcomes particularly surprising to the study team?
A: The results did not support dose reduction for treating TD, but definitive conclusions could not be reached because of possible withdrawal dyskinesias, the limited duration of follow-up, use of anticholinergics, and underreporting of the diagnosis in this claims database.
Q: What implications do these findings have for the treatment of tardive dyskinesia?
A: While antipsychotic dose reduction may be indicated to reduce dose-related side effects (sedation, parkinsonism, etc.), there is still no convincing evidence it reduces symptoms of existing TD. On the contrary, dose reduction may transiently worsen or unmask TD, while these findings imply it may lead to increased risk of hospitalization in some patients with mood disorders.
Therefore, decisions on dose reduction of antipsychotics in patients with severe, psychotic, or recurrent mood disorders who require maintenance antipsychotic treatment should be carefully considered on an individualized basis. These results highlight the need for more long-term studies of maintenance antipsychotic dosing in patients with mood disorders, and of alternative management strategies to address TD that emerges during treatment.
Caroff SN, Mu F, Ayyagari R, Schilling T, Abler V, Carroll B. Hospital utilization rates following antipsychotic dose reduction in mood disorders: implications for treatment of tardive dyskinesia. BMC Psychiatry. 2020, 20:365.
Stanley N. Caroff, MD, is Professor of Psychiatry at the Perelman School of Medicine of the University of Pennsylvania, Philadelphia. His area of special interest is the neurobiology and psychopharmacology of psychotic disorders. His investigations address neurological aspects of severe mental disorders and antipsychotic-induced movement disorders, such as neuroleptic malignant syndrome, tardive dyskinesia, and catatonia. Dr. Caroff is certified by the American Board of Psychiatry and Neurology and is a Distinguished Life Fellow of the American Psychiatric Association and a founding member of the Academy of Master Clinicians at the Perelman School of Medicine. He served as Director of the Inpatient Psychiatry Program at the Michael J. Crescenz Veterans Affairs Medical Center in Philadelphia for more than 35 years.