Calling for More Research of Medication Effects in Bipolar Disorder: Response to Ketter and Dell’Osso

To the Editor: We thank Dr. Ketter and Dr. Dell’Osso for the interest in our study (1) published in the April 2017 issue of the Journal and for raising important questions.

With respect to the issue of bipolar subtypes, individuals in our study were identified as having bipolar disorder based on a validated search algorithm (2), which required at least two inpatient or outpatient admissions with a discharge diagnosis of bipolar disorder in the Swedish National Patient Register. However, the ICD system used in this register does not reliably distinguish between bipolar I and bipolar II disorder. Therefore, all subtypes of bipolar disorder were included in the analyses. This is a limitation of the study, and more research is needed to examine if the effects observed in the study are limited to, or are more pronounced in, a specific subtype of bipolar disorder. The same limitation affected a previous study of ours (3) published in the Journal in 2014, investigating antidepressant-induced manic switch in patients with bipolar disorder. Therefore, we have read with interest the recent study by Altshuler and colleagues (4), published in the March 2017 issue of the Journal, which observed similar switch and treatment response rates in participants with bipolar II depression associated with lithium monotherapy, sertraline monotherapy, or lithium/sertraline combination therapy.

Regarding the issues of dose and administration, the data used in our study include number of pills dispensed, dose per pill, and dispensation dates. Unfortunately, the mean daily dose is not available in the register. Calculating the mean daily dose would therefore need to rely on a number of assumptions regarding each individual’s pattern of consumption that may not be true for every individual. Nevertheless, we ran a new analysis on the cohort used in the study (1). Table 1 presents the distribution of methylphenidate dispensed in the different groups according to the mean dose of methylphenidate per pill dispensed in milligrams and the immediate release, slow release, or combination thereof. There were no discernible differences between the monotherapy group and the group that also received a mood stabilizer.

We agree with Dr. Ketter and Dr. Dell’Osso that more details are needed in the extent to which stimulants and antidepressants can be safely used, not only regarding dose, medication combinations, and bipolar disorder subtypes, but also regarding interindividual variation in the form of genetic or environmental factors.