Commentary on the Risk of Treatment-Emergent Mania With Methylphenidate in Bipolar Disorder

To the Editor: The article by Alexander Viktorin and colleagues (1), published in the April 2017 issue of the Journal, reported findings from Swedish national registers regarding the risk of treatment-emergent mania associated with methylphenidate, administered as monotherapy or with a concomitant mood stabilizer, in patients with bipolar disorder. The authors found that patients taking methylphenidate monotherapy had a significantly increased risk of manic episodes within 3 months of medication initiation, with similar results for the subsequent 3 months. On the other hand, the risk of mania for patients already taking antimanic medications was not increased after starting methylphenidate.

We found this article of particular relevance, providing new evidence to the pharmacotherapeutic field of bipolar disorder and, particularly, in relation to the use of stimulants, which continues to be a point of debate (2, 3). In our view, the results of Viktorin and associates’ study are consistent with recent controlled reports in the field (4, 5) and confirm what many clinicians with experience in treating bipolar patients are already aware of: monotherapy with stimulants—methylphenidate in this particular case—entails the risks of eliciting elevated or mixed episodes, rapid cycling, and overall mood destabilization, whereas the cautious use of adjunctive stimulants, after patients have been already adequately stabilized with antimanic agents (lithium, valproate, carbamazepine, and second-generation antipsychotics), may be useful in certain circumstances. Such an approach may not only be limited to cases of comorbid attention deficit hyperactivity disorder, as the authors highlighted, but may extend to cases of partial or poor response to treatments for bipolar depression and the presence of residual symptoms, such as fatigue, weight gain, and cognitive impairment, persisting beyond acute depressive episodes.

Having read Viktorin and colleagues’ study with the utmost interest, we wonder whether the analyzed registry included only patients with bipolar I disorder, as there was no mention of diagnostic subtype in the article. This seems likely, as the authors aimed at detecting the occurrence of only manic (and not hypomanic) episodes. Nonetheless, there is the possibility that some patients with a previous diagnosis of bipolar II disorder had a substance-induced manic episode and, therefore, a transition to bipolar I disorder, with methylphenidate monotherapy. It would also be beneficial to know the mean daily methylphenidate dosage patients were taking in the two groups and whether the sample was mostly prescribed immediate or extended-release methylphenidate.

A growing body of evidence has been generated over the last decade about the contexts in which bipolar disorder patients may have beneficial, as opposed to detrimental, effects with stimulants (and antidepressants) added to their therapeutic regimens. However, further insight is needed in relation to the durations of exposure to stimulants or antidepressants for bipolar patients in the long term and to the possibility of safely tapering stimulants and antidepressants with patients maintaining clinical benefit once these compounds are discontinued.