ADHD medications for cognitive impairment in bipolar disorders

People with bipolar disorders (BD) often display cognitive dysfunction, especially in verbal and working memory, processing speed and executive functions, which lead to poor occupational outcomes even more than residual symptoms.¹ Consequently, there is a constant effort to find treatments that might improve cognition and eventually global functioning in BD.

Several observations point to hypodopaminergic state as a driver of cognitive impairment in BD; therefore, increasing dopamine levels has been attempted as a strategy to ameliorate cognition.

Both stimulant and non-stimulant ADHD medications increase dopamine and norepinephrine brain levels, making them good candidates for treating cognitive dysfunction in BD. However, there has been a concern as to whether these medications are well tolerated, and specifically whether their use may induce (hypo)manic symptoms or episodes in persons with BD.

Stemming from these premises, the Targeting Cognition task force of the International Society for Bipolar Disorders (ISBD) conducted a systematic review on the efficacy and tolerability of ADHD medications in treating cognitive dysfunction in BD.²

The review reassures on tolerability, concluding that when BD is properly stabilized, the risk of treatment-emergent manic episodes due to the use of stimulant or non-stimulant ADHD medications is not higher than with placebo or other control conditions. Thus, methylphenidate, lisdexamfetamine, armodafinil, modafinil or bupropion can be safely employed unless BD is pharmacologically stabilized. Beyond the reviewed evidence coming from Randomized Controlled Trials, a large Swedish registry study on 2307 adults with BD who later initiated methylphenidate for concurrent ADHD found no evidence for an association between methylphenidate and treatment-emergent mania among those on concomitant mood stabilizers. On the other hand, those treated with the stimulant alone had a 6.7 times increased rate of manic episodes within 3 months of medication initiation.³ Hence, we might say that there is sufficient evidence not to discourage the use of ADHD medications in adequately stabilized BD.

However, the most compelling research aim was to review the efficacy of ADHD medications as cognitive enhancers in BD: the authors, based on evidence coming from three studies, concluded that there is insufficient data to assert that ADHD medications can improve cognition in BD. The first reviewed study was designed to assess the efficacy of adjunctive methylphenidate in reducing manic symptoms in acutely manic subjects. For safety reasons, the study lasted 2.5 days, after which methylphenidate was deemed ineffective and therefore stopped. The very short period of observation likely speaks for the observed lack of cognitive effect of methylphenidate. The second study, which evaluated the pro-cognitive effects of clonidine on manic subjects, employed the Mini-Mental State Examination, which is a general cognitive screening tool for dementia in the elderly and most likely lacks the sensitivity to assess subtle changes in specific cognitive functions.

Of note, both studies evaluated cognition during an acute manic episode. The assessment of cognition in mania is inherently difficult because of the distractibility, impulsivity and oftentimes lack of cooperation. Moreover, it can be argued that cognitive impairment influenced or caused by manic core symptoms would mostly resolve when the episode ends; therefore, cognition should preferably be assessed during euthymia rather than the acute phases of the disorder, as pointed out by the ISBD panel itself.⁴ Of the three studies reported, only one was specifically designed to assess the effect of adjunctive modafinil on cognition in BD. The study was conducted on either euthymic or minimally ill subjects with BD and employed a comprehensive battery to assess cognition. However, the greater improvement in processing speed and verbal learning with modafinil than with placebo was only marginally significant, clearly due to the very small sample size (12 subjects overall).

In recent years, two metanalyses evaluated the effect of methylphenidate and other ADHD medications on cognitive impairment in children/adolescents and adults with ADHD.^{5, 6} The effect was small in domains such as processing speed, memory spam and working memory, although—in children/adolescents—a dose-effect correlation was demonstrated for methylphenidate, with higher doses leading to greater improvements.⁵ Nevertheless, both papers concluded that the magnitude of effect exerted by ADHD medications is much greater on ADHD symptoms than on cognitive functions, where in most cases only small-to-moderate effect sizes could be retrieved.

One lesson that can be drawn from these metanalyses and from Miskowiak et al. systematic review is that future studies assessing the impact of cognitive enhancers on cognition in BD should employ a sounder methodology. In other words, researchers will need to include adequately numbered samples of subjects with BD in euthymic or at least partially remitted state and assess their cognitive functions with a comprehensive cognitive battery over several weeks of treatment. Finally, since the improvement of at least some cognitive domains may depend upon the dose, future studies should ideally assess the differential efficacy of different dosages of the index compound on cognition.