Candidate gene polymorphisms and clinical implications of the use of psychostimulants in adults with mood or attentional deficit disorders: A systematic review

Psychostimulants are FDA-approved for treating attention deficit hyperactivity disorder (ADHD). They are often prescribed off-label for mood disorders (in the majority of cases for augmentation of major depressive disorder [MDD] or treatment-resistant cases) with particular concerns in patients with comorbid ADHD and bipolar disorder (BD). We aimed to systematically appraise the current knowledge on genetic associations of psychostimulant treatment responses for mood disorders and ADHD. A comprehensive search was conducted from database inception until March 21st, 2023. We included randomized controlled studies and non-randomized studies of intervention in adults (>18 years) with a DSM-IV/DSM-5 diagnosis of MDD, BD, or ADHD. We specifically included studies that reported the use of psychostimulants (e.g., methylphenidate [MPH]) and explored genetic associations with dopamine receptors and transporters (DRD4, DRD2, SLC6A3) reuptake inhibitors, norepinephrine transporters (SLC6A2) and serotonin transporters (SLC6A4). We identified and screened 1,479 abstracts and selected 17 articles for full-text review. Five studies met the inclusion criteria (N=498; mean age 37.13±12.26), including two randomized controlled trials (n= 121, mean age 41.16±14.86) which analyzed genetic polymorphisms in SLC6A3 and SLC6A4. Three non-randomized intervention studies were included: one study (n=171, mean age 35±11) analyzed several SLC6A3 variants, and two studies (n=206, mean age 36.5±11.01) analyzed DRD4, SLC6A3, and SLC6A4 variants. Evidence from the selected studies did not consistently show statistically significant differences in treatment response for either MDD or ADHD in association with genetic polymorphisms. No studies evaluating BD were found, and MPH was the only psychostimulant assessed in the selected articles. The most reported adverse events were moderate nausea, anxiety, and polyuria, with a higher percentage for headaches (38.1%), gastrointestinal complaints (21.2%), and decreased appetite (19.08%). None of the included studies reported serious adverse events which required discontinuation. Further research is necessary to determine the implications of genetic polymorphisms on clinical response to stimulants with mood disorders and ADHD. Moreover, studies examining a broader range of stimulant medications as well as duration/dose of treatment, including individuals with BD, are crucial to understanding possible genetic influences on treatment response with the