Functional Variation in RGS12 Should Not Preclude Methylphenidate Use in Bipolar Disorder with Established Mood Stabilization: Preclinical Evidence

Our goal in this study was to determine whether functional variation in the human RGS12 gene influences behavioral responses to psychostimulants such as methylphenidate, thereby informing whether such genetic findings should affect the clinical use of this central nervous system (CNS)-stimulating agent in bipolar disorder (BD) patients with comorbid attention-deficit/hyperactivity disorder (ADHD). The use of psychostimulants for ADHD in BD remains controversial due to concerns about mood destabilization, although recent systematic reviews indicate that methylphenidates and amphetamines can be safe and effective when used with mood stabilizers. RGS12, a striatally enriched regulator of κ-opioid receptor signaling and dopamine transporter (DAT) function, has been implicated in altered dopaminergic responses to psychostimulants. A recently characterized R59Q reduction-of-function mutation within RGS12 has been associated with familial bipolar disorder, further highlighting its potential relevance to mood and psychostimulant responsiveness. Rgs12-deficient mice were evaluated for behavioral responses to methylphenidate (i.e., locomotor hyperactivity) and compared with responses to dopamine transporter-dependent stimulants. Rgs12 deficiency was seen to reduce hyperlocomotion with amphetamine, and with methamphetamine but not with methylphenidate, which was instead observed to elicit normal hyperlocomotor responses across all doses. Methylphenidate responsiveness remains intact despite the loss of RGS12 function, suggesting that RGS12 functional variation in the human condition should not contraindicate methylphenidate use in mood-stabilized BD/ADHD comorbidity.