Dopamine, Striatum, Antipsychotics, and Questions About Weight Gain.

Abstract

For decades, psychiatrists worried about the adverse motor effects of antipsychotics and tried tounderstandwhat caused them and why some patients developed them and others did not. In the late 1990s, the game changed. The new atypical antipsychotics caused fewer adverse motor effects but causedmoreweight gain. At present, a large number of patients with schizophrenia experience a clinically important (>7%) weight increase after starting therapy with an antipsychotic. Thisweight gain contributes to type 2diabetes mellitus, dyslipidemia, andhypertension,which increase the risk for cardiovascular events. What causes this weight gain? Why do some patients gain weight and others not? Some drugs clearly are more likely to induce weight gain (eg, olanzapine, quetiapine fumarate, and clozapine) than others (eg, ziprasidone and lurasidone hydrochloride).1 The reason for these differences is not known for certain, but the serotonin2C receptors and the H1 receptors are often implicated.2 However, no drug is completely free of a weight gain effect, andnonecausesweight gain in everypatient.Why somepatientsaremoresusceptible thanothers remains largely unexplained. Previous studies have explored the genetic reasons for individual susceptibility,3 and others have explored diet and lifestyle predictors. In this issue of JAMAPsychiatry, Nielsen and colleagues4 report on a study exploring the association between brain activity in the striatum during reward anticipation and antipsychotic-induced weight gain. Dopamine is known to be one of the key agents for food reward and control of food intake.5 Dopamine is also central to schizophrenia and to antipsychotic action. Furthermore, in a healthy population, a reduction in the dopaminergic striatal response has been shown to be an important contributor toweight increase and obesity6 and is one of the pillars of the reward-deficiency hypothesis of obesity. Therefore, we may hypothesize that differences in baseline function related to dopamineandstriatal activity account for thevariability in antipsychotic-induced obesity. Nielsen and colleagues4 report on an important study in thisdirection.Theyrecruitedpatientswithfirst-episodeschizophrenia whowere antipsychotic naive and treated themwith amisulpride for 6 weeks. Amisulpride is a relatively selective dopamine D2 receptor antagonist antipsychotic used widely inEurope (althoughnotavailable in theUnitedStates).Amisulpride is relatively selective for dopamine D2 receptor, unlike the other atypical antipsychotics (eg, risperidone, olanzapine, and quetiapine); therefore, the weight gain as a consequenceof amisulpridehelps rule out the contributionof other neurotransmitter systems (serotonin andhistamine) conventionally associated with weight gain. To measure striatal activity, the investigators asked the patients to perform a reward task while undergoing functional magnetic resonance imaging.Thetaskrequiredthepatient to react toavisual stimulus to win or to avoid losing a monetary reward. This paradigm allows a detailed examination of the different stages of reward processing, such as the reward anticipation and consumption. Although the taskwas not specifically designed to assess the striatal response to food, it provides a generalmeasure of striatal response to a rewarding stimulus. The authors were able to assess the relationship of antipsychotic-related weight gainwith thebaseline (before treatment) level of striatal activity and its change during the 6 weeks of treatment. Theauthors founda significant associationbetweenbaseline striatal activity and subsequent weight gain during antipsychotic treatment. Patientswith lower baseline reward activity in the right-sidedputamenhad themost pronounced weight gain.After6weeksof amisulpride treatment, thosepatients with the most weight gain showed the greatest change (increase) in right-sided putamen striatal activity. At first glance, the results are straightforward. Thosewith low baseline striatal activity (and hence putative reward deficiency) gainedmoreweightwhen treatedwith anantipsychotic; this result is associated with the subsequent normalization of their striatal signaling. However, on closer inspection, the implicationsaremorecomplicated. If baseline reward deficiency is what drives the weight gain, one would assume that this deficiency should have existed before the first functional magnetic resonance imaging investigation. One must wonderwhy thosepatientshadnotputonweight already.One could argue that the antipsychotic (a dopamine antagonist) served as a trigger to weight gain, but reconciling that argumentwith thewell-described finding ofweight increase after dopaminergic agonist medication therapy, such as that seen in patients with Parkinson disease, is difficult.7 Other complex factors are likely at play. Recent data suggested that antipsychotic-induced weight gain has a high genetic contribution,3 although none of the single-nucleotide polymorphisms identified in genome-wide association studies have implicated the dopaminergic pathway, which suggests that alternativebiologicalmechanismsare involved.Furthermore, in this study, the weight gain was induced by amisulpride, a dopamine-selective antipsychotic. How this finding translates to antipsychotics, which act on multiple transmitters, has not been determined. Finally, antipsychotRelated article page 121 Opinion