Atypical Antipsychotic-Induced Weight Gain

Abstract

Prescriptions for second-generation antipsychotics (SGAs) have surpassed those for first-generation agents in the treatment of schizophrenia and bipolar disorder. While SGAs have the benefit of a much reduced risk of causing movement disorders, they have been associated with weight gain and metabolic effects. These adverse reactions are not uncommon, and threaten to have a significant impact on the patient's health over the long-term treatment that the patient requires. Currently, the aetiology of these effects is not known. This article reviews the data exploring the weight gain phenomenon. The literature was reviewed from searches of PubMed and the references of major articles in the field. The SGAs present a heterogeneous risk for weight gain. In addition, different individuals receiving the same drug can exhibit substantially different weight changes. This pattern suggests that a group of factors are associated with the weight gain phenomenon rather than a single mechanism. Coupled with the genetic profile that the patient brings to the treatment, the risk for SGA-induced weight gain will be different for different drugs and different individuals. Targets for exploration of the weight gain phenomenon include receptor interactions involving serotonin, histamine, dopamine, adrenergic, cannabinoid and muscarinic receptors. The association of SGA-induced weight gain and the role of orexigenic and anorexigenic peptides are reviewed. Also, a brief discussion of genetic factors associated with SGA-induced weight gain is presented, including that of the serotonin 5-HT(2C) receptor gene (HTR2C) and the cannabinoid 1 receptor gene (CNR1). The most promising data associated with SGA-induced weight gain include investigations of the histamine H(1), 5-HT(2A), 5-HT(2C), muscarinic M(3) and adrenergic receptors. In addition, work in the genetic area promises to result in a better understanding of the variation in risk associated with different individuals.

Serum peroxisome proliferator-activated receptor-gamma levels in acute phase of male patients with schizophrenia and their relationship with metabolic parameters

“…In a study examining the relationship between PPARγ gene polymorphism and the metabolic disorders in schizophrenia and schizoaffective disorder patients, it was reported that the obesity or MetS seen in schizophrenia patients was not found to be related with the polymorphism of this gene [20]. Similarly, there are also studies in the literature supporting our finding that there were no relationships between PPARγ and metabolic disorders in schizophrenia [11,21].…”

The Role of Hypothalamic H1 Receptor Antagonism in Antipsychotic-Induced Weight Gain

“…Previous studies have indicated that numerous factors in the brain and peripheral tissues regulating appetite, metabolism and body weight are involved in SGA-induced obesity (reviewed in [2,5] ). SGAs directly interact with a range of neurotransmitter receptors that are involved in energy homeostasis, such as histaminergic H1, serotoninergic 2A and 2C, adrenergic α, muscarinic M3 and dopaminergic D2 receptors (reviewed in [3,[5][6] ). Notably, the antagonistic effect on histamine H1 receptors has been identified as a primary contributor of SGA-induced obesity, particularly with the use of olanzapine and clozapine.…”

“…Central histamine and H1 receptors may also increase WAT lipolysis but decrease lipogenesis, possibly by activating the sympathetic neurons, decreasing fat accumulation and body weight (5) In summary, antagonism of hypothalamic H1 receptors by SGAs may timedependently affect the hypothalamus-brainstem circuits to cause weight gain by stimulating appetite and fat accumulation but reducing energy expenditure. The H1 receptor and its downstream signaling molecules could be valuable targets for the design of new compounds for treating SGAinduced weight gain/obesity.…”

Changes in weight and metabolic parameters following long-term iloperidone use: A meta-analysis of data from 9 Phase II and III trials of iloperidone

“…Weight gain in the placebo-controlled studies was lower than in long-term, comparator-controlled studies (2.0 kg versus 3.8 kg) (Data on file, Novartis) [10,11]. The mechanistic basis of weight gain with iloperidone is unknown, however iloperidone binds to serotonin 5-HT 2A , 5-HT 2C , and histamine H 1 receptors [15][16][17][18], which have been implicated in antipsychotic-associated weight gain [19].…”