CNS Drugs

, Volume 27, Issue 6, pp 423–434 | Cite as

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

  • Meng He
  • Chao Deng
  • Xu-Feng Huang
Review Article


Treatment with second generation antipsychotics (SGAs), notably olanzapine and clozapine, causes severe obesity side effects. Antagonism of histamine H1 receptors has been identified as a main cause of SGA-induced obesity, but the molecular mechanisms associated with this antagonism in different stages of SGA-induced weight gain remain unclear. This review aims to explore the potential role of hypothalamic histamine H1 receptors in different stages of SGA-induced weight gain/obesity and the molecular pathways related to SGA-induced antagonism of these receptors. Initial data have demonstrated the importance of hypothalamic H1 receptors in both short- and long-term SGA-induced obesity. Blocking hypothalamic H1 receptors by SGAs activates AMP-activated protein kinase (AMPK), a well-known feeding regulator. During short-term treatment, hypothalamic H1 receptor antagonism by SGAs may activate the AMPK—carnitine palmitoyltransferase 1 signaling to rapidly increase caloric intake and result in weight gain. During long-term SGA treatment, hypothalamic H1 receptor antagonism can reduce thermogenesis, possibly by inhibiting the sympathetic outflows to the brainstem rostral raphe pallidus and rostral ventrolateral medulla, therefore decreasing brown adipose tissue thermogenesis. Additionally, blocking of hypothalamic H1 receptors by SGAs may also contribute to fat accumulation by decreasing lipolysis but increasing lipogenesis in white adipose tissue. In summary, antagonism of hypothalamic H1 receptors by SGAs may time-dependently 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 SGA-induced weight gain/obesity.


Clozapine Olanzapine Aripiprazole Brown Adipose Tissue White Adipose Tissue 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The study is supported by an Australian National Health and Medical Research Council (NHMRC) grant to Xu-Feng Huang and Chao Deng (ID 635231). Meng He is supported by the China Scholarship Council—University of Wollongong Joint Postgraduate Scholarship. Prof. Huang, Ms. He and A/Prof. Deng have no conflicts of interest.


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Copyright information

© Springer International Publishing Switzerland 2013

Authors and Affiliations

  1. 1.Centre for Translational Neuroscience, School of Health Sciences32.305, Illawarra Health and Medical Research Institute, University of WollongongWollongongAustralia
  2. 2.Schizophrenia Research InstituteNSWAustralia

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