Literature Reviewed

Atypical Antipsychotics and Metabolic Syndrome: From Molecular Mechanisms to Clinical Differences by Carli M, Kolachalam S, Longoni B, et al. Pharmaceuticals (Basel). 2021 Mar 8;14(3):238.


Original Abstract

Atypical antipsychotics (AAPs) are commonly prescribed medications to treat schizophrenia, bipolar disorder and other psychotic disorders. However, they might cause metabolic syndrome (MetS) in terms of weight gain, dyslipidemia, type 2 diabetes (T2D), and high blood pressure, which are responsible for reduced life expectancy and poor adherence. Importantly, there is clear evidence that early metabolic disturbances can precede weight gain, even if the latter still remains the hallmark of AAPs use. In fact, AAPs interfere profoundly with glucose and lipid homeostasis acting mostly on the hypothalamus, liver, pancreatic beta-cells, adipose tissue, and skeletal muscle. Their actions on hypothalamic centers via dopamine, serotonin, acetylcholine, and histamine receptors affect neuropeptides and 5’AMP-activated protein kinase (AMPK) activity, thus producing a supra-physiological sympathetic outflow augmenting levels of glucagon and hepatic glucose production. In addition, altered insulin secretion, dyslipidemia, fat deposition in the liver and adipose tissues, and insulin resistance become aggravating factors for MetS. In clinical practice, among AAPs, olanzapine and clozapine are associated with the highest risk of MetS, whereas quetiapine, risperidone, asenapine and amisulpride cause moderate alterations. The new AAPs such as ziprasidone, lurasidone and the partial agonist aripiprazole seem more tolerable on the metabolic profile. However, these aspects must be considered together with the differences among AAPs in terms of their efficacy, where clozapine still remains the most effective. Intriguingly, there seems to be a correlation between AAPs higher clinical efficacy and increased risk of metabolic alterations. Finally, a multidisciplinary approach combining psychoeducation and therapeutic drug monitoring (TDM) is proposed as a first-line strategy to avoid MetS. In addition, pharmacological treatments are discussed as well.

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First- and Second-General Antipsychotics: Commentary and Clinical Takeaways

This article by Carli et al reviews the differences between second-generation antipsychotics (SGAs) compared to first-generation antipsychotics (FGAs) and examines differences within the class of SGAs and the unintended consequences associated with their use in the treatment of schizophrenia, bipolar disorder, and other psychotic disorders.

First- and Second-Generation Antipsychotics Side Effects

As described, each FGA’s mechanism of action involves D2 blockade whereas SGAs act beyond D2 antagonism working at other receptor targets such as serotonin receptors (5-HT2A and 5-HT2C as well as partial 5-HT1 agonism), histamine 1 (H1) antagonism, alpha-2 antagonism, muscarinic antagonism (M3, M4, and M1), brain-derived neurotrophic factor (BDNF) production, and glycine transporter (GlyT) blocking.2 The degree of action at each of these receptors provides unique side effect profiles for each medication.

In the CNS, the hypothalamus controls glucose and lipid regulation by coordinating the liver, pancreas, adipose tissue, and skeletal muscles through the autonomic nervous system and neuroendocrine system. Sympathetic stimulation (fight or flight) increases norepinephrine and epinephrine levels, glucose secretion and production of glucose, and lipolysis (reduces insulin secretion and an increase in blood glucose). The parasympathetic (rest and digest) activation causes an increase in insulin secretion and inhibits the production of glucose which lowers blood glucose levels. For example, blocking histamine receptor H1 activity has been shown to cause “hyperphagia” (extreme hunger), “weight gain and metabolic dysregulation” as H1 activity has been shown to regulate glucose and lipids levels. The liver, pancreas, and adipose tissues impact glucose production, insulin release, and lipid accumulation. Various actions on M3, alpha-2, D2, 5-HT2A and 5-HT2C by SGAs result in increased glucose production, insulin resistance, cholesterol production, and lipid accumulation.2

Antipsychotics for the Treatment of Psychotic Disorders

The main takeaway from the Carli et al paper is that, while antipsychotics prove to be the mainstay of treatment for patients with psychotic disorders, it is important to recognize their side effect profiles and promptly assess patients to prevent further complications from metabolic syndrome seen with SGAs as well as movement disorders seen with FGAs. The American Psychiatric Association (APA) recommends metabolic laboratory tests (including hemoglobin A1c, lipid panel, body weight, and BMI) at baseline and routine monitoring at 4 to 6 months after starting therapy with an antipsychotic (predominantly SGAs).10 With increased risks of metabolic side effects with antipsychotic use, it is important to consider early interventions in supportive treatment to prevent significant impacts on a patient’s health moving forward.

The first-line intervention to combat metabolic side effects consists of psychoeducation including cognitive behavioral therapy as well as promoting a healthy diet and physical activity. Augmentation with psychoeducation serves a purpose to help patients change dysfunctional beliefs and biases toward healthy foods as well as make them more aware of their current diagnoses and the importance of managing side effects.

Carli et al point out that there are medication options to mitigate weight gain, promote weight loss, and treat diabetes and dyslipidemia that can be used as second-line therapy. For example, metformin has the most literature available supporting use for weight mitigation as well as type 2 diabetes treatment caused by SGA.2 Rosiglitazone can be used to regulate liver and adipose metabolism as well as decrease insulin resistance. GLP-1 agonists, such as liraglutide and exenatide, have been used to improve glucose control, assist in weight loss as well as decrease BMI. Medications, like amantadine, topiramate and fluoxetine, can also be used to decrease appetite.2 To improve dyslipidemia, statins can be utilized. PPAR antagonists (such as fenofibrate or gemfibrozil) work in an opposing mechanism to antipsychotics by inhibiting SREBP elements to reduce hepatic steatosis.

Additionally, the authors suggest personalized therapy, therapeutic drug monitoring, and genetic testing to assist in recommending medications for schizophrenia and bipolar disorder, tailoring therapy, and monitoring patient levels of treatment adherence.2


Next Paper in the Literature Review: Switching Antipsychotics to Support the Physical Health of People with Severe Mental Illness: A Qualitative Study of Healthcare Professionals’ Perspectives by Nash A, Kingstone T, Farooq S, et al. BMJ Open. 2021.

Prior Paper in the Literature Review: The Pharmacologic Treatment of Schizophrenia 2021 by DC Goff. JAMA. 2021.

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Last Updated: Sep 1, 2021