Attenuating antipsychotic-induced weight gain and metabolic side effects

Pharmacological strategies to counteract antipsychotic-induced weight gain and metabolic adverse effects in schizophrenia: a systematic review and meta-analysis.

  • Metformin was the most extensively studied drug in regard to body weight, the mean difference amounting to -3.17 kg (95% CI: -4.44 to -1.90 kg) compared to placebo.
  • Topiramate, sibutramine, aripiprazole, and reboxetine were also more effective than placebo.
  • Metformin and rosiglitazone improved insulin resistance, while aripiprazole, metformin, and sibutramine decreased blood lipids.

 “…literature supports the use of concomitant metformin as first choice among pharmacological interventions to counteract antipsychotic-induced weight gain and other metabolic adversities in schizophrenia.”

  • “Metformin could be considered an adjunctive therapy with clozapine to prevent metabolic syndrome in schizophrenic patients”

Metformin for weight loss in schizophrenia: safe but not a panacea.

On the contrary, a recent systematic review and meta-analysis of agents for reducing olanzapine and clozapine-induced weight gain in schizophrenia concluded: “topiramate and aripiprazole are more efficacious than other medications in regard to weight reduction and less burden of critical adverse effects as well as being beneficial for clinical improvement.”

In clozapine treated patients:

“Aripiprazole, fluvoxamine, metformin, and topiramate appear to be beneficial; however, available data are limited to between one and three randomized controlled trials per intervention. Orlistat shows beneficial effects, but in males only. Behavioral and nutritional interventions also show modest effects on decreasing clozapine-associated weight gain, although only a small number of such studies exist.” [1]

Use of melatonin is a promising strategy:

“Our results show that melatonin is effective in attenuating SGAs’ adverse metabolic effects, particularly in bipolar disorder. The clinical findings allow us to propose that SGAs may disturb a centrally mediated metabolic balance that causes adverse metabolic effects and that nightly administration of melatonin helps to restore. Melatonin could become a safe and cost-effective therapeutic option to attenuate or prevent SGA metabolic effects.” [2]

“…in patients treated with olanzapine, short-term melatonin treatment attenuates weight gain, abdominal obesity, and hypertriglyceridemia. It might also provide additional benefit for treatment of psychosis.” [3]

Melatonin is appropriate to consider for any patient who will be started on a psychotropic drug that is potentially associated with weight gain or other adverse metabolic effects [link]

Functional foods as potential therapeutic options for metabolic syndrome.

Obesity as part of metabolic syndrome is a major lifestyle disorder throughout the world. Current drug treatments for obesity produce small and usually unsustainable decreases in body weight with the risk of major adverse effects. Surgery has been the only treatment producing successful long-term weight loss. As a different but complementary approach, lifestyle modification including the use of functional foods could produce a reliable decrease in obesity with decreased comorbidities. Functional foods may include fruits such as berries, vegetables, fibre-enriched grains and beverages such as tea and coffee. Although health improvements continue to be reported for these functional foods in rodent studies, further evidence showing the translation of these results into humans is required. Thus, the concept that these fruits and vegetables will act as functional foods in humans to reduce obesity and thereby improve health remains intuitive and possible rather than proven.

High dose green tea extract is promising [link]

Saffron aqueous extract (SAE) appears to be potentially beneficial: [link]

Alpha-lipoic acid (ALA), a potent antioxidant may be helpful in reducing weight for patients taking antipsychotics:

“ALA was well tolerated and was particularly effective for individuals taking strongly antihistaminic antipsychotics” [5, 6]

Berberine shows promise in animal models [7]

Vitamin D deficiency exacerbates atypical antipsychotic-induced metabolic side effects in rats [8] and vitamin D supplementation may be promising in the prevention and treatment of metabolic disorders caused by antipsychotic medications.

Dehydroepiandrosterone (DHEA) supplementation “results in stabilization of BMI, waist circumference and fasting glycaemia values in schizophrenic patients treated with olanzapine” [8]

It has recently shown that the microbiota plays a critical role in olanzapine-induced weight gain in rats (Davey et al., 2013 and Davey et al., 2012) which has been confirmed in germ-free mice study (Morgan et al., 2014) [9].

Figure 1
Managing cardiovascular disease risk in patients treated with antipsychotics: a multidisciplinary approach.

My weight loss journey started with the addition of 10mg aripiprazole per day to clozapine (300mg) and venlafaxine (375mg). Aripiprazole augmentation of clozapine has been demonstrated to have beneficial effects on weight [10].

In addition, morning and lunch meals were replaced with a 30g high protein/no carbohydrate meal (Whey Protein Isolate, mixed in water)

I increased my daily exercise to 1 x 45min brisk walk in the morning and a 20min walk later in the day.

I managed to lose ~25kg and have reached a healthy BMI


A systematic review found:

“Psychiatric symptoms were significantly reduced by interventions using around 90 min of moderate-to-vigorous exercise per week (standardized mean difference: 0.72, 95% confidence interval -1.14 to -0.29). This amount of exercise was also reported to significantly improve functioning, co-morbid disorders and neurocognition.” [11]

To conclude:

“The management of weight gain and obesity in patients with schizophrenia centers on behavioural interventions using caloric intake reduction, dietary restructuring, and moderate-intensity physical activity. The decision to switch antipsychotics to lower-liability medications should be individualized, and metformin may be considered for adjunctive therapy, given its favorable risk-benefit profile.” [12]

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