Metabolic syndrome and obesity among users of second generation antipsychotics: A global challenge for modern psychopharmacology (2015)

Having experienced weight gain side effects from clozapine, it’s nice to see some progress being made towards ameliorating them… I’m particularly impressed by the authors in depth discussion of the potential use of phytochemicals. I’ve included some highlights.

Metabolic syndrome and obesity among users of second generation antipsychotics: A global challenge for modern psychopharmacology

Second generation antipsychotics (SGAs), such as clozapine, olanzapine, risperidone and quetiapine, are among the most effective therapies to stabilize symptoms schizophrenia (SZ) spectrum disorders. In fact, clozapine, olanzapine and risperidone have improved the quality of life of billions SZ patients worldwide. Based on the broad spectrum of efficacy and low risk of extrapyramidal symptoms displayed by SGAs, some regulatory agencies approved the use of SGAs in non-schizophrenic adults, children and adolescents suffering from a range of neuropsychiatric disorders. However, increasing number of reports have shown that SGAs are strongly associated with accelerated weight gain, insulin resistance, diabetes, dyslipidemia, and increased the cardiovascular risk. These metabolic alterations can develop in as short as six months after the initiation of pharmacotherapy, which is now a controversial fact in public disclosure. Although the percentage of schizophrenic patients, the main target group of SGAs, is estimated in only 1% of the population, during the past ten years there was an exponential increase in the number of SGAs users, including millions of non-SZ patients. The scientific bases of SGAs metabolic side effects are not yet elucidated, but the evidence shows that the activation of transcriptional factor SRBP1c, the D1/D2 dopamine, GABA2 and 5HT neurotransmitions are implicated in the SGAs cardiovascular toxicity. Polypharmacological interventions are either non- or modestly effective in maintaining low cardiovascular risk in SGAs users. In this review we critically discuss the clinical and molecular evidence on metabolic alterations induced by SGAs, the evidence on the efficacy of classical antidiabetic drugs and the emerging concept of antidiabetic polyphenols as potential coadjutants in SGA-induced metabolic disorders.

“…we summarized the results of 20 clinical studies and three preclinical studies, assessing the efficacy of pharmacological interventions (i.e. metformin, nizatadine, orlistat, ranitidine, topiramate, etc.) against SGA-induced metabolic side effects. This summarized evidence shows that one out of five studies with metformin resulted in negative results. The other four positive studies concluded that weight gain, insulin resistance can be efficiently controlled, but lipid profile may even worsen. Metformin reduced body weight in clozapine-treated patients, but its beneficial effects disappeared after discontinuing this medication. Orlistat in overweight/obese clozapine-or olanzapine-treated patients failed to prevent obesity and lipid accumulation, which suggest that the intestinally absorbed lipids may not be relevant for SGAs-induced obesity. Atomoxetine, a selective norepinepherine reuptake inhibitor with appetite suppressant activity, was not effective in preventing obesity in patients treated with olanzapine and clozapine.”

  • With respect to the serotoninergic hypothesis, the interventions with fluoxetine also failed. The use of sertraline in clozpaine-induced weight gain resulted in cardiac death in rodents.
  • Tetradecylthioacetic acid (TTA), a modified fatty acid, recently showed a minor protective effect against hypertriglyceridemia, but failed to prevent weight gain induced by clozapine in rodents.
  • Berberine, a natural alkaloid, inhibited in vitro adipogenesis and SREBP-1 overexpression induced by clozapine and risperidone in 3T3 adipocytes: “Berberine is an example of an antidiabetic phytochemical with potential protective effect against lipid accumulation induced by clozapine.”
  • Resveratrol and green tea, showed some efficacy in decreasing weight gain and fat mass accumulation induced by olanzapine in rodents.

“Our group and others have demonstrated that specific polyphenols from dietary sources ameliorate insulin resistance, inflammation and obesity.”

  • Anthocyanins, a family polyphenols, have shown significant clinical effect in improving insulin sensitivity in obese, nondiabetic, insulin-resistant patients.

“Polyphenols are family of polar compounds found in fruits and vegetables, they have been popular for their potent antioxidant effect, but in the past 5 years increasing evidence has shown that, anthocyanins, a specific category of polyphenols, are effective in ameliorating obesity and insulin resistance.

The mode of action and pharmacokinetic profile of these compounds is not yet fully elucidated and their bioavailability after oral administration is a matter of continuous controversy. However, there is robust evidence on their efficacy in cardiometabolic problems. Kurimoto et al. reported that anthocyanins from black soy bean increased insulin sensitivity via the activation of AMP-activated protein kinase (AMPK) in skeletal muscle and liver of in type 2 diabetic mice. AMPK, a regulator of glucose and lipid metabolism in liver and muscle cells, is inhibited by olanzapine, which may contribute to the olanzapine-induced hepatic lipid accumulation. Anthocyanins also display insulin-like effects even after intestinal biotransformation.

We have previously demonstrated that anthocyanins ameliorate signs of diabetes and metabolic syndrome in obese mice fed with a high fat diet have. Delphinidin 3-sambubioside-5-glucoside (D3S5G), an anthocyanin from Aristotelia chilensis, is as potent as Metformin in decreasing glucose production in liver cells, and it displays insulin-like effect in liver and muscle cells. The anti-diabetic mode of action of anthocyanins have been associated with the transcriptional down-regulation of the enzymes PEPCK and G6P gene in hepatocytes. Prevention of adipogenesis is also another reported mechanmis for some anthocyanins from Aristotelia chilensis. Anthocyanins also induce significant increase in circulating levels of adiponectin in murine models of MetS. This is relevant, since adiponectin is reduced in clozapine-treated patients and weight reduction is associated with higher circulating levels of adiponectin. In a recent study Roopchand et al., demonstrated that blueberry anthocyanins are as potent as metformin in correcting hyperglycemia and obesity in obese hyperglyceminc mice. Dietary anthocyanins have also proven efficacy in decreasing les of the inflammatory mediators PAI-1 and retinol binding protein 4 in obesity and type 2 diabetes . Recent medical and nutritional studies suggest that anthocyanins from diverse dietary sources are potent anti-diabetic, anti-obesity and cardioprotective molecules. Another fact that makes anthocyanins candidates for preventing clozapine-induced lipogenesis is that they are capable of suppressing the inflammatory response through targeting the phospholipase A2, PI3K/Akt and NF-kappaB pathways. These pre-clinical findings were corroborated by clinical evidence showing the dietary anthocyanins from blueberries improve insulin resistance in young obese, non-diabetic adults. The clinical efficacy of polyphenols in SGAs-induced MetS has not yet been established, but a recent pre-clinical demonstrated that, resveratrol, a polyphenol found in grapes, decreases olanzapine-induced weight gain.”

Some  polyphenols showing positive outcomes for diabetes, obesity and metabolic syndrome [see article for more information]:

Purified anthocyanins 160 mg  twice a day
Cinnamon extract 250 mg, twice a day
Whole  blueberries 22.5 g twice a day
Resveratrol 150 mg
Pomegranate juice 1.5 mL/Kg
Raisins (Vitis vinifera) 36 g/day
Green tea extract 375 mg  (270mg catechins) per day

See more:

Attenuating antipsychotic-induced weight gain and metabolic side effects


Diet, metabolic syndrome and schizophrenia/ASD – a convergence on PPAR-α?

Peroxisome proliferator-activated receptor alpha plays a crucial role in behavioral repetition and cognitive flexibility in mice

Nuclear peroxisome proliferator activated receptor-α (PPAR-α) plays a fundamental role in the regulation of lipid homeostasis and is the target of medications used to treat dyslipidemia. However, little is known about the role of PPAR-α in mouse behavior.


To investigate the function of Ppar-α in cognitive functions, a behavioral phenotype analysis of mice with a targeted genetic disruption of Ppar-α was performed in combination with neuroanatomical, biochemical and pharmacological manipulations. The therapeutic exploitability of PPAR-α was probed in mice using a pharmacological model of psychosis and a genetic model (BTBR T + tf/J) exhibiting a high rate of repetitive behavior.


An unexpected role for brain Ppar-α in the regulation of cognitive behavior in mice was revealed. Specifically, we observed that Ppar-α genetic perturbation promotes rewiring of cortical and hippocampal regions and a behavioral phenotype of cognitive inflexibility, perseveration and blunted responses to psychomimetic drugs. Furthermore, we demonstrate that the antipsychotic and autism spectrum disorder (ASD) medication risperidone ameliorates the behavioral profile of Ppar-α deficient mice. Importantly, we reveal that pharmacological PPAR-α agonist treatment in mice improves behavior in a pharmacological model of ketamine-induced behavioral dysinhibition and repetitive behavior in BTBR T + tf/J mice.


Our data indicate that Ppar-α is required for normal cognitive function and that pharmacological stimulation of PPAR-α improves cognitive function in pharmacological and genetic models of impaired cognitive function in mice. These results thereby reveal an unforeseen therapeutic application for a class of drugs currently in human use.

“In rodents, Ppar-α has been linked to brain dopamine function, a neurotransmitter system that is a target of some antipsychotic and autism spectrum disorder (ASD) medications. Specifically, Ppar-α activation improves antipsychotic medication adverse event oral tardive dyskinesia and indirectly reduces the activity of dopamine cells in the ventral tegmental area in rodents. In humans, dyslipidemia is more prevalent in individuals with schizophrenia and ASD compared to the general population.

…genetic inactivation of Ppar-α resembles a behavioral and cognitive phenotype consistent with preclinical models of schizophrenia and ASD. In an effort to elucidate the mechanism through which this phenotype is mediated, we analyzed the brain. We observed that the genetic prevention of Ppar-α activity produced a reduction in cortical PV + GABAergic interneurons, consistent with post-mortem analyses of brains from patients with schizophrenia. We also report that the behavioral profile of Ppar-α null mice was improved with antipsychotic risperidone treatment. Thus, Ppar-α deficient mice may represent a new preclinical model to investigate the etiology and/or treatment of schizophrenia. The behavioral profile of Ppar-α null mice also shows similarities with ASD mouse model BTBR, which displayed an improved repetitive behavior with PPAR-α agonist treatment. Furthermore, risperidone is also used to alleviate hyperactivity, self-injurious, and repetitive behavior symptoms in humans suffering with ASD. Together, these results highlight PPAR-α as a potential point of commonality between schizophrenia and ASD worthy of further investigation.

Considering that repetitive behaviors can arise from a disruption in the direct cortico-striatal circuit, it is possible that PPAR-α plays an instrumental role in the organization and orchestration of PV + interneuron-pyramidal neuron cortical microcircuitry, and the absence of this regulation contributes to a net increase in cortical firing and output onto striatal structures. Supporting this possibility, GABAergic interneurons are crucial for synchronization of network activity, Ppar-α −/− mice exhibit abnormal EEG waves, and Ppar-α −/− mice are resistant to the behavioral disinhibition caused by the administration of NMDA receptor antagonists, which inhibit the activity of cortical PV + interneurons.

Given our observation that PPAR-α agonist treatment improves behavior in a pharmacological model of psychosis (ketamine) and a mouse model that displays face validity for ASD (BTBR), our research suggests that patients with schizophrenia and ASD co-prescribed fibrates to improve dyslipidemia may show a greater benefit in cognitive symptom amelioration. This possibility warrants further investigation in patient populations. Moreover, it is possible that at least a subset of these patients may receive direct therapeutic benefit from fibrates. If this were the case, it would have the added benefit of overcoming the metabolic disturbance associated with many current antipsychotic medications. Of interest, loss of function of Ppar-α results in middle age-onset obesity/weight gain in mice. Thus, increasing the activity of PPAR-α with compounds such as fibrates in patients may serve a further metabolic-protective role.

In conclusion, our findings disclose a previously unknown role for Ppar-α in cognitive function in mice. In addition to highlighting a neurological phenotype resulting from the loss of function of Ppar-α, our findings also suggest that this receptor may represent a target for the pharmacological amelioration of neurological conditions associated with behavioral perseveration/repetition. This is a particularly attractive prospect given that naturally occurring and synthetic PPAR-α agonists are currently used in clinical practice.”

Recent research has revealed that metabolic syndrome may be linked to sensory gating deficit in patients with schizophrenia and that the relationship between neurocognitive function and sensory gating deficits could be affected by the metabolic status of the patients [1]. Similarly, medical treatment of certain components of the metabolic syndrome could affect cognitive performance in patients with schizophrenia [2]. Weinstein et al. [3] recently found that hyperglycemia is associated with subtle brain injury and impaired attention and memory even in young adults, indicating that brain injury is an early manifestation of impaired glucose metabolism. Labouesse et al. [4] found that chronic consumption of a high-fat diet impairs sensorimotor gating in mice and this impairment was related to neural circuitry abnormalities, in particular to the striatal dopaminergic circuit: “It has been suggested that metabolic syndrome could affect the integrity of striatal dopaminergic circuits through the effect of metabolic circulating factors such as glucose, insulin or leptin”

Dietary interventions?

Peroxisome proliferator-activated receptors (PPARs) are transcription factors that belong to the superfamily of nuclear hormone receptors and regulate the expression of several genes involved in metabolic processes that are potentially linked to the development of some diseases such as hyperlipidemia, diabetes, and obesity. One type of PPAR, PPAR-α, is a transcription factor that regulates the metabolism of lipids, carbohydrates, and amino acids and is activated by ligands such as polyunsaturated fatty acids and drugs used to treat dyslipidemias. PPAR-α acts as a key nutritional and environmental sensor for metabolic adaptation [5]

Natural ligands such as PUFAs are provided by the diet (linoleic, α-linolenic, γ-linolenic, and arachidonic acids) and bind to PPAR-α at physiologic concentrations

The beneficial effects of fish oil are thought to be, in part, mediated by activation of the nuclear receptor PPAR-α by omega-3 polyunsaturated fatty acids and the resulting upregulation of lipid catabolism [6]

It is well-known that dietary PUFAs have effects on diverse biological processes such as insulin action, cardiovascular function, neural development, and immune function, some of them mediated via PPARα.

Other natural compounds such as polyphenols have been described as ligands of PPAR-α: resveratrol, a natural polyphenol found in grapes, peanuts, and berries, and some of its derivatives and analogs, activate PPAR-α, resulting in brain protection against stroke. Genistein, another polyphenol that is the main soy isoflavone, induced the expression of PPAR-α at both messenger RNA (mRNA) and protein levels and enhanced expression of genes involved in fatty acid catabolism through activation of PPAR-α. Additional PPAR-α ligands from diet with hypolipidemic activity have been reported, such as the natural carotenoid abundant in seafood, astaxanthin, and the active compound extracted from the tomato, 9-oxo-10(E),12(E)-octadecadienoic acid. It has been demonstrated that phytanic acid, a branched-chain fatty acid generated from phytol present in dairy products, is also a natural ligand of PPAR-α.

Linalool is another orally active PPAR-α agonist [7]

Intriguingly, PPAR-α activation may stimulate allopregnanolone synthesis [8]

A recent study [9] found that autistic children exhibit decreased levels of essential fatty acids in red blood cells and increased levels of PUFA-derived metabolites such as prostaglandin E2.

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]