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.
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