Current and Future Treatment Options for Preventing Metabolic Syndrome Due to Atypical Antipsychotics

Results of a randomized placebo-controlled trial of metformin and lifestyle intervention

Atypical antipsychotics are used to reduce relapses, decrease positive symptoms, and improve negative symptoms associated with schizophrenia.¹ Unfortunately, due in part to the metabolic adverse-effect profile of atypical antipsychotics, adherence has been an increasing problem.

Decreased adherence poses a threat of relapse. On the other hand, the medications’ adverse effects may cause iatrogenic harm, including diabetes and other health issues related to weight gain. The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study showed that 30% of patients with schizophrenia treated with olanzapine (known for its weight gain effect) gained more than 7% of their body weight after starting the drug; other trials have shown an even greater effect.²

The weight gain effects of atypical antipsychotics on a younger population are even more alarming. In a study of patients with a psychiatric disorder aged 4 to 19 years, more than half gained more than 7% of their body weight while taking aripiprazole, risperidone, or quetiapine. A similar effect was found in 84% of patients after treatment with olanzapine for 12 weeks.³

In addition, meta-analysis of the association of atypical antipsychotics with diabetes showed that in young patients treated with clozapine, the risk of type 2 diabetes mellitus (T2DM) was double that in young patients treated with a typical antipsychotic.⁴ The underlying mechanisms for these effects are not understood. Among other causal factors may be the sedentary lifestyles of patients treated with antipsychotics.

Atypical antipsychotics are also linked with increased appetite and decreased physical activity. The antagonism of histamine H1 causes sedation, and the antagonism of serotonin 2C receptors may down-regulate leptin-mediated satiety, leading to weight gain and insulin resistance.

Atypical antipsychotics reduce levels of heat shock protein 72 (Hsp72); decreased levels of Hsp72 produce metabolic symptoms. The primary function of Hsp72 is to act as a molecular chaperone that stabilizes protein conformation and controls transport of mutant proteins. This function has been shown to protect against insulin resistance, which may lead to ways of minimizing metabolic effects of atypical antipsychotics.

Treatment approaches

Metformin and lifestyle intervention. Metformin is a biguanide oral antidiabetic medication whose primary mechanism of action is suppression of gluconeogenesis by the liver. Metformin may decrease weight gain by inhibiting the degradation of glucagon-like peptide 1 (GLP-1), which results in appetite suppression.⁵

A 12-week, randomized, double-blind, placebo-controlled trial tested the efficacy of metformin (750 mg/d) alone and in combination with lifestyle intervention, in preventing weight gain and abnormal insulin sen-sitivity.⁶ The study included 128 patients who received olanzapine, clozapine, risperidone, or sulpiride, divided into 4 groups: metformin alone, lifestyle changes alone, the combination of the two, or placebo alone. The lifestyle interventions included in this study were diet, exercise, and a psychoeducational program.

An insulin resistance index was determined using a formula of homeostasis assessment, including fasting insulin and fasting glucose measures.⁶ The combination of metformin and lifestyle intervention had the greatest effect on weight loss (Table). In addition, no adverse effects were reported for metformin. One caveat to the study is that it used a Chinese population exclusively, so the results may not be generalizable.

Although results from other studies are mixed, overall findings indicate that metformin may be effective in young populations and in those who have significant weight gain within a year of starting treatment with atypical antipsychotics.⁷

BGP-15 (O-[3-piperidin-2-hydroxy-1propyl]nicotinic amidoxime dihydrocholoride): a possible future agent. T2DM is associated with an accumulation of misfolded proteins that occurs after proteins undergo a conformational change from an alpha helix into a beta sheet. Once a protein undergoes this incorrect folding, it is able to cause other proteins to undergo this conformational change. The misfolded proteins accumulate (in the case of T2DM, they accumulate in the pancreas as amyloid plaques) and eventually lead to disease. A normal function of protein folding involves Hsp, a molecular chaperone that helps other proteins find their native conformation and thus prevent misfolding and disease.

Loss of Hsp with atypical antipsychotic use can result in metabolic symptoms; ongoing studies are exploring whether BGP-15 (an Hsp co-inducer) can prevent these symptoms. The exact mechanism of action of BGP-15 is not well understood. It has been hypothesized that BGP-15, through its lipid interactions, interferes with membrane hyperstructures and causes enhancement of stress signals that activate Hsp genes.^8,9

BGP-15 has been shown to affect insulin resistance in rats through its inhibition of c-Jun amino-terminal kinase and κB kinase, both of which induce insulin resistance.¹⁰ It does this by activating Hsp72, which prevents c-Jun amino-terminal kinase phosphorylation.

A preclinical study tested the efficacy of BGP-15 in preventing the metabolic adverse effects related to atypical antipsychotics, and compared the efficacy of BGP-15 with that of metformin and rosiglitazone (an insulin-sensitizing antidiabetic drug).¹¹ Wistar rats were treated with risperidone (0.005 mg/kg or 0.05 mg/kg) alone and in combination with BGP-15 (20 mg/kg). Risperidone had a significant effect, with a mean weight gain of 40 g after 21 days, compared with about 27.5 g in the control group.

The group that received risperidone and was treated with BGP-15 had a significant decrease in weight gain; results were comparable to those of the control group. Another experiment looked at rats given olanzapine (1 mg/kg) and then treated with either BGP-15 (10 mg/kg), metformin (100 mg/kg), rosiglitazone (3 mg/kg), or olanzapine alone. Insulin sensitivity was measured using a euglycemic glucose clamp: a constant glucose concentration was maintained using variable glucose infusion rates (low rates of glucose infusion mean increased insulin resistance).

Olanzapine resulted in a significant increase in insulin resistance in the rats. The group that received olanzapine plus BGP-15 had a significantly smaller decrease in glucose utilization (BGP-15 had a significant beneficial effect on preventing insulin resistance). BGP-15 also inhibited weight gain associated with olanzapine. There was no pre-ventive effect on insulin resistance and weight gain with metformin and rosiglitazone.

Another experiment tested BGP-15’s effect on improving insulin sensitivity in Wistar rats who were subjected to 1 month of clozapine (10 mg/kg) and then a month of either 10 mg/kg of clozapine plus 20 mg/kg of BGP-15 or clozapine alone. Compared with clozapine alone, clozapine plus BGP-15 demonstrated a more favorable (ie, higher) glucose infusion rate.¹¹

The efficacy of BGP-15 on treating metabolic effects associated with olanzapine was studied in 37 healthy people. The volunteers were divided into 2 groups: one group received 10 mg of olanzapine and placebo, the other received 10 mg of olanzapine plus 400 mg of BGP-15.¹² Both groups had an undesirable decrease in total body glucose utilization on day 18 of the trial; however, the group that received olanzapine plus BGP-15 had a significantly smaller decrease. There was a significant increase in body weight in all participants. No adverse effects were seen with BGP-15 in any of these trials.

Conclusion

Not only can metabolic symptoms associated with atypical antipsychotics lead to life-threatening illnesses, they also can increase medical costs. In addition, they may cause many patients to discontinue the medication. Metformin, especially when combined with lifestyle intervention, appears effective in preventing weight gain and insulin resistance in younger populations and people who have significant weight gain within a year of beginning an atypical antipsychotic. These interventions may be especially useful in patients who need higher doses of medication.

The investigational drug BGP-15 has shown promising effects on decreasing insulin resistance both in rat models and in humans, with mixed results in preventing weight gain caused by atypical antipsychotics. If effective, a mechanism of action similar to that of BGP-15 may lead to new treatments for prevention not only of metabolic symptoms but also of other diseases linked with protein misfolding. More research is needed for this promising drug.

Disclosures:

Dr Khalafian is a Resident and Dr Tucker is Professor and Arnold and Bess Ungerman Endowed Chair in Psychiatry and Vice Chair of Education in the department of psychiatry and behavioral sciences at the University of Oklahoma Health Sciences Center, Oklahoma City. They report no conflicts of interest concerning the subject matter of this article.

References:

1. Gilbert PL, Harris MJ, McAdams LA, Jeste DV. Neuroleptic withdrawal in schizophrenic patients: a review of the literature. Arch Gen Psychiatry. 1995;52:173-188.

2. Lieberman JA, Stroup TS, McEvoy JP, et al; Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia [published correction appears in N Engl J Med. 2010;363:1092-1093]. N Engl J Med. 2005;353:1209-1223.

3. Correll CU, Manu P, Olshanskiy V, et al. Cardiometabolic risk of second-generation antipsychotic medications during first-time use in children and adolescents [published correction appears in JAMA. 2009;302:2322]. JAMA. 2009;302:1765-1773.

4. Lambert BL, Cunningham FE, Miller DR, et al. Diabetes risk associated with use of olanzapine, quetiapine, and risperidone in veterans health administration patients with schizophrenia. Am J Epidemiol. 2006;164:672-681.

5. Ellinger LK, Ipema HJ, Stachnik JM. Efficacy of metformin and topiramate in prevention and treatment of second-generation antipsychotic-induced weight gain. Ann Pharmacother. 2010;44:668-679.

6. Wu RR, Zhao JP, Jin H, et al. Lifestyle intervention and metformin for treatment of antipsychotic-induced weight gain: a randomized controlled trial. JAMA. 2008;299:185-193.

7. Newall H, Myles N, Ward PB, et al. Efficacy of metformin for prevention of weight gain in psychiatric populations: a review. Int Clin Psychopharmacol. 2012;27:69-75.

8. Török Z, Tsvetkova NM, Balogh G, et al. Heat shock protein coinducers with no effect on protein denaturation specifically modulate the membrane lipid phase. Proc Natl Acad Sci U S A. 2003;100:3131-3136.

9. Literáti-Nagy Z, Tory K, Literáti-Nagy B, et al. The HSP co-inducer BGP-15 can prevent the metabolic side effects of the atypical antipsychotics. Cell Stress Chaperones. 2012;17:517-521.

10. Chung J, Nguyen AK, Henstridge DC, et al. HSP72 protects against obesity-induced insulin resistance. Proc Natl Acad Sci U S A. 2008;105:1739-1744.

11. Literáti-Nagy Z, Tory K, Literáti-Nagy B, et al. A novel insulin sensitizer drug candidate-BGP-15-can prevent metabolic side effects of atypical antipsychotics. Pathol Oncol Res. 2012;18:1071-1076.

12. Literáti-Nagy B, Péterfai E, Kulcsár E, et al. Beneficial effect of the insulin sensitizer (HSP inducer) BGP-15 on olanzapine-induced metabolic disorders. Brain Res Bull. 2010;83:340-344.