Current and Future Treatment Options for Preventing Metabolic Syndrome

Due to Atypical Antipsychotics
June 12, 2014;Psychopharmacology, Metabolic Disorders, Schizophrenia;

By A. Khalafian, MD and P. Tucker, MD

Atypical antipsychotics are employed to reduce relapses, decrease positive symptoms, and improve negative symptoms linked to schizophrenia. Unfortunately, due partly to the metabolic adverse-effect profile of atypical antipsychotics, adherence has become an increasing problem.

Decreased adherence poses a threat of relapse. On one other hand, the medications’ adverse effects might cause iatrogenic harm, including diabetes along with other health issues associated with weight gain. The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study showed that 30% of patients with schizophrenia treated with olanzapine (famous for its fat gain effect) gained over 7% of these body weight after starting the drug; other trials show an even greater effect.

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

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

Atypical antipsychotics may also be 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 fat 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 usually to act as a molecular chaperone that stabilizes protein conformation and controls transport of mutant proteins. This function has been shown to control insulin resistance, which may lead to means of minimizing metabolic results of atypical antipsychotics.

Treatment approaches

Metformin and lifestyle intervention.

Metformin can be a biguanide oral antidiabetic medication whose primary mechanism of action is suppression of gluconeogenesis with the liver. Metformin may decrease extra weight by inhibiting the degradation of glucagon-like peptide 1 (GLP-1), which ends up in appetite suppression.

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

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

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

BGP-15 (O-3-piperidin-2-hydroxy-1propylnicotinic amidoxime dihydrocholoride): any future agent. T2DM is connected with an accumulation of misfolded proteins that develops after proteins undergo a conformational consist of an alpha helix right into a beta sheet. Once a protein undergoes this incorrect folding, it can cause other proteins to endure this conformational change. The misfolded proteins accumulate (in the case of T2DM, they accumulate in the pancreas as amyloid plaques) and in the end lead to disease. A normal function of protein folding involves Hsp, a molecular chaperone which enables other proteins find their native conformation thereby prevent misfolding and disease.

Loss of Hsp with atypical antipsychotic use may lead to 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 just not well understood. It has been hypothesized that BGP-15, through its lipid interactions, disrupts membrane hyperstructures and causes enhancement of stress signals that activate Hsp genes.

BGP-15 has become shown to affect insulin resistance in rats through its inhibition of c-Jun amino-terminal kinase and κB kinase, each of which induce insulin resistance. 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 in connection with atypical antipsychotics, and compared the efficacy of BGP-15 your of metformin and rosiglitazone (an insulin-sensitizing antidiabetic drug). Wistar rats were helped by risperidone (0.005 mg/kg or 0.05 mg/kg) alone plus combination with BGP-15 (20 mg/kg). Risperidone a significant effect, with a mean weight gain of 40 g after a 3 week period, in comparison with about 27.5 g within the control group.

The group that received risperidone and was given BGP-15 stood a significant decrease in putting on weight; results were comparable to those from the control group. Another experiment looked at rats given olanzapine (1 mg/kg) and then given 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 consistent glucose concentration was maintained using variable glucose infusion rates (low rates of glucose infusion mean increased insulin resistance).

Olanzapine led to a significant rise in insulin resistance inside rats. The group that received olanzapine plus BGP-15 had a significantly smaller decrease in glucose utilization (BGP-15 a significant beneficial impact on preventing insulin resistance). BGP-15 also inhibited weight gain associated with olanzapine. There was no pre-ventive relation to insulin resistance and putting on weight with metformin and rosiglitazone.

Another experiment tested BGP-15’s influence on improving insulin sensitivity in Wistar rats who were subjected to 1 month of clozapine (10 mg/kg) after which 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 much more favorable (ie, higher) glucose infusion rate.

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

Conclusion

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

The investigational drug BGP-15 has shown promising effects on decreasing insulin resistance at rat models along with humans, with mixed results in preventing weight gain caused by atypical antipsychotics. If effective, a mechanism of action comparable to that of BGP-15 may cause new treating prevention not only of metabolic symptoms but also of other diseases related to protein misfolding. More principals are needed for this promising drug.

 

 

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