Metformin weight loss antipsychotics

An RCT reported that switching from olanzapine, quetiapine or risperidone to aripiprazole resulted in improvement in metabolic parameters, but increased the rate of discontinuation. One year extension of three switch studies comparing patients who switched from olanzapine, risperidone or FGA to ziprasidone noted significant reduction of weight for switchers from olanzapine and risperidone, but not from FGAs.

Introduction

Most studies have focused on weight reduction strategies as opposed to preventive strategies. Preventive and early intervention strategies are more important than weight reduction strategies in patient management. Nonpharmacologic strategies include cognitive and behavioral interventions, nutritional counseling and exercise. There is significant heterogeneity in studies evaluating these strategies in terms of study duration, duration of follow-up and intensity of the intervention.

Cognitive strategies include understanding eating behaviors and physical well-being. Behavioral interventions include training in problem solving, goal setting, social support and monitoring exercise and eating habits. Subgroup analysis showed no significant differences between trials designed to prevent weight gain and trials designed to treat weight gain.

This is in contrast to data from pharmacologic approaches. There were no significant differences between individual and group interventions. The interventions consisted of supervised or nonstructured exercise, dietary counseling, motivational interviewing and cognitive-behavioral therapy. Comparison of individual trials did not show superiority over any specific intervention. Lifestyle interventions had significant beneficial effects on weight loss, waist circumference, triglycerides, fasting glucose and insulin.

Original Research ARTICLE

There was no significant effect on blood pressure or cholesterol. However, the evidence for routine use of pharmacologic adjuvants is not strong. A meta-analysis of RCTs of behavioral and pharmacologic interventions reported that short-term modest weight loss is possible with nonpharmacologic and selective pharmacologic interventions. A meta-analysis of 40 trials reported that metformin was the most extensively studied drug. The adjunctive treatment for weight gain was mostly initiated when nonpharmacologic interventions alone were not sufficient or impractical and switching antipsychotics was not practicable.

Metformin has the most evidence of efficacy, while topiramate, sibutramine, aripiprazole and reboxetine are also effective. For example, metformin and rosiglitazone improve insulin resistance, while aripiprazole, metformin and sibutramine decrease lipid levels. Other drugs investigated are ephedrine, orlistat, nizatidine, cimetidine, naltrexone, amantadine, reboxetine, fluoxetine, dextroamphetamine, d-fenfluramine, famotidine, fluvoxamine, phenylpropanolamine and rosiglitazone.

Metformin is an antihyperglycemic agent which has been in use for many decades.

It exerts its action by inhibiting hepatic gluconeogenesis and improving the sensitivity of insulin in skeletal muscles via adenosine monophosphate kinase. Aripiprazole has partial agonist activity at dopamine D2 and serotonin 5-HT1A receptors and antagonist activity at serotonin 5-HT2A receptors. The other advantage is that aripiprazole is an antipsychotic.

The antiepileptic medication, topiramate, has shown promising results in managing AIWG. Topiramate exerts its action of weight loss by stimulating lipoprotein lipase while inhibiting carbonic anhydrase and lipogenesis. It also suppresses appetite and increases satiety.

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Topiramate reduced olanzapine-induced weight gain in healthy male volunteers who received olanzapine for 14 days. A study by Ko et al using topiramate or mg established a dose—response relationship for weight loss. Norepinephrine reuptake inhibitors NRIs act by inhibiting the reuptake of norepinephrine. They are postulated to reduce appetite, causing weight loss. Poyurovsky et al conducted two RCTs where reboxetine was added on in patients treated with olanzapine.

Both trials reported significantly lower weight gain in the reboxetine add-on group compared to placebo. Sibutramine has been withdrawn from the market following a clinical trial that demonstrated increased cardiovascular risk. It also worsens symptoms of psychosis. Sibutramine exerts its action by inhibiting the reuptake of norepinephrine and serotonin.

It promotes release of dopamine by exocytosis that results in increased extracellular dopamine. The two small RCTs of sibutramine yielded contrasting results. One study reported significant weight loss 3. Goodall et al conducted the only RCT to examine the effect of d-fenfluramine on antipsychotic-induced weight gain. This drug was removed from the US market in after reports of heart valve disease and pulmonary hypertension.

Exact mechanism of action of the novel antiepileptic drug zonisamide is unknown. It may act by altering the fast inactivation threshold of voltage-dependent sodium channels. It also reduces sustained high-frequency repetitive firing of action potentials and inhibits low-threshold T-type calcium channels in neurons. Amantadine increases the synthesis and release of dopamine with some inhibition of the reuptake of dopamine.

It is also an N -methyl- D -aspartate receptor antagonist. H2 receptor antagonists such as famotidine and nizatidine are postulated to reduce weight by suppression of appetite secondary to increased cholecystokinin levels.

RCT of metformin—sibutramine combination did not show significant benefits. Two trials conducted in lean, healthy men have shown that the glucocorticoid and progesterone antagonist mifepristone is effective in reducing weight gain in patients treated with risperidone or olanzapine. Modafinil exerts its action by stimulating monoaminergic receptors. One RCT showed that modafinil resulted in significantly less weight gain compared to placebo in patients treated with olanzapine. A pilot study investigating the effect of modafinil in stabilized patients on clozapine did not find any difference in metabolic parameters or weight compared to placebo.

Betahistine is a histaminergic H1 receptor agonist and H3 antagonist which has been investigated as a co-treatment for olanzapine-induced weight gain. Weight-reducing potential of betahistine has been linked to its action on hypothalamus and liver to induce thermogenesis and reduce food intake. An added benefit was the reduction in Epworth sleepiness scores in the treatment group.

GLP-1 is a gut hormone synthesized in the intestinal mucosa. GLP-1 stimulates glucose-induced insulin secretion in the pancreas and inhibits secretion of glucagon. Additionally, it reduces appetite and food intake by activating central and peripheral GLP-1 receptors. A meta-analysis showed that GLP-1 reduced weight in obese diabetic and nondiabetic patients, when compared to other antidiabetic drugs including metformin.

Diethylpropion and phentermine are dopamine agonists which stimulate secretion of dopamine. They are postulated to increase the energy expenditure, leading to weight loss.

Both these drugs are indicated for the short-term treatment of obesity. However, these two medications have not been studied for AIWG. Some antiobesity medications have not been investigated for treatment of AIWG. Rimonabant, a cannabinoid CB1 receptor antagonist, has been shown to reduce weight compared to placebo in obese individuals. RCTs of amylin derivative pramlintide, serotonin—dopamine—NRI tesofensine and selective 5-HT2c agonist lorcaserin have shown promising results in reducing weight in healthy, obese individuals.

An RCT combining the leptin analog metreleptin with pramlintide demonstrated better results than either alone. Fluoxetine, orlistat, L -carnitine, phenylpropanolamine and rosiglitazone have not shown any benefit. Almost all antipsychotics cause weight gain.

Weight gain increases the risk of metabolic complications and physical ill health and can reduce compliance. Several strategies have been tried to reduce AIWG. Clinicians select antipsychotics based on patient preference, efficacy and side effects profile.

Haloperidol, lurasidone, ziprasidone, aripiprazole and amisulpiride carry lesser risk of weight gain, compared to other antipsychotics. However, risk of AIWG is not the only factor which governs selection of antipsychotics.

Clozapine, the medication with the highest risk of weight gain, is also the only antipsychotic so far licensed for treatment of resistant schizophrenia. Similarly, olanzapine which ranks high in terms of efficacy carries higher risk of weight gain than most other antipsychotics. Since the risk of weight gain appears to be highest in the first year of treatment, careful monitoring and early intervention are the first step in managing AIWG.

The available data describe several strategies to attenuate AIWG. They are reducing the dose, switching to an antipsychotic with less weight gaining potential, adding pharmaceutical adjuvants and nonpharmacologic interventions. Selecting effective interventions is difficult as most studies have methodological limitations. They are of short duration, ranging from a few weeks to 6 months.

Studies investigating strategies to prevent AIWG have included first-episode patients. Other studies have investigated treatment of AIWG. The response may be different in these two groups. Other confounding factors such as genetic susceptibility to weight gain, sedentary lifestyles and other medications that the patient is prescribed will also influence the outcome. Nonpharmacologic interventions are important in the management of AIWG. Dietary counseling, exercise interventions, cognitive and behavioral strategies appear to be equally effective as individual and group therapies.

All patients who are commenced on antipsychotics should be routinely provided with nutritional counseling and advice about a healthy lifestyle. Those who gain weight should be enrolled in structured program which monitors the adherence of patients to the management plan. Nonpharmacologic interventions appear to be more effective in patients treated with antipsychotics with a high propensity for weight gain.

There is some evidence that combining lifestyle modification and metformin is more effective than either intervention alone.