New Guideline Advises Metformin to Prevent Antipsychotic-Induced Weight Gain

Clinicians should prescribe metformin when initiating an antipsychotic in order to prevent weight gain in many cases, according to a new evidence-based guideline issued by Schizophrenia Bulletin yesterday.

“A 2022 Cochrane review of pharmacological interventions for the prevention of AIWG (antipsychotic-induced weight gain) found that metformin was the only pharmacological agent that may be effective for preventing weight gain when started with an antipsychotic,” wrote Aoife Carolan, M.Pharm., at Saint John of God Hospital and the Royal College of Surgeons in Dublin, and colleagues. “Despite this, metformin for the prevention of AIWG is not routinely offered in psychiatric practice.”

Carolan and colleagues developed the guideline utilizing the Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrument to ensure a high standard was followed. This included undertaking a comprehensive review of the literature and having the guideline findings reviewed by an independent panel of experts.

The guideline offered three core recommendations:

• Initiate metformin when prescribing a high-risk weight-inducing antipsychotic, such as olanzapine or clozapine.
• Initiate metformin with a medium-risk antipsychotic (quetiapine, paliperidone or risperidone) in patients with one or more cardiometabolic risk factors; in people ages 10 to 25 years; or for those with a BMI between 25 and 30.
• Initiate metformin with any antipsychotic if >3% increase in baseline body weight is observed during the first year of treatment.

In terms of dose, the new guideline recommends escalating from 500 mg daily to 500 mg twice daily over two weeks, followed by biweekly increases of 500 mg as tolerated up to 1 g twice daily at week 6. Metformin should be discontinued if risks for lactic acidosis are present, or the condition is suspected; if body mass index falls below 20; or if the antipsychotic medicine is discontinued. Metformin should be avoided where there is harmful use of alcohol.

Though the guideline focused on metformin, it also recommended that, if available, GLP-1 agonists should be considered for patients with a BMI above 30, certain cardiometabolic diseases, or obstructive sleep apnea.

For related information, see the Psychiatric News article “Metformin May Reduce Weight Gain in Youth Taking Antipsychotics.”

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Sertraline-Olanzapine Combo Found to Reduce the Risk of Relapse in Patients With Psychotic Depression

A study in JAMA supports the combined use of an antidepressant and antipsychotic for maintenance treatment of patients with psychotic depression. In this 36-week study, patients with psychotic depression who achieved remission while taking sertraline plus olanzapine were far less likely to relapse if they continued on this combination therapy compared with those who discontinued olanzapine.

An antidepressant-antipsychotic combination is a frontline strategy for the acute treatment of psychotic depression, but once patients respond, there is no clear-cut long-term strategy, explained study author Alistair Flint, M.B., of the University of Toronto and colleagues. “This is a critical question because premature discontinuation of antipsychotic medication has the risk of relapse of a severe life-threatening disorder. In contrast, the unnecessary continuation of an antipsychotic agent exposes a patient to potentially serious adverse effects.”

For the study, Flint and colleagues relied on data from the second part of a large multistage trial known as The Study of the Pharmacotherapy of Psychotic Depression. The participants included 126 adults aged 18 and older with psychotic depression who had achieved remission or “near remission” of their symptoms following up to 12 weeks of sertraline (150 mg/day to 200 mg/day) and olanzapine (15 mg/day to 20 mg/day) combination therapy. Remission was defined as the absence of delusions and hallucinations as well as a score of 10 or less on the Hamilton Depression Rating Scale (HDRS) for two consecutive weeks; “near remission” was defined as the absence of delusions and hallucinations, an HDRS score of 11 to 15 with a drop in HDRS score of 50% from baseline, and being rated as “very much improved” or “much improved” on the Clinical Global Impression scale.

After remaining on both medications for eight additional weeks, the participants were randomly assigned to either continue their combination therapy of sertraline and olanzapine or have their olanzapine pills switched over to placebo pills over a four-week period. The participants were monitored for up to 36 weeks.

At the end of the trial, 20.3% of patients randomized to olanzapine and 54.8% randomized to placebo experienced at least one relapse. Patients who continued taking olanzapine experienced greater increases in weight gain than those who discontinued olanzapine.

“Relapses resulted in a high frequency of psychiatric hospitalization, highlighting the severity and cost of this disorder and the importance in preventing relapse,” Flint and colleagues wrote.

For related information, see the Psychiatric News article “Benefits of Maintenance Antipsychotics Outweigh Risks, International Panel Concludes.”

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Ziprasidone Augmentation for MDD Appears Safe, But Precautions Advised

Although the atypical antipsychotic ziprasidone has shown promise as an add-on therapy for patients with major depressive disorder (MDD), little is known of possible side effects from this intervention. A study in the Journal of Clinical Psychiatry now suggests that patients with MDD who take ziprasidone in combination with escitalopram may be at greater risk of weight gain, akathisia, and an increase in the QT interval compared with those taking escitalopram alone. 

The findings were based on a randomized, double-blind, placebo-controlled trial of 139 adults with MDD who were assigned to take ziprasidone (mean dose of 98 mg/d) or placebo in combination with escitalopram for eight weeks after failing to respond to escitalopram alone. As was previously reported in the American Journal of Psychiatry, ziprasidone used adjunctively with escitalopram demonstrated greater antidepressant efficacy in patients with MDD compared with adjunctive placebo. As part of this trial, the researchers regularly measured metabolic and cardiac effects, and the Barnes Akathisia Scale and Abnormal Involuntary Movement Scale were used to assess akathisia and extrapyramidal symptoms, respectively.

In a follow-up analysis, David Mischoulon, M.D., Ph.D., of Massachusetts General Hospital and colleagues reported that patients on ziprasidone treatment had a significant increase in weight compared with placebo—with the ziprasidone-treated patients averaging a weight gain of 7.7 pounds compared with 2.2 pounds in the placebo-escitalopram group. Patients taking ziprasidone experienced a greater corrected QT interval (QTc) increase (8.8 milliseconds), which the authors noted is “generally in line with the known risks of ziprasidone on the QTc.” Ziprasidone-treated patients also encountered a greater increase in global akathisia scores compared with placebo, and about one-third of the patients on the combination therapy experienced sedation.

“Our findings, in the context of the risk of QTc prolongation with ziprasidone and SSRIs, suggest that the combination of ziprasidone and SSRIs is very likely safe but should be undertaken with caution, and clinicians who administer such combinations should monitor ECGs regularly,” the authors wrote. They also advised regular monitoring of weight, extrapyramidal symptoms, and involuntary movements.

For related information, see the Psychiatric News article “Ziprasidone May Be Effective as Adjunctive Therapy for Depression.”

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Study Finds Metformin Most Effective Intervention for Antipsychotic-Induced Weight Gain

What is the best pharmacological strategy for countering antipsychotic-induced weight gain? By pooling the effects of 40 studies representing 19 interventions for antipsychotic-induced weight gain, researchers have found the diabetes drug Metformin to be the most effective. The study's senior scientist was Hiroyuki Uchida of Keio University School of Medicine in Tokyo. The results are published in Schizophrenia Bulletin.

"Schizophrenia is like a perfect storm for metabolic syndrome, and reduced life span is alarming," William Carpenter, M.D., director of the Maryland Psychiatric Research Center at the University of Maryland and a schizophrenia expert, told Psychiatric News. "Metabolic abnormalities are associated with the illness, then lifestyle behavioral risks are added, and finally adverse effects of many antipsychotic drugs. Uchida and colleagues provide clinicians with a comprehensive review on the role of medications to address metabolic abnormalities associated with schizophrenia."

"Obesity and associated metabolic consequences represent a serious concern in patients with schizophrenia," Deanna Kelly, Pharm.D., director and chief of the Treatment Research Program at the Maryland Psychiatric Research Center, said. "Attenuation and reversal of weight gain is difficult, and behavioral modifications are challenging in this population. Accumulating evidence, as in this meta-analysis, suggests that some pharmacologic treatments may help attenuate weight gain. Metformin, despite its modest ability to attenuate weight gain, may be an important addition for many patients who are at risk for weight and related consequences."

For more information about this topic, see the American Journal of Psychiatry article, "Metformin for Weight Loss and Metabolic Control in Overweight Outpatients With Schizophrenia and Schizoaffective Disorder." More information about antipsychotic medications and their side effects can be found in American Psychiatric Publishing's "Essentials of Clinical Psychopharmacology, Third Edition."

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