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Metformin Prevents Antipsychotic-Induced Weight Gain: A Saudi Study Finds

Research suggests that metformin may reduce weight gain associated with antipsychotic medications.

Key facts:

  • Antipsychotics are linked to weight gain, especially clozapine and olanzapine.
  • Metformin may counteract antipsychotic-induced weight gain through effects on insulin resistance and appetite.
  • Study found metformin reduced mean weight gain on antipsychotics from 2.5 kg to -0.04 kg.
  • Younger patients ages 20-29 experienced the most weight gain, while the oldest patients ages 60-69 gained the least.

Source: Frontiers in Psychiatry 2022

Antipsychotics & Weight Gain: A Common Occurrence

Antipsychotic medications are commonly prescribed for schizophrenia, bipolar disorder, and other psychiatric conditions.

While antipsychotics can be highly effective, weight gain is a troublesome side effect that affects a significant number of patients.

Research shows that some antipsychotics lead to more pronounced weight gain than others.

In particular, clozapine and olanzapine are associated with high weight gain risk.

The weight gain effects of antipsychotics can increase cardiovascular disease risk and negatively impact medication adherence.

Recent studies suggest that metformin may be an effective adjunct treatment to counteract antipsychotic-induced weight gain.

Metformin for Antipsychotic-Induced Weight Gain (Saudi Arabia Study)

A retrospective cohort study from King Abdulaziz Medical City in Saudi Arabia adds to the evidence on antipsychotic-related weight changes and metformin’s potential role in mitigating weight gain.

Researchers analyzed medical records from 395 patients who were prescribed antipsychotic medications over a 5 year period: 309 patients on standalone antipsychotics vs. 86 on antipsychotics PLUS metformin.

The study examined differences in weight gain between the two groups across age, gender, and specific antipsychotic medications.

What were the findings?

The antipsychotics-only group gained an average of 2.5 kg in body weight.

The antipsychotics plus metformin group had virtually no weight change, with an average change (loss) of just -0.04 kg.

Only 21.7% of the antipsychotics-only group lost weight, compared to 40.7% of the metformin group.

64.4% of the antipsychotics-only group gained weight, versus just 38.4% of the metformin group.

Younger patients ages 20-29 gained the most weight, with an average gain of 4.66 kg.

Patients ages 60-69 gained the least at just 0.15 kg on average.

Metformin use was more common among older patients.

Just 4% of 20-29 year olds took metformin versus over 50% of patients ages 60-69.

These real-world findings align with prior randomized controlled trials.

Collectively, the evidence indicates metformin may help attenuate or even reverse antipsychotic-related weight gain.

The benefits appear most pronounced in younger antipsychotic users who tend to experience the greatest weight changes.

How Antipsychotics Cause Weight Gain (Mechanisms)

Antipsychotics are categorized as first generation “typical” antipsychotics and second generation “atypical” antipsychotics.

First generation antipsychotics like haloperidol mainly act by blocking dopamine D2 receptors.

Atypical antipsychotics target serotonin 5-HT receptors and have lower D2 affinity, resulting in reduced movement side effects but increased metabolic effects like weight gain.

The biological mechanisms behind antipsychotic-induced weight gain are not fully understood but likely involve effects on appetite regulation.

Antipsychotics can alter levels of leptin, ghrelin, adiponectin and other hormones and neuropeptides linked to energy balance and satiety signaling.

Some antipsychotics seem more prone to interfere with metabolic homeostasis.

In particular, clozapine and olanzapine bind strongly to histamine H1 receptors, muscarinic acetylcholine receptors, and other receptors that may disrupt satiety mechanisms when blocked.

While medication effects are a key driver, lifestyle and demographic factors also contribute to weight changes in those taking antipsychotics.

Sedentary behavior, poor diet, and effects of psychiatric hospitalization can promote weight gain.

Younger patients may be especially susceptible.

Metformin’s Potential Role to Treat Antipsychotic Weight Gain

Metformin is a commonly prescribed oral medication for type 2 diabetes that helps control blood sugar levels.

It reduces hepatic glucose production and improves insulin sensitivity.

Metformin may also have beneficial effects on appetite regulation.

Some evidence indicates metformin could help counteract antipsychotic-induced weight gain through several mechanisms:

  • Improving insulin resistance
  • Modulating ghrelin, leptin, and other hormones involved in appetite/satiety signaling
  • Reducing appetite and caloric intake

Small clinical studies report that metformin reduced mean weight gain in patients taking antipsychotics compared to placebo.

Adding metformin may also have broader metabolic benefits for antipsychotic-treated patients in terms of lipid profiles, glucose regulation, and diabetes risk.

Using Metformin to Prevent Weight Gain on Antipsychotics

Weight gain is a major concern when prescribing antipsychotics, and can negatively impact medication adherence.

Strategies to prevent or reduce weight gain are important, especially for younger patients.

Metformin looks quite promising based on recent studies. It is safe, well-tolerated, and may improve insulin resistance along with modestly mitigating weight gain.

Metformin could be a valuable option for patients who experience significant weight gain on antipsychotics.

It likely works best when combined with diet and exercise counseling.

More research is still needed, but current evidence suggests metformin should be part of the conversation when addressing antipsychotic-induced weight changes.

Factors Influencing Antipsychotic-Related Weight Gain

Along with metformin use, the Saudi Arabia study results highlight other factors that may influence the degree of antipsychotic-related weight gain including:

Age: Younger patients appear most susceptible to antipsychotic-induced weight gain. In this study, patients aged 20-29 gained over 4 kg on average, while those aged 60-69 gained only 0.15 kg. Teens and young adults may experience endocrine changes on antipsychotics along with lifestyle changes that contribute to rapid early weight gain. Older patients tend to gain modestly or not at all.

Sex/Gender: Some research indicates females may gain slightly more weight on antipsychotics. However, this study found no significant differences between males and females in terms of antipsychotic-related weight changes. Females did use metformin at slightly higher rates, possibly due to other indications like polycystic ovarian syndrome.

Specific antipsychotic: Considerable evidence shows certain antipsychotics like clozapine and olanzapine confer higher weight gain risk. However, this study did not find differences among the antipsychotics assessed, possibly due to limited sample sizes for each medication. Larger comparative studies are needed.

Duration of treatment: Multiple studies find the greatest weight changes occur within the first 6 months after starting an antipsychotic. This study did not show differences based on duration of use, but had relatively few patients with longer-term follow-up on a single medication.

Conclusions & Implications: Metformin, Antipsychotics, Body Weight

In conclusion, this retrospective study provides further real-world data that metformin may help mitigate weight gain associated with antipsychotic medications.

While confirmation through large randomized trials is still needed, these findings suggest metformin is a reasonable option to consider in antipsychotic-treated patients who experience significant weight gain.

Younger patients may stand to benefit the most relative to other age groups.

From a clinical perspective, providers should discuss weight gain risk when prescribing antipsychotics, especially in younger populations.

Counseling patients on diet, exercise, and lifestyle choices is prudent.

If weight gain occurs, metformin may be a relatively safe pharmacological option to counteract excess weight.

For researchers, larger randomized placebo-controlled trials are warranted to firmly establish metformin’s efficacy and safety for antipsychotic-induced weight gain.

Head-to-head comparisons of metformin versus other potential treatments like statins or GLP-1 agonists would also be informative.

Elucidating the precise mechanisms underlying antipsychotic-related weight changes could uncover novel drug targets and preventative approaches as well.

In summary, weight gain remains a major concern with antipsychotic therapy.

Metformin shows promise for mitigating this troublesome side effect.

Additional research and clinical experience will shed more light on metformin’s role in helping patients achieve the best possible mental health outcomes.


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