Over the past five decades, there has been a global surge in the use of psychiatric medications, coinciding with a nearly tripled prevalence of obesity and associated metabolic diseases.
Is there a connection?
Medications prescribed for severe mental illnesses like depression, bipolar disorder, and schizophrenia often incur significant metabolic side effects, such as heightened appetite, weight gain, and the development of long-term metabolic syndrome. Disregarding these sequelae can be common, suggesting that better therapeutic approaches are needed.
Mental illness and the antidepressants, mood stabilizers, and antipsychotics used for treatment impact gut microbiota in ways that promote obesity. This blog will explore evidence for targeting the gut microbiome to reduce harmful metabolic side effects in patients taking these medications.
Psychiatric medications and metabolic side effects, in brief
Individuals suffering from severe mental disorders, such as schizophrenia, major depression, and bipolar disorders have a reduced life expectancy compared to the general population of up to 10–25 years. While unhealthy lifestyle behaviors, limited access to services, and lack of focus on physical health contribute to a higher mortality rate and increased morbidity, the metabolic side effects of antipsychotic medication are partly responsible.
Side effects of many psychiatric medications include weight gain and obesity. Excess weight, especially obesity, is indicative of heightened cardiovascular risk, metabolic syndrome, and type 2 diabetes mellitus along with a higher risk of developing cancer.
As illustration, patients with schizophrenia are at higher risk of developing obesity and metabolic syndrome than the general population—with a prevalence rate of these conditions ranging from 40 to 70% in patients with schizophrenia.
Meta-analyses report that that some antipsychotics lead to weight gain with several including clozapine and olanzapine inducing severe weight gain. Others such as ziprasidone may be less likely to induce weight gain but switching medications is not always recommended.
These medications can affect neurotransmitter systems in the brain that regulate appetite and metabolism, leading to increased food intake and reduced energy expenditure. The prolonged length of time that patients usually take these medications compounds the unhealthy changes.
In addition to reducing the quality and length of life, metabolic side effects can lead to the patient stopping the medication, increasing mental health risks.
Mental disorders & the microbiome
Animal studies provide compelling yet indirect evidence supporting the involvement of intestinal microbiota in psychiatric symptoms and have established connections between the microbiome and neuropsychiatric disorders.
Clinical studies also point to links between the gut microbiome and mental disorders.
In a recent systematic review encompassing 18 studies, it was noted that subjects with various psychiatric disorders exhibit a reduction in fermentative taxa compared to controls, leading to decreased production of short-chain fatty acids (SCFAs) and an uptick in opportunistic or pathogenic bacteria, potentially fostering a proinflammatory environment, all of which could contribute to the worsening of these conditions.
A systematic review and meta-analysis of 59 studies across 8 disorders revealed that disruptions in gut microbiota were linked to a reduction in specific anti-inflammatory bacteria that produce butyrate, along with an increase in pro-inflammatory bacteria, among individuals suffering from depression, bipolar disorder, schizophrenia, and anxiety.
A systematic review that included 44 studies in patients with mental disorders observed fewer bacterial genera that produce short-chain fatty acids and higher levels of lactic acid-producing bacteria.
Psychiatric drug-induced obesity & the microbiome
Apart from the altered microbiota observed in mental disorders, psychiatric medications (including antidepressants, antipsychotics, and mood stabilizers) often induce weight gain and other metabolic side effects.
Considerable progress has been made in understanding the weight gain caused by atypical antipsychotics and the involvement of the microbiota. Research shows that they consistently cause substantial weight gain across all age groups, with studies in humans and rodents supporting the involvement of the microbiome through various proposed mechanisms.
Collectively, these findings indicate that the microbiota serves as a crucial bridge between psychiatric treatment and weight changes, suggesting a role of the gut microbiota in promoting weight gain and metabolic changes.
Gut microbiota composition is altered by some psychiatric medications. Diversity is reduced. Research has shown that reduced gut microbial diversity may change how energy is harvested and stored leading to weight gain and metabolic disorders. Therefore, these medications may not only disturb weight regulation through dysregulation in neurotransmitter systems but also through altered microbiota.
One mechanism appears to be that microbiota dysbiosis alters communication across the gut-brain axis (GBA), which is critical in the maintenance of energy balance. The intestinal microbiota and their byproducts may impact the brain either through direct vagal stimulation or indirectly via immune-neuroendocrine pathways. They influence various aspects such as metabolism, adiposity, energy balance, appetite, and food reward signaling. Disruption may lead to weight gain and obesity.
However, questions arise regarding whether abnormal gut microbiota precedes mental disorders, if psychopharmacologic treatment causes secondary microbiota abnormalities, or if obesity and its associated microbiota changes result from the negative symptoms of mental illness. One study reported that the transplantation of fecal microbiota from drug-free patients with schizophrenia into antibiotic-treated (pathogen-free) mice could cause schizophrenia-like behavioral abnormalities.
Targeting the gut microbiome
The dysbiosis observed in patients with mental disorders and those on antipsychotics has led to the question of whether probiotics and/or prebiotics may help mitigate metabolic side effects.
It is established that obesity is associated with a less diverse gut microbiome and alterations in microbial composition and functionality, potentially influencing inflammation, metabolism, hormone regulation, and dietary impact. Microbiota-targeted interventions may benefit host metabolism by several mechanisms, including increasing short-chain fatty acid (SCFA) and other beneficial metabolite-producing bacteria, decreasing lipopolysaccharide tissue damage and inflammation, and limiting opportunistic pathogens and their metabolites. For example, the SCFAs butyrate and propionate stimulate the secretion of gut peptides which can modulate appetite and food intake, enhance glucose metabolism, and reduce inflammation. As noted before, many studies support the concept of gut microbiota and their metabolites communicating in a bidirectional manner along the GBA in obesity’s pathophysiology, involving metabolic, endocrine, neural, and immune mechanisms.
Probiotics
Studies indicate that probiotics have demonstrated efficacy in reducing weight gain and restoring metabolic parameters in both obese patients and animal models of obesity. Research conducted on probiotics and their effects on obesity-causing factors is briefly summarized here.
However, studies on weight gain in patients on psychoactive medications are few.
One study with patients taking olanzapine concluded that probiotics had no significant effect on weight gain in patients compared to the control group. Another study tested a probiotic mixture plus selenium and found no impact on weight compared to the control group; metabolic parameters however were improved in the probiotic group.
Some research involving schizophrenia patients treated with antipsychotics suggests that probiotics may modify immune parameters and alleviate gastrointestinal symptoms. Weight changes were not assessed.
Prebiotics
Prebiotics are known to bring various health benefits including an increase in beneficial bacteria, a decrease in pathogenic bacteria, effects on gut barrier permeability and immune system defense, and positive impacts on insulin resistance and blood sugar levels.
One big driver of such providence is the microbial fermentation of prebiotics which produces many beneficial metabolites, including lactic acid and SCFAs, and are associated with weight loss and various health benefits.
Prebiotics, such as galacto-oligosaccharides tested in a study with rats receiving olanzapine, have shown promising benefits in preventing weight gain and improving cognitive function, possibly through the alteration of cytokine levels and levels of circulating acetate.
In a 2022 clinical study, combining prebiotics with probiotics significantly attenuated olanzapine-induced weight gain in patients compared to olanzapine-treatment alone. Insulin resistance was lower in the in the olanzapine plus probiotics group compared with the group receiving olanzapine monotherapy.
Takeaway
The increasing use of psychiatric medications over the past decades has been linked to a rise in obesity and metabolic diseases, particularly due to the significant weight gain and metabolic side effects associated with these drugs. Evidence suggests that these medications not only disrupt neurotransmitter systems but also alter gut microbiota, potentially exacerbating weight gain and metabolic disorders. Targeting the gut microbiome through interventions like probiotics and prebiotics may help mitigate these adverse effects and improve metabolic parameters, indicating a potential avenue for better therapeutic approaches in psychiatric treatment.
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