Although it is crucial to address the issue of obesity in patients with serious mental illness (SMI) to improve their metabolic health and reduce risk factors for cardiovascular diseases, treating these patients with psychopharmacotherapeutics presents difficulties (22). Nevertheless, the primary contributor to weight gain in individuals with SMI is the use of antipsychotic medications, which can provoke, to a greater extent, a significant weight gain as an adverse effect and thus are considered as with obesogenic potential, affecting a substantial portion of patients with rates ranging from 15–72% (23). Additionally, other types of psychotropic medications, including antidepressants and mood-stabilizing drugs like lithium and sodium valproate, are commonly prescribed to individuals with schizophrenia or schizoaffective disorder. However, these medicaments may also contribute to significant weight gain, bearing an higher risk for a metabolic syndrome (24). Weight gain is often a reason for discontinuation of medication (non-adherence) and a potential factor for disease relapse. We suggest that implementing effective weight-management strategies could potentially improve adherence to antipsychotic medication and reduce relapse and hospitalization rates in individuals who discontinue their medication due to weight gain caused by antipsychotic use. However, despite some studies indicating that short-term lifestyle interventions may help with weight reduction in individuals with SMI, most studies did not find a significant effect of lifestyle interventions on body weight in patients with schizophrenia (25, 26). These findings indicate that weight management in individuals with schizophrenia may require a different approach compared to other SMIs. In this systematic review and meta-analysis, we aimed to assess the effectiveness of liraglutide for weight loss and glycemic control in obese and prediabetic patients with schizophrenia.
The results of our analysis showed that liraglutide has a statistically significant impact on body weight, BMI, waist circumference (WC), fasting glucose, HbA1c, and total cholesterol levels. Specifically, our analysis of three studies found a statistically significant reduction in body weight (-4.09 kg) and BMI (-0.92 kg/m2) in the liraglutide group compared to the placebo group. The study's results were supported by a reduction in WC of -3.65 cm, adding further evidence to the effectiveness of weight loss with liraglutide. Several previous studies have established a significant association between WC and cardiovascular health risk factors (27). Multiple studies have demonstrated that individuals with a normal BMI but a higher WC are at an elevated risk for cardiovascular health issues (28). Furthermore, our meta-analysis revealed that liraglutide played a significant role in blood glucose control, as evidenced by statistically significant reductions in fasting glucose (-9.23), HbA1c levels (-4.24), and total cholesterol levels (-19.00) in the liraglutide group compared to the control group (29). Overall, the results of this meta-analysis suggest that liraglutide may be a viable treatment option for managing weight loss and glycemic control in overweight and prediabetic patients with schizophrenia.
Liraglutide is a GLP-1-receptor agonist with 97% homology to human GLP-1, and it is approved for the treatment of both obesity and diabetes (6, 30). Its main mechanism for reducing body weight is by decreasing calorie intake through reduced gastric motility and increased satiety rather than by increasing energy expenditure (31). When administered peripherally, it can pass through the blood-brain barrier in substantial quantities (32). Liraglutide directly stimulates neurons that suppress appetite which are proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) in the arcuate nucleus while inhibiting neurons that stimulate appetite such as neuropeptide Y/agouti-related protein (NPY/AgRP) (33). Liraglutide has also been found to promote neurogenesis and exhibit neuroprotective effects similar to those of second-generation antipsychotics, suggesting potential use in psychiatric disorders (32, 34–36). The exact mechanism of action of liraglutide is not fully understood. However, several proposed mechanisms could contribute to its effects in these areas. Firstly, liraglutide activates GLP-1 receptors in the brain, which play a role in appetite regulation and satiety. By targeting these receptors, liraglutide can potentially reduce food intake and promote weight loss in individuals with schizophrenia who are overweight or obese (37). Secondly, liraglutide has been shown to improve insulin secretion and enhance insulin sensitivity in peripheral tissues (38). This can lead to better glucose utilization and regulation, helping to manage prediabetes or impaired glucose tolerance in schizophrenic patients. It has been suggested that liraglutide affects dopamine and serotonin systems in the brain, which are implicated in both glucose regulation and the pathophysiology of schizophrenia (37). By influencing these neurotransmitter systems, liraglutide might have indirect effects on glucose metabolism and potentially improve metabolic parameters. Additionally, liraglutide has been associated with a reduction in inflammation and oxidative stress, which are factors that can contribute to insulin resistance and impaired glucose regulation (39, 40). By mitigating these processes, liraglutide could improve glucose homeostasis in schizophrenic patients.
There are other known pharmacological strategies that have been tried as add-on to adipogenic antipsychotics and are still used in clinical practice, e.g., Metformin, which is an anti-diabetic drug that has proven efficacy in wight loss among patients who take antipsychotics and suffer weight gain (41, 42). The use of metformin as adjunctive therapy to treat weight gain was implemented when non-pharmacological treatment failed. Metformin works by increasing insulin resistance and decreasing blood lipids. Greater effects are produced by metformin which are presented in decreased blood glucose levels (43). In the same direction, another GLP-1 agonist (semaglutide) was investigated by Prasad et al. in a case series to evaluate its efficacy in patients who gained weight due to antipsychotic drugs and failed to respond to metformin. A statistically and clinically significant weight improvement (i.e., > 5% body weight) was seen in the treated cohort. Despite the fact that a third of patients (4 of 12) initially reported mild GIT side-effects, semaglutide was generally well tolerated and correlated with the drug's known GIT adverse effects (44).
The variation in liraglutide dosage among the included studies in our study poses an important consideration in interpreting the findings. The use of different doses of liraglutide across the studies can introduce heterogeneity and potentially impact the overall conclusions. It is crucial to recognize that varying doses may yield different treatment outcomes, efficacy levels, and safety profiles. The observed variations in liraglutide dosing make it challenging to determine the optimal dose specifically for prediabetic and obese schizophrenic patients. The heterogeneity in dosage calls for a cautious interpretation of the pooled results and underscores the need for further research. Future investigations, such as well-designed randomized controlled trials, should be conducted to directly compare different doses of liraglutide in this specific population. Considering individual patient characteristics and tailoring the dose accordingly may also be beneficial. Addressing the dosage variation in liraglutide studies enhances the understanding of the limitations and highlights the importance of establishing an optimal dosing strategy for the targeted population.
The strengths of the study are present at several points. These include the comprehensiveness of our study, which included a variety of outcomes related to weight gain, pre-diabetes, and associated complications. It provides recent evidence of liraglutide use in prediabetic and obese schizophrenic patients. In addition, the methodological quality of the included studies was assessed using validated tools, ensuring a rigorous assessment of the risk of bias. Finally, the results of this systematic review and meta-analysis are reported following the PRISMA guidelines, ensuring transparency and replicability of the study. On the other hand, it has some limitations: The differences in patient characteristics and diagnosis across the analysed studies may impact the applicability of the findings to different patient populations, so we used the random effect model during the analysis to account for this difference, and the analysis was limited in its scope as it was based on a limited number of studies with small sample sizes. Additionally, the analysis was restricted to a sample population from only three countries, with three trials conducted in the same country. Further research is necessary to validate these findings. Moreover, while the overall quality of the included studies was moderate, one study had a high risk of bias, which could have impacted the overall results. As a result, it is important to approach these findings with caution, and more high-quality studies are needed to strengthen the evidence supporting the efficacy of liraglutide in this population.
Finally, to strengthen the evidence base on this topic, several recommendations can be made. Firstly, conducting randomized controlled trials (RCTs) with larger sample sizes and different countries’ populations and ethnicities would provide more robust evidence of its effectiveness. Comparative studies that compare liraglutide with other weight management interventions, such as lifestyle modification, other medications, or combination therapies, in this population of overweight or prediabetic schizophrenic patients would enhance our understanding of its relative effectiveness and safety compared to other treatment options. Secondly, further research is needed to thoroughly evaluate the safety and tolerability of liraglutide in patients with schizophrenia, monitor for potential adverse effects, and assess its impact on psychiatric symptoms and medication adherence. Finally, investigating the underlying mechanisms of action of liraglutide in patients with schizophrenia, such as its effects on appetite regulation, neurogenesis, and neuroprotection, would provide a deeper understanding of its potential therapeutic benefits and contribute to a better understanding of its effectiveness, safety, and utility as a potential treatment option for managing overweight in the studied population.