Impacts of Glucagon-like Peptide-1 Receptor-Agonist (GLP-1 RA) Treatment for Metabolic Disturbances and Weight Gain in Patients on Clozapine/Olanzapine: A Systematic Review

Abstract

Clozapine and olanzapine are important medications in the management of psychiatric conditions such as schizophrenia. However, metabolic disturbances and weight gain are common side effects of these drugs. We aimed to evaluate the effects of GLP-1 RAs treatment for metabolic disturbances and weight gain in patients on clozapine/olanzapine. For this systematic review, searches were conducted in eight different databases. After screening, outcome data was synthesized regarding weight gain and biochemical and clinical indicators of metabolic disturbance, as well as for adverse events/side effects, and any other benefits of GLP-1 RA treatment. A total of 14 studies were included in this medical systematic review, of which four were unique randomized control trials (RCTs), with study contexts including Australia and Denmark. GLP-1 RAs that were utilized include semaglutide, exenatide, and liraglutide. It was consistently demonstrated across studies that, when followed-up, those on GLP-1 RAs had achieved statistically lower levels of weight gain compared to those receiving placebo. A similar effect was seen on fasting glucose levels and glycated haemoglobin levels. Effects on other metabolic parameters were inconsistent. There were minimal gastrointestinal, psychological, cardiac, and other side effects noted across studies. GLP-1 RAs may offer utility in addressing the metabolic side effects of olanzapine/clozapine, but further research is needed. There remains a need to better understand impacts and potential side effects in larger and more diverse populations, as well as a need to better evaluate the long-term outcomes for patients.

1. Introduction

1.1. Schizophrenia and Its Health Burden

Schizophrenia is a chronic psychiatric disorder with an estimated more than 23.6 million affected individuals worldwide [1,2]. Individuals afflicted with schizophrenia experience a mean life expectancy of approximately 10–20 years shorter than the general population, with reductions in life expectancy due to comorbid cardiovascular disease and metabolic disorders, as well as suicide risk [3,4]. Furthermore, there is strong social stigma associated with the disease, with this being demonstrated by such factors as high rates of unemployment, homelessness, and social isolation, as well as increased comorbidities such as substance use and depression [5].

1.2. Management of Schizophrenia

The use of antipsychotic medication is critical for the medical treatment for schizophrenia recommended by the American Psychiatric Association and other international guidelines [6]. The use of both first-generation (typical) and second-generation (atypical) antipsychotics are most effective for positive symptoms, which are changes in thoughts and behaviours, such as hallucinations, delusions, and disorganized speech or behaviour [7,8]. The use of second-generation agents (e.g., risperidone, olanzapine, quetiapine, aripiprazole) is generally preferred as first-line therapy due to a lower risk of extrapyramidal side effects [7,8].

1.3. Olanzapine and Clozapine

The choice of selection for a second-generation antipsychotic agent is often an interplay between clinician familiarity with specific agents; patient comorbidities—which may dictate side effects; degree of psychiatric symptoms, such as agitation level; and side effects of the medication; as well as other potential pharmacodynamic interplay between a patient’s regular medications [9]. Olanzapine is one such second antipsychotic agent, with some studies showing superior efficacy to other second-generation antipsychotics (SGAs), except for clozapine [10]. Notably, olanzapine also has important utility in bipolar disorder, as well as in some cases of treatment-resistant depression.

Clozapine is the most effective antipsychotic for treatment-resistant schizophrenia and has consistently demonstrated superior efficacy for positive and negative symptoms compared to other antipsychotics, including olanzapine, in both randomized controlled trials and meta-analyses [10,11,12,13]. Clozapine’s effectiveness is most noted in those patients who have previously failed at least two adequate antipsychotic trials, and it is associated with lower rates of treatment failure and psychiatric rehospitalization in real-world cohorts [12,13].

1.4. Metabolic Side Effects

Despite their effectiveness, both olanzapine and clozapine are associated with a significant side-effect profile. These side effects have important clinical implications and are also a major reason as to why some patients choose to discontinue treatment [14]. Amongst the most significant of these drugs are the metabolic side effects that can occur at a high magnitude, with the most predominant side effect being weight gain and increases in blood glucose levels [15,16]. These side effects can have significant impacts on the quality of life, mental health, and physical health outcomes of patients and can occur at a high frequency; a prior systematic review has demonstrated that, among 18 different antipsychotics, metabolic side effects are most significant in terms of severity and frequency with olanzapine and clozapine [17].

Notably, while current approaches to management, including dietary interventions, physical activity programmes, and usage of metformin, have been shown to result in some amelioration of these side effects [18,19,20], they also can frequently be insufficient in addressing the extent of these problems for clozapine/olanzapine patients [21,22,23,24]; in some cases, these metabolic changes can be resistant to metformin [21,22,23,24], hence necessitating different and perhaps new forms of management.

1.5. Glucagon-like Peptide-1 Receptor Agonists (GLP-1 RAs)

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are a class of incretin-based therapies used primarily for the management of type 2 diabetes mellitus and obesity. They mimic the action of endogenous GLP-1, which acts to stimulate insulin secretion while also suppressing glucagon release in a glucose-dependent manner, in turn promoting improved glycaemic control and weight loss [25,26]. A systematic review has shown that, across several RCTs that involved over 10,000 obese participants without diabetes, GLP-1 receptor agonists (GLP-1 RAs) led to substantial improvements in cardiometabolic health factors such as body weight, blood pressure, body mass index (BMI), and lipid profile [27]. In totality, the review noted a weight reduction across the study population with a mean difference −8.77 kg, along with a reduced systolic (−4.13 mmHg) and diastolic (−1.39 mmHg) blood pressure, as well as noted improvements across lipid profiles [27].

1.6. GLP-1 RAs with Olanzapine/Clozapine

There is a basis to the possibility that GLP-1 RAs could have significant benefits as adjunct therapy to improve antipsychotic-induced metabolic disturbances by improving both weight and blood glucose, based on some of the existing literature. A prior systematic review in 2018, on the usage of GLP-1 RAs in patients on antipsychotic medications, demonstrated the effectiveness of these drugs in improving cardiometabolic outcomes in these patients [28]. They showed that utilization of the GLP-1 RAs resulted in notably lower levels of blood glucose and body mass, with limited concerns of severe side effects. Notably, the authors of that review noted that there was minimal evidence for patients treated on olanzapine/clozapine [28] due to limited sample sizes. Another review was conducted in 2023, which showed comparable, encouraging findings [29]. However, that review did not focus specifically on olanzapine/clozapine and instead focused on antipsychotic drugs in totality. Therefore, the findings of the review did not provide adequately stratified data to make clinical recommendations for users of clozapine/olanzapine. This is especially important in the case of these two forms of management due to the uniquely severe metabolic side-effect risk profile of clozapine/olanzapine in comparison of other antipsychotic medications. For these reasons, clear recommendations cannot be made based on prior reviews regarding the safety and effectiveness of GLP-1 RAs for patients on clozapine/olanzapine.

1.7. Objectives

In consideration of the need for a synthesis of the available evidence, we have conducted a systematic review on the impacts of GLP-1 RA treatment for patients on olanzapine/clozapine. More precisely, we have focused on a study population of patients requiring olanzapine/clozapine due to a mental health diagnosis, the intervention being GLP-1 RAs for these patients, the comparator groups (when available) being those on standard treatments or placebos, and the outcomes being impact on weight and metabolic parameters (most pertinently, blood glucose levels), as well as any other benefits or adverse effects of treatment. Therefore, the objectives of this review were to evaluate the impacts of GLP-1 RAs on weight and other metabolic parameters for patients on olanzapine/clozapine; the secondary objectives were to evaluate the safety and tolerability of the GLP-1 RAs in this population and to evaluate for any additional benefits of these treatments in this population.

2. Materials and Methods

2.1. Guidelines and Registration

For this systematic review, we followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines [30]; the completed PRISMA checklist is available in Supplementary Table S1. The review protocol, which describes the methodology in detail, is publicly available on the Open Science Framework (OSF; https://osf.io/8fpzk/ (accessed on 6 October 2025)).

2.2. Search Terms

On 6 August 2025, we conducted searches across eight different databases: Scopus, PubMed, Web of Science, PsycINFO, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Medline, Embase, and Global Health. Search terms were developed to have groupings for clozapine and olanzapine, respectively, as well as for GLP-1 RAs and the individual drugs within this class. Searches were intended to be relatively broad to ensure that as many relevant articles as possible would be retrieved; there were no restrictions on the date of publications for the search. A complete list of search terms, by database, along with the number of results by database, is shown in Supplementary Table S2.

2.3. Screening Process

Articles retrieved from the searches were compiled with Covidence software [31], with the first step in the actual screening process being the removal of duplicate articles. Next, the remaining articles were assessed for eligibility based on title and abstract analysis. Thereafter, all articles deemed eligible for further assessment were analysed by full text to ultimately evaluate if the article was to be included in the systematic review. The screening process was completed independently by two reviewers (K.V. and S.P.).

Articles were eligible to be included if they fulfilled all of the following criteria:

(a)

Available in English;

(b)

Original research that has a peer-reviewed full-text manuscript or conference abstract;

(c)

Has a quantitative methodology;

(d)

Includes outcome data on metabolic parameters and/or weight changes;

(e)

Includes stratified data for at least one patient on a GLP-1 RA and at least one of either clozapine or olanzapine.

Reviews, commentaries/editorials, and qualitative studies were not eligible for inclusion, and studies only available in other languages were not to be included. As studies were required to be peer-reviewed to be included, grey literature was not eligible for inclusion.

2.4. Data Extraction

The primary outcome of interest in this review was the impact of GLP-1 RAs on metabolic parameters and/or weight on patients with olanzapine, and the secondary outcomes were any additional benefits (such as those on mental health outcomes) and any adverse side effects while on the treatment. Data extracted for this review was hence focused on these outcomes, as well as the details of the studies and their associated methodologies. We extracted the following data on study characteristics: author (year), study location (country), objective(s), study design, details of the study methodology (specifically, the data collected and how it was collected/evaluated), total number of participants in the study, and number of participants specifically on both GLP-1 RAs and olanzapine/clozapine, respectively. In addition to this, the following data was extracted on patient and outcome characteristics: time to follow-up, demographics (such as age, gender, and ethnicity), past medical history, including both psychiatric and physical health diagnoses, types of treatments that patients were on (including dosages and length of treatment), impact/changes to weight (including body mass index, waist circumference, total body fat), impact changes/to metabolic parameters (which included blood glucose levels, glycosylated haemoglobin levels, cholesterol/triglyceride levels, liver function), any other benefits/trends associated with the GLP-1 RA treatment, and adverse effects/side effects. Data was extracted independently by two authors, with the data being presented in tabular format.

2.5. Data Synthesis and Analysis

Data synthesis involved quantitatively analysing trends with pooling of the findings where possible, as well as with a description in the text regarding the notable patterns, relationships, and trends in the data in totality. Due to the high heterogeneity of study designs (randomised control trials and their associated secondary data analyses, case reports, case series, and observational cohort studies) and data presented across included studies (manner in which body mass and changes in body mass, blood glucose control and changes, differences other metabolic parameters, and type of and extent of side effects were measured—as well as follow-up time and type of drug) an effective meta-analysis was not possible for this systematic review.

2.6. Quality Assessment

To assess quality of study methodology and to analyse the potential risk of bias, quality assessments were conducted for all included studies in this review; this was performed using the Joanna Briggs Institute (JBI) critical appraisal tools [32]. This specific set of tools was chosen as it provides a single set of tools that can be used across differing study methodologies and hence allows for comparisons of study quality across these methodologies. Scoring of quality was performed by two authors using the checklist independently, with discrepancies being resolved by a third author. As has been performed in approaches taken in prior reviews [33,34], the numeric score was calculated to assess each study’s quality, with a ‘yes’ being given for the respective critical appraisal parameter providing a single point, and a ‘no’/’unclear’ response providing zero points (therefore, an ‘unclear’ was given the same score as a ‘no’). Mean scores and standard deviation were calculated for each methodology, and, following an approach taken previously [35], scores were described as a percentage to allow for comparisons across study methodologies.

3. Results

3.1. Screening

A depiction of the screening process is shown in Figure 1. Searches from all eight databases resulted in 670 articles being retrieved. After removal of duplicates, a total of 303 remained for screening. Of these, 25 full-text studies were further assessed for eligibility, and there were ultimately 14 articles deemed to be eligible for inclusion in this review [36,37,38,39,40,41,42,43,44,45,46,47,48,49]. Reasons for the exclusion of studies included a lack of stratified data for patients on olanzapine/clozapine, not being original research, and a lack of evaluation of the impacts of treatment of GLP-1 RAs. A list of studies [50,51,52,53,54,55,56,57,58,59,60] excluded after full-text analysis, with reason for exclusion, is shown in Supplementary Table S3.

3.2. Characteristics of Included Studies

In terms of study characteristics, studies were published from 2016 to 2022, and were conducted in five different countries: China, Canada, USA, Australia, and Denmark. Study designs of eligible studies were case reports (n = 5), case series (n = 2), a single cohort study (n = 1), and randomised control trials (RCTs) (n = 6, though only 4 unique RCTs). Two included studies [38,40] were secondary data analyses from other, already included RCTs [38,44] for which there was additional follow-up, without ongoing treatment. Time to follow-up in studies ranged from 16 weeks up to 2 years. Of the RCTs, one evaluated the impacts of liraglutide, two evaluated the effects of exenatide, and one semaglutide; additional studies (with more limited sample sizes) also evaluated the effects of dulaglutide and tirzepatide. Characteristics of included studies are shown in Supplementary Table S4.

3.3. Critical Appraisal

Completed critical appraisals, by study, are shown in Supplementary Tables S5–S8. The quality of studies was generally shown to be quite high after assessment with the JBI critical appraisal tools. The overall quality score (in %) for all included studies was 88.18% (SD = 12.34%; range: 60.00–100.00%). The mean score for included case reports was 85.00%, 80.00% for the case series, 72.73% for the single cohort study, and 95.38% for the randomised control trials. Noted methodological flaws across included studies were unclear reporting as to whether participants had been adequately blinded to their assigned group (placebo or treatment group) and a lack of adequate time to follow-up.

3.4. Patient Characteristics

A complete list of data by study on patient characteristics and outcomes is shown in Supplementary Table S9. The review included a total 139 unique patients on a GLP-1 RA and clozapine/olanzapine treatment; 67 were on a GLP-1 RA and clozapine, and 72 were on a GLP-1 and olanzapine. No patients on a GLP-1 RA were concurrently on both clozapine and olanzapine. Fifty patients were treated on liraglutide, thirty-nine on exenatide, twenty-four on semaglutide, two on dulaglutide, and one on tirzepatide. In the treatment groups, there was a specified total of 67 males and 38 females. The age of patients in the included study groups tended to be in the early 40s. Race/ethnicity was inconsistently described across studies, but in the three studies where it was described, it was demonstrated that those described as ‘white’ formed between 30 and 73% of the study population.

3.5. Impacts on Weight

It was consistently demonstrated across studies that those on GLP-1 RAs and clozapine/olanzapine had statistically significant decreases in body weight. A 14-week RCT evaluating the impacts of liraglutide for clozapine and olanzapine users showed that, compared to placebo controls, body weight decreased by an average of 5.3 kg (−7.0 to −3.7, p < 0.001), and there were also significant decreases in waist circumference in cm (−4.1, p < 00.001), body mass index (−1.8, p < 0.001), mean visceral fat in grams (−250.19, p = 0.02), and relative body fat (0.96, p = 0.01) [38]. An RCT on exenatide among olanzapine users showed a 2.6 kg decrease in 16 weeks compared to the placebo group (p = 0.002), and a 1.3 kg/m² decrease in BMI (p = 0.02) [40], with the statistical decreases emerging from week 8. A differing RCT on exenatide and clozapine users showed a mean decrease in body weight of 4.16 kg (p = 0.015) and a 1.42 decrease in BMI (p = 0.019) over 24 weeks [44]. The single RCT on semaglutide (which was evaluated among clozapine users), resulted in a 13.46% decrease in body weight % in 36 weeks, when compared with placebo controls (p < 0.0001); this meant an average decrease in body mass of −15.18 kg (p < 0.0001), 4.83 decrease in BMI (p < 0.0001), 4.44% decrease in body fat (p < 0.01), 3.95 kg decrease in lean mass (p = 0.0009), 8.93 kg decrease in fat mass (p = 0.0004), and a 0.72 kg decrease in visceral fat (p = 0.01) [46].

There are also some relevant findings from smaller scale studies, but it is to be noted that sample sizes from these studies were sometimes as low as one. A case series on dulaglutide showed a 16% and 22% decrease in body weight among two patients after 12 months [36]. For a case report on tirzepatide, there was a 60 pound (lb) decrease in 12 months, with the weight loss having immediate reversal after pausing treatment, and continual decreases once again with recommencement of treatment [39]. The largest body mass decrease was demonstrated in a single study, with a patient on clozapine given exenatide (while also on metformin) and losing 41.5 kg in 6 months, along with a 10 unit decrease in BMI [43].

One study provided follow-up 1 year after 16 weeks of treatment with liraglutide according to a single RCT; this secondary data analysis showed that after stopping treatment on week 16, there was no difference at 1 year between the placebo and treatment group in weight, BMI, and waist circumference [40]. A differing secondary analysis of an RCT involved analysing patients’ outcomes 6 months after they stopped their treatment of exenatide for 6 months. The analysis demonstrated that while patients had gained weight since stopping exenatide, their body weight still, on average, was ultimately lower compared to baseline levels [45].

3.6. Impacts on Metabolic Parameters

Findings across studies regarding impacts on metabolic parameters were not always consistently reported, but there were some notable trends in impacts on blood glucose parameters. One trial on exenatide [40] showed significant improvements in insulin sensitivity compared to a placebo group (percent improvement in treatment group compared to placebo group: 5.9%; p = 0.03), with a second trial on exenatide showing improvements in fasting mean glucose levels (−0.72, p = 0.036), and HbA1c (−0.24, p = 0.0004) when compared to placebo controls [44]. Similarly, a 16-week RCT on the impacts of liraglutide showed improvement in a number of metabolic parameters; compared to the control group, there were decreases in fasting plasma glucose levels (−2.1; p < 0.001), decreased impaired glucose tolerance (−2.1; p = 0.002), a decrease in glycated haemoglobin levels (−0.2%; p < 0.001), a decrease in 2 h oral glucose tolerance test (0.77; p < 0.001), and decreases in mean cholesterol levels (−19.3 mg/dL; p < 0.001) [48]. An RCT on the impacts of semaglutide showed a statistically significant decrease in HbA1c levels when compared to a placebo group, in 36 weeks (−0.42; p = 0.0001) [46].

In the secondary data analyses of two of these trials at a 12-month timepoint, there was instead worsening of metabolic parameters after the treatment had stopped. Fifty-two weeks after stopping treatment of liraglutide (sixteen weeks of treatment), there were significant increases—compared to the placebo—in HbA1c levels, fasting glucose levels, total cholesterol levels, amylase levels, and amount in beta cell functioning (p < 0.05 for all findings) [47]. The other RCT secondary analysis showed comparable findings, with statistical increases in HbA1c levels (0.81, p = 0.009) compared to controls at the 12-month period (6 months after stopping exenatide) [45].

3.7. Other Benefits/Trends

There were a number of different, additional benefits noted across studies. In an RCT on liraglutide [38], it was demonstrated that those in the treatment group had lower rates of admission to the hospital for worsening of schizophrenia when compared with the placebo group (p = 0.08). A finding from a different trial on exenatide showed that the treatment group had decreases both in ratings of hunger (p = 0.007), as well as decreases in disinhibition (p = 0.02) [40]. At 24 weeks, in another trial on exenatide [44], 100% of participants reported satisfaction with treatment on exenatide.

3.8. Adverse Effects and Tolerability

Across the studies included in this review, it was consistently noted that the number of side effects were limited in severity; the GLP-1 RAs were generally very well tolerated across all studies. In the RCTs, side effects were consistently equal to, or below, those of placebo groups. For example, Larsen et al. [38] denote that the total number of adverse events was lower in the liraglutide group when compared with the placebo group. In a trial on semaglutide [46], there was no difference in adverse events/side effects for the treatment group and placebo group. A comparable finding was demonstrated in a different trial on exenatide, with no difference in adverse events for the treatment and placebo groups [40]. However, despite the side effects generally being low in severity, some side effects were nonetheless still seen across participants in treatment groups. In the previously mentioned study [40], three participants discontinued the trial due to nausea, diarrhoea and dizziness, exacerbation of depression, and exacerbation of a Mallory–Weiss tear [40]. A different study recorded that treatment groups had higher rates of nausea (p = 0.008) and orthostatic hypotension (p = 0.04) [38]. Specific side effects noted in the treatment group of another RCT were transient nausea (n = 8), vomiting (n = 7), dizziness (n = 7), and diarrhea (n = 7) [44]. However, other side effects of higher severity were not noted in this study [44]. Aside from the exacerbation of depression of one patient from the aforementioned study, across all other studies included in this review, there was no worsening of psychological/psychosocial health outcomes amongst all participants who were on the GLP-1 RAs.

4. Discussion

4.1. Key Findings and Implications

In this review, it has been demonstrated that GLP-1 RAs have consistently been shown to serve as effective forms of management in improving metabolic outcomes—specifically, weight and blood glucose levels—in patients on olanzapine and clozapine. This was shown to be the case for drugs across the class, most pertinently semaglutide, exenatide, and liraglutide. Some of the largest decreases in body mass and blood glucose levels occurred with the usage of semaglutide [46]. However, the trials on liraglutide and exenatide also showed clinically significant improvement in these parameters; liraglutide treatment was also associated with lower rates of hospitalization due to schizophrenia [38].

Importantly, the existing body of evidence overwhelmingly demonstrates that this form of treatment does not have a negative impact on the psychological and psychosocial outcomes of patients; in fact, there is some evidence, albeit weak, that some aspects of mental health may improve for these patients. One possible hypothesis for this is that the usage of the GLP-1 RAs may improve patient adherence to clozapine/olanzapine as it reduces some of the very undesirable side effects of these medications. In psychiatric patient populations, adherence to treatment is a common notable concern, as some may forego treatment due to impacts of their illness, as well as for reasons such as a strong desire not to continue treatment, a lack of follow-up care, and a shortage of resources [61]. While this may possibly improve for clozapine/olanzapine patients due to addressing side effects via GLP-1 RAs, it should also be noted that there may also be inherent challenges for patients to adhere to regular administration of GLP-1 RAs via injection. Regardless, it should be noted that this hypothesis and discussion regarding medication adherence was not formally analysed or evaluated in depth in the studies included, and the implications regarding adherence remain unclear.

In addition to the minimal negative impacts on psychological health, overall adverse effects of the GLP-1 RAs were low in both frequency and severity, often being lower in treatment groups than in placebo groups.

However, it must be noted that this evidence has come from a small number of RCTs, most of which were relatively short in duration; additional evidence beyond this came from considerably weaker data sources such as case reports, case series, and observational cohort studies. Therefore, it is important to exercise caution regarding the extent of the generalizability of the findings of this review.

Regardless of the aforementioned limitations of the data, there are a number of potential implications for practice based on these findings. The findings of the studies in this review demonstrate efficacy of treatment, along with tolerability and high degrees of safety with low rates of adverse events; when adverse events occurred, they were typically low in severity, and occurring at rates that are comparable to, or lower than placebos. Therefore, the evidence of the review indicates that usage of GLP-1 RAs, across the drug class, has the potential to offer improved physical health outcomes for patients who are experiencing—or at risk of—the severe metabolic side effects of clozapine/olanzapine. In the future, it may be worthwhile to re-evaluate treatment guidelines to ensure that there are clearer, more concrete recommendations for GLP-1 RAs based on the demonstrated efficacy, safety, and tolerability. As the side effects of olanzapine/clozapine have such a severe impact on quality of life and overall treatment outcomes, there may be potential for future revisions of these guidelines to address the severe metabolic side effects of these drugs. However, it is important to reiterate that, at this time, the evidence remains preliminary and limited by the studies that are heterogeneous, have small sample sizes, and have limited long-term follow-up.

4.2. Need for Further Research

To synergise this research on the effectiveness of these drugs, there is also a need to evaluate the barriers to both usage and prescribing of GLP-1 RAs for patients on clozapine and olanzapine. Considering that patients on olanzapine/clozapine are at risk for numerous different comorbidities and side effects from their existing psychiatric diagnoses and medications, care providers may have concerns regarding the safety of utilising GLP-1 RAs for these patients due to safety profiles. While the studies from this review have demonstrated a high level of safety of these drugs, with no cases of severe/life-threatening side effects being reported because of these drugs, efforts are evidently required to ensure that clinicians are effectively made aware of the actual risks for these medications, along with the benefits against the severe medications of olanzapine/clozapine. Additional research will be beneficial to understand other reasons that limit the prescribing of these drugs for patients, such as financial barriers for patients.

Additional research on the longer-term impacts of the treatment with GLP-1 RAs will be highly beneficial. Some studies were restricted to short time periods of only 16 weeks. Studies with longer-term follow-up did occur, but the additional follow-up occurred for patients who had stopped treatment up to 6–12 months earlier. Therefore, future studies with longer term follow-up need to occur for patients who remain on the treatment regimens for an extended time, which should be a minimum of 52 weeks. Beyond this, it is also urged that future qualitative research be conducted to further understand the tolerability and perspectives for those who commence these drugs. This will provide valuable insights regarding factors that may not have been easily captured in the larger-scale quantitative studies.

4.3. Limitations

While there are important strengths and implications of the findings of this review, there are also a number of limitations that need to be recognised. First, while this review demonstrates a broad level of effectiveness and safety across the class of GLP-1 RAs, there was a limited number of large-scale studies on specific individual drugs; for example, there was only a single RCT on semaglutide. This has important clinical implications because it demonstrates that there remains a need for a stronger evidence base so that clearer recommendations can be made regarding GLP-1 RAs for patients on clozapine/olanzapine. Connected to this point, due to the limited available of studies on this topic, this review had to partially rely on available evidence from case series and case reports, indicating that there is still a need for more larger-scale studies. Despite these limits, it is also worth reiterating that the quality assessments conducted for the included studies showed high levels of study quality across methodologies (though this should also be considered alongside recognition that problems linked with follow-up were a common issue).

While clozapine and olanzapine are antipsychotics that are used worldwide, the majority of patients came from only a select number of countries, indicating limits to the generalizability of these findings. In addition, a lack of grey literature inclusion may have introduced bias into this review, and studies being restricted to English may have also potentially produced language bias. Lastly, due to heterogeneity of data, a nuanced statistical meta-analysis was not possible for this systematic review. Regardless of these notable limitations, this review shows the high potential utility for GLP-1 RAs as part of the treatment regimen for patients who are facing many of the severe metabolic side effects of clozapine and olanzapine.

5. Conclusions

It has been demonstrated in this review that GLP-1 RAs may offer an important role in addressing the metabolic side effects of olanzapine/clozapine. These drugs have shown high effectiveness in improving metabolic parameters—specifically body weight and blood glucose levels—while also offering a high degree of safety and tolerability. While these findings may have valuable treatment implications, it is also necessary to recognize that further research is needed on GLP-1 RAs in patients receiving clozapine/olanzapine.