Antipsychotic‐induced weight gain: Is the weight over? New guidelines needed

Antipsychotic medication increases the risk of obesity in people with severe mental illness (SMI). The average increase in bodyweight following antipsychotic treatment initiation is 4.85 kg. The increased cardiovascular morbidity and mortality and decreased life expectancy in people with SMI is partly attributable to this higher obesity rate. Furthermore, antipsychotic-induced weight gain (AiWG) negatively impacts treatment adherence, readmission rates, quality of life and the likelihood of developing type 2 diabetes.6–8 Therefore, prevention and treatment of AiWG is essential in SMI. Just like obesity, in the general population, prevention and treatment consists of non-pharmacological and pharmacological interventions in SMI. Firstly, clinicians should take into account the individual metabolic risk profiles when choosing an antipsychotic. Secondly, lifestyle interventions can be started immediately after initiating antipsychotics. Although the majority of antipsychotics is associated with weight gain, clozapine and olanzapine have the highest propensity for weight gain followed by quetiapine and risperidone. As for treatment of AiWG, most guidelines recommend lifestyle interventions and switching antipsychotics. However, studies demonstrated variable efficacy of lifestyle interventions. Moreover, it is well known that long-term maintenance of weight loss following lifestyle interventions is challenging. Depressive and negative symptoms may negatively impact the implementation of lifestyle interventions. Furthermore, participants of clinical trials are potentially better able to stay motivated and to follow structured lifestyle programs than patients in clinical practice depending on the severity of illness. In addition to non-pharmacological interventions, switching antipsychotics and addition of adjunctive medication can be considered. A meta-analysis showed that switching antipsychotics to aripiprazole resulted in significant weight reduction ( 5.52 kg) compared to continuation of antipsychotics. Conversely, switching to clozapine or olanzapine was associated with weight gain compared to baseline. Clinicians need to consider efficacy of the prescribed antipsychotics, other side-effects and the risk of relapse when switching antipsychotics. Additionally, it has been shown that the majority of antipsychotics is associated with long-term weight gain. Hence, the usability of switching antipsychotics seems to be limited. Dose reduction of antipsychotics is also not an appropriate intervention, as a meta-analysis showed no significant effect of dose reduction as treatment for AiWG and dose reduction could also cause a risk of relapse. Considering the variable efficacy of lifestyle interventions and the limited impact of switching antipsychotics, additional management strategies are necessary to clinically significantly reduce AiWG. Multiple pharmacological interventions have been examined as adjunctive therapy for the prevention and treatment of AiWG. Currently, there is no pharmacological intervention approved for this indication. Nevertheless, in the treatment of obesity, orlistat, naltrexon/ bupropion and liraglutide are registered by the EMA. Orlistat is a lipase-inhibitor and reduces fat absorption. However, orlistat is not appropriate for treatment of AiWG due to gastro-intestinal side effects such as fecal incontinence and limited evidence. Naltrexon/bupropion stimulates the secretion of anorectic neuropeptides. Since registration in 2015, one study randomized 21 participants with schizophrenia, obesity and antipsychotics to placebo or naltrexone/bupropion 25 mg/day and 300 mg/day, respectively, for 24 weeks. No significant differences were found regarding weight or BMI. Furthermore, naltrexone/bupropion may potentially increase the risk of psychosis as bupropion is a dopamine reuptakeinhibitor. Hence, naltrexone/bupropion currently has no place in the treatment of AiWG also due to limited evidence in people with SMI. The glucagon-like peptide (GLP)-1 agonist liraglutide stimulates insulin secretion, reduces appetite and potentially improves cognition. Since registration in 2015, one clinical study has randomized 103 participants with schizophrenia spectrum disorder, clozapine or olanzapine use and overweight or obesity to liraglutide 1,8 mg/day or placebo injections subcutaneously (s.c.) for 16 weeks. Liraglutide significantly reduced bodyweight compared to placebo ( 5.3 kg). Adverse events were mainly gastro-intestinal. A more recent placebo-controlled pilot-study randomized 47 participants with schizophrenia spectrum disorder and first-episode psychosis to liraglutide 3.0 mg/day s.c. or Received: 19 July 2022 Accepted: 21 July 2022