Insights into metabolic dysregulations associated with antipsychotics
Authors: Yoav Domany, Mark Weiser
Journal: The Lancet Psychiatry (2019)

Metabolic dysregulation following antipsychotic use is very common and of major concern for clinicians treating patients with schizophrenia spectrum disorders. In The Lancet Psychiatry, Toby Pillinger and colleagues1Pillinger T McCutcheon RA Vano L et al.Comparative effects of 18 antipsychotics on metabolic function in schizophrenia, predictors of metabolic dysregulation, and association with psychopathology: a systematic review and network meta-analysis.Lancet Psychiatry. 2019; (published online Dec 17)https://doi.org/10.1016/S2215-0366(19)30416-XSummary Full Text Full Text PDF PubMed Scopus (281) Google Scholar report a clinically relevant meta-analysis on the metabolic adverse effects of antipsychotics. The metabolic adverse effects of antipsychotics, particularly the so-called second generation antipsychotics, are well known.2Rummel-Kluge C Komossa K Schwarz S et al.Head-to-head comparisons of metabolic side effects of second generation antipsychotics in the treatment of schizophrenia: a systematic review and meta-analysis.Schizophr Res. 2010; 123: 225-233Crossref PubMed Scopus (513) Google Scholar The unique aspect of this study is that antipsychotics are ranked in an orderly fashion, from those with the most serious adverse effects to those with the least. Although on the whole clozapine and olanzapine are associated with the most severe metabolic adverse effects, the authors differentiate between the metabolic adverse effects caused by each medication. For example, risperidone and paliperidone are associated with weight gain but are not associated with substantial increases in fasting blood glucose. Additionally, the authors identified risk factors for metabolic adverse effects, showing that increases in fasting glucose are more prevalent in men than in women (p=0·0082) and in patients with higher weight at baseline (p=0·0015), and non-white ethnicity was associated with greater increases in total cholesterol (p=0·040). The results of this study can be taken together with a network meta-analysis2Rummel-Kluge C Komossa K Schwarz S et al.Head-to-head comparisons of metabolic side effects of second generation antipsychotics in the treatment of schizophrenia: a systematic review and meta-analysis.Schizophr Res. 2010; 123: 225-233Crossref PubMed Scopus (513) Google Scholar on the efficacy and adverse effects of anti-psychotics. In that study, 32 antipsychotics were ranked on their effect on reducing overall, positive, negative, and depressive symptoms. The authors reported that clozapine was most efficacious in reducing overall symptoms (standardised mean difference −0·89 [95% CI −1·08 to −0·71]), and amisulpride was the most efficacious in reducing positive symptoms (−0·69 [–0·86 to −0·52]). One would hope that data on efficacy and adverse events could be taken together with the detailed information on metabolic adverse events from this study to consider a personalised medicine approach in treating patients with schizophrenia. For some patients, the combination of certain symptoms together with certain adverse effects would suggest the use of one drug, whereas for patients with a different set of symptoms and risk factors, a different drug would be indicated. This approach could be part of a shared decision-making process, based on a discussion with the patient weighing the benefits and disadvantages of each treatment option.3Hamann J Cohen R Leucht S Busch R Kissling W Shared decision making and long-term outcome in schizophrenia treatment.J Clin Psychiatry. 2007; 68: 992-997Crossref PubMed Scopus (136) Google Scholar Such an approach is hampered by the fact that clozapine and olanzapine, which consistently come out among the best in terms of efficacy, are also consistently associated with the highest rates of metabolic adverse effects, hindering such a process at this stage. Particularly interesting and challenging is the finding by Pillinger and colleagues1Pillinger T McCutcheon RA Vano L et al.Comparative effects of 18 antipsychotics on metabolic function in schizophrenia, predictors of metabolic dysregulation, and association with psychopathology: a systematic review and network meta-analysis.Lancet Psychiatry. 2019; (published online Dec 17)https://doi.org/10.1016/S2215-0366(19)30416-XSummary Full Text Full Text PDF PubMed Scopus (281) Google Scholar that improvement in symptomatology and metabolic adverse effects, particularly BMI, are correlated (r=0·84, p<0·0001). One simplistic explanation is that patients who take their medication more consistently are more likely to respond and improve clinically, and more likely to have adverse effects. An alternative explanation is that the neurotransmitters that mediate metabolic adverse effects, including serotoninergic, histaminergic, and muscarinergic agents4Weiner D Meltzer H Veinbergs I et al.The role of M1 muscarinic receptor agonism of N-desmethylclozapine in the unique clinical effects of clozapine.Psychopharmacology. 2004; 177: 207-216Crossref PubMed Scopus (205) Google Scholar might, together with D2 dopamine receptor blockade, contribute to clinical improvement. The finding by Pillinger and colleagues that fasting glucose increased more in patients with higher, rather than lower, weight at baseline (p=0·0015) is important. Previous studies reported that patients with low body weight gained the most weight with olanzapine,5Basson BR Kinon BJ Taylor CC Szymanski KA Gilmore JA Tollefson GD Factors influencing acute weight change in patients with schizophrenia treated with olanzapine, haloperidol, or risperidone.J Clin Psychiatry. 2001; 62: 231-238Crossref PubMed Scopus (258) Google Scholar, 6Raben AT Marshe VS Chintoh A Gorbovskaya I Müller DJ Hahn MK The complex relationship between antipsychotic-induced weight gain and therapeutic benefits: a systematic review and implications for treatment.Front Neurosci. 2018; 11: 741Crossref PubMed Scopus (52) Google Scholar implying that one can administer olanzapine to patients who are already obese with less risk of weight gain and presumably other metabolic adverse effects. The data presented by Pillinger and colleagues do not support that notion, but rather discourage treatment of obese patients with olanzapine and clozapine. Rates of the metabolic adverse effects caused by haloperidol and perphenazine did not differ from placebo.1Pillinger T McCutcheon RA Vano L et al.Comparative effects of 18 antipsychotics on metabolic function in schizophrenia, predictors of metabolic dysregulation, and association with psychopathology: a systematic review and network meta-analysis.Lancet Psychiatry. 2019; (published online Dec 17)https://doi.org/10.1016/S2215-0366(19)30416-XSummary Full Text Full Text PDF PubMed Scopus (281) Google Scholar These benefits are offset by the increased risk of extra-pyramidal adverse effects,7Solmi M Murru A Pacchiarotti I et al.Safety, tolerability, and risks associated with first- and second-generation antipsychotics: a state-of-the-art clinical review.Ther Clin Risk Manag. 2017; 13: 757-777Crossref PubMed Scopus (223) Google Scholar, 8Novick D Haro JM Bertsch J Haddad PM Incidence of extrapyramidal symptoms and tardive dyskinesia in schizophrenia: thirty-six-month results from the European schizophrenia outpatient health outcomes study.J Clin Psychopharmacol. 2010; 30: 531-540Crossref PubMed Scopus (62) Google Scholar which were not included in the study by Pillinger and colleagues. These first-generation drugs must be considered when treating patients with metabolic syndrome. An important limitation of this study, which complicates the ability to draw conclusions for clinical practice, is the short median treatment duration of 6 weeks, which is particularly important because most patients receive chronic treatment. Pillinger and colleagues' study expands on previous knowledge of the harmful effects of antipsychotics by ranking the risk for each metabolic adverse effect for each antipsychotic. Future research should attempt to identify genetic characteristics associated with efficacy and adverse effects to facilitate personalised psychiatry. We declare no competing interests. Comparative effects of 18 antipsychotics on metabolic function in patients with schizophrenia, predictors of metabolic dysregulation, and association with psychopathology: a systematic review and network meta-analysisMarked differences exist between antipsychotics in terms of metabolic side-effects, with olanzapine and clozapine exhibiting the worst profiles and aripiprazole, brexpiprazole, cariprazine, lurasidone, and ziprasidone the most benign profiles. Increased baseline weight, male sex, and non-white ethnicity are predictors of susceptibility to antipsychotic-induced metabolic change, and improvements in psychopathology are associated with metabolic disturbance. Treatment guidelines should be updated to reflect our findings. Full-Text PDF Open Access