Balancing body and mind: selecting the optimal antipsychotic
Authors: Dan Siskind, Steve Kisely
Journal: The Lancet (2019)

The burden of schizophrenia remains high, with one in 100 people affected globally over a lifetime.1McGrath J Saha S Chant D Welham J Schizophrenia: a concise overview of incidence, prevalence, and mortality.Epidemiol Rev. 2008; 30: 67-76Crossref PubMed Scopus (1333) Google Scholar Symptoms are disabling, with auditory hallucinations, delusions, lack of motivation, cognitive impairment, and functional deficits. Despite advances in our understanding of the biological underpinnings of the illness, cure remains elusive. Antipsychotic medications are the mainstay of pharmacological treatment, but selecting the optimal medication for the individual patient is a delicate balance between efficacy and physical side-effects. People with schizophrenia die up to 18 years earlier than the general population, largely due to avertable cardiometabolic diseases,2Lawrence D Hancock KJ Kisely S The gap in life expectancy from preventable physical illness in psychiatric patients in Western Australia: retrospective analysis of population based registers.BMJ. 2013; 346f2539Crossref PubMed Scopus (562) Google Scholar with a standardised mortality ratio of more than 3.3Oakley P Kisely S Baxter A et al.Increased mortality among people with schizophrenia and other non-affective psychotic disorders in the community: a systematic review and meta-analysis.J Psychiatric Res. 2018; 102: 245-253Crossref PubMed Scopus (72) Google Scholar The risks are multifactorial, and include a genetic predisposition for abnormal glucose, poor diet, sedentary behaviour, and, notably, metabolic adverse reactions to antipsychotic medications.4Firth J Siddiqi N Koyanagi A et al.The Lancet Psychiatry Commission: a blueprint for protecting physical health in people with mental illness.Lancet Psychiatry. 2019; 6: 675-712Summary Full Text Full Text PDF PubMed Scopus (527) Google Scholar In The Lancet, Maximilian Huhn and colleagues5Huhn M Nikolakopoulou A Schneider-Thoma J et al.Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis.Lancet. 2019; 394: 939-951Summary Full Text Full Text PDF PubMed Scopus (546) Google Scholar report a network meta-analysis of antipsychotic medications for the acute management of schizophrenia that includes 402 studies of 32 different antipsychotics with data for 53 463 participants (mean age 37·40 years [SD 5·96], 29 949 [56·02%] male and 23 514 [43·98%] female, mean illness duration 11·90 years [SD 5·19]). This is the largest and most comprehensive meta-analysis of antipsychotic medication for acute psychosis to date. The use of a network meta-analysis allows comparisons between agents that might not have been directly compared in clinical trials. Other strengths include consideration of the placebo response rate, study sample size, publication year, baseline severity, sponsorship, comparability of doses, and patient demographics, using both meta-regression and sensitivity analyses of excluding poorer-quality studies. None of these factors greatly altered outcomes. Many of the results are unsurprising. Clozapine remains the most effective antipsychotic for acute psychotic symptoms; however, it is now reserved for patients with treatment-refractory schizophrenia.6Siskind D McCartney L Goldschlager R Kisely S Clozapine v. first-and second-generation antipsychotics in treatment-refractory schizophrenia: systematic review and meta-analysis.Br J Psychiatry. 2016; 209: 385-392Crossref PubMed Google Scholar Several commonly used second-generation antipsychotics, including amisulpride, risperidone, and olanzapine, were among the most effective treatments for psychotic symptoms; however, the differences in efficacy between the antipsychotics were more gradual than discrete. The most interesting results related to adverse drug reactions. Among second-generation antipsychotics, olanzapine, quetiapine, risperidone, and paliperidone were associated with marked weight gain, which the authors rated as being of high certainty of evidence. Amisulpride, risperidone, and paliperidone were associated with elevation of prolactin concentrations, whereas ziprasidone, amisulpride, and sertindole were associated with QTc prolongation. Second-generation antipsychotics (except quetiapine) had relatively low frequencies of anticholinergic adverse drug reactions. First-generation antipsychotics such as haloperidol and perphenazine were also effective for psychotic symptoms. Although high-potency first-generation antipsychotics might not be associated with weight gain, they led to higher rates of akathisia, raised prolactin, and parkinsonian symptoms. However, the strength and generalisability of the findings for first-generation antipsychotics might have been affected by a lower placebo response than that found in later trials of second-generation antipsychotics and the relatively small number of study participants. Social functioning was also comparatively under-researched compared to other outcomes, possibly reflecting a focus on clinician-defined as opposed to participant-defined outcomes. How should this information influence our choice of medications for managing acute psychotic episodes for people with schizophrenia? Antipsychotic medications are unequivocally more effective than placebo for treating acute psychotic episodes in schizophrenia. Moreover, antipsychotic use versus no treatment is associated with significant reduction in all-cause mortality.7Vermeulen J van Rooijen G Doedens P Numminen E van Tricht M de Haan L Antipsychotic medication and long-term mortality risk in patients with schizophrenia; a systematic review and meta-analysis.Psychol Med. 2017; 47: 2217-2228Crossref PubMed Scopus (56) Google Scholar However, there must be a balance between the need to treat psychotic symptoms and the need to protect patient's physical health. Increasingly, clinical practice guidelines recommend against using second-generation antipsychotics commonly associated with high frequencies of weight gain, such as olanzapine or quetiapine, as first-line agents.8Galletly C Castle D Dark F et al.Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for the management of schizophrenia and related disorders.Aust N Z J Psychiatry. 2016; 50: 410-472Crossref PubMed Scopus (468) Google Scholar More weight-neutral antipsychotics, such as amisulpride or aripiprazole, should be selected first. If medications with high weight gain potential are selected, then they might need to be switched to weight-neutral agents once symptoms are more stable. The precise role of first-generation antipsychotics in practice is still unclear and merits further research, given the relatively small numbers and low placebo response in existing studies. As Huhn and colleagues5Huhn M Nikolakopoulou A Schneider-Thoma J et al.Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis.Lancet. 2019; 394: 939-951Summary Full Text Full Text PDF PubMed Scopus (546) Google Scholar highlight, their research could be particularly relevant for low-income and middle-income countries, where lower-cost first-generation antipsychotics might be more commonly used. Patient involvement in both research outcomes and treatment choice is also crucial, particularly given evidence that this improves subsequent adherence.9Campbell L Kisely S Prescribing preferred medications improves adherence in people with severe mental illness.Evid Based Ment Health. 2010; 13: 108Crossref PubMed Google Scholar Prescribers should, therefore, partner with patients to assist them in making informed choices, balancing evidence for efficacy of treatments with potential adverse drug reactions. Monitoring and evidence-based treatment of cardiometabolic adverse events also remains essential.4Firth J Siddiqi N Koyanagi A et al.The Lancet Psychiatry Commission: a blueprint for protecting physical health in people with mental illness.Lancet Psychiatry. 2019; 6: 675-712Summary Full Text Full Text PDF PubMed Scopus (527) Google Scholar This approach should combine advice and support around exercise, diet, and medications, such as metformin.10Vancampfort D Firth J Correll CU et al.The impact of pharmacological and non-pharmacological interventions to improve physical health outcomes in people with schizophrenia: a meta-review of meta-analyses of randomized controlled trials.World Psychiatry. 2019; 18: 53-66Crossref PubMed Scopus (101) Google Scholar Management of acute schizophrenia should not be limited to medications. For instance, strong evidence supports the beneficial effects of psychosocial treatments, such as family therapy, cognitive interventions, and community-based rehabilitation.11Dixon LB Dickerson F Bellack AS et al.The 2009 schizophrenia PORT psychosocial treatment recommendations and summary statements.Schizophr Bull. 2009; 36: 48-70Crossref PubMed Scopus (571) Google Scholar Huhn and colleagues5Huhn M Nikolakopoulou A Schneider-Thoma J et al.Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis.Lancet. 2019; 394: 939-951Summary Full Text Full Text PDF PubMed Scopus (546) Google Scholar have provided crucial information to inform antipsychotic prescribing. It is now time for prescribers to partner with patients and use this information to balance the needs of the mind and the needs of the body. DS is partially supported by an National Health and Medical Research Council Early Career Fellowship (APP1111136). SK has received speaker's honoraria from Janssen, outside the area of work commented on here. Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysisThere are some efficacy differences between antipsychotics, but most of them are gradual rather than discrete. Differences in side-effects are more marked. These findings will aid clinicians in balancing risks versus benefits of those drugs available in their countries. They should consider the importance of each outcome, the patients' medical problems, and preferences. Full-Text PDF Open Access