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VIEW Open Access Controversies in Bipolar Disorder; Role of Second‑Generation Antipsychotic for Maintenance Therapy Sameer Jauhar1,2* and Allan H

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VIEW Open Access Controversies in Bipolar Disorder; Role of Second‑Generation Antipsychotic for Maintenance Therapy Sameer Jauhar1,2* and Allan H Jauhar and Young Int J Bipolar Disord (2019) 7:10 https://doi.org/10.1186/s40345-019-0145-0 REVIEW Open Access Controversies in bipolar disorder; role of second-generation antipsychotic for maintenance therapy Sameer Jauhar1,2* and Allan H. Young1 Abstract In this narrative review, we discuss use of second-generation antipsychotics (SGAs) in maintenance treatment of bipo- lar disorder. We compare their use to historically more established treatments (particularly lithium, the gold standard). To compare we review evidence on efcacy, efectiveness and tolerability across illness poles, possible mechanisms of treatment response, guidance given by guideline groups and pragmatic clinical considerations. We then illustrate the controversies in maintenance antipsychotic use, with the example of frst episode mania and its treatment within frst episode psychosis services. Finally, we make suggestions for future studies to unpick these diferences. Introduction aripiprazole, olanzapine, quetiapine (immediate-release) Bipolar disorder (BD), as defned by modern classifca- and ziprasidone. Approval has also been given to risperi- tion systems, encompasses episode of mania/hypomania done long acting injection as monotherapy or adjunct, as and usually depression. Although acute episodes are sig- well as aripiprazole long acting injection for monother- nifcant, it is the recurrent nature of the illness that has apy in Bipolar 1 disorder (Vieta et al. 2018). implications for longer-term functioning and places it as the 4th leading cause of disability adjusted life years in Evidence for the gold standard‑lithium people aged 10–24 (Gore et al. 2011). Lithium has been a cornerstone of maintenance treat- A careful review on illness course in the pre-medica- ment in BD since the 1960s, the frst report of pro- tion and post-medication era suggests recurrence to be phylactic efects that we are aware of being a report by very much the rule, as opposed to the exception (Good- Hartigan in (1963). Initial methodological problems (e.g., win and Jamison 2007). High rates of recurrence are seen discontinuation efects causing rebound mania (Sup- uniformly throughout illness course, from frst episode pes et al. 1991) were addressed by subsequent trials, in onwards (Gignac et al. 2015). Because of the high risk which lithium was used as comparator to placebo, and in of episode recurrence, prophylactic treatment is usu- latter studies, antipsychotics. Meta-analyses versus pla- ally an essential part of treatment. Given that a signif- cebo, from 7 trials, indicated benefts of lithium in pre- cantly higher proportion of people experience periods venting all mood episodes (RR = 0.66), manic episodes of depression than (hypo)mania (Judd et al. 2002) treat- (RR = 0.52) and to a lesser extent, depressive episodes ments should be examined for efcacy for this pole of the (RR = 0.78). When compared to anticonvulsants, lithium illness in addition to mania. demonstrated superiority in preventing manic episodes Current drugs approved for maintenance therapy (RR = 0.66), though not depressive episodes. Te long- in bipolar disorder by the United States (US) Food and est trial length was 2 years, and all but one trial included Drugs Administration (FDA) are; lithium, lamotrigine, people with Bipolar 1 disorder (Severus et al. 2014). Lith- ium has also been suggested to have anti-suicide efects *Correspondence: [email protected] (Lewitzka et al. 2015). Efects on cognitive function are 1 Department of Psychological Medicine, Institute of Psychiatry, heterogenous, with small impairments in verbal learn- Psychology and Neuroscience, King’s College, London SE5 8AF, UK Full list of author information is available at the end of the article ing and memory, though no efects on domains such as © The Author(s) 2019. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat iveco mmons .org/licen ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. Jauhar and Young Int J Bipolar Disord (2019) 7:10 Page 2 of 9 executive function or processing speed, with a suggestion examined included olanzapine (4 trials), quetiapine (4 of worsening in psychomotor speed over time (Wingo trials), aripiprazole (3 trials), risperidone (3 trials) and et al. 2009). ziprasidone (1 trial). Meta-analyses showed antipsychotic Te risks of lithium are clearly delineated and include monotherapy to be superior to placebo for reducing side-efects of treatment (Shine et al. 2015) and rebound overall relapse risk (olanzapine: RR 0.52 (95% CI 0.38– mania upon discontinuation (Suppes et al. 1991). In the 0.71), 2 studies; quetiapine: HR 0.37 95% CI 0.31–0.45), 2 former review, the authors examined laboratory data in studies; risperidone: RR 0.61 (95% CI 0.47–0.80), 2 stud- people taking lithium, versus controls fnding increased ies), though the quality of studies, using GRADE, was risk for stage 3 kidney disease (HR = 1.93), hypothyroid- very poor. As an adjunct to conventional mood stabilizers ism (HR = 2.31), raised calcium (HR = 1.43). Real-world (lithium/valproate/lamotrigine), when given to people data on lithium discontinuation taken from an epide- who had responded to acute treatment, there was a ben- miologically defned area over a 48-year period, of peo- efcial efect for aripiprazole (RR 0.65, 95% CI 0.50–0.85; ple taking lithium, suggested 54% stopped it completely. 2 studies), olanzapine (RR = 0.49 (95% CI 0.27–0.91; one Of the 561 episodes of discontinuation, the majority of study), quetiapine (RR 0.38, 95% CI 0.32–0.46; 2 studies) people stopped due to adverse events (62%), the most and ziprasidone (RR 0.62, 95% CI 0.40–0.96; 1 study). prevalent being renal disease, diarrhoea and tremor. Psy- One trial with risperidone long-acting injection (LAI) chiatric reasons caused discontinuation in 44% of people, in people with Bipolar 1 disorder and 4 or more episode the most common being non-adherence and perceived in the prior year, was not statistically signifcant in the lack of efectiveness (Öhlund et al. 2018). meta-analysis for relapse to mania or depression, though did show beneft in a 52 week follow-up compared to pla- Evidence for second‑generation cebo as an add-on to treatment as usual, with a 2.3 fold antipsychotics‑how do they compare? decreased risk of relapse to any mood episode (Macfad- Te use of antipsychotics in BD dates back to the 1960s, den et al. 2009). Adjunctive treatment with quetiapine predominantly in the acute phase, compared to placebo was the only drug that reduced both manic (RR 0.39, 95% (Klein and Oaks 1967) and lithium, in acute mania (Prien CI 0.30–0.52; 2 studies) and depressive (RR 0.38, 95% CI et al. 1972), as well as functional psychosis (Johnstone 0.29–0.49; 2 studies) episodes. All but one study had an et al. 1988). Te Prien et al. trial found comparable ef- enriched design, i.e., patients were taking the drug prior cacy to lithium in acute mania, and the latter signifcant to randomization, essentially a form of selection bias. efects of pimozide, though not lithium, on psychotic Two of the RCTs included people with Bipolar 2 disorder symptoms, in undiferentiated psychosis. Antipsychotic (Table 1). efcacy in acute mania is clear, meta-analytic evidence Discontinuation rates as adjunct varied from a hazard suggesting greater efcacy for haloperidol than lithium ratio of 0.66 (ziprasidone) to 0.89 (aripiprazole), with (SMD 0.19), with heterogeneity between compounds, weight gain (defned as increase of > 7%) noted when with predominantly dopamine antagonists such as halop- meta-analyzing all antipsychotics. eridol having greatest efcacy (Cipriani et al. 2011). An antipsychotic not examined in this review was lur- Te earliest observational study of antipsychotics for asidone, which has an FDA license as monotherapy and maintenance treatment appears to be the use of clozapine adjunctive treatment to lithium and divalproex for acute in people attending a service for resistant mood disorders treatment of bipolar depression, and asenapine, which (Zarate et al. 1995). An advantage of the second-gener- has recently been examined in a maintenance trial. Fol- ation antipsychotics (SGAs) was their decreased pro- lowing a 6 week double blind placebo controlled RCT of pensity to cause movement disorder, in comparison to lurasidone monotherapy or adjunctive treatment with frst-generation antipsychotics (FGAs), a 2017 meta- lithium or divalproex, participants were randomised to analysis showing a statistically signifcant diference in extended 6-month trial of lurasidone as monotherapy or tardive dyskinesia between classes (around 20% com- adjunct. Tough not primary outcome, treatment‐emer- pared to 30%), with lower prevalence in FGA naïve sub- gent mania occurred in 1.3% in the monotherapy group, jects (around 7%) (Carbon et al. 2017). Other side-efects, and in 3.8% in the adjunctive group. Among extension such as metabolic efects are more prevalent with SGAs study baseline responders, 10.2% met post hoc crite- (see below). A 2017 systematic review and meta-analysis ria for depression relapse during 6 months of treatment of SGAs in maintenance treatment of BD included 15 in the monotherapy group, 10.2% meeting relapse cri- RCTs, lasting from 6 months to 2 years, and one obser- teria in the adjunctive therapy group. Te nature of the vational study lasting 4 years (Lindström et al. 2017). trial makes it difcult to compare depression and mania Tis examined monotherapy and adjunctive therapy to relapse to other treatments, though the low incidence lithium, sodium valproate or lamotrigine. Antipsychotics of manic relapse should be noted (Ketter et al.
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