Suzuki T.
Which rating scales are regarded as 'the standard' in clinical trials for schizophrenia? A critical review.
Psychopharmacol Bull. 2011;44(1):18-31.
Abstract/Text
BACKGROUND: This paper reviewed which rating scales past studies adopted as an outcome measure in clinical trials for schizophrenia, for which a consensus has been lacking.
METHODS: A PubMed search was conducted using keywords 'outcome', 'rating scales' and 'schizophrenia'. Studies published in 1999, 2004 and 2009 were examined to globally see if a trend has changed over the last decade.
RESULTS: One-hundred fifty articles were inspected. As for psychopathology, the positive and negative syndrome scale (PANSS) has been by far the most frequently utilized scale (46%, 79%, and 78% in the respective years), followed by the brief psychiatric rating scale. Affective/anxiety symptoms have been only rarely recorded Extrapyramidal symptoms have been assessed mostly with the Simpson Angus scale (SAS), more frequently in combination with the abnormal involuntary movement scale (AIMS) and Barnes akathisia scale (BARS) recently. Non-motor adverse effects have been typically reported without a usage of formal rating scales. Depending on the interest of investigation, other critical domains of the illness including functioning, cognition and subjective perspectives have been sporadically reported through the rating scales. The assessment scales were similarly utilized across the years, except for a numerical rise in scale utilization to rate the latter three domains in 2009.
CONCLUSIONS: The PANSS and set of AIMS, BARS and SAS, which are expected to take about 60 minutes to complete, are frequently utilized and may be regarded as a 'standard' in clinical trials for schizophrenia. Clinical implication of the findings and practical challenges with the existing scales are discussed.
Stroup TS.
Heterogeneity of treatment effects in schizophrenia.
Am J Med. 2007 Apr;120(4 Suppl 1):S26-31. doi: 10.1016/j.amjmed.2007.02.005.
Abstract/Text
The treatment of mental illness presents an opportunity to examine the heterogeneity of treatment effects. The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial was sponsored by the National Institute of Mental Health (NIMH) to evaluate the effectiveness of antipsychotic medications for schizophrenia in broad patient populations and in scenarios representative of standard clinical practice. Trial inclusion criteria were broad and exclusion criteria were minimal, allowing for a heterogeneous study population. The majority of patients in each phase 1 treatment group discontinued their randomly assigned treatment owing to inadequate efficacy, intolerable side effects, or other reasons. Phase 2 of CATIE featured 2 treatment pathways (efficacy and tolerability) with randomized follow-up medication based on the reason for discontinuation of the previous antipsychotic drug. Outcome differences between treatment groups and variable responses to medications across the study suggest why multiple medication trials are common and may be necessary in the treatment of schizophrenia. Collectively, the CATIE results highlight variable response in the treatment of schizophrenia and demonstrate the need for individualized therapy based on variations in drug efficacy and tolerability among patients.
Taipale H, Schneider-Thoma J, Pinzón-Espinosa J, Radua J, Efthimiou O, Vinkers CH, Mittendorfer-Rutz E, Cardoner N, Pintor L, Tanskanen A, Tomlinson A, Fusar-Poli P, Cipriani A, Vieta E, Leucht S, Tiihonen J, Luykx JJ.
Representation and Outcomes of Individuals With Schizophrenia Seen in Everyday Practice Who Are Ineligible for Randomized Clinical Trials.
JAMA Psychiatry. 2022 Mar 1;79(3):210-218. doi: 10.1001/jamapsychiatry.2021.3990.
Abstract/Text
IMPORTANCE: Most evidence about efficacy and safety of antipsychotics in schizophrenia spectrum disorders relies on randomized clinical trials (RCTs). However, owing to their strict eligibility criteria, RCTs represent only a part of the real-world population (ie, unselected patients seen in everyday clinical practice), which may result in an efficacy-effectiveness gap.
OBJECTIVE: To quantify the proportion of real-world individuals with schizophrenia spectrum disorders who would be ineligible for participation in RCTs, and to explore whether clinical outcomes differ between eligible and ineligible individuals.
DESIGN, SETTING, AND PARTICIPANTS: This study applied eligibility criteria typically used in RCTs for relapse prevention in schizophrenia spectrum disorders to real-world populations. Individuals with diagnoses of schizophrenia spectrum disorders recorded in national patient registries in Finland and Sweden were identified. Individuals who had used antipsychotics continuously for 12 weeks in outpatient care were selected. Individuals were followed up for up to 1 year while they were receiving maintenance treatment with any second-generation antipsychotic (excluding clozapine). Follow-up was censored at treatment discontinuation, initiation of add-on antipsychotics, death, and end of database linkage.
MAIN OUTCOMES AND MEASURES: Proportions of RCT-ineligible individuals with schizophrenia spectrum disorders owing to any and specific RCT exclusion criteria. The risk of hospitalization due to psychosis within 1-year follow-up in ineligible vs eligible persons were compared using hazard ratios (HR) and corresponding 95% CIs.
RESULTS: The mean (SD) age in the Finnish cohort (n = 17 801) was 47.5 (13.8) years and 8972 (50.4%) were women; the mean (SD) age in the Swedish cohort (n = 7458) was 44.8 (12.5) years and 3344 (44.8%) were women. A total of 20 060 individuals (79%) with schizophrenia spectrum disorders would be ineligible for RCTs (Finnish cohort: 14 221 of 17 801 [79.9%]; Swedish cohort: 5839 of 7458 [78.3%]). Most frequent reasons for ineligibility were serious somatic comorbidities and concomitant antidepressant/mood stabilizer use. Risks of hospitalization due to psychosis was higher among ineligible than eligible individuals (Finnish cohort: 18.4% vs 17.2%; HR, 1.14 [95% CI, 1.04-1.24]; Swedish cohort: 20.1% vs 14.8%; HR, 1.47 [95% CI, 1.28-1.92]). The largest risks of hospitalization due to psychosis were observed in individuals ineligible owing to treatment resistance, tardive dyskinesia, and history of suicide attempts. Finally, with more ineligibility criteria met, larger risks of hospitalization due to psychosis were observed in both countries.
CONCLUSIONS AND RELEVANCE: RCTs may represent only about a fifth of real-world individuals with schizophrenia spectrum disorders. Underrepresented (ineligible) patients with schizophrenia spectrum disorders have moderately higher risks of admission due to psychosis while receiving maintenance treatment than RCT-eligible patients. These findings set the stage for future studies targeting real-world populations currently not represented by RCTs.
Suzuki T, Takeuchi H, Nakajima S, Nomura K, Uchida H, Yagi G, Watanabe K, Kashima H.
Magnitude of rater differences in assessment scales for schizophrenia.
J Clin Psychopharmacol. 2010 Oct;30(5):607-11. doi: 10.1097/JCP.0b013e3181f0bae1.
Abstract/Text
The magnitude of rater differences, instead of interrater reliability, in the assessment scales of schizophrenia has rarely been investigated and was therefore addressed in this study. Thirty-six patients with schizophrenia were independently assessed by 4 expert physicians, using clinical rating scales including the Positive and Negative Syndrome Scale (PANSS). The scores obtained by the physician in charge (PIC), who had a long close contact with the patients, served as the referent answer for the purpose of this study. The scores rated by the other 3 non-PIC psychiatrists, who had a first formal examination with them, were evaluated for percentage deviance from the referent answer. The results showed that the PIC raters endorsed the numerically highest score in 20 (56%) of the 36 patients, whereas they rated the lowest in only 2 (6%) in the PANSS total score. The non-PIC assessors on the average underrated the PANSS total score by 10%, and such a tendency of underestimating the severity was noted across other clinical scales. Furthermore, the PANSS total score by one of the non-PIC physicians was deviant from the referent answer by at least 20% in 15 (42%) of 36 instances. Importantly, this magnitude of deviance was noted in the context of an intraclass correlation coefficient of 0.92. This unique investigation disclosed clinically pertinent differences among raters, even under an excellent interrater reliability. The magnitude of differences described herein seems to be an underestimation, and the baseline scores by the independent new raters might need to be corrected for those by the PICs.
Suzuki T, Uchida H, Sakurai H, Ishizuki T, Tsunoda K, Takeuchi H, Mimura M.
Relationships between global assessment of functioning and other rating scales in clinical trials for schizophrenia.
Psychiatry Res. 2015 Jun 30;227(2-3):265-9. doi: 10.1016/j.psychres.2015.02.024. Epub 2015 Apr 1.
Abstract/Text
The relationship between the Global Assessment of Functioning (GAF) with other scales in schizophrenia has rarely been investigated. A systematic literature search was conducted to identify articles that reported the GAF score together with scores in the Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression (CGI) or Brief Psychiatric Rating Scale (BPRS), using MEDLINE, EMBASE and PsycINFO, with keywords of schizophrenia, clinical trial and global assessment of functioning (last search 30 June 2013). Correlational analyses with weighting by the study participant numbers across these rating scales were performed. In 40 clinical trials (n=8000) that reported cross-sectional data on the GAF and PANSS, a significant but modest correlation was noted (Pearson׳s r=-0.401, p<0.0001). Furthermore, a correlation between the GAF and CGI-severity (CGI-S) at study baseline in 38 studies (n=11,315) was robust (r=-0.893, p<0.0001). In longitudinal studies, changes in the GAF scores were negatively correlated with those in the PANSS as well as CGI-S scores (p<0.0001 for both). Data on the BPRS were all statistically significant although relatively scarce. While optimal degree of concordance is undetermined among psychiatric scales that are presumed to be measuring different but overlapping constructs, this study found significant correlations in the GAF and CGI-S or PANSS, both cross-sectionally and longitudinally. The GAF-CGI-S relationship was especially tighter, making it a reliable clinical indicator.
Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
Hjorthøj C, Stürup AE, McGrath JJ, Nordentoft M.
Years of potential life lost and life expectancy in schizophrenia: a systematic review and meta-analysis.
Lancet Psychiatry. 2017 Apr;4(4):295-301. doi: 10.1016/S2215-0366(17)30078-0. Epub 2017 Feb 22.
Abstract/Text
BACKGROUND: Several studies and meta-analyses have shown that mortality in people with schizophrenia is higher than that in the general population but have used relative measures, such as standardised mortality ratios. We did a systematic review and meta-analysis to estimate years of potential life lost and life expectancy in schizophrenia, which are more direct, absolute measures of increased mortality.
METHODS: We searched MEDLINE, PsycINFO, Embase, Cinahl, and Web of Science for published studies on years of potential life lost and life expectancy in schizophrenia. Data from individual studies were combined in meta-analyses as weighted averages. We did subgroup analyses for sex, geographical region, timing of publication, and risk of bias (estimated with the Newcastle-Ottawa Scale).
FINDINGS: We identified 11 studies in 13 publications covering all inhabited continents except South America (Africa n=1, Asia n=1, Australia n=1, Europe n=7, and North America n=3) that involved up to 247 603 patients. Schizophrenia was associated with a weighted average of 14·5 years of potential life lost (95% CI 11·2-17·8), and was higher for men than women (15·9, 13·8-18·0 vs 13·6, 11·4-15·8). Loss was least in the Asian study and greatest in Africa. The overall weighted average life expectancy was 64·7 years (95% CI 61·1-71·3), and was lower for men than women (59·9 years, 95% CI 55·5-64·3 vs 67·6 years, 63·1-72·1). Life expectancy was lowest in Asia and Africa. Timing of publication and risk of bias had little effect on results.
INTERPRETATION: The effects of schizophrenia on years potential life lost and life expectancy seem to be substantial and not to have lessened over time. Development and implementation of interventions and initiatives to reduce this mortality gap are urgently needed.
FUNDING: None.
Copyright © 2017 Elsevier Ltd. All rights reserved.
Olfson M, Blanco C, Liu SM, Wang S, Correll CU.
National trends in the office-based treatment of children, adolescents, and adults with antipsychotics.
Arch Gen Psychiatry. 2012 Dec;69(12):1247-56. doi: 10.1001/archgenpsychiatry.2012.647.
Abstract/Text
CONTEXT Although antipsychotic treatment has recently increased, little is known about how this development has differentially affected the office-based care of adults and young people in the United States. OBJECTIVE To compare national trends and patterns in antipsychotic treatment of adults and youths in office-based medical practice. DESIGN Trends between 1993 and 2009 in visits with antipsychotics for children (0-13 years), adolescents (14-20 years), and adults (≥21 years) are described on a per population basis and as a proportion of total medical office visits. Background and clinical characteristics of recent (2005-2009) antipsychotic visits are also compared by patient age. SETTING Outpatient visits to physicians in office-based practice. PARTICIPANTS Visits from the 1993-2009 National Ambulatory Medical Care Surveys (N = 484 889). MAIN OUTCOME MEASURES Visits with a prescription of antipsychotic medications. RESULTS Between 1993-1998 and 2005-2009, visits with a prescription of antipsychotic medications per 100 persons increased from 0.24 to 1.83 for children, 0.78 to 3.76 for adolescents, and 3.25 to 6.18 for adults. The proportion of total visits that included a prescription of antipsychotics increased during this period from 0.16% to 1.07% for youths and from 0.88% to 1.73% for adults. From 2005 to 2009, disruptive behavior disorders were the most common diagnoses in child and adolescent antipsychotic visits, accounting for 63.0% and 33.7%, respectively, while depression (21.2%) and bipolar disorder (20.2%) were the 2 most common diagnoses in adult antipsychotic visits. Psychiatrists provided a larger proportion of the antipsychotic visits for children (67.7%) and adolescents (71.6%) than to adults (50.3%) (P < .001). From 2005 to 2009, antipsychotics were included in 28.8% of adult visits and 31.1% of youth visits to psychiatrists. CONCLUSIONS On a population basis, adults make considerably more medical visits with a prescription of antipsychotics than do adolescents or children. Yet antipsychotic treatment has increased especially rapidly among young people, and recently antipsychotics have been prescribed in approximately the same proportion of youth and adult visits to psychiatrists.
Leucht S, Tardy M, Komossa K, Heres S, Kissling W, Salanti G, Davis JM.
Antipsychotic drugs versus placebo for relapse prevention in schizophrenia: a systematic review and meta-analysis.
Lancet. 2012 Jun 2;379(9831):2063-71. doi: 10.1016/S0140-6736(12)60239-6. Epub 2012 May 3.
Abstract/Text
BACKGROUND: Relapse prevention with antipsychotic drugs compared with placebo in patients with schizophrenia has not been sufficiently addressed by previous systematic reviews. We aimed to assess the association between such drugs and various outcomes in patients with schizophrenia to resolve controversial issues.
METHODS: We searched the Cochrane Schizophrenia Group's specialised register for reports published before Nov 11, 2008; and PubMed, Embase, and ClinicalTrials.gov for those before June 8, 2011. We also contacted pharmaceutical companies and searched the reference lists of included studies and previous reviews. Randomised trials of patients with schizophrenia continued on or withdrawn from any antipsychotic drug regimen after stabilisation were eligible. Our primary outcome was relapse between 7 and 12 months. We also examined safety and various functional outcomes. We used the random effects model and verified results for the primary outcome with a fixed effects model. Heterogeneity was investigated with subgroup and meta-regression analyses.
FINDINGS: We identified 116 suitable reports from 65 trials, with data for 6493 patients. Antipsychotic drugs significantly reduced relapse rates at 1 year (drugs 27%vs placebo 64%; risk ratio [RR] 0·40, 95% CI 0·33-0·49; number needed to treat to benefit [NNTB] 3, 95% CI 2-3). Fewer patients given antipsychotic drugs than placebo were readmitted (10%vs 26%; RR 0·38, 95% CI 0·27-0·55; NNTB 5, 4-9), but less than a third of relapsed patients had to be admitted. Limited evidence suggested better quality of life (standardised mean difference -0·62, 95% CI -1·15 to -0·09) and fewer aggressive acts (2%vs 12%; RR 0·27, 95% CI 0·15-0·52; NNTB 11, 6-100) with antipsychotic drugs than with placebo. Employment data were scarce and too few deaths were reported to allow significant differences to be identified. More patients given antipsychotic drugs than placebo gained weight (10%vs 6%; RR 2·07, 95% CI 2·31-3·25), had movement disorders (16%vs 9%; 1·55, 1·25-1·93), and experienced sedation (13%vs 9%; 1·50, 1·22-1·84). Substantial heterogeneity in size of effect was recorded. In subgroup analyses, number of episodes, whether patients were in remission, abrupt or gradual withdrawal of treatment, length of stability before trial entry, first-generation or second-generation drugs, and allocation concealment method did not significantly affect relapse risk. Depot preparations reduced relapse (RR 0·31, 95% CI 0·21-0·41) more than did oral drugs (0·46, 0·37-0·57; p=0·03); depot haloperidol (RR 0·14, 95% CI 0·04-0·55) and fluphenazine (0·23, 0·14-0·39) had the greatest effects. The effects of antipsychotic drugs were greater in two unblinded trials (0·26, 0·17-0·39) than in most blinded studies (0·42, 0·35-0·51; p= 0·03). In a meta-regression, the difference between drug and placebo decreased with study length.
INTERPRETATION: Maintenance treatment with antipsychotic drugs benefits patients with schizophrenia. The advantages of these drugs must be weighed against their side-effects. Future studies should focus on outcomes of social participation and clarify the long-term morbidity and mortality of these drugs.
FUNDING: German Ministry of Education and Research.
Copyright © 2012 Elsevier Ltd. All rights reserved.
Takeuchi H, Siu C, Remington G, Fervaha G, Zipursky RB, Foussias G, Agid O.
Does relapse contribute to treatment resistance? Antipsychotic response in first- vs. second-episode schizophrenia.
Neuropsychopharmacology. 2019 May;44(6):1036-1042. doi: 10.1038/s41386-018-0278-3. Epub 2018 Nov 22.
Abstract/Text
Although some studies have suggested that relapse may be associated with antipsychotic treatment resistance in schizophrenia, the number and quality of studies is limited. The current analysis included patients with a diagnosis of first-episode schizophrenia or schizoaffective disorder who met the following criteria: (1) referral to the First-Episode Psychosis Program between 2003 and 2013; (2) treatment with an oral second-generation antipsychotic according to a standardized treatment algorithm; (3) positive symptom remission; (4) subsequent relapse (i.e., second episode) in association with non-adherence; and (5) reintroduction of antipsychotic treatment with the same agent used to achieve response in the first episode. The following outcomes were used as an index of antipsychotic treatment response: changes in the brief psychiatric rating scale (BPRS) total and positive symptom scores and number of patients who achieved positive symptom remission and 20 and 50% response. A total of 130 patients were included in the analyses. Although all patients took the same antipsychotic in both episodes, there were significant episode-by-time interactions for all outcomes of antipsychotic treatment response over 1 year in favor of the first episode compared to the second episode (50% response rate: 48.7 vs. 10.4% at week 7; 88.2 vs. 27.8% at week 27, respectively). Although antipsychotic doses in the second episode were significantly higher than those in the first episode, results remained unchanged after adjusting for antipsychotic dose. The present findings suggest that antipsychotic treatment response is reduced or delayed in the face of relapse following effective treatment of the first episode of schizophrenia.
Emsley R, Chiliza B, Asmal L, Harvey BH.
The nature of relapse in schizophrenia.
BMC Psychiatry. 2013 Feb 8;13:50. doi: 10.1186/1471-244X-13-50. Epub 2013 Feb 8.
Abstract/Text
BACKGROUND: Multiple relapses characterise the course of illness in most patients with schizophrenia, yet the nature of these episodes has not been extensively researched and clinicians may not always be aware of important implications.
METHODS: We critically review selected literature regarding the nature and underlying neurobiology of relapse.
RESULTS: Relapse rates are very high when treatment is discontinued, even after a single psychotic episode; a longer treatment period prior to discontinuation does not reduce the risk of relapse; many patients relapse soon after treatment reduction and discontinuation; transition from remission to relapse may be abrupt and with few or no early warning signs; once illness recurrence occurs symptoms rapidly return to levels similar to the initial psychotic episode; while most patients respond promptly to re-introduction of antipsychotic treatment after relapse, the response time is variable and notably, treatment failure appears to emerge in about 1 in 6 patients. These observations are consistent with contemporary thinking on the dopamine hypothesis, including the aberrant salience hypothesis.
CONCLUSIONS: Given the difficulties in identifying those at risk of relapse, the ineffectiveness of rescue medications in preventing full-blown psychotic recurrence and the potentially serious consequences, adherence and other factors predisposing to relapse should be a major focus of attention in managing schizophrenia. The place of antipsychotic treatment discontinuation in clinical practice and in placebo-controlled clinical trials needs to be carefully reconsidered.
Sampson S, Mansour M, Maayan N, Soares-Weiser K, Adams CE.
Intermittent drug techniques for schizophrenia.
Cochrane Database Syst Rev. 2013 Jul 20;(7):CD006196. doi: 10.1002/14651858.CD006196.pub2. Epub 2013 Jul 20.
Abstract/Text
BACKGROUND: Antipsychotic medication is considered the mainstay of treatment for schizophrenia and is generally regarded as highly effective, especially in controlling positive symptoms. However, long-term antipsychotic exposure has been associated with a range of adverse effects, including extra-pyramidal symptoms (EPS), neuroleptic malignant syndrome (NMS), tardive dyskinesia and death. Intermittent drug techniques refers to the 'use of medication only during periods of incipient relapse or symptom exacerbation rather than continuously'. The aim is to reduce the risk of typical adverse effects of antipsychotics by 'reducing long-term medication exposure for patients who are receiving maintenance treatment while limiting the risk of relapse', with a further goal of improving social functioning resulting from the reduction of antipsychotic-induced side effects
OBJECTIVES: To review the effects of different intermittent drug techniques compared with maintenance treatment in people with schizophrenia or related disorders.
SEARCH METHODS: We searched The Cochrane Schizophrenia Group Trials Register (April 2012) and supplemented this by contacting relevant study authors, handsearching relevant intermittent drug treatment articles and manually searching reference lists.
SELECTION CRITERIA: All randomised controlled trials (RCTs) that compared intermittent drug techniques with standard maintenance therapy for people with schizophrenia. Primary outcomes of interest were relapse and hospitalisation.
DATA COLLECTION AND ANALYSIS: At least two review authors selected trials, assessed quality and extracted data. We calculated risk ratios (RR) and 95% confidence intervals (CI) of homogeneous dichotomous data and estimated the 95% confidence interval (CI) around this. For non-skewed continuous endpoint data extracted from valid scales, we estimated mean difference (MD) between groups with a 95% CI. Where data displayed heterogeneity, these were analysed using a random-effects model. Skewed data are presented in tables. We assessed overall quality for clinically important outcomes using the GRADE approach.
MAIN RESULTS: Of 241 records retrieved by the search, 17 trials conducted between 1961 and 2011, involving 2252 participants with follow-up from six weeks to two years, were included. Homogenous data demonstrated that instances of relapse were significantly higher in people receiving any intermittent drug treatment in the long term (n = 436, 7 RCTs, RR 2.46, 95% CI 1.70 to 3.54, moderate quality evidence). Intermittent treatment was shown to be more effective than placebo, however, and demonstrated that significantly less people receiving intermittent antipsychotics experienced full relapse by medium term (n = 290, 2 RCTs, RR 0.37, 95% CI 0.24 to 0.58, very low quality evidence). Hospitalisation rates were higher for people receiving any intermittent drug treatment by long term (n = 626, 5 RCTs, RR 1.65, 95% CI 1.33 to 2.06, moderate quality evidence). Results demonstrated little difference in instances of tardive dyskinesia in groups with any intermittent drug technique versus maintenance therapy, with equivocal results (displaying slight heterogeneity) at long term (n = 165, 4 RCTs, RR 1.15, 95% CI 0.58 to 2.30, low quality evidence).
AUTHORS' CONCLUSIONS: Results of this review support the existing evidence that intermittent antipsychotic treatment is not as effective as continuous, maintained antipsychotic therapy in preventing relapse in people with schizophrenia. More research is needed to assess any potential benefits or harm of intermittent treatment regarding adverse effects typically associated with maintained antipsychotic treatment, as well as any cost-effectiveness of this experimental treatment.
Uchida H, Suzuki T, Takeuchi H, Arenovich T, Mamo DC.
Low dose vs standard dose of antipsychotics for relapse prevention in schizophrenia: meta-analysis.
Schizophr Bull. 2011 Jul;37(4):788-99. doi: 10.1093/schbul/sbp149. Epub 2009 Nov 27.
Abstract/Text
BACKGROUND: It remains unknown as to whether the antipsychotic dose needed for the acute-phase treatment of schizophrenia is also necessary for relapse prevention.
AIM: To compare the efficacy between standard dose [(World Health Organization daily defined dose (DDD)] vs low dose (≥50% to <1 DDD) or very low dose (<50% DDD) for relapse prevention in schizophrenia.
DATA SOURCE: Double-blind, randomized, controlled trials with a follow-up duration of ≥24 weeks, including ≥2 dosage groups of the same antipsychotic drug for relapse prevention in schizophrenia, were searched using MEDLINE, the Cochrane Central Register of Controlled Trials, and EMBASE (last search: August 2009).
DATA EXTRACTION: Data on overall treatment failure, hospitalization, relapse, and dropouts due to side effects were extracted and combined in a meta-analysis.
DATA SYNTHESIS: Thirteen studies with 1395 subjects were included in this meta-analysis. Compared with the standard-dose treatment, the low-dose therapy did not show any statistically significant difference in overall treatment failure or hospitalization, while the standard dose showed a trend-level (P = .05) superiority in risk of relapse. The very low-dose group was inferior to the standard-dose group in all efficacy parameters. No significant difference was found in the rate of dropouts due to side effects between either standard dose vs low dose or very low dose.
CONCLUSIONS: Although antipsychotic treatment with ≥50% to <1 DDD may be as effective as standard-dose therapy, there are insufficient clinical trial data to draw firm conclusions on standard- vs low-dose maintenance antipsychotic therapy for schizophrenia.
Antipsychotic treatment in the maintenance phase of schizophrenia: An updated systematic review of the guidelines and algorithms. - PubMed - NCBI [Internet]. [cited 2020 Jan 8]. Available from: https://www.ncbi.nlm.nih.gov/pubmed/?term=31784340
Takeuchi H, Suzuki T, Remington G, Bies RR, Abe T, Graff-Guerrero A, Watanabe K, Mimura M, Uchida H.
Effects of risperidone and olanzapine dose reduction on cognitive function in stable patients with schizophrenia: an open-label, randomized, controlled, pilot study.
Schizophr Bull. 2013 Sep;39(5):993-8. doi: 10.1093/schbul/sbt090. Epub 2013 Jul 1.
Abstract/Text
Impact of dose reduction of atypical antipsychotics on cognitive function has not been investigated in stable patients with schizophrenia. In this open-label, 28-week, randomized controlled trial, stable patients with schizophrenia treated with risperidone or olanzapine were randomly assigned to the reduction group (dose reduced by 50% in 4 weeks and then maintained) or maintenance group (dose kept constant). Assessments at baseline and week 28 included the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Positive and Negative Syndrome Scale (PANSS), and Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS). Sixty-one patients were enrolled; 2 of 31 (6.5%) and 5 of 30 (16.7%) patients prematurely withdrew from the study in the reduction and maintenance groups, respectively. While no significant differences in change in the PANSS total score were observed between the 2 groups, the reduction group showed significantly greater improvements in the RBANS and DIEPSS total scores compared with the maintenance group (mean ± SD, +7.0±7.1 vs -0.1±8.0, P < .001; -0.9±1.7 vs +0.1±1.2, P = .010, respectively). This 6-month pilot study suggests that risperidone or olanzapine dose reduction of 50% can improve cognitive function for stable patients with schizophrenia. Due to the open-label design, small sample size, and short study duration, however, there is a need to confirm the finding through double-blind, larger scale trials with longer follow-up periods. Moreover, potential risks of relapse following antipsychotic dose reduction should be thoroughly investigated in longer term studies.
Suzuki T.
A further consideration on long-acting injectable versus oral antipsychotics in the treatment of schizophrenia: a narrative review and critical appraisal.
Expert Opin Drug Deliv. 2016;13(2):253-64. doi: 10.1517/17425247.2016.1115479. Epub 2015 Dec 4.
Abstract/Text
INTRODUCTION: Many patients with schizophrenia exhibit difficulties in maintaining adherence to oral antipsychotics, calling for more reliable drug delivery systems.
AREAS COVERED: While non-randomized studies have indicated consistent effectiveness of long-acting injectable antipsychotics (LAIs) over oral counterparts to prevent negative consequences such as relapse, hospitalization and all-cause discontinuation, efficacy results from randomized controlled comparative trials have not been that impressive. The results rely heavily on the study design and the population studied. Further, LAIs are frequently used as an adjunctive to ongoing other antipsychotics or psychotropics, but not solely, in the real world.
EXPERT OPINION: To put LAI-oral comparisons into clinical context, the following information is urgently necessary: (1) How LAIs compare with each other in head-to-head comparisons? (2) How effective is it to switch among different LAIs? (3) How early in the treatment stage should LAIs be utilized? (4) How long the interval of LAI administration can be extended? (5) How LAIs compare with clozapine in head-to-head comparisons? (6) How effective are LAIs when clozapine is ineffective? (7) How effective is clozapine when LAIs are ineffective? (8) How effective is it to combine clozapine and LAIs when neither is effective alone? This paper narratively discusses these critical perspectives.
Leucht S, Corves C, Arbter D, Engel RR, Li C, Davis JM.
Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis.
Lancet. 2009 Jan 3;373(9657):31-41. doi: 10.1016/S0140-6736(08)61764-X. Epub 2008 Dec 6.
Abstract/Text
BACKGROUND: Because of the debate about whether second-generation antipsychotic drugs are better than first-generation antipsychotic drugs, we did a meta-analysis of randomised controlled trials to compare the effects of these two types of drugs in patients with schizophrenia.
METHODS: We compared nine second-generation antipsychotic drugs with first-generation drugs for overall efficacy (main outcome), positive, negative and depressive symptoms, relapse, quality of life, extrapyramidal side-effects, weight gain, and sedation.
FINDINGS: We included 150 double-blind, mostly short-term, studies, with 21 533 participants. We excluded open studies because they systematically favoured second-generation drugs. Four of these drugs were better than first-generation antipsychotic drugs for overall efficacy, with small to medium effect sizes (amisulpride -0.31 [95% CI -0.44 to -0.19, p<0.0001], clozapine -0.52 [-0.75 to -0.29, p<0.0001], olanzapine -0.28 [-0.38 to -0.18, p<0.0001], and risperidone -0.13 [-0.22 to -0.05, p=0.002]). The other second-generation drugs were not more efficacious than the first-generation drugs, even for negative symptoms. Therefore efficacy on negative symptoms cannot be a core component of atypicality. Second-generation antipsychotic drugs induced fewer extrapyramidal side-effects than did haloperidol (even at low doses). Only a few have been shown to induce fewer extrapyramidal side-effects than low-potency first-generation antipsychotic drugs. With the exception of aripiprazole and ziprasidone, second-generation antipsychotic drugs induced more weight gain, in various degrees, than did haloperidol but not than low-potency first-generation drugs. The second-generation drugs also differed in their sedating properties. We did not note any consistent effects of moderator variables, such as industry sponsorship, comparator dose, or prophylactic antiparkinsonian medication.
INTERPRETATION: Second-generation antipsychotic drugs differ in many properties and are not a homogeneous class. This meta-analysis provides data for individualised treatment based on efficacy, side-effects, and cost.
Schneider-Thoma J, Chalkou K, Dörries C, Bighelli I, Ceraso A, Huhn M, Siafis S, Davis JM, Cipriani A, Furukawa TA, Salanti G, Leucht S.
Comparative efficacy and tolerability of 32 oral and long-acting injectable antipsychotics for the maintenance treatment of adults with schizophrenia: a systematic review and network meta-analysis.
Lancet. 2022 Feb 26;399(10327):824-836. doi: 10.1016/S0140-6736(21)01997-8.
Abstract/Text
BACKGROUND: Schizophrenia is a common, severe, and usually chronic disorder. Maintenance treatment with antipsychotic drugs can prevent relapse but also causes side-effects. We aimed to compare the efficacy and tolerability of antipsychotics as maintenance treatment for non-treatment resistant patients with schizophrenia.
METHODS: In this systematic review and network meta-analysis, we searched, without language restrictions, the Cochrane Schizophrenia Group's specialised register between database inception and April 27, 2020, PubMed from April 1, 2020, to Jan 15, 2021, and the lists of included studies from related systematic reviews. We included randomised controlled trials (RCTs; ≥12 weeks of follow-up) that recruited adult participants with schizophrenia or schizoaffective disorder with stable symptoms who were treated with antipsychotics (monotherapy; oral or long-acting injectable) or placebo. We excluded RCTs of participants with specific comorbidities or treatment resistance. In duplicate, two authors independently selected eligible RCTs and extracted aggregate data. The primary outcome was the number of participants who relapsed and was analysed by random-effects, Bayesian network meta-analyses. The study was registered on PROSPERO, CRD42016049022.
FINDINGS: We identified 4157 references through our search, from which 501 references on 127 RCTs of 32 antipsychotics (comprising 18 152 participants) were included. 100 studies including 16 812 participants and 30 antipsychotics contributed to our network meta-analysis of the primary outcome. All antipsychotics had risk ratios (RRs) less than 1·00 when compared with placebo for relapse prevention and almost all had 95% credible intervals (CrIs) excluding no effect. RRs ranged from 0·20 (95% CrI 0·05-0·41) for paliperidone oral to 0·65 (0·16-1·14) for cariprazine oral (moderate-to-low confidence in estimates). Generally, we interpret that there was no clear evidence for the superiority of specific antipsychotics in terms of relapse prevention because most comparisons between antipsychotics included a probability of no difference.
INTERPRETATION: As we found no clear differences between antipsychotics for relapse prevention, we conclude that the choice of antipsychotic for maintenance treatment should be guided mainly by their tolerability.
FUNDING: The German Ministry of Education and Research and Oxford Health Biomedical Research Centre.
Copyright © 2022 Elsevier Ltd. All rights reserved.
Leucht S, Leucht C, Huhn M, Chaimani A, Mavridis D, Helfer B, Samara M, Rabaioli M, Bächer S, Cipriani A, Geddes JR, Salanti G, Davis JM.
Sixty Years of Placebo-Controlled Antipsychotic Drug Trials in Acute Schizophrenia: Systematic Review, Bayesian Meta-Analysis, and Meta-Regression of Efficacy Predictors.
Am J Psychiatry. 2017 Oct 1;174(10):927-942. doi: 10.1176/appi.ajp.2017.16121358. Epub 2017 May 25.
Abstract/Text
OBJECTIVE: Antipsychotic drug efficacy may have decreased over recent decades. The authors present a meta-analysis of all placebo-controlled trials in patients with acute exacerbations of schizophrenia, and they investigate which trial characteristics have changed over the years and which are moderators of drug-placebo efficacy differences.
METHOD: The search included multiple electronic databases. The outcomes were overall efficacy (primary outcome); responder and dropout rates; positive, negative, and depressive symptoms; quality of life; functioning; and major side effects. Potential moderators of efficacy were analyzed by meta-regression.
RESULTS: The analysis included 167 double-blind randomized controlled trials with 28,102 mainly chronic participants. The standardized mean difference (SMD) for overall efficacy was 0.47 (95% credible interval 0.42, 0.51), but accounting for small-trial effects and publication bias reduced the SMD to 0.38. At least a "minimal" response occurred in 51% of the antipsychotic group versus 30% in the placebo group, and 23% versus 14% had a "good" response. Positive symptoms (SMD 0.45) improved more than negative symptoms (SMD 0.35) and depression (SMD 0.27). Quality of life (SMD 0.35) and functioning (SMD 0.34) improved even in the short term. Antipsychotics differed substantially in side effects. Of the response predictors analyzed, 16 trial characteristics changed over the decades. However, in a multivariable meta-regression, only industry sponsorship and increasing placebo response were significant moderators of effect sizes. Drug response remained stable over time.
CONCLUSIONS: Approximately twice as many patients improved with antipsychotics as with placebo, but only a minority experienced a good response. Effect sizes were reduced by industry sponsorship and increasing placebo response, not decreasing drug response. Drug development may benefit from smaller samples but better-selected patients.
Andreasen NC, Carpenter WT Jr, Kane JM, Lasser RA, Marder SR, Weinberger DR.
Remission in schizophrenia: proposed criteria and rationale for consensus.
Am J Psychiatry. 2005 Mar;162(3):441-9. doi: 10.1176/appi.ajp.162.3.441.
Abstract/Text
New advances in the understanding of schizophrenia etiology, course, and treatment have increased interest on the part of patients, families, advocates, and professionals in the development of consensus-defined standards for clinical status and improvement, including illness remission and recovery. As demonstrated in the area of mood disorders, such standards provide greater clarity around treatment goals, as well as an improved framework for the design and comparison of investigational trials and the subsequent evaluation of the effectiveness of interventions. Unlike the approach to mood disorders, however, the novel application of the concept of standard outcome criteria to schizophrenia must reflect the wide heterogeneity of its long-term course and outcome, as well as the variable effects of different treatments on schizophrenia symptoms. As an initial step in developing operational criteria, an expert working group reviewed available definitions and assessment instruments to provide a conceptual framework for symptomatic, functional, and cognitive domains in schizophrenia as they relate to remission of illness. The first consensus-based operational criteria for symptomatic remission in schizophrenia are based on distinct thresholds for reaching and maintaining improvement, as opposed to change criteria, allowing for alignment with traditional concepts of remission in both psychiatric and nonpsychiatric illness. This innovative approach for standardizing the definition for outcome in schizophrenia will require further examination of its validity and utility, as well as future refinement, particularly in relation to psychosocial and cognitive function and dysfunction. These criteria should facilitate research and support a positive, longer-term approach to studying outcome in patients with schizophrenia.
Howes OD, Kambeitz J, Kim E, Stahl D, Slifstein M, Abi-Dargham A, Kapur S.
The nature of dopamine dysfunction in schizophrenia and what this means for treatment.
Arch Gen Psychiatry. 2012 Aug;69(8):776-86. doi: 10.1001/archgenpsychiatry.2012.169.
Abstract/Text
CONTEXT: Current drug treatments for schizophrenia are inadequate for many patients, and despite 5 decades of drug discovery, all of the treatments rely on the same mechanism: dopamine D(2) receptor blockade. Understanding the pathophysiology of the disorder is thus likely to be critical to the rational development of new treatments for schizophrenia.
OBJECTIVE: To investigate the nature of the dopaminergic dysfunction in schizophrenia using meta-analysis of in vivo studies.
DATA SOURCES: The MEDLINE, EMBASE, and PsycINFO databases were searched for studies from January 1, 1960, to July 1, 2011.
STUDY SELECTION: A total of 44 studies were identified that compared 618 patients with schizophrenia with 606 controls, using positron emission tomography or single-photon emission computed tomography to measure in vivo striatal dopaminergic function.
DATA EXTRACTION: Demographic, clinical, and imaging variables were extracted from each study, and effect sizes were determined for the measures of dopaminergic function. Studies were grouped into those of presynaptic function and those of dopamine transporter and receptor availability. Sensitivity analyses were conducted to explore the consistency of effects and the effect of clinical and imaging variables.
DATA SYNTHESIS: There was a highly significant elevation (P.<001) in presynaptic dopaminergic function in schizophrenia with a large effect size (Cohen d=0.79). There was no evidence of alterations in dopamine transporter availability. There was a small elevation in D(2/3) receptor availability (Cohen d=0.26), but this was not evident in drug-naive patients and was influenced by the imaging approach used.
CONCLUSIONS: The locus of the largest dopaminergic abnormality in schizophrenia is presynaptic, which affects dopamine synthesis capacity, baseline synaptic dopamine levels, and dopamine release. Current drug treatments, which primarily act at D(2/3) receptors, fail to target these abnormalities. Future drug development should focus on the control of presynaptic dopamine synthesis and release capacity.
Huhn M, Nikolakopoulou A, Schneider-Thoma J, Krause M, Samara M, Peter N, Arndt T, Bäckers L, Rothe P, Cipriani A, Davis J, Salanti G, Leucht S.
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 Sep 14;394(10202):939-951. doi: 10.1016/S0140-6736(19)31135-3. Epub 2019 Jul 11.
Abstract/Text
BACKGROUND: Schizophrenia is one of the most common, burdensome, and costly psychiatric disorders in adults worldwide. Antipsychotic drugs are its treatment of choice, but there is controversy about which agent should be used. We aimed to compare and rank antipsychotics by quantifying information from randomised controlled trials.
METHODS: We did a network meta-analysis of placebo-controlled and head-to-head randomised controlled trials and compared 32 antipsychotics. We searched Embase, MEDLINE, PsycINFO, PubMed, BIOSIS, Cochrane Central Register of Controlled Trials (CENTRAL), WHO International Clinical Trials Registry Platform, and ClinicalTrials.gov from database inception to Jan 8, 2019. Two authors independently selected studies and extracted data. We included randomised controlled trials in adults with acute symptoms of schizophrenia or related disorders. We excluded studies in patients with treatment resistance, first episode, predominant negative or depressive symptoms, concomitant medical illnesses, and relapse-prevention studies. Our primary outcome was change in overall symptoms measured with standardised rating scales. We also extracted data for eight efficacy and eight safety outcomes. Differences in the findings of the studies were explored in metaregressions and sensitivity analyses. Effect size measures were standardised mean differences, mean differences, or risk ratios with 95% credible intervals (CrIs). Confidence in the evidence was assessed using CINeMA (Confidence in Network Meta-Analysis). The study protocol is registered with PROSPERO, number CRD42014014919.
FINDINGS: We identified 54 417 citations and included 402 studies with data for 53 463 participants. Effect size estimates suggested all antipsychotics reduced overall symptoms more than placebo (although not statistically significant for six drugs), with standardised mean differences ranging from -0·89 (95% CrI -1·08 to -0·71) for clozapine to -0·03 (-0·59 to 0·52) for levomepromazine (40 815 participants). Standardised mean differences compared with placebo for reduction of positive symptoms (31 179 participants) varied from -0·69 (95% CrI -0·86 to -0·52) for amisulpride to -0·17 (-0·31 to -0·04) for brexpiprazole, for negative symptoms (32 015 participants) from -0·62 (-0·84 to -0·39; clozapine) to -0·10 (-0·45 to 0·25; flupentixol), for depressive symptoms (19 683 participants) from -0·90 (-1·36 to -0·44; sulpiride) to 0·04 (-0·39 to 0·47; flupentixol). Risk ratios compared with placebo for all-cause discontinuation (42 672 participants) ranged from 0·52 (0·12 to 0·95; clopenthixol) to 1·15 (0·36 to 1·47; pimozide), for sedation (30 770 participants) from 0·92 (0·17 to 2·03; pimozide) to 10·20 (4·72 to 29·41; zuclopenthixol), for use of antiparkinson medication (24 911 participants) from 0·46 (0·19 to 0·88; clozapine) to 6·14 (4·81 to 6·55; pimozide). Mean differences compared to placebo for weight gain (28 317 participants) ranged from -0·16 kg (-0·73 to 0·40; ziprasidone) to 3·21 kg (2·10 to 4·31; zotepine), for prolactin elevation (21 569 participants) from -77·05 ng/mL (-120·23 to -33·54; clozapine) to 48·51 ng/mL (43·52 to 53·51; paliperidone) and for QTc prolongation (15 467 participants) from -2·21 ms (-4·54 to 0·15; lurasidone) to 23·90 ms (20·56 to 27·33; sertindole). Conclusions for the primary outcome did not substantially change after adjusting for possible effect moderators or in sensitivity analyses (eg, when excluding placebo-controlled studies). The confidence in evidence was often low or very low.
INTERPRETATION: There 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.
FUNDING: German Ministry of Education and Research and National Institute for Health Research.
Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.
Koblan KS, Kent J, Hopkins SC, Krystal JH, Cheng H, Goldman R, Loebel A.
A Non-D2-Receptor-Binding Drug for the Treatment of Schizophrenia.
N Engl J Med. 2020 Apr 16;382(16):1497-1506. doi: 10.1056/NEJMoa1911772.
Abstract/Text
BACKGROUND: An oral compound, SEP-363856, that does not act on dopamine D2 receptors but has agonist activity at trace amine-associated receptor 1 (TAAR1) and 5-hydroxytryptamine type 1A (5-HT1A) receptors, may represent a new class of psychotropic agent for the treatment of psychosis in schizophrenia.
METHODS: We performed a randomized, controlled trial to evaluate the efficacy and safety of SEP-363856 in adults with an acute exacerbation of schizophrenia. The patients were randomly assigned in a 1:1 ratio to receive once-daily treatment with SEP-363856 (50 mg or 75 mg) or placebo for 4 weeks. The primary end point was the change from baseline in the total score on the Positive and Negative Symptom Scale (PANSS; range, 30 to 210; higher scores indicate more severe psychotic symptoms) at week 4. There were eight secondary end points, including the changes from baseline in the scores on the Clinical Global Impressions Severity (CGI-S) scale and the Brief Negative Symptom Scale (BNSS).
RESULTS: A total of 120 patients were assigned to the SEP-363856 group and 125 to the placebo group. The mean total score on the PANSS at baseline was 101.4 in the SEP-363856 group and 99.7 in the placebo group, and the mean change at week 4 was -17.2 points and -9.7 points, respectively (least-squares mean difference, -7.5 points; 95% confidence interval, -11.9 to -3.0; P = 0.001). The reductions in the CGI-S and BNSS scores at week 4 were generally in the same direction as those for the primary outcome, but the results were not adjusted for multiple comparisons. Adverse events with SEP-363856 included somnolence and gastrointestinal symptoms; one sudden cardiac death occurred in the SEP-363856 group. The incidence of extrapyramidal symptoms and changes in the levels of lipids, glycated hemoglobin, and prolactin were similar in the trial groups.
CONCLUSIONS: In this 4-week trial involving patients with an acute exacerbation of schizophrenia, SEP-363856, a non-D2-receptor-binding antipsychotic drug, resulted in a greater reduction from baseline in the PANSS total score than placebo. Longer and larger trials are necessary to confirm the effects and side effects of SEP-363856, as well as its efficacy relative to existing drug treatments for patients with schizophrenia. (Funded by Sunovion Pharmaceuticals; ClinicalTrials.gov number, NCT02969382.).
Copyright © 2020 Massachusetts Medical Society.
Brannan SK, Sawchak S, Miller AC, Lieberman JA, Paul SM, Breier A.
Muscarinic Cholinergic Receptor Agonist and Peripheral Antagonist for Schizophrenia.
N Engl J Med. 2021 Feb 25;384(8):717-726. doi: 10.1056/NEJMoa2017015.
Abstract/Text
BACKGROUND: The muscarinic receptor agonist xanomeline has antipsychotic properties and is devoid of dopamine receptor-blocking activity but causes cholinergic adverse events. Trospium is a peripherally restricted muscarinic receptor antagonist that reduces peripheral cholinergic effects of xanomeline. The efficacy and safety of combined xanomeline and trospium in patients with schizophrenia are unknown.
METHODS: In this double-blind, phase 2 trial, we randomly assigned patients with schizophrenia in a 1:1 ratio to receive twice-daily xanomeline-trospium (increased to a maximum of 125 mg of xanomeline and 30 mg of trospium per dose) or placebo for 5 weeks. The primary end point was the change from baseline to week 5 in the total score on the Positive and Negative Syndrome Scale (PANSS; range, 30 to 210, with higher scores indicating more severe symptoms of schizophrenia). Secondary end points were the change in the PANSS positive symptom subscore, the score on the Clinical Global Impression-Severity (CGI-S) scale (range, 1 to 7, with higher scores indicating greater severity of illness), the change in the PANSS negative symptom subscore, the change in the PANSS Marder negative symptom subscore, and the percentage of patients with a response according to a CGI-S score of 1 or 2.
RESULTS: A total of 182 patients were enrolled, with 90 assigned to receive xanomeline-trospium and 92 to receive placebo. The PANSS total score at baseline was 97.7 in the xanomeline-trospium group and 96.6 in the placebo group. The change from baseline to week 5 was -17.4 points with xanomeline-trospium and -5.9 points with placebo (least-squares mean difference, -11.6 points; 95% confidence interval, -16.1 to -7.1; P<0.001). The results for the secondary end points were significantly better in the xanomeline-trospium group than in the placebo group, with the exception of the percentage of patients with a CGI-S response. The most common adverse events in the xanomeline-trospium group were constipation, nausea, dry mouth, dyspepsia, and vomiting. The incidences of somnolence, weight gain, restlessness, and extrapyramidal symptoms were similar in the two groups.
CONCLUSIONS: In a 5-week trial, xanomeline-trospium resulted in a greater decrease in the PANSS total score than placebo but was associated with cholinergic and anticholinergic adverse events. Larger and longer trials are required to determine the efficacy and safety of xanomeline-trospium in patients with schizophrenia. (Funded by Karuna Therapeutics and the Wellcome Trust; ClinicalTrials.gov number, NCT03697252.).
Copyright © 2021 Massachusetts Medical Society.
Hartling L, Abou-Setta AM, Dursun S, Mousavi SS, Pasichnyk D, Newton AS.
Antipsychotics in adults with schizophrenia: comparative effectiveness of first-generation versus second-generation medications: a systematic review and meta-analysis.
Ann Intern Med. 2012 Oct 2;157(7):498-511. doi: 10.7326/0003-4819-157-7-201210020-00525.
Abstract/Text
BACKGROUND: Debate continues about the comparative benefits and harms of first-generation antipsychotics (FGAs) and second-generation antipsychotics (SGAs) in treating schizophrenia.
PURPOSE: To compare the effects of FGAs with those of SGAs in the treatment of adults aged 18 to 64 years with schizophrenia and related psychosis on illness symptoms, diabetes mellitus, mortality,tardive dyskinesia, and a major metabolic syndrome.
DATA SOURCES: English-language studies from 10 electronic databases to March 2012, reference lists of relevant articles, and gray literature.
STUDY SELECTION: Randomized trials for efficacy and cohort studies at least 2 years in duration for adverse events.
DATA EXTRACTION: Two independent reviewers extracted data from 114 studies involving 22 comparisons and graded the strength of evidence for primary outcomes as insufficient, low, moderate, or high using the Grading of Recommendations Assessment, Development and Evaluation approach.
DATA SYNTHESIS: Few differences of clinical importance were found for core illness symptoms; lack of precision in effect estimates precluded firm conclusions for many comparisons. Moderate-strength evidence showed a clinically important benefit of haloperidol over olanzapine for improving positive symptoms, but the benefit was scale-dependent: It was seen when the Scale for the Assessment of Positive Symptoms was used but not when the Positive and Negative Syndrome Scale (PANSS) was used. Moderate-strength evidence showed a clinically important benefit of olanzapine over haloperidol in improving negative symptoms when the PANSS and the Scale for the Assessment of Negative Symptoms were used. Low-strength evidence showed no difference in mortality for chlorpromazine verus clozapine or haloperidol versus aripiprazole,increased incidence of the metabolic syndrome for olanzapine versus haloperidol (risk differences, 2% and 22%), and higher incidence of tardive dyskinesia for chlorpromazine versus clozapine (risk differences, 5% and 9%). Evidence was insufficient to draw conclusions for diabetes mellitus.
LIMITATIONS: All studies had high or unclear risk of bias. Length of study follow-up was often too brief to adequately measure adverse events. Medication comparisons, dosage, and outcome measurement were heterogenous for head-to-head comparisons. Selective patient populations limit generalizability.
CONCLUSION: Clear benefits of FGAs versus SGAs for treating schizophrenia remain inconclusive because of variation in assessing outcomes and lack of clinically important differences for most comparisons. The strength of evidence on safety for major medical events is low or insufficient.
PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality.
Barnes TR; Schizophrenia Consensus Group of British Association for Psychopharmacology.
Evidence-based guidelines for the pharmacological treatment of schizophrenia: recommendations from the British Association for Psychopharmacology.
J Psychopharmacol. 2011 May;25(5):567-620. doi: 10.1177/0269881110391123. Epub 2011 Feb 3.
Abstract/Text
These guidelines from the British Association for Psychopharmacology address the scope and targets of pharmacological treatment for schizophrenia. A consensus meeting, involving experts in schizophrenia and its treatment, reviewed key areas and considered the strength of evidence and clinical implications. The guidelines were drawn up after extensive feedback from the participants and interested parties, and cover the pharmacological management and treatment of schizophrenia across the various stages of the illness, including first-episode, relapse prevention, and illness that has proved refractory to standard treatment. The practice recommendations presented are based on the available evidence to date, and seek to clarify which interventions are of proven benefit. It is hoped that the recommendations will help to inform clinical decision making for practitioners, and perhaps also serve as a source of information for patients and carers. They are accompanied by a more detailed qualitative review of the available evidence. The strength of supporting evidence for each recommendation is rated.
Leucht S, Kissling W, Davis JM.
Second-generation antipsychotics for schizophrenia: can we resolve the conflict?
Psychol Med. 2009 Oct;39(10):1591-602. doi: 10.1017/S0033291709005455. Epub 2009 Apr 1.
Abstract/Text
The initial enthusiasm about the second-generation or atypical antipsychotic drugs soon changed into criticism and debate, culminating in the controversial CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness), CUtLASS (Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study) and EUFEST (European First-Episode Schizophrenia Trial) effectiveness trials. This review summarizes the results of three recent meta-analyses that compared second-generation antipsychotics (SGAs) with placebo, with conventional antipsychotics, and with SGAs head-to-head. We compare the meta-analyses with previous reviews and put them in the perspective of CATIE, CUtLASS and EUFEST. The data show that the SGAs are not a homogeneous group and that this confusing classification should be abandoned. We find that, overall, the data are consistent but experts interpret the same results differently. The debate seems to be driven more by values than by data; some place an emphasis on cost, others focus on extrapyramidal side-effects (EPS), weight gain, or efficacy. In our opinion, the SGAs are not the breakthrough that industry would like to maintain. They have different properties, so a clinician may individualize a treatment plan to a given patient's problems, a decision that should be shared with the patient. However, these drugs are important contributions to treatment, and most psychiatrists, let alone patients, would probably not want to do without them.
Moore TA, Buchanan RW, Buckley PF, Chiles JA, Conley RR, Crismon ML, Essock SM, Finnerty M, Marder SR, Miller DD, McEvoy JP, Robinson DG, Schooler NR, Shon SP, Stroup TS, Miller AL.
The Texas Medication Algorithm Project antipsychotic algorithm for schizophrenia: 2006 update.
J Clin Psychiatry. 2007 Nov;68(11):1751-62. doi: 10.4088/jcp.v68n1115.
Abstract/Text
BACKGROUND: A panel of academic psychiatrists and pharmacists, clinicians from the Texas public mental health system, advocates, and consumers met in June 2006 in Dallas, Tex., to review recent evidence in the pharmacologic treatment of schizophrenia. The goal of the consensus conference was to update and revise the Texas Medication Algorithm Project (TMAP) algorithm for schizophrenia used in the Texas Implementation of Medication Algorithms, a statewide quality assurance program for treatment of major psychiatric illness.
METHOD: Four questions were identified via premeeting teleconferences. (1) Should antipsychotic treatment of first-episode schizophrenia be different from that of multiepisode schizophrenia? (2) In which algorithm stages should first-generation antipsychotics (FGAs) be an option? (3) How many antipsychotic trials should precede a clozapine trial? (4) What is the status of augmentation strategies for clozapine? Subgroups reviewed the evidence in each area and presented their findings at the conference.
RESULTS: The algorithm was updated to incorporate the following recommendations. (1) Persons with first-episode schizophrenia typically require lower antipsychotic doses and are more sensitive to side effects such as weight gain and extrapyramidal symptoms (group consensus). Second-generation antipsychotics (SGAs) are preferred for treatment of first-episode schizophrenia (majority opinion). (2) FGAs should be included in algorithm stages after first episode that include SGAs other than clozapine as options (group consensus). (3) The recommended number of trials of other antipsychotics that should precede a clozapine trial is 2, but earlier use of clozapine should be considered in the presence of persistent problems such as suicidality, comorbid violence, and substance abuse (group consensus). (4) Augmentation is reasonable for persons with inadequate response to clozapine, but published results on augmenting agents have not identified replicable positive results (group consensus).
CONCLUSIONS: These recommendations are meant to provide a framework for clinical decision making, not to replace clinical judgment. As with any algorithm, treatment practices will evolve beyond the recommendations of this consensus conference as new evidence and additional medications become available.
Kane J, Honigfeld G, Singer J, Meltzer H.
Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine.
Arch Gen Psychiatry. 1988 Sep;45(9):789-96. doi: 10.1001/archpsyc.1988.01800330013001.
Abstract/Text
The treatment of schizophrenic patients who fail to respond to adequate trials of neuroleptics is a major challenge. Clozapine, an atypical antipsychotic drug, has long been of scientific interest, but its clinical development has been delayed because of an associated risk of agranulocytosis. This report describes a multicenter clinical trial to assess clozapine's efficacy in the treatment of patients who are refractory to neuroleptics. DSM-III schizophrenics who had failed to respond to at least three different neuroleptics underwent a prospective, single-blind trial of haloperidol (mean dosage, 61 +/- 14 mg/d) for six weeks. Patients whose condition remained unimproved were then randomly assigned, in a double-blind manner, to clozapine (up to 900 mg/d) or chlorpromazine (up to 1800 mg/d) for six weeks. Two hundred sixty-eight patients were entered in the double-blind comparison. When a priori criteria were used, 30% of the clozapine-treated patients were categorized as responders compared with 4% of chlorpromazine-treated patients. Clozapine produced significantly greater improvement on the Brief Psychiatric Rating Scale, Clinical Global Impression Scale, and Nurses' Observation Scale for Inpatient Evaluation; this improvement included "negative" as well as positive symptom areas. Although no cases of agranulocytosis occurred during this relatively brief study, in our view, the apparently increased comparative risk requires that the use of clozapine be limited to selected treatment-resistant patients.
Wimberley T, MacCabe JH, Laursen TM, Sørensen HJ, Astrup A, Horsdal HT, Gasse C, Støvring H.
Mortality and Self-Harm in Association With Clozapine in Treatment-Resistant Schizophrenia.
Am J Psychiatry. 2017 Oct 1;174(10):990-998. doi: 10.1176/appi.ajp.2017.16091097. Epub 2017 Jul 28.
Abstract/Text
OBJECTIVE: This study evaluated rates of all-cause mortality and self-harm in association with clozapine treatment in individuals with treatment-resistant schizophrenia.
METHOD: A population-based cohort of 2,370 individuals with treatment-resistant schizophrenia after Jan. 1, 1996, was followed until death, first episode of self-harm, emigration, or June 1, 2013. Time to all-cause death and time to first episode of self-harm were analyzed in Cox regression models with time-varying treatment, adjusted for clinical and sociodemographic covariates.
RESULTS: The rate of all-cause mortality was higher for patients not receiving clozapine than for those given clozapine (hazard ratio: 1.88, 95% confidence interval [CI]: 1.16-3.05). This was driven mainly by periods of no antipsychotic treatment (hazard ratio: 2.50, 95% CI: 1.50-4.17), with nonsignificantly higher mortality during treatment with other antipsychotics (hazard ratio: 1.45, 95% CI: 0.86-2.45). Excess mortality was observed in the year after clozapine discontinuation (hazard ratio: 2.65, 95% CI: 1.47-4.78). The rate of self-harm was higher for nonclozapine antipsychotics than for clozapine (hazard ratio: 1.36, 95% CI: 1.04-1.78).
CONCLUSIONS: The results demonstrate a nearly twofold higher mortality rate among individuals with treatment-resistant schizophrenia not treated with clozapine compared with clozapine-treated individuals. Furthermore, the results suggest a harmful effect of other antipsychotics regarding self-harm compared with clozapine. It remains to be investigated to what extent the observed excess mortality after clozapine discontinuation is confounded by nonadherence and other unobserved factors and to what extent it is mediated by adverse effects from recent clozapine exposure or deterioration in physical or mental health precipitated by clozapine discontinuation.
Howes OD, Vergunst F, Gee S, McGuire P, Kapur S, Taylor D.
Adherence to treatment guidelines in clinical practice: study of antipsychotic treatment prior to clozapine initiation.
Br J Psychiatry. 2012 Dec;201(6):481-5. doi: 10.1192/bjp.bp.111.105833. Epub 2012 Sep 6.
Abstract/Text
BACKGROUND: Clozapine is the only antipsychotic drug licensed for treatment-resistant schizophrenia but its use is often delayed. Since previous studies, national guidelines on the use of clozapine and other antipsychotics have been disseminated to clinicians.
AIMS: To determine the theoretical delay to clozapine initiation and to quantify the prior use of antipsychotic polypharmacy and high-dose antipsychotic treatment.
METHOD: Clinico-demographic data were extracted from the treatment records of all patients commencing clozapine in our centre between 2006 and 2010.
RESULTS: Complete records were available for 149 patients. The mean theoretical delay in initiating clozapine was 47.7 months (s.d. = 49.7). Before commencing clozapine, antipsychotic polypharmacy and high-dose treatment was evident in 36.2 and 34.2% of patients respectively. Theoretical delay was related to illness duration (β = 0.7, P<0.001) but did not differ by gender or ethnicity.
CONCLUSIONS: Substantial delays to clozapine initiation remain and antipsychotic polypharmacy and high doses are commonly used prior to clozapine, despite treatment guidelines.
Pai NB, Vella SC.
Reason for clozapine cessation.
Acta Psychiatr Scand. 2012 Jan;125(1):39-44. doi: 10.1111/j.1600-0447.2011.01776.x. Epub 2011 Oct 24.
Abstract/Text
OBJECTIVE: Approximately 30% of individuals diagnosed with schizophrenia suffer from treatment-resistant or refractory schizophrenia. The gold standard for treatment of refractory schizophrenia is clozapine. However, a significant number of patients cease clozapine therapy; therefore this study explores patient's motives for cessation.
METHOD: The motives for cessation and duration of clozapine treatment from a retrospective database of 151 patients with schizophrenia or schizo-affective disorder who had ceased clozapine once or more were reviewed, with the motives for cessation coded. The general motives for cessation were non-compliance, own decision, medical, poor response and other. In addition, the medical reasons for cessation were further codified: cardiac complications, neutropenia, fevers, other side effects and pregnancy.
RESULTS: The majority of patients ceased clozapine owing to non-compliance with medical protocols or citing their own decision. Approximately half ceased after a period of 6 months or less. Seventeen per cent of patients ceased owing to medical reasons, with the largest proportions discontinuing treatment because of other side effects or neutropenia.
CONCLUSION: Future research should seek to further investigate why patients decide to be non-compliant and formulate their own decision to cease treatment, as this will facilitate strategies to promote adherence amongst these two groups that are potentially the most amenable to change.
© 2011 John Wiley & Sons A/S.
Nordström AL, Farde L, Nyberg S, Karlsson P, Halldin C, Sedvall G.
D1, D2, and 5-HT2 receptor occupancy in relation to clozapine serum concentration: a PET study of schizophrenic patients.
Am J Psychiatry. 1995 Oct;152(10):1444-9. doi: 10.1176/ajp.152.10.1444.
Abstract/Text
OBJECTIVE: Central D1, D2, and 5-HT2 receptor occupancy in schizophrenic patients treated with clozapine was determined and related to clozapine serum concentrations.
METHOD: Seventeen patients treated with clozapine (125-600 mg/day) were examined with positron emission tomography (PET) and one to three of the following selective radioligands: [11C]SCH23390 (N = 11), [11C]raclopride (N = 16), and [11C]N-methylspiperone (N = 5). Clozapine concentration in serum was determined by gas chromatography/mass spectrometry.
RESULTS: D2 receptor occupancy (20%-67%) was lower than that previously determined in patients treated with classical neuroleptics (70%-90%). D1 receptor occupancy (36%-59%) was higher than that induced by classical neuroleptics (0%-44%). 5-HT2 receptor occupancy was very high (84%-94%), even at low clozapine doses. Despite a 20-fold range in clozapine serum concentration (105-2121 ng/ml) at the time of PET examination, D2 receptor occupancy was low in all patients and was not described by the curvilinear relationship between serum drug concentration and receptor occupancy that has been demonstrated for classical antipsychotics.
CONCLUSIONS: The results confirm in an extended series of patients that clozapine is atypical with regard to degree of D2 receptor occupancy, a finding that may explain the lack of extrapyramidal side effects. The combination of relatively high D1, low D2, and very high 5-HT2 receptor occupancy values is unique to clozapine. Clozapine serum concentrations have not been unequivocally shown to predict clinical effects. In this study, concentration did not predict degree of occupancy in brain. Thus, careful clinical titration cannot be replaced by monitoring of drug concentrations for optimization of clozapine treatment in individual patients.
Howes OD, McCutcheon R, Agid O, de Bartolomeis A, van Beveren NJ, Birnbaum ML, Bloomfield MA, Bressan RA, Buchanan RW, Carpenter WT, Castle DJ, Citrome L, Daskalakis ZJ, Davidson M, Drake RJ, Dursun S, Ebdrup BH, Elkis H, Falkai P, Fleischacker WW, Gadelha A, Gaughran F, Glenthøj BY, Graff-Guerrero A, Hallak JE, Honer WG, Kennedy J, Kinon BJ, Lawrie SM, Lee J, Leweke FM, MacCabe JH, McNabb CB, Meltzer H, Möller HJ, Nakajima S, Pantelis C, Reis Marques T, Remington G, Rossell SL, Russell BR, Siu CO, Suzuki T, Sommer IE, Taylor D, Thomas N, Üçok A, Umbricht D, Walters JT, Kane J, Correll CU.
Treatment-Resistant Schizophrenia: Treatment Response and Resistance in Psychosis (TRRIP) Working Group Consensus Guidelines on Diagnosis and Terminology.
Am J Psychiatry. 2017 Mar 1;174(3):216-229. doi: 10.1176/appi.ajp.2016.16050503. Epub 2016 Dec 6.
Abstract/Text
OBJECTIVE: Research and clinical translation in schizophrenia is limited by inconsistent definitions of treatment resistance and response. To address this issue, the authors evaluated current approaches and then developed consensus criteria and guidelines.
METHOD: A systematic review of randomized antipsychotic clinical trials in treatment-resistant schizophrenia was performed, and definitions of treatment resistance were extracted. Subsequently, consensus operationalized criteria were developed through 1) a multiphase, mixed methods approach, 2) identification of key criteria via an online survey, and 3) meetings to achieve consensus.
RESULTS: Of 2,808 studies identified, 42 met inclusion criteria. Of these, 21 studies (50%) did not provide operationalized criteria. In the remaining studies, criteria varied considerably, particularly regarding symptom severity, prior treatment duration, and antipsychotic dosage thresholds; only two studies (5%) utilized the same criteria. The consensus group identified minimum and optimal criteria, employing the following principles: 1) current symptoms of a minimum duration and severity determined by a standardized rating scale; 2) moderate or worse functional impairment; 3) prior treatment consisting of at least two different antipsychotic trials, each for a minimum duration and dosage; 4) systematic monitoring of adherence and meeting of minimum adherence criteria; 5) ideally at least one prospective treatment trial; and 6) criteria that clearly separate responsive from treatment-resistant patients.
CONCLUSIONS: There is considerable variation in current approaches to defining treatment resistance in schizophrenia. The authors present consensus guidelines that operationalize criteria for determining and reporting treatment resistance, adequate treatment, and treatment response, providing a benchmark for research and clinical translation.
Suzuki T, Uchida H, Takeuchi H, Nakajima S, Nomura K, Tanabe A, Yagi G, Watanabe K, Kashima H.
Augmentation of atypical antipsychotics with valproic acid. An open-label study for most difficult patients with schizophrenia.
Hum Psychopharmacol. 2009 Dec;24(8):628-38. doi: 10.1002/hup.1073.
Abstract/Text
OBJECTIVE: Most difficult inpatients with schizophrenia are in serious needs but obviously underrepresented in clinical trials.
METHODS: Very challenging patients received open-label treatment with atypical antipsychotics concurrently augmented with valproic acid. The primary outcome was the newly developed Functional Assessment for Comprehensive Treatment of Schizophrenia (FACT-Sz). Patients improving more than 20 points were classified as responders.
RESULTS: Mean age and illness duration of 28 participants (22 male) were 42 y.o. and 20 years, respectively. They had spent a half of their life admitted after the onset. The average Brief Psychiatric Rating Scale (BPRS) and Clinical Global Impression-Severity (CGI-S) were very severe at 79 and 6.1, respectively, with the baseline Global Assessment of Functioning (GAF) of as low as 21. As a result of augmentation, there were nine responders, 12 partial responders, and seven non-responders including only two patients who got worse. The main antipsychotics were mostly either risperidone or olanzapine. Mean maximum oral dose and blood level of valproic acid were 1907 mg and 91.7 microg/ml, respectively. Overall significant improvements whilst to an inadequate degree were noted in clinical parameters. Valproate augmentation was generally well tolerated but serious adverse effects included thrombocytopenia, anaemia and sedation/falls.
CONCLUSIONS: While these preliminary results need to be tested against tenacious monotherapy or polypharmacy involving clozapine, augmenting atypical antipsychotics with valproic acid can be useful for very severe schizophrenia.
Copyright (c) 2009 John Wiley & Sons, Ltd.
Porcelli S, Balzarro B, Serretti A.
Clozapine resistance: augmentation strategies.
Eur Neuropsychopharmacol. 2012 Mar;22(3):165-82. doi: 10.1016/j.euroneuro.2011.08.005. Epub 2011 Sep 9.
Abstract/Text
BACKGROUND: Clozapine (CLZ) is not effective in more than 50% of treatment-resistant schizophrenic patients. In these cases, several pharmacological strategies are used in clinical practice, with different levels of evidence for both safety and efficacy.
OBJECTIVES: In the present paper we critically reviewed literature data regarding the efficacy and safety of adjunctive agents in CLZ-resistant schizophrenics. The following classes of agents were considered: 1) antipsychotics, 2) antidepressants, 3) mood stabilizers, 4) other agents (e.g. fatty acid supplement and glutamatergic agents), 5) electroconvulsive therapy (ECT). For lamotrigine and risperidone sufficient data were available to perform a meta-analysis.
METHODS: A Medline literature search covering a 20-year period was performed. For the meta-analysis, data were entered and analyzed with the Cochrane Collaboration Review Manager Software (RevMan version 5).
RESULTS: 62 pertinent studies were identified, including 1556 schizophrenic or schizoaffective patients. Among treatments investigated, there is evidence for CLZ augmentation with 1) amisulpride and aripiprazole, 2) mirtazapine and 3) ethyl eicosapentaenoic acid (E-EPA). Although promising, ECT augmentation needs further validation. The meta-analyses did not support either the use of risperidone or lamotrigine as CLZ adjunct.
CONCLUSION: Overall, there is scarce evidence of efficacy and safety as regards adjunctive strategies for CLZ-resistant patients. However, several limitations do not allow to draw any definitive conclusion; among these we underline the small sample size of clinical trials, the variable definitions of CLZ resistance, the heterogeneity of outcome measures and methodological designs.
Copyright © 2011 Elsevier B.V. and ECNP. All rights reserved.
Zervas IM, Theleritis C, Soldatos CR.
Using ECT in schizophrenia: a review from a clinical perspective.
World J Biol Psychiatry. 2012 Feb;13(2):96-105. doi: 10.3109/15622975.2011.564653. Epub 2011 Apr 12.
Abstract/Text
OBJECTIVES: Despite the fact that many studies have addressed the use of ECT in schizophrenia questions on clinical use remain poorly answered and clinical application is largely based on data originating from depressed patients.
METHODS: We review data on the use of ECT in schizophrenic patients drawn from original studies indicated by a Pubmed search and referenced in recent and older expert reviews with a specific focus on four issues: symptom response, technical application, continuation/maintenance ECT and combination with medication.
RESULTS: Catatonic patients are the most responsive. Positive symptoms such paranoid delusions and affective symptoms follow. There are indications that ECT may improve responsivity to medication. No particular technical features stand out in studies except lengthier courses, but not for catatonia. Combination with medication appears to be preferable over either treatment alone and effective combination particularly with clozapine is supported by data. Use of continuation and maintenance treatments in responders appears beneficial.
CONCLUSION: Certain schizophrenic patients may benefit significantly from the use of ECT. More specific research is required to address particular questions.
Petrides G, Malur C, Braga RJ, Bailine SH, Schooler NR, Malhotra AK, Kane JM, Sanghani S, Goldberg TE, John M, Mendelowitz A.
Electroconvulsive therapy augmentation in clozapine-resistant schizophrenia: a prospective, randomized study.
Am J Psychiatry. 2015 Jan;172(1):52-8. doi: 10.1176/appi.ajp.2014.13060787. Epub 2014 Oct 31.
Abstract/Text
OBJECTIVE: Up to 70% of patients with treatment-resistant schizophrenia do not respond to clozapine. Pharmacological augmentation to clozapine has been studied with unimpressive results. The authors examined the use of ECT as an augmentation to clozapine for treatment-refractory schizophrenia.
METHOD: In a randomized single-blind 8-week study, patients with clozapine-resistant schizophrenia were assigned to treatment as usual (clozapine group) or a course of bilateral ECT plus clozapine (ECT plus clozapine group). Nonresponders from the clozapine group received an 8-week open trial of ECT (crossover phase). ECT was performed three times per week for the first 4 weeks and twice weekly for the last 4 weeks. Clozapine dosages remained constant. Response was defined as ≥40% reduction in symptoms based on the psychotic symptom subscale of the Brief Psychiatric Rating Scale, a Clinical Global Impressions (CGI)-severity rating <3, and a CGI-improvement rating ≤2.
RESULTS: The intent-to-treat sample included 39 participants (ECT plus clozapine group, N=20; clozapine group, N=19). All 19 patients from the clozapine group received ECT in the crossover phase. Fifty percent of the ECT plus clozapine patients met the response criterion. None of the patients in the clozapine group met the criterion. In the crossover phase, response was 47%. There were no discernible differences between groups on global cognition. Two patients required the postponement of an ECT session because of mild confusion.
CONCLUSIONS: The augmentation of clozapine with ECT is a safe and effective treatment option. Further research is required to determine the persistence of the improvement and the potential need for maintenance treatments.
Suzuki T, Uchida H, Takeuchi H, Tsunoda K, Ishizuki T, Mimura M.
Optimization of psychopharmacotherapy for schizophrenia in a male, locked, non-acute unit serving for persistently ill patients over one year.
Psychiatry Res. 2015 Jul 30;228(1):26-30. doi: 10.1016/j.psychres.2015.03.019. Epub 2015 Mar 31.
Abstract/Text
We describe real-world psychopharmacological treatment in a Japanese, male, closed psychiatric unit where clozapie was still unavailable. Fifty-five persistently-ill patients with schizophrenia (ICD-10), mean ± S.D. age: 57.5 ± 13.0 y.o., duration of illness and admissions: 30.9 ± 15.2 years and 20.7 ± 14.5 years, respectively) treated longitudinally were evaluated. The rule was to treat with a simplest possible psychotropic regimen without polypharmacy. Compared to the baseline, the number and dose of antipsychotics were reduced from 1.9 to 1.1 and 1012 mg/day to 607 mg/day, respectively. The number of total psychotropics was minimized from 4.7 to 2.1, with a simplified once or twice daily dosing. Overall, the CGI-Severity and FACT-Sz (global functioning) improved slightly from 5.8 to 5.5 and 28.7 to 32.6, respectively. Of note, no patients got worse in comparison with the baseline clinical presentation. Forty-four patients were successfully treated with a single antipsychotic; only seven needed two antipsychotics simultaneously while 36 had been treated with antipsychotic polypharmacy at baseline. Benzodiazepines (mostly lorazepam) and antiparkinsonian drugs were prescribed in 28 and only two, respectively. Nineteen needed adjunctive valproate (average blood levels: 99.3 ± 21.8 μg/mL) and nine used lithium (0.61 ± 0.26 mEq/L). Optimization of psychopharmacotherapy is still possible for difficult-to-treat patients and, while augmentation of an antipsychotic with mood stabilizers is frequently needed, antipsychotic polypharmacy should be exceptional.
Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
Shimomura Y, Kikuchi Y, Suzuki T, Uchida H, Mimura M, Takeuchi H.
Antipsychotic treatment in the maintenance phase of schizophrenia: An updated systematic review of the guidelines and algorithms.
Schizophr Res. 2020 Jan;215:8-16. doi: 10.1016/j.schres.2019.09.013. Epub 2019 Nov 26.
Abstract/Text
BACKGROUND: We updated our previous systematic review regarding clinical guidelines and algorithms on antipsychotic treatment in the maintenance phase of schizophrenia (doi: 10.1016/j.schres.2011.11.021) to incorporate and synthesize more recent findings to guide clinical practice.
METHODS: We conducted a systematic literature search to identify clinical guidelines and algorithms describing antipsychotic treatment in the maintenance phase of schizophrenia using MEDLINE and Embase. We assessed overall quality of the guidelines/algorithms according to the AGREE II instrument and extracted information on treatment recommendations.
RESULTS: We identified 20 guidelines/algorithms from various regions, including 11 updated or newly launched ones after the previous systematic review in 2012. All of the guidelines/algorithms satisfied a certain level of quality. Where mentioned, endorsements were sorted into "recommended", "partially recommended", or "not recommended". As for antipsychotic discontinuation strategy, a majority of guidelines/algorithms that mentioned this strategy did not recommend it for multiple-episode schizophrenia (N = 5/6). On the other hand, the guidelines/algorithms tended to shift from "not recommended" to "partially recommended" both for schizophrenia in general (N = 7/13, N = 7/8 for those published after 2013) and first-episode schizophrenia (N = 10/11, N = 7/7 for those published after 2013) regarding this strategy. All guidelines/algorithms (N = 9/9) converged to discourage antipsychotic intermittent/targeted strategy. Similar to antipsychotic discontinuation strategy, all of the updated or new guidelines/algorithms (N = 6/6) endorsed antipsychotic dose reduction/lower dose strategy.
CONCLUSION: Recent clinical guidelines and algorithms on antipsychotic maintenance treatment in schizophrenia shifted more toward a possibility of antipsychotic discontinuation and dose reduction/lower dose strategies. Nonetheless, clinicians need to contemplate on the risk-benefit balance of these strategies for individual patients.
Copyright © 2019 Elsevier B.V. All rights reserved.
Buchanan RW, Kreyenbuhl J, Kelly DL, Noel JM, Boggs DL, Fischer BA, Himelhoch S, Fang B, Peterson E, Aquino PR, Keller W; Schizophrenia Patient Outcomes Research Team (PORT).
The 2009 schizophrenia PORT psychopharmacological treatment recommendations and summary statements.
Schizophr Bull. 2010 Jan;36(1):71-93. doi: 10.1093/schbul/sbp116. Epub 2009 Dec 2.
Abstract/Text
In light of the large number of studies published since the 2004 update of Schizophrenia Patient Outcomes Research Team psychopharmacological treatment recommendations, we conducted an extensive literature review to determine whether the current psychopharmacological treatment recommendations required revision and whether there was sufficient evidence to warrant new treatment recommendations for prespecified outcomes of interest. We reviewed over 400 articles, which resulted in 16 treatment recommendations: the revision of 11 previous treatment recommendations and 5 new treatment recommendations. Three previous treatment recommendations were eliminated. There were 13 interventions and/or outcomes for which there was insufficient evidence for a treatment recommendation, and a statement was written to summarize the current level of evidence and identify important gaps in our knowledge that need to be addressed. In general, there was considerable consensus among the Psychopharmacology Evidence Review Group and the expert consultants. Two major areas of contention concerned whether there was sufficient evidence to recommend specific dosage ranges for the acute and maintenance treatment of first-episode and multi-episode schizophrenia and to endorse the practice of switching antipsychotics for the treatment of antipsychotic-related weight gain. Finally, there continue to be major gaps in our knowledge, including limited information on (1) the use of adjunctive pharmacological agents for the treatment of persistent positive symptoms or other symptom domains of psychopathology, including anxiety, cognitive impairments, depressive symptoms, and persistent negative symptoms and (2) the treatment of co-occurring substance or medical disorders that occur frequently in individuals with schizophrenia.
Gardner DM, Murphy AL, O'Donnell H, Centorrino F, Baldessarini RJ.
International consensus study of antipsychotic dosing.
Am J Psychiatry. 2010 Jun;167(6):686-93. doi: 10.1176/appi.ajp.2009.09060802. Epub 2010 Apr 1.
Abstract/Text
OBJECTIVE: Potency equivalents for anti-psychotic drugs are required to guide clinical dosing and for designing and interpreting research studies. Available dosing guidelines are limited by the methods and data from which they were generated.
METHOD: With a two-step Delphi method, the authors surveyed a diverse group of international clinical and research experts, seeking consensus regarding antipsychotic dosing. The authors determined median clinical dosing equivalents and recommended starting, target range, and maximum doses for 61 drugs, adjusted for selected clinical circumstances.
RESULTS: Participants (N=43) from 18 countries provided dosing recommendations regarding treatment of psychotic disorders for 37 oral agents and 14 short-acting and 10 long-acting parenteral agents. With olanzapine 20 mg/day as reference, estimated clinical equivalency ratios of oral agents ranged from 0.025 for sulpiride to 10.0 for trifluperidol. Seventeen patient and treatment characteristics, including age, hepatic and renal function, illness stage and severity, sex, and diagnosis, were associated with dosing modifications.
CONCLUSIONS: In the absence of adequate prospective, randomized drug-drug comparisons, the present findings provide broad, international, expert consensus-based recommendations for most clinically employed antipsychotic drugs. They can support clinical practice, trial design, and interpretation of comparative antipsychotic trials.
Suzuki T, Uchida H, Takeuchi H, Tsuboi T, Hirano J, Mimura M.
A review on schizophrenia and relapse--a quest for user-friendly psychopharmacotherapy.
Hum Psychopharmacol. 2014 Sep;29(5):414-26. doi: 10.1002/hup.2421.
Abstract/Text
OBJECTIVE: Schizophrenia in general is notoriously associated with relapses rendering the illness progressive to worse outcomes, a concept of which is compatible with neurotoxicity. Therefore, relapse prevention is of utmost clinical relevance.
METHODS: In this review, we aim to put relapse into clinical context in the realm of natural history of, or heterogeneity in, schizophrenia and summarize risk factors of relapse. We discuss how to effectively 'define' relapse in schizophrenia and recent meta-analytic studies on this topic to highlight the importance of continuous antipsychotic treatment.
RESULTS: The following issues emerged: 'How low maintenance antipsychotic dosage could be?’, 'How extended dosing could be?’, 'Who could be successfully withdrawn from antipsychotics?’ and 'How relapse could be defined in the first place?’ The question in particular is how better to deliver antipsychotics at the lowest possible, whereby dose and dosing interval are relevant. While ongoing antipsychotic treatment is the rule, recent works are pointing to a possibility of lower dosage in the maintenance phase of the illness.
CONCLUSIONS: Bearing in mind that suboptimal adherence and withdrawal from antipsychotics are an established and unequivocal risk factor for relapse, further investigations are certainly needed to explore user-friendly manner of psychopharmacotherapy to prevent relapse in schizophrenia.
Suzuki T, Remington G, Mulsant BH, Uchida H, Rajji TK, Graff-Guerrero A, Mimura M, Mamo DC.
Defining treatment-resistant schizophrenia and response to antipsychotics: a review and recommendation.
Psychiatry Res. 2012 May 15;197(1-2):1-6. doi: 10.1016/j.psychres.2012.02.013. Epub 2012 Mar 18.
Abstract/Text
Treatment-resistant schizophrenia (TRS) has been defined mainly by severity of (positive) symptoms and response to antipsychotics derived from a relative change in the representative scales (most frequently ≥ 20% decrease in the Positive and Negative Syndrome Scale: PANSS), but these definitions have not necessarily been consistent. Integrating past evidence and real-world practicability, we propose that TRS be defined by at least two failed adequate trials with different antipsychotics (at chlorpromazine-equivalent doses of ≥ 600mg/day for ≥ 6 consecutive weeks) that could be retrospective or preferably include prospective failure to respond to one or more antipsychotic trials. In addition, our proposed criteria require both a score of ≥ 4 on the Clinical Global Impression (CGI)-Severity and a score of ≤ 49 on the Functional Assessment for Comprehensive Treatment of Schizophrenia (FACT-Sz) or ≤ 50 on the Global Assessment of Functioning (GAF) scales to define TRS. Once TRS is established, we propose that subsequent treatment response be defined based on a CGI-Change score of ≤ 2, a ≥ 20% decrease on the total PANSS or Brief Psychiatric Rating Scale (BPRS) scores, and an increase of ≥ 20 points on the FACT-Sz or GAF. While these suggestions provide a pragmatic framework for TRS classification, they need to be tested in future trials.
Copyright © 2012 Elsevier Ltd. All rights reserved.
Gallego JA, Bonetti J, Zhang J, Kane JM, Correll CU.
Prevalence and correlates of antipsychotic polypharmacy: a systematic review and meta-regression of global and regional trends from the 1970s to 2009.
Schizophr Res. 2012 Jun;138(1):18-28. doi: 10.1016/j.schres.2012.03.018. Epub 2012 Apr 24.
Abstract/Text
OBJECTIVE: To assess the prevalence and correlates of antipsychotic polypharmacy (APP) across decades and regions.
METHODS: Electronic PubMed/Google Scholar search for studies reporting on APP, published from 1970 to 05/2009. Median rates and interquartile ranges (IQR) were calculated and compared using non-parametric tests. Demographic and clinical variables were tested as correlates of APP in bivariate and meta-regression analyses.
RESULTS: Across 147 studies (1,418,163 participants, 82.9% diagnosed with schizophrenia [IQR=42-100%]), the median APP rate was 19.6% (IQR=12.9-35.0%). Most common combinations included first-generation antipsychotics (FGAs)+second-generation antipsychotics (SGAs) (42.4%, IQR=0.0-71.4%) followed by FGAs+FGAs (19.6%, IQR=0.0-100%) and SGAs+SGAs (1.8%, IQR=0.0-28%). APP rates were not different between decades (1970-1979:28.8%, IQR=7.5-44%; 1980-1989:17.6%, IQR=10.8-38.2; 1990-1999:22.0%, IQR=11-40; 2000-2009:19.2% IQR=14.4-29.9, p=0.78), but between regions, being higher in Asia and Europe than North America, and in Asia than Oceania (p<0.001). APP increased numerically by 34% in North America from the 1980s 12.7%) to 2000s (17.0%) (p=0.94) and decreased significantly by 65% from 1980 (55.5%) to 2000 (19.2%) in Asia (p=0.03), with non-significant changes in Europe. APP was associated with inpatient status (p<0.001), use of FGAs (p<0.0001) and anticholinergics (<0.001), schizophrenia (p=0.01), less antidepressant use (p=0.02), greater LAIs use (p=0.04), shorter follow-up (p=0.001) and cross-sectional vs. longitudinal study design (p=0.03). In a meta-regression, inpatient status (p<0.0001), FGA use (0.046), and schizophrenia diagnosis (p=0.004) independently predicted APP (N=66, R(2)=0.44, p<0.0001).
CONCLUSIONS: APP is common with different rates and time trends by region over the last four decades. APP is associated with greater anticholinergic requirement, shorter observation time, greater illness severity and lower antidepressant use.
Copyright © 2012 Elsevier B.V. All rights reserved.
Xiang YT, Wang CY, Si TM, Lee EH, He YL, Ungvari GS, Chiu HF, Yang SY, Chong MY, Tan CH, Kua EH, Fujii S, Sim K, Yong KH, Trivedi JK, Chung EK, Udomratn P, Chee KY, Sartorius N, Shinfuku N.
Antipsychotic polypharmacy in inpatients with schizophrenia in Asia (2001-2009).
Pharmacopsychiatry. 2012 Jan;45(1):7-12. doi: 10.1055/s-0031-1286345. Epub 2011 Oct 11.
Abstract/Text
OBJECTIVE: This study aimed to identify trends in the use of antipsychotic polypharmacy (APP) and their demographic and clinical correlates in the treatment of schizophrenia in Asia between 2001 and 2009.
METHOD: A total of 6,761 schizophrenia inpatients in 9 Asian countries and territories were examined; 2,399 in 2001, 2,136 in 2004, and 2,226 in 2009. Patients’ socio-demographic and clinical characteristics and prescriptions of psychotropic drugs were recorded using a standardized protocol and data collection procedure.
RESULTS: The proportion of APP prescription decreased from 46.8 % in 2001, to 38.3 % in 2004, and increased to 43.4 % in 2009, with wide intercountry variations at each survey. Multiple logistic regression analysis of the whole sample revealed that patients on APP were younger, had a higher dose of antipsychotics in chlorpromazine equivalents, and more severe positive and negative symptoms. They were also more likely to receive depot and fi rst-generation antipsychotic drugs.
CONCLUSIONS: The frequency of APP prescription varied between countries and territories, suggesting that a host of clinical and socio-cultural factors played a role in determining APP use in Asia. To resolve the discrepancy between treatment recommendation and clinical practice, regular reviews of prescription patterns are needed.
© Georg Thieme Verlag KG Stuttgart · New York.
Galling B, Roldán A, Hagi K, Rietschel L, Walyzada F, Zheng W, Cao XL, Xiang YT, Zink M, Kane JM, Nielsen J, Leucht S, Correll CU.
Antipsychotic augmentation vs. monotherapy in schizophrenia: systematic review, meta-analysis and meta-regression analysis.
World Psychiatry. 2017 Feb;16(1):77-89. doi: 10.1002/wps.20387.
Abstract/Text
Antipsychotic polypharmacy in schizophrenia is much debated, since it is common and costly with unclear evidence for its efficacy and safety. We conducted a systematic literature search and a random effects meta-analysis of randomized trials comparing augmentation with a second antipsychotic vs. continued antipsychotic monotherapy in schizophrenia. Co-primary outcomes were total symptom reduction and study-defined response. Antipsychotic augmentation was superior to monotherapy regarding total symptom reduction (16 studies, N=694, standardized mean difference, SMD=-0.53, 95% CI: -0.87 to -0.19, p=0.002). However, superiority was only apparent in open-label and low-quality trials (both p<0.001), but not in double-blind and high-quality ones (p=0.120 and 0.226, respectively). Study-defined response was similar between antipsychotic augmentation and monotherapy (14 studies, N=938, risk ratio = 1.19, 95% CI: 0.99 to 1.42, p=0.061), being clearly non-significant in double-blind and high-quality studies (both p=0.990). Findings were replicated in clozapine and non-clozapine augmentation studies. No differences emerged regarding all-cause/specific-cause discontinuation, global clinical impression, as well as positive, general and depressive symptoms. Negative symptoms improved more with augmentation treatment (18 studies, N=931, SMD=-0.38, 95% CI: -0.63 to -0.13, p<0.003), but only in studies augmenting with aripiprazole (8 studies, N=532, SMD=-0.41, 95% CI: -0.79 to -0.03, p=0.036). Few adverse effect differences emerged: D2 antagonist augmentation was associated with less insomnia (p=0.028), but more prolactin elevation (p=0.015), while aripiprazole augmentation was associated with reduced prolactin levels (p<0.001) and body weight (p=0.030). These data suggest that the common practice of antipsychotic augmentation in schizophrenia lacks double-blind/high-quality evidence for efficacy, except for negative symptom reduction with aripiprazole augmentation.
© 2017 World Psychiatric Association.
Suzuki T, Uchida H, Watanabe K, Nomura K, Takeuchi H, Tomita M, Tsunoda K, Nio S, Den R, Manki H, Tanabe A, Yagi G, Kashima H.
How effective is it to sequentially switch among Olanzapine, Quetiapine and Risperidone?--A randomized, open-label study of algorithm-based antipsychotic treatment to patients with symptomatic schizophrenia in the real-world clinical setting.
Psychopharmacology (Berl). 2007 Dec;195(2):285-95. doi: 10.1007/s00213-007-0872-2. Epub 2007 Aug 14.
Abstract/Text
RATIONALE: Evidence on sequential trial with atypical antipsychotics has been scarce.
OBJECTIVES: We conducted an algorithm-based antipsychotic pharmacotherapy.
MATERIALS AND METHODS: In this open-label study, patients with schizophrenia (DSM-IV) were treated with antipsychotic monotherapy, step-by-step, with each trial lasting up to 8 weeks. At baseline, they were highly symptomatic to score more than 54 in the total Brief Psychiatric Rating Scale (BPRS(1-7)) score. When the posttreatment BPRS score was above 70% of the baseline, they were subsequently treated with another and up to three atypicals. Basically, anticholinergics were prohibited, and only adjunctive allowed was lorazepam. The secondary endpoint was a clinical status good enough to be discharged for 66 inpatients and a successful continuation therapy with the same antipsychotic agent for more than 6 months for 12 outpatients.
RESULTS: Three groups of 26 patients each were randomized to Olanzapine, Quetiapine, or Risperidone. Thirty-nine (50%) responded to the first agent (Olanzapine16, Quetiapine9, Risperidone14), and 14 responded to the second. Only two showed response to the third, and 16 failed to respond to all three antipsychotics, with only 7 dropouts. Overall, there were 22 Olanzapine, 14 Quetiapine, and 19 Risperidone responders. Based on the secondary outcome, 20 Olanzapine-treated (average maximum dose, 15.4 mg), 10 Quetiapine-treated (418 mg), and 20 Risperidone-treated (4.10 mg) patients responded. The difference in response as the first choice was significant (p < 0.05). Relative doses of those failing to respond were comparable (Olanzapine 18.3 mg, Quetiapine 564 mg, Risperidone5.47 mg). Extrapyramidal symptoms did not change significantly.
CONCLUSIONS: When the first atypical antipsychotic is inadequate, switching to the second is worth trying, although some remain treatment-refractory. Quetiapine may be inferior to Olanzapine and Risperidone in symptomatic patients.
