Tolerability of atypical antipsychotics in the treatment of adults with schizophrenia or bipolar disorder: A mixed treatment comparison of randomized controlled trials

doi:10.1016/j.clinthera.2009.07.004

Clinical Therapeutics

Volume 31, Part 1, 2009, Pages 1345-1359

https://doi.org/10.1016/j.clinthera.2009.07.004 Get rights and content

Abstract

Objective: This article reviews and compares the tolerability profiles of atypical antipsychotics in adults with schizophrenia or bipolar disorder in randomized controlled trials (RCTs).

Methods: A systematic search of the BIOSIS, Cochrane Central Register of Controlled Trials, EMBASE, MEDLINE, and PsycINFO databases was conducted for English-language papers and abstracts that reported RCTs comparing ≥2 atypical antipsychotics (aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone) in the treatment of adult patients with schizophrenia or bipolar disorder. The search was completed in December 2007. A panel of 4 psychiatrists with expertise in the treatment of schizophrenia, schizoaffective disorder, or bipolar disorder identified potentially relevant outcomes that would reflect patients' subjective perception of adverse effects during treatment with antipsychotic medications. These outcomes were daily activities, anxiety or depression, bodily anxiety or restlessness, dizziness or nausea, extrapyramidal symptoms (EPS), sexual dysfunction, stiffness or tremor, tiredness or weakness, and weight gain. Data on these outcomes were extracted from relevant studies, and mixed treatment comparisons were conducted using Bayesian Markov Chain Monte Carlo simulation. Summary effect estimates (odds ratios [ORs] and 95% credible intervals [95% CrIs]) were calculated and reported in comparison with risperidone.

Results: The search identified 2963 potentially relevant publications, of which 50 provided data on 48 RCTs comparing ≥2 atypical antipsychotics. Outcomes that were statistically significant compared with risperi-done at the 5% level were decreased bodily anxiety or restlessness with quetiapine (OR = 0.506; 95% CrI = 0.290, 0.789), decreased EPS with quetiapine (OR = 0.441; 95% CrI = 0.129, 0.910), increased weight gain with olanzapine (OR = 2.139; 95% CrI = 1.764, 2.626), and decreased weight gain with ziprasidone (OR = 0.466; 95% CrI = 0.317, 0.657).

Conclusion: The atypical antipsychotics had mixed tolerability profiles in this mixed treatment comparison, with some agents having significantly greater tolerability than others depending on the outcome assessed.

References (86)

R Tandon et al.
Efficacy of newer generation antipsychotics in the treatment of schizophrenia
Psychoneuroendocrinology
(2003)
D Moher et al.
Does quality of reports of randomised trials affect estimates of intervention efficacy reported in meta-analyses?
Lancet
(1998)
RS Keefe et al.
One-year double-blind study of the neurocognitive efficacy of olanzapine, risperidone, and haloperidol in schizophrenia
Schizophr Res.
(2006)
DL Kelly et al.
A randomized double-blind 12-week study of quetiapine, risperidone or fluphenazine on sexual functioning in people with schizophrenia
Psychoneuroendocrinology
(2006)
J Mullen et al.
A comparison of the relative safety, efficacy, and tolerability of quetiapine and risperidone in outpatients with schizophrenia and other psychotic disorders: The Quetiapine Experience with Safety and Tolerability (QUEST) study
Clin Ther.
(2001)
O Gureje et al.
Olanzapine vs risperidone in the management of schizophrenia: A randomized double-blind trial in Australia and New Zealand
Schizophr Res.
(2003)
SG Potkin et al.
A double-blind comparison of risperidone, quetiapine and placebo in patients with schizophrenia experiencing an acute exacerbation requiring hospitalization
Schizophr Res.
(2006)
SL Tunis et al.
Cost-effectiveness of olanzapine as first-line treatment for schizophrenia: Results from a randomized, open-label, 1-year trial
Value Health.
(2006)
X Wang et al.
Efficacy of risperidone versus olanzapine in patients with schizophrenia previously on chronic conventional antipsychotic therapy: A switch study
J Psychiatr Res.
(2006)
LA Arvanitis et al.
Multiple fixed doses of “Seroquel” (quetiapine) in patients with acute exacerbation of schizophrenia: A comparison with haloperidol and placebo
Biol Psychiatry.
(1997)

AJ Cutler

Sexual dysfunction and antipsychotic treatment

Psychoneuroen-docrinology.

(2003)

PJ Weiden et al.

Obesity as a risk factor for an-tipsychotic noncompliance

Schizophr Res.

(2004)

CM Beasley et al.

Olanzapine versus placebo and haloperidol: Acute phase results of the North American doubleblind olanzapine trial

Neuropsychopharmacology.

(1996)

Clozaril (clozapine) 25 mg and 100 mg tablets [product characteristics]

(October 2005)

A Essali et al.

Clozapine versus typical neuroleptic medication for schizophrenia

Cochrane Database Syst Rev.

(2009)

DC Henderson et al.

Clozapine, diabetes mellitus, weight gain, and lipid abnormalities: A five-year naturalistic study

Am J Psychiatry.

(2000)

DE Tenback et al.

Effects of antipsychotic treatment on tardive dyskinesia: A 6-month evaluation of patients from the European Schizophrenia Outpatient Health Outcomes (SOHO) Study

J Clin Psychiatry.

(2005)

V Folnegović-Šmalc et al.

Side effect profile of atypical antipsychotic medications and comparison to conventional antipsychotics

Soc Psihijatrija.

(2003)

L Motlová et al.

Are there any differences in the efficacy among second generation antipsychotics in the treatment of schizophrenia and related disorders?

Ann Clin Psychiatry.

(2007)

RH Perlis et al.

Atypical antipsychotics in the treatment of mania: A meta-analysis of randomized, placebo-controlled trials

J Clin Psychiatry.

(2006)

A Serretti et al.

New antipsychotics and schizophrenia: A review on efficacy and side effects

Curr Med Chem.

(2004)

M Srisurapanont et al.

Comparison of the efficacy and acceptability of atypical antipsychotic drugs: A meta-analysis of randomized, placebo-controlled trials

J Med Assoc Thai.

(1999)

Schizophrenia: Core interventions in the treatment and management of schizophrenia in primary and secondary care

(December 2002)

KS Khan et al.

Development of a review protocol

TC Chalmers et al.

Bias in treatment assignment in controlled clinical trials

N Engl J Med.

(1983)

KF Schulz et al.

Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials

JAMA.

(1995)

DJ Lunn et al.

WinBUGS—a Bayesian modelling framework: Concepts, structure, and extensibility

Stat Comput.

(2000)

DM Caldwell et al.

Simultaneous comparison of multiple treatments: Combining direct and indirect evidence

BMJ.

(2005)

G Lu et al.

Combination of direct and indirect evidence in mixed treatment comparisons

Stat Med.

(2004)

AP Dempster

The direct use of likelihood for significance testing

Stat Comput.

(1997)

SJ Edwards et al.

Indirect comparisons of treatments based on systematic reviews of randomised controlled trials

Int J Clin Pract.

(2009)

JA Lieberman et al.

Effectiveness of antipsychotic drugs in patients with chronic schizophrenia

N Engl J Med.

(2005)

PV Tran et al.

Double-blind comparison of olanzapine versus risperidone in the treatment of schizophrenia and other psychotic disorders

J Clin Psychopharmacol.

(1997)

SE Purdon et al.

Neuropsychological change in early phase schizophrenia during 12 months of treatment with olan-zapine, risperidone, or haloperidol

Arch Gen Psychiatry.

(2000)

RR Conley et al.

A randomized double-blind study of risperidone and olanzapine in the treatment of schizophrenia or schizoaffective disorder [published correction appears in Am J Psychiatry. 2001;158:1759]

Am J Psychiatry.

(2001)

PD Harvey et al.

Changes in cognitive functioning with risperidone and olanzapine treatment: A large-scale, double-blind, randomized study

Psychopharmacology (Berl).

(2003)

BJ Kinon et al.

Randomized, double-blind 6-month comparison of olanzapine and quetiapine in patients with schizophrenia or schizoaffective disorder with prominent negative symptoms and poor functioning

J Clin Psychopharmacol.

(2006)

BJ Kinon et al.

A 24-week randomized study of olanzapine versus ziprasidone in the treatment of schizophrenia or schizoaffective disorder in patients with prominent depressive symptoms

J Clin Psychopharmacol.

(2006)

J Volavka et al.

Clozapine, olanzapine, risperidone, and haloperidol in the treatment of patients with chronic schizophrenia and schizoaffective disorder [published correction appears in Am J Psychiatry. 2002;159:2132]

Am J Psychiatry.

(2002)

P Czobor et al.

Antipsychotic-induced weight gain and therapeutic response: A differential association

J Clin Psychopharmacol

(2002)

H Knegtering et al.

A randomized open-label comparison of the impact of olanzapine versus risperidone on sexual functioning

J Sex Marital Ther.

(2006)

DE Casey et al.

Effect of divalproex combined with olanzapine or risperidone in patients with an acute exacerbation of schizophrenia

Neuropsychopharmacology

(2003)

Cited by (40)

The prevention of relapses in first episodes of schizophrenia: The 2EPs Project, background, rationale and study design
2021, Revista de Psiquiatria y Salud Mental
Citation Excerpt :
The complete methods and the inter-rater reliability results have been described previously in a specific work.76 The assessment of adherence has been performed with standardized scales and complemented with various biochemical measurements such as drug concentrations in blood or saliva; The Scale to Assess Unawareness of Mental Disorder (SUMD),77 which is a semi-structured open interview that evaluates global insight, insight into illness and insight into symptoms; the Morisky Green Levine Medication Adherence Scale (MGLS), used for measuring the extent of medication non-adherence,78 and the Tolerability and Quality of Life Questionnaire (TOOL), which evaluates the impact of the adverse effects of antipsychotic drugs on patients.79 Monitoring of antipsychotic concentrations is recommended for all these therapeutic agents that have limited therapeutic ranges and are at high risk for associated severe adverse effects.
Up to 80% of first-episode psychosis patients suffer a relapse within five years of the remission. Relapse should be an important focus of prevention given the potential harm to the patient and family. It threatens to disrupt their psychosocial recovery, increases the risk of resistance to treatment and has been associated with greater direct and indirect costs for society.
Based on a previous project entitled “Genotype–phenotype and environment. Application to a predictive model in first psychotic episodes” (PEPs Project), the project “Clinical and neurobiological determinants of second episodes of schizophrenia. Longitudinal study of first episode of psychosis” was designed, also known as the 2EPs Project. It aimed to identify and characterize those factors that predict a relapse within the years immediately following a first episode. This project has focused on following the clinical course, with neuropsychological assessments, biological and neuroanatomical measures, genetic adherence and physical health monitoring in order to compare a subgroup of patients with a second episode to another group of patients which remains in remission. The main objective of the present article is to describe the rationale of the 2EPs Project, explaining the measurement approach adopted and providing an overview of the selected clinical and functional measures.
2EPs Project is a multicenter, coordinated, naturalistic, longitudinal follow-up study over three years in a Spanish sample of patients in remission after a first-psychotic episode of schizophrenia. It is closely monitoring the clinical course of the cases recruited to compare the subgroup of patients with a second episode to that which remains in remission. The sample is composed of 223 subjects recruited from 15 clinical centres in Spain with experience of the preceding PEPs Study project, albeit 2EPs being an expanded version with new basic groups in biological research. From the total sample recruited, 63 patients presented a relapse (44%).
2EPs arose to characterize first episodes in an exhaustive, novel and multimodal way, thus contributing towards the development of a predictive model of relapse. Identifying the characteristics of patients who relapse could improve early detection and intervention.
Hasta el 80% de los pacientes con un primer episodio de psicosis experimentan una recaída dentro del plazo de 5 años desde la remisión. Dicha recidiva debería constituir un importante enfoque de prevención, dado el daño potencial al paciente y sus familiares, ya que amenaza con perturbar su recuperación psicosocial, incrementa el riesgo de resistencia al tratamiento y se ha asociado a mayores costes directos e indirectos para la sociedad.
Basado en un proyecto anterior denominado «Genotipo-fenotipo y entorno. Aplicación a un modelo predictivo en primeros episodios psicóticos –Proyecto PEPs–» (Genotype-phenotype and environment. Application to a predictive model in first psychotic episodes –PEPs Project–), se diseñó el proyecto «Determinantes clínicos y neurobiológicos de segundos episodios de esquizofrenia. Estudio longitudinal del primer episodio de psicosis» (Clinical and neurobiological determinants of second episodes of schizophrenia. Longitudinal study of first episode of psychosis), también conocido como proyecto 2EPs. Su objetivo fue identificar y caracterizar aquellos factores predictivos de recaída dentro del periodo inmediatamente posterior al primer episodio. Este proyecto se centró también en el seguimiento de la evolución clínica, con evaluaciones neuropsicológicas, medidas biológicas y neuroanatómicas, adherencia genética y supervisión de la salud física, a fin de comparar un subgrupo de pacientes que había tenido un segundo episodio con otro grupo de pacientes que sigue en remisión. El principal objetivo del presente artículo es describir el fundamento del Proyecto 2EPs, explicando el enfoque de medición adoptado y aportando una perspectiva general de las medidas clínicas y funcionales seleccionadas.
El Proyecto 2EPs es un estudio multicéntrico, coordinado, naturalista y de seguimiento longitudinal, realizado a lo largo de 3 años, en una muestra de pacientes españoles en remisión tras un primer episodio psicótico de esquizofrenia. Supervisa estrechamente la evolución clínica de los casos seleccionados, para comparar el subgrupo de pacientes que había presentado un segundo episodio con aquellos que siguen en remisión. La muestra se compone de 223 sujetos seleccionados de 15 centros clínicos en España con experiencia en el proyecto del Estudio PEPs anterior, aunque el Proyecto 2EPs constituye una versión ampliada con nuevos grupos básicos en investigación biológica. De la muestra total seleccionada, 63 pacientes presentaron una recaída (44%).
El Proyecto 2EPs surgió para caracterizar los primeros episodios de modo exhaustivo, novedoso y multimodal, contribuyendo así al desarrollo de un modelo predictivo de una recaída. Identificar las características de los pacientes con recidiva podría mejorar la detección e intervención tempranas.
Second generation antipsychotics in bipolar depression: A new therapeutic option?
2011, Encephale
La dépression bipolaire est extrêmement fréquente et a des conséquences pronostiques et fonctionnelles majeures pour les sujets souffrant de troubles bipolaires.
Si les antidépresseurs restent des molécules d’emploi difficile dans cette indication, à côté des anticonvulsivants, ce sont les antipsychotiques de seconde génération (APIIG) qui possèdent le profil d’action le plus intéressant tant en ce qui concerne l’efficacité en phase aiguë qu’en phase de maintenance.
Dans ce groupe hétérogène c’est la quétiapine et l’olanzapine qui montrent la plus grande efficacité ; toutefois pour l’emploi en monothérapie les recommandations professionnelles internationales préconisent la quétiapine en traitement de première ligne.
Il reste impératif de considérer le profil d’action de ces molécules qui possèdent des caractéristiques distinctes des autres composés utilisés (anticonvulsivants, Lithium). Ceci permet aujourd’hui de définir les stratégies les plus adaptées pour favoriser l’observance au long cours.
Bipolar depression, the most common phase of bipolar disorder, causes significant morbidity and mortality. Lithium, anticonvulsivants or antidepressants offer some clinical efficacy. However, efficacy can be limited and side effects are sometimes problematic. There is still a major unmet need for effective, well-tolerated agents for the treatment of bipolar depression. The second-generation antipsychotics, with their proven efficacy against manic symptoms, are emerging as candidates for use against the depressive phase of bipolar disorder. Several studies have shown that some second-generation antipsychotics may improve depressive symptoms in mixed episodes in patients with bipolar disorder. More recently, specific studies have been performed in patients with bipolar depressive episodes. Quetiapine or olanzapine, as monotherapy or associated with other compounds, demonstrate an interesting efficacy. The international guidelines for the treatment of bipolar depression have identified quétiapine as a first line treatment in monotherapy. Second generation antipsychotics may prove to be important future treatments for patients with bipolar depression.
Exhaustive in silico design and screening of novel antipsychotic compounds with improved pharmacodynamics and blood-brain barrier permeation properties
2023, Journal of Biomolecular Structure and Dynamics
Pharmacotherapy of neuropsychiatric disturbances
2021, Brain Injury Medicine, Third Edition: Principles and Practice
Prevalence and pattern of antipsychotic induced movement disorders in a tertiary care teaching hospital in India–a cross-sectional study
2018, International Journal of Psychiatry in Clinical Practice
Inflammation: Opportunities for treatment stratification among individuals diagnosed with mood disorders
2017, Dialogues in Clinical Neuroscience

View all citing articles on Scopus

View full text

Tolerability of atypical antipsychotics in the treatment of adults with schizophrenia or bipolar disorder: A mixed treatment comparison of randomized controlled trials

Abstract

Psychoneuroendocrinology

Lancet

Schizophr Res.

Psychoneuroendocrinology

Clin Ther.

Schizophr Res.

Schizophr Res.

Value Health.

J Psychiatr Res.

Biol Psychiatry.

Psychoneuroen-docrinology.

Schizophr Res.

Neuropsychopharmacology.

Clozaril (clozapine) 25 mg and 100 mg tablets [product characteristics]

Clozapine versus typical neuroleptic medication for schizophrenia

Cochrane Database Syst Rev.

Clozapine, diabetes mellitus, weight gain, and lipid abnormalities: A five-year naturalistic study

Am J Psychiatry.

Effects of antipsychotic treatment on tardive dyskinesia: A 6-month evaluation of patients from the European Schizophrenia Outpatient Health Outcomes (SOHO) Study

J Clin Psychiatry.

Side effect profile of atypical antipsychotic medications and comparison to conventional antipsychotics

Soc Psihijatrija.

Are there any differences in the efficacy among second generation antipsychotics in the treatment of schizophrenia and related disorders?

Ann Clin Psychiatry.

Atypical antipsychotics in the treatment of mania: A meta-analysis of randomized, placebo-controlled trials

J Clin Psychiatry.

New antipsychotics and schizophrenia: A review on efficacy and side effects

Curr Med Chem.

Comparison of the efficacy and acceptability of atypical antipsychotic drugs: A meta-analysis of randomized, placebo-controlled trials

J Med Assoc Thai.

Schizophrenia: Core interventions in the treatment and management of schizophrenia in primary and secondary care

Development of a review protocol

Bias in treatment assignment in controlled clinical trials

N Engl J Med.

Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials

JAMA.

WinBUGS—a Bayesian modelling framework: Concepts, structure, and extensibility

Stat Comput.

Simultaneous comparison of multiple treatments: Combining direct and indirect evidence

BMJ.

Combination of direct and indirect evidence in mixed treatment comparisons

Stat Med.

The direct use of likelihood for significance testing

Stat Comput.

Indirect comparisons of treatments based on systematic reviews of randomised controlled trials

Int J Clin Pract.

Effectiveness of antipsychotic drugs in patients with chronic schizophrenia

N Engl J Med.

Double-blind comparison of olanzapine versus risperidone in the treatment of schizophrenia and other psychotic disorders

J Clin Psychopharmacol.

Neuropsychological change in early phase schizophrenia during 12 months of treatment with olan-zapine, risperidone, or haloperidol

Arch Gen Psychiatry.

A randomized double-blind study of risperidone and olanzapine in the treatment of schizophrenia or schizoaffective disorder [published correction appears in Am J Psychiatry. 2001;158:1759]

Am J Psychiatry.

Changes in cognitive functioning with risperidone and olanzapine treatment: A large-scale, double-blind, randomized study

Psychopharmacology (Berl).

Randomized, double-blind 6-month comparison of olanzapine and quetiapine in patients with schizophrenia or schizoaffective disorder with prominent negative symptoms and poor functioning

J Clin Psychopharmacol.

A 24-week randomized study of olanzapine versus ziprasidone in the treatment of schizophrenia or schizoaffective disorder in patients with prominent depressive symptoms

J Clin Psychopharmacol.

Clozapine, olanzapine, risperidone, and haloperidol in the treatment of patients with chronic schizophrenia and schizoaffective disorder [published correction appears in Am J Psychiatry. 2002;159:2132]

Am J Psychiatry.

Antipsychotic-induced weight gain and therapeutic response: A differential association

J Clin Psychopharmacol

A randomized open-label comparison of the impact of olanzapine versus risperidone on sexual functioning

J Sex Marital Ther.

Effect of divalproex combined with olanzapine or risperidone in patients with an acute exacerbation of schizophrenia

Neuropsychopharmacology