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TITLE: Combination Atypical Antipsychotics in Adolescents or Adults with Bipolar
Disorder with Psychotic Features: A Review of Clinical and Cost-Effectiveness
and Guidelines
DATE: 06 September 2016
CONTEXT AND POLICY ISSUES
Bipolar disorder is a mental condition characterized by episodic mood swings between euphoric
or irritable mania and hopeless depression which can affect social activities, functioning, and
relationships.1 Episodes are typically followed by symptom-free periods referred to as
euthymia.1 According to a survey conducted in 2002, one percent (1%) of Canadians 15 years
and older demonstrated symptoms satisfying the criteria for bipolar disorder in the previous 12
months.2 Multiple types of bipolar disorders exist such as bipolar I, bipolar II and are defined in
the Diagnostic and Statistical Manual (5th edition; DSM-V) from the American Psychiatric
Association.3
Symptoms associated with mania can include increased creativity and productivity; however,
mania can also lead to immediate hospitalization or involuntary committal under the Mental
Health Act. Symptoms associated with depression can lead to increased rates of suicide and
suicide ideation.1 Bipolar disorder with psychotic features refers to manic or depressive
episodes including psychotic symptoms such as delusions or hallucinations. Psychotic features
manifest in over 50% of manic episodes and are more common in the latter than in depressive
episodes.4
Pharmacological treatment usually depends on the type of bipolar disorder (manic or
depressive); however, the most common treatments include lithium and valproic acid.5
Antipsychotic medications are also used to treat bipolar disorder and can be classified as typical
(first generation) or atypical (second generation).6 First generation antipsychotics mitigate
bipolar disorder symptoms by antagonizing dopamine D 2 receptors, while second generation
antipsychotics have an affinity for serotonin 5-hydroxytryptamine receptors and adrenergic
receptors in addition to being D2 receptor antagonists.6
Atypical antipsychotics, such as aripiprazole, olanzapine, quetiapine, risperidone and
ziprasidone can be prescribed as monotherapy or in combination with mood stabilizers and
Disclaimer: The Rapid Response Service is an information service for those involved in planning and providing health care in
Canada. Rapid responses are based on a limited literature search and are not comprehensive, systematic review s. The intent is to
provide a list of sources of the best evidence on the topic that the Canadian Agency for Drugs and Technologies in Health (CADTH)
could identify using all reasonable efforts within the time allow ed. Rapid responses should be considered along w ith other ty pes of
information and health care considerations. The information included in this response is not intended to replace professional medical
advice, nor should it be construed as a recommendation for or against the use of a particular health technology. Readers are also
cautioned that a lack of good quality evidence does not necessarily mean a lack of effectiveness particularly in the case of new and
emerging health technologies, for w hich little information can be found, but w hich may in future prove to be effective. While CADTH
has taken care in the preparation of the report to ensure that its contents are accurate, complete and up to date, CADTH does not
make any guarantee to that effect. CADTH is not liable for any loss or damages resulting from use of the information in the report.
Copyright: This report contains CADTH copyright material and may contain material in w hich a third party ow ns copyright. This
report m ay be used for the purposes of research or private study only. It may not be copied, posted on a w eb site,
redistributed by email or stored on an electronic system w ithout the prior w ritten permission of CADTH or applicable copyrigh t
ow ner.
Links: This report may contain links to other information available on the w ebsites of third parties on the Internet. CADTH does not
have control over the content of such sites. Use of third party sites is governed by the ow ners’ ow n terms and conditions.
antidepressants, as well as other treatment options.5 Although combinations of atypical
antipsychotics have been used for the treatment of other disorders, such as schizophrenia, the
effectiveness of combination therapy in bipolar disorder is unclear.7-9 This Rapid Response
report aims to review the clinical and cost-effectiveness of combination atypical antipsychotics in
adolescents or adults with bipolar disorder with psychotic features. Guidelines associated with
the use of combination atypical antipsychotics in adolescents or adults with bipolar disorder with
psychotic features will also be examined.
RESEARCH QUESTIONS
1.
What is the clinical effectiveness of combination atypical antipsychotics in adolescent or
adult patients with bipolar disorder with psychotic features?
2.
What is the cost-effectiveness of combination atypical antipsychotics in adolescent or
adult patients with bipolar disorder with psychotic features?
3.
What are the evidence-based guidelines associated with the use of combination atypical
antipsychotics in adolescent or adult patients with bipolar disorder with psychotic
features?
KEY FINDINGS
No relevant literature was identified pertaining to the clinical or cost effectiveness of combination
treatment of any atypical antipsychotics in adolescents and adults suffering from bipolar
disorder with psychotic features. Similarly, no evidence-based guidelines were identified from
the literature search
METHODS
Literature Search Methods
A limited literature search was conducted on key resources including Medline, PsychInfo,
Embase, PubMed, The Cochrane Library, University of York Centre for Reviews and
Dissemination (CRD) databases, Canadian and major international health technology agencies,
as well as a focused Internet search. Methodological filters were applied to limit retrieval to
health technology assessments, systematic reviews, meta-analyses, guidelines, economic
studies, randomized controlled trials and non-randomized studies. Where possible, retrieval was
limited to the human population. The search was also limited to English language documents
published between January 1, 2011 and August 4, 2016.
Selection Criteria and Methods
One reviewer screened citations and selected studies. In the first level of screening, titles and
abstracts were reviewed and potentially relevant articles were retrieved and assessed for
inclusion. The final selection of full-text articles was based on the inclusion criteria presented in
Table 1.
Combination Atypical Antipsychotics in Adolescents or Adults with Bipolar Disorder with Psychotic Features
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Population
Intervention
Comparator
Outcomes
Study Designs
Table 1: Selection Criteria
Adolescents and adults with bipolar disorder with psychotic features
Combination of any atypical antipsychotics (using either high or
regular dosing regimens)
Other drug combinations, atypical antipsychotics monotherapy,
placebo alone or in combination with an atypical antipsychotic, no
comparator
Clinical effectiveness, safety, cost-effectiveness and guidelines
Health technology assessment, systematic reviews, meta-analyses,
randomized controlled trials, non-randomized trials, economic
evaluations and guidelines
Exclusion Criteria
Articles were excluded if they did not meet the selection criteria outlined in Table 1, they were
duplicate publications, or were published prior to 2011.
SUMMARY OF EVIDENCE
Quantity of Research Available
A total of 874 citations were identified in the literature search. Following screening of titles and
abstracts, 848 citations were excluded and 26 potentially relevant reports from the electronic
search were retrieved for full-text review. No relevant reports were identified in the grey
literature. Of these potentially relevant articles, all 26 publications were excluded because they
did not meet the inclusion criteria. Appendix 1 describes the PRISMA flowchart of the study
selection.
Summary of Findings
No relevant literature on the clinical or cost effectiveness of combination treatment of any
atypical antipsychotics in adolescents and adults suffering from bipolar disorder with psychotic
features was identified. Similarly, no evidence-based guidelines were identified.
CONCLUSIONS AND IMPLICATIONS FOR DECISION OR POLICY MAKING
No relevant clinical evidence or guidelines of combination treatment of any atypical
antipsychotics in adolescents and adults suffering from bipolar disorder with psychotic features
were identified. However, NICE guidance on the assessment and management of bipolar
disorder in adults, children and young people in primary and secondary care may provide some
insight on atypical antipsychotic combination treatments.10 Based on evidence related to
schizophrenia, the guideline suggests not to initiate regular combined antipsychotic medication,
except for short periods of time (e.g. when changing medication). Although the NICE guideline
does not recommend the combination of atypical antipsychotics for treatment of bipolar
disorder, it should be noted that the recommendation is made on the basis that antipsychotics
will have the same metabolic effects on people with bipolar disorder as they do on people with
schizophrenia and based on the general bipolar population (i.e. not necessarily patients
suffering from bipolar disorder with psychotic features).10
Combination Atypical Antipsychotics in Adolescents or Adults with Bipolar Disorder with Psychotic Features
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PREPARED BY:
Canadian Agency for Drugs and Technologies in Health
Tel: 1-866-898-8439
www.cadth.ca
Combination Atypical Antipsychotics in Adolescents or Adults with Bipolar Disorder with Psychotic Features
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REFERENCES
1.
Bipolar disorder: identifying and supporting patients in primary care. BPJ [Internet]. 2014
Jul [cited 2016 Aug 10];62:7-17. Available from:
http://bpac.org.nz/BPJ/2014/July/docs/BPJ62-bipolar.pdf
2.
What should I know about bipolar disorder (manic-depression)? [Internet]. Ottawa: Public
Health Agency of Canada; 2016. [cited 2016 Aug 10]. Available from: http://www.phacaspc.gc.ca/cd-mc/mi-mm/bipolar-bipolaire-eng.php
3.
Diagnostic and statistical manual of mental disorders: DSM-V. Arlington (VA): American
Psychiatric Association; 2013.
4.
Hirschfeld R, Bowden CL, Gitlin MJ, Keck PE, Suppes T, Thase ME, et al. Practice
guideline for the treatment of patients with bipolar disorder [Internet]. 2nd ed. Arlington
(VA): American Psychiatric Association Publishing; 2016. [cited 2016 Aug 10]. Available
from:
http://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/bipolar.pd
f
5.
Severus E, Schaaff N, Moller HJ. State of the art: treatment of bipolar disorders. CNS
Neurosci Ther. 2012 Mar;18(3):214-8.
6.
Chauhan A, Mittal A, Arora OK. Atypical antipsychotics from scratch to the present.
International Journal of Pharmaceutical Sciences and Research. 2013;4(1):184-204.
7.
Yasui-Furukori N, Kaneda A, Sugawara N, Tomita T, Kaneko S. Effect of adjunctive
treatment with aripiprazole to atypical antipsychotics on cognitive function in schizophrenia
patients. J Psychopharmacol. 2012 Jun;26(6):806-12.
8.
Kontis D, Theochari E, Ritsner MS. Antipsychotic polypharmacy in psychosis. Directions in
Psychiatry. 2014;34(2):85-99.
9.
Gee S, Taylor D. Overview of pharmacological treatments and guidelines. In: Buckley PF,
Gaughran F, editors. Treatment--refractory schizophrenia. Cham (CH): Springer; 2014 Jan
28. Chapter 5. p. 65-80.
10.
National Collaborating Centre for Mental Health. Bipolar disorder: The assessment and
management of bipolar disorder in adults, children and young people in primary and
secondary care [Internet]. Updated ed. London (GB): The British Psychological Society
and The Royal College of Psychiatrists; 2014. [cited 2016 Sep 23]. (National clinical
guideline no. 185). Available from: https://www.nice.org.uk/guidance/cg185/evidence/fullguideline-193212829
Combination Atypical Antipsychotics in Adolescents or Adults with Bipolar Disorder with Psychotic Features
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APPENDIX 1: Selection of Included Studies
874 citations identified from
electronic literature search and
screened
848 citations excluded
26 potentially relevant articles
retrieved for scrutiny (full text, if
available)
0 potentially relevant
reports retrieved from
other sources (grey
literature, hand
search)
26 potentially relevant reports
26 reports excluded:
-irrelevant population (5)
-irrelevant intervention (20)
-other (review articles, editorials)(1)
0 reports included in review
Combination Atypical Antipsychotics in Adolescents or Adults with Bipolar Disorder with Psychotic Features
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