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Solved by verified expert:Please answer the following questions for medications below: Abilify (aripiprazole) Lithobid (Lithium) and risperidone- answer questions below for each medicationIntroductionWhy is this good medication for bipolar with mania? What is your rationale for choosing this medication?Are there any contraindications or safety issues associated with this medication?Please answer for each medication separately. Please include in text citations within the last 10 years. And references. you may search additonal than the ones below. 2 pages.


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DOI: 10.1111/bdi.12609
Canadian Network for Mood and Anxiety Treatments (CANMAT)
and International Society for Bipolar Disorders (ISBD) 2018
guidelines for the management of patients with bipolar disorder
Lakshmi N Yatham1 | Sidney H Kennedy2
David J Bond
| Benicio N Frey
| Serge Beaulieu
Soham Rej
| Sagar V Parikh3 | Ayal Schaffer2
| Verinder Sharma
| Benjamin I Goldstein
| Martin Alda
| Glenda MacQueen
| Diane McIntosh1 |
Roumen V Milev
| Arun Ravindran
Raymond W Lam1
| Gustavo Vazquez10 | Flavio Kapczinski5 | Roger S McIntyre2
Jan Kozicky
| Shigenobu Kanba
Joseph R Calabrese
| Claire O’Donovan
| Beny Lafer
| Eduard Vieta
| Trisha Suppes
| Gin Malhi
| Robert M Post
Michael Berk
Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada
Department of Psychiatry, University of Toronto, Toronto, ON, Canada
Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA
Department of Psychiatry, University of Minnesota, Minneapolis, MN, USA
Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON, Canada
Departments of Psychiatry and Obstetrics & Gynaecology, Western University, London, ON, Canada
Department of Psychiatry, McGill University, Montreal, QC, Canada
Department of Psychiatry, Dalhousie University, Halifax, NS, Canada
Department of Psychiatry, University of Calgary, Calgary, AB, Canada
Departments of Psychiatry and Psychology, Queen’s University, Kingston, ON, Canada
School of Population and Public Health, University of British Columbia, Vancouver, BC, Canada
Department of Neuropsychiatry, Kyushu University, Fukuoka, Japan
Department of Psychiatry, University of Sao Paulo, Sao Paulo, Brazil
Bipolar and Depression Research Program, VA Palo Alto, Department of Psychiatry & Behavioral Sciences Stanford University, Stanford, CA, USA
Department of Psychiatry, University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, OH, USA
Bipolar Unit, Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain
Department of Psychiatry, University of Sydney, Sydney, NSW, Australia
Department of Psychiatry, George Washington University, Washington, DC, USA
Deakin Univeristy, IMPACT Strategic Research Centre, School of Medicine, Barwon Health, Geelong, Vic., Australia
Lakshmi N Yatham, Department of Psychiatry,
University of British Columbia, Vancouver, BC,
Bipolar Disorders. 2018;20:97–170.
© 2018 John Wiley & Sons A/S.
Published by John Wiley & Sons Ltd
YATHAM et al.
The Canadian Network for Mood and Anxiety Treatments (CANMAT) previously published treatment guidelines for bipolar disorder in 2005, along with international commentaries and subsequent updates in 2007, 2009, and 2013. The last two updates
were published in collaboration with the International Society for Bipolar Disorders
(ISBD). These 2018 CANMAT and ISBD Bipolar Treatment Guidelines represent the
significant advances in the field since the last full edition was published in 2005, including updates to diagnosis and management as well as new research into pharmacological and psychological treatments. These advances have been translated into clear and
easy to use recommendations for first­, second, and third- line treatments, with consideration given to levels of evidence for efficacy, clinical support based on experience,
and consensus ratings of safety, tolerability, and treatment-­emergent switch risk. New
to these guidelines, hierarchical rankings were created for first­and second-­line treatments recommended for acute mania, acute depression, and maintenance treatment in
bipolar I disorder. Created by considering the impact of each treatment across all
phases of illness, this hierarchy will further assist clinicians in making evidence-­based
treatment decisions. Lithium, quetiapine, divalproex, asenapine, aripiprazole, paliperidone, risperidone, and cariprazine alone or in combination are recommended as first-­
line treatments for acute mania. First-­line options for bipolar I depression include
quetiapine, lurasidone plus lithium or divalproex, lithium, lamotrigine, lurasidone, or
adjunctive lamotrigine. While medications that have been shown to be effective for
the acute phase should generally be continued for the maintenance phase in bipolar I
disorder, there are some exceptions (such as with antidepressants); and available data
suggest that lithium, quetiapine, divalproex, lamotrigine, asenapine, and aripiprazole
monotherapy or combination treatments should be considered first-line for those initiating or switching treatment during the maintenance phase. In addition to addressing
issues in bipolar I disorder, these guidelines also provide an overview of, and recommendations for, clinical management of bipolar II disorder, as well as advice on specific
populations, such as women at various stages of the reproductive cycle, children and
adolescents, and older adults. There are also discussions on the impact of specific psychiatric and medical comorbidities such as substance use, anxiety, and metabolic disorders. Finally, an overview of issues related to safety and monitoring is provided. The
CANMAT and ISBD groups hope that these guidelines become a valuable tool for practitioners across the globe.
of the range of interventions available for this complex and varied illness, with the goal of providing clear, easy to use recommendations
In the 20 years since the Canadian Network for Mood and Anxiety
for clinicians to improve outcomes in their patients.
Treatments (CANMAT) first published guidelines on the management
Given that 13 years have elapsed since the publication of the last
of BD (BD),1 there has been an explosion of research on treatment of
full edition in 2005, the objective of these 2018 CANMAT and ISBD
this illness. During this time period, CANMAT has strived to translate
Bipolar Disorder Management Guidelines is to provide a compre-
advances in research into international consensus on evidence-­based
hensive, up-to-date review of research evidence on the treatment
clinical management; first by publishing 2005 guidelines accompanied
of various phases of BD, translated into clinical recommendations
by expert commentaries, then by providing updates in 2007,2 20093
for evidence-­based management. Updated principles related to di-
and 20134 in collaboration with the International Society for Bipolar
agnosis and management are also included, in response to signif-
Disorders (ISBD). The main objective of these publications was to syn-
icant changes made in the 5th edition of the American Psychiatric
thesize the wealth of evidence on the efficacy, safety, and tolerability
Association Diagnostic and Statistical Manual for Mental Disorders
YATHAM et al.
(DSM-­5).5 With increased research into various treatments for BD,
the evidence ratings have also been modified to increase rigor; for
instance, minimum sample sizes are now specified for randomized
controlled trials (RCTs) at each level of evidence (Table 1).
Definitions for line of treatment ratings
Evidence level
Level 1 or level 2 evidence for efficacy plus
clinical support for safety/tolerability and no
risk of treatment-­emergent switcha
Level 3 or higher evidence for efficacy plus
clinical support for safety/tolerability and low
risk of treatment-­emergent switcha
Level 4 evidence or higher for efficacy plus
clinical support for safety/tolerability
Not recommended
Level 1 evidence for lack of efficacy, or level 2
evidence for lack of efficacy plus expert
As with previous editions of CANMAT guidelines, clinical support
for efficacy was an important consideration in arriving at the final
treatment recommendations (Table 2). Major conflicting data are addressed in blue text boxes (figures) to clarify the rationale for arriving
at a specific level of evidence for efficacy.
In the current edition, an additional distinction is made between
safety and tolerability, and a consensus rating is assigned to each
medication on these two measures when used in both the acute
and maintenance phase. Further, a rating is also assigned to each
medication for its propensity to switch patients into mania or depression (treatment-emergent switch). More information on these
ratings can be found in the respective treatment sections, as well
The text will specifically note when lack of clinical support for safety/
tolerability or risk of treatment-emergent switch has impacted
as in Section 8.
The final grading of recommendations into first, second, or third-
previous ongoing treatment was partially effective, and the addition of
line considers levels of evidence for efficacy, clinical support based
the new agent will provide benefits in either an additive or synergistic
on experience, and consensus ratings of safety, tolerability, and risk
manner. In contrast, agents specifically listed as adjunctive therapy may
of treatment-­emergent switch. In addition, hierarchical rankings were
have no evidence for efficacy as monotherapy, and/or may have safety
created and are listed in the tables for first­and second line recom-
concerns if prescribed as monotherapy (eg. antidepressants), and are
mendations for acute mania, depression and maintenance treatment
only recommended for use in combination with other evidence-­based
in bipolar I disorder (BDI). This hierarchy was created by considering
the impact of each treatment across all phases of illness (Figure 1).
As with previous editions, these guidelines also have a “not rec-
The rationale for the hierarchical approach is that BD is a chronic
ommended” category which includes treatments that have clearly
lifetime condition with recurrent mood episodes and subsyndromal
been shown to be ineffective in double-­blind RCTs. Further, we have
mood symptoms, and most if not all patients will require maintenance
included another category called “no specific recommendation/agents
treatment. Since treatments that are prescribed for an acute mood ep-
that require further study” to list treatments with insufficient evidence
isode are usually continued into maintenance treatment, maintenance
or clinical experience to make a recommendation, or where there is a
efficacy should be considered when choosing acute-­phase treatments.
reason to believe that negative trials failed because of methodologi-
Treatments that have demonstrated efficacy across the spectrum
cal problems-especially when the results are inconsistent with what is
of the illness should thus be tried first before treatments that have
expected based on the pharmacological properties of treatment and
demonstrated efficacy for only selective phases of the disorder. As an
clinical experience. Inclusion in this category means the efficacy of
example, if two treatments are shown to be similarly effective in acute
these agents is unknown at this time.
mania, and if only one of these treatments has demonstrated efficacy
As in previous editions, these guidelines are organized into eight
for maintenance treatment, the treatment with evidence for mainte-
sections (Table 3), including the Introduction. Foundations of man-
nance would be placed higher in the hierarchical ranking.
agement (Section 2) discusses the epidemiology of BD, screening
Of note, when a treatment is listed as a monotherapy, that implies
and diagnostic considerations, the importance of monitoring risk for
that it may be used on its own or in combination with other ongoing
suicide, the chronic disease management model and patient-­centred
treatments, even if there are no specific studies demonstrating the ef-
care (including shared decision making), as well the importance of
ficacy of that combination. In this situation, the assumption is that the
incorporating psychoeducation and other psychosocial treatment
Definitions for level of evidence ratings
Meta-­analysis with narrow confidence interval or replicated double-­blind (DB), randomized controlled trial (RCT) that
includes a placebo or active control comparison (n ≥ 30 in each active treatment arm)
Meta-­analysis with wide confidence interval or one DB RCT with placebo or active control comparison condition
(n ≥ 30 in each active treatment arm)
At least one DB RCT with placebo or active control comparison condition (n = 10-­29 in each active treatment arm) or
health system administrative data
Uncontrolled trial, anecdotal reports, or expert opinion
YATHAM et al.
What are hierarchical rankings?
Hierarchical rankings of treatment op ons are new to the 2018 Guidelines. They were created for first and second line treatment
recommenda ons for acute mania, depression, and maintenance treatment of bipolar I disorder; and will further assist clinicians in making
evidence based treatment decisions.
These orders were created by considering the efficacy of each treatment across all phases, as well as acute and maintenance safety and
tolerability and the risk for treatment emergent switch. Thus, for example if two treatments were shown to be similarly effec ve in acute
mania, and if only one of these treatments has demonstrated efficacy for maintenance treatment, or had be€er safety or tolerability, that
treatment would be placed higher in the hierarchical recommenda on.
When making treatment decisions, we recommend that agents listed higher in the hierarchy be tried first, unless there are pa ent-specific
reasons for choosing an agent lower in the order (such as pa ent preference, prior treatment non/response, or clinical features which favor
treatments lower in the ranking).
F I G U R E 1 Hierarchical rankings of treatment recommendations: How were they arrived at? [Colour figure can be viewed at]
Section 1: Introduction
Section 2: Foundations of management
Section 3: Acute management of bipolar mania
Section 4: Acute management of bipolar I depression
Section 5: Maintenance therapy for bipolar I disorder
applicable for practitioners from across the globe. As with previous
publications, CANMAT will strive to publish regular updates to these
guidelines, incorporating new knowledge useful for practising clinicians.
As not all medications included in these guidelines will be available
in all countries, including Canada, clinicians are advised to follow the
recommendations of local regulatory bodies.
Section 6: Bipolar II disorder
Section 7: Specific populations
Section 8: Safety and monitoring
strategies into treatment. Additional information on presentation
and hierarchical rankings of treatment options for acute mania
(Section 3) and depression (Section 4) are reviewed, and include
descriptions of clinical features that may help direct treatment
choices. The importance of long-­term maintenance treatment and
promotion of treatment adherence for mood stability, as well as hierarchical rankings of treatment options are discussed in Section 5.
An expert review of the available evidence for treatments of bipolar
II disorder (BDII) and recommendations based on those findings are
presented in Section 6. The management issues related to specific
populations, including women at various stages of the reproductive
cycle, children and adolescents, older adults, and those with psychiatric or medical comorbidity are each discussed in Section 7. Finally,
2.1 | Epidemiology
2.1.1 | Prevalence
Bipolar disorder is a common and disabling mental illness with significant morbidity and mortality. The estimates of prevalence of BD vary.
The World Mental Health Survey Initiative reported total lifetime (and
12-­month) prevalence estimates of 2.4% (1.5%) across BDI, BDII and
subthreshold BD subtypes. While the prevalence rates for each subtype varied across the nine countries studied, subthreshold BD was
the most common at 1.4% (0.8%), followed by BDI at 0.6% (0.4%) and
BDII at 0.4% (0.3%).6 While Canada was not included in this study,
similar results were reported from the Canadian Community Health
Survey-­Mental Health, which found the lifetime prevalence of BDI
was 0.87% and that of BDII was 0.67%.7
the principles of medical monitoring and an overview of safety and
tolerability concerns for recommended treatments are provided in
Section 8.
2.1.2 | Age of onset
For convenience and to avoid confusion, these guidelines also
Bipolar disorder frequently manifests in late adolescence and
include a table of commonly used terms (with an explanation of the
young adulthood, with an overall average age of onset of 25 years.
intended meaning) that may have overlapping definitions or criteria in
Statistical models suggest the presence of three age of onset sub-
the literature (Table 4).
groups within BDI and these can be categorized into a large early-­
These guidelines are intended for use by psychiatrists and primary
onset group (mean ± standard deviation (SD) 17.24 ± 3.20 years),
care providers who care for patients with BD throughout the lifespan,
and smaller middle-­
o nset (23.93 ± 5.12 years) and late-­
o nset
supporting them to provide evidence-­based assessment, treatment of
(32.20 ± 11.96 years) groups, with the proportion of individu-
acute symptoms, prevention of episode recurrence, and management of
als falling into each category being 41.7%, 24.7% and 33.6%
comorbidities. These guidelines are not meant to replace clinical judge-
of the total sample, respectively. 8 However, the ages of onset
ment or define standards of care. While designed with Canadian physi-
tend to differ somewhat depending upon the origins of sam-
cians in mind, input from experts from the ISBD makes these guidelines
ples analysed. For instance, a recent study showed that the
YATHAM et al.
Clarifying overlapping terminology
Mood stabilizer
Use in the literature is inconsistent, and so this term will not be used in these guidelines
Encompasses valproate, valpromide, valproic acid and divalproex sodium
Include first-­generation antipsychotics with high affinity for dopamine D2 receptors. Note these are referred to as dopamine
receptor antagonists (D2) in the new neuroscience-­based nomenclature
Comprise second-­generation antipsychotics with affinity for dopamine D2 and serotonin 5-­HT2 receptors as well as those that
have partial agonist effects at D2/D3 receptors. Note these are referred to as dopamine and serotonin receptor antagonists (D2
and 5-­HT2A), dopamine 2 partial agonists and serotonin receptor antagonists, and dopamine 2/3 partial agonists in the new
neuroscience-­based nomenclature
Re-­emerging episode(s) of mania or depression whether it be within the previous episode or a new episode. Note that, while the
literature may use “relapse” and “recurrence”, respectively, inconsistencies in how they are applied and their irrelevance to
treatment decisions mean we will use “recurrence” to refer to both
Prophylactic therapy after stabilization of acute manic or depressive episodes
mean age of onset for a USA sample was 20 years, with ages
a systematic review addressing cost of illness studies, with findings
of onset of 14.5 ± 4.9 years (63%), 26.5 ± 7.6 years (28.5%),
demonstrating that the worldwide annual costs per person with BD
and 39.5 ± 12.5 years (8.5%) for early-­, middle-­ and late- …
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