Bipolar Disorders 2005: 7(Suppl. 3): 5–69
Copyright a Blackwell Munksgaard 2005 BIPOLAR DISORDERS
Canadian Network for Mood and Anxiety Treatments (CANMAT) guidelines for the management of patients with bipolar disorder: consensus and controversies
Yatham LN, Kennedy SH, O’Donovan C, Parikh S, MacQueen G, McIntyre R, Sharma V, Silverstone P, Alda M, Baruch P, Beaulieu S, Daigneault A, Milev R, Young T, Ravindran A, Schaffer A,
Connolly M, Gorman CP. Canadian Network for Mood and Anxiety Treatments (CANMAT) guidelines for the management of patients with bipolar disorder: consensus and controversies.
Bipolar Disord 2005: 7 (Suppl. 3): 5–69. a Blackwell Munksgaard, 2005
Since the previous publication of Canadian Network for Mood and Anxiety Treatments (CANMAT) guidelines in 1997, there has been a substantial increase in evidence-based treatment options for bipolar disorder. The present guidelines review the new evidence and use criteria to rate strength of evidence and incorporate effectiveness, safety, and tolerability data to determine global clinical recommendations for treatment of various phases of bipolar disorder. The guidelines suggest that although pharmacotherapy forms the cornerstone of management, utilization of adjunctive psychosocial treatments and incorporation of chronic disease management model involving a healthcare team are required in providing optimal management for patients with bipolar disorder. Lithium, valproate and several atypical antipsychotics are first-line treatments for acute mania. Bipolar depression and mixed states are frequently associated with suicidal acts; therefore assessment for suicide should always be an integral part of managing any bipolar patient. Lithium, lamotrigine or various combinations of antidepressant and mood-stabilizing agents are first-line treatments for bipolar depression. First-line options in the maintenance treatment of bipolar disorder are lithium, lamotrigine, valproate and olanzapine. Historical and symptom profiles help with treatment selection. With the growing recognition of bipolar II disorders, it is anticipated that a larger body of evidence will become available to guide treatment of this common and disabling condition. These guidelines also discuss issues related to bipolar disorder in women and those with comorbidity and include a section on safety and monitoring.
Co-Chairs: Lakshmi N Yathama, Sidney H Kennedyb
Section Leaders: Claire O’Donovanc, Sagar Parikhb, Glenda MacQueend, Roger McIntyreb, Verinder Sharmae, Peter Silverstonef
Guidelines Committee: Martin Aldac, Philippe Baruchg, Serge Beaulieuh, Andree Daigneaulti, Roumen Milevj, L. Trevor Youngb, Arun Ravindranb, Ayal Schafferb, Mary Connollyk & Chris P Gormanl
aDepartment of Psychiatry, University of British Columbia, Vancouver, BC, bDepartment of Psychiatry, University of Toronto, Toronto, ON, cDepartment of Psychiatry, Dalhousie University, Halifax, NS, dMcMaster University, Hamilton, ON, eDepartment of Psychiatry, University of Western Ontario, ON, fDepartments of Psychiatry and Neuroscience, Alberta, Edmonton, AB, gDepartment of Psychiatry, Laval University, Quebec City, QC, hDepartment of Psychiatry, McGill University, Montreal, iDepartment of Psychiatry, University of Montreal, jDepartment of Psychiatry, Queen’s University, Kingston, ON, kMood Disorders Service, Victoria, BC, lUniversity of Calgary, Calgary, AB, Canada
This project was supported by unrestricted educational grants from Lilly, AstraZeneca and Janssen-Ortho.
Section 1: Introduction
There has been an explosion of research into treatment of bipolar disorder since the publication
of the first guidelines for the treatment of bipolar disorder by the American Psychiatric Association in 1994 (1). Over the past decade, novel anti- convulsants (2), atypical antipsychotics (3), and
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psychosocial treatments (4, 5) have been widely studied for their efficacy in bipolar disorder. In order to capture and distil these advances in treatment to clinicians, several regional (6), national (7–10) and expert groups (11–15) have published treatment guidelines for bipolar disorder over the past 10 years. Some of these guidelines have already gone through a second revision (16, 17) while others will probably be revised in the near future.
This publication represents a timely update to the Canadian Network for Mood and Anxiety Treatments (CANMAT) guidelines published in 1997 (7). The previous guidelines used periodic health examination guidelines for rating strength of evidence and clinical recommendations. In order to make these more clinician friendly, we have modified the criteria for rating strength of evidence for intervention and a clinical recommendation is made for each intervention based on global impression of efficacy, effectiveness, and side effects. The new criteria for rating strength of evidence and clinical recommendations are out- lined below (Tables 1.1 and 1.2).
These guidelines are divided into eight sections, including this introductory section. In Section 2, the basic principles of management are discussed. These include early and accurate diagnosis, educa- ting the patients and significant others about the disorder and its treatment, and incorporation of psychosocial strategies and a chronic disease man- agement model into patient care. The treatment of acute mania, acute bipolar depression and main- tenance treatment are, respectively, reviewed in Sections 3, 4 and 5. The section on acute mania not
Table 1.1. Evidence criteria
1. Meta-analysis or replicated double-blind (DB), randomized controlled trial (RCT) that includes a placebo condition
2. At least one DB-RCT with placebo or active comparison condition
3. Prospective uncontrolled trial with 10 or more subjects
4. Anecdotal reports or expert opinion
Table 1.2. Treatment recommendation
only includes emergency management but also a treatment algorithm that provides options at var- ious steps, depending upon the previous medica- tion status of the patient and level of response. Similarly, in Section 4, a treatment algorithm provides management options for patients with acute bipolar depression while Section 5 addresses long-term treatment, emphasizing the importance of treatment adherence in achieving mood stability as well as current evidence-based pharmacothera- pies. Clinical features that might help clinicians to make choices between those options are also reviewed.
Treatment of bipolar disorder in women who are contemplating pregnancy, during pregnancy or in the postpartum period poses unique challenges, as clinicians have to carefully balance risks and benefits. As well, management of bipolar disorder in children and adolescents and those with comor- bidity can be equally challenging and these issues are covered in Section 6. Although bipolar II disorder is very common, it has been neglected as an area of research, and until now few, if any, guidelines have specifically addressed treatment of this condition. Section 7 of these guidelines reviews the limited data available on evidence-based treat- ments for bipolar II disorder, and provides treat- ment recommendations while acknowledging the limitations of such recommendations. Treatment adherence is a substantial challenge in the man- agement of bipolar disorder and one of the major reasons for non-adherence is adverse events. Hence, the monitoring of patients for adverse effects is of paramount importance. This is dis- cussed in Section 8, in addition to the principles of medical monitoring.
A clinical case is interwoven throughout these guidelines to illustrate how treatment evidence can be incorporated into the management of a patient with bipolar disorder and controversial topics are raised at the end of different sections.
Although these guidelines were developed by Canadian experts on bipolar disorder, we have attempted to make them applicable to physicians and other health professionals elsewhere in the world and are pleased that they will be published in the Bipolar Disorders journal. To add to their international relevance, we have invited experts from North America, Europe, Australasia, South America, and Africa to provide complementary written commentaries in this supplement on these 2005 CANMAT guidelines for bipolar disorder. We hope that this initiative might contribute to future development of international guidelines for treatment of bipolar disorder.
Level 1 or level 2 evidence plus clinical support for efficacy and safety Level 3 evidence or higher plus clinical support for efficacy and safety
Level 4 evidence or higher plus clinical support for efficacy and safety
Level 1 or level 2 evidence for
lack of efficacy
Section 2: Foundations of management
Prevalence. Bipolar disorder is a relatively com- mon and highly disabling mood disorder. Bipolar disorder has been sub-categorized into bipolar I, bipolar II, and bipolar disorder not otherwise specified (NOS). According to the DSM-IV, indi- viduals may also experience bipolar symptoms as part of cyclothymia, substance-induced mood dis- orders, secondary to a medical disorder, and schizoaffective disorder-bipolar subtype (18). The term bipolar spectrum disorder captures a variety of clinical conditions that are thought to be closely related to bipolar disorder and are discussed below.
In the general population, the prevalence of bipolar I disorder is estimated at approximately 0.5–2.4% (19–26), and the prevalence of bipolar II disorder at 0.2–5.0% (20, 27, 28). Higher preval- ence rates are reported for bipolar spectrum disorder as defined by subsyndromal manic symp- toms (3.0–6.5%) (27, 29, 30). However, determin- ing the true prevalence of bipolar disorder is hampered by serious deficits in virtually all popu- lation-based surveys, due primarily to the lack of a reliable instrument for diagnosis of the disorder (31). The prevalence of bipolar I disorder is similar in both men and women (32–34). Comorbid anxiety disorders and substance abuse are reported in almost half of patients with bipolar disorder (35).
Age of onset. The mean age of onset is between 17 and 21 years (36, 37). Functional impairment may be more pronounced in individuals who develop the illness prior to age 19, as early onset frequently disrupts subsequent education, career, and social development (38).
Burden of illness. Bipolar disorder results in signi- ficant disability and negative impact on quality of life (23, 29, 39–42). Compared with healthy subjects, patients with bipolar disorder report significantly more difficulties with work-related performance, leisure activities, as well as social and family interactions (29, 39); however, treat- ment can improve many of these difficulties. In 1990, the World Health Organization identified bipolar disorder as the world’s sixth leading cause of disability-adjusted life years among people aged 15–44 years (41). Individuals with bipolar disorder also demonstrate significant increases in lifetime health service utilization and the need for welfare and disability benefits, compared to populations with no mental disorder (29). The lifetime cost for
all individuals in the United States with onset of bipolar disorder in 1998 has been estimated at US$24 billion (43).
Suicide risk. There is an increased lifetime risk of suicide among patients with bipolar disorder, estimated at 17–19%, or 15–20 times more than that of the general population (44–51). As many as 25–50% of patients with bipolar disorder attempt suicide at least once during their lifetime (45, 49– 54). While some controversies exist over the research methods used to make these estimates, the high risk of suicidality is undeniable.
Several risk factors for suicidal behaviour have been identified, and many of these are additive (Table 2.1) (51, 53, 55–58). Therefore, in addition to obtaining a history of personal and family suicidal behaviour, it is important to assess a patient’s history of depression, current level of pessimism, aggressive/impulsive traits, and comor- bidity with substance use disorders, to help identify patients at risk for suicidal behaviour (55, 57, 59).
A treatment programme in a maximally sup- portive clinical environment can reduce suicidal behaviour in high-risk patients. Long-term main- tenance pharmacotherapy with lithium may sub- stantially reduce the risk of suicide in these patients (60–64), however, this must be balanced against its risk of toxicity and high lethality in overdose.
DSM-IV diagnostic criteria. Bipolar I disorder is characterized by the occurrence of one or more manic (Table 2.2) or mixed episodes. Although the occurrence of a depressive episode is not required for a diagnosis of bipolar I disorder, almost all patients experience depressive episodes, which in fact are more common than manic episodes. Bipolar II disorder is characterized by the occur- rence of one or more major depressive episodes accompanied by at least one hypomanic episode (Table 2.2). To meet criteria, mood symptoms must cause clinically significant distress or impair-
Table 2.1. Risk factors for suicidal behaviour in patients with bipolar dis- order (51, 53, 55–58)
History of suicide attempt
Family history of suicidal behaviour Severity/number of depressive episodes Alcohol/substance abuse
Level of pessimism
Level of aggression/impulsivity
Younger age of onset
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Table 2.2. Bipolar disorder – diagnostic features (DSM-IV) (18)
A distinct period of abnormally and persistently elevated, expansive, or irritable mood, lasting at least 1 week (any duration if hospitalization is necessary)
Persistence of three or more of the following symptoms to a significant degree:
1. Inflated self-esteem or grandiosity
2. Decreased need for sleep (e.g. feels rested after only 3 h of
3. More talkative than usual or pressure to keep talking
4. Flight of ideas or subjective experience that thoughts are
6. Increase in goal-directed activity or psychomotor agitation
7. Excessive involvement in pleasurable activities that have a
high potential for painful consequences (e.g. engaging in unrestrained buying sprees, sexual indiscretions or foolish business investments)
A distinct period of persistently elevated, expansive or irritable mood, lasting throughout at least 4 days, that is clearly different from the usual non-depressed mood
Persistence of three or more of the symptoms necessary for a manic episode
The presence of numerous periods with hypomanic symptoms and numerous periods with depressive symptoms that do not meet criteria for a major depressive episode, for at least 2 years During the above 2-year period, the person has not been without the symptoms for more than 2 months at a time
No major depressive episode, manic episode, or mixed episode has been present during the first 2 years of the disturbance Bipolar disorder not otherwise specified
1. Very rapid alternation (days) between manic and depressive
symptoms that do not meet duration criteria
2. Recurrent hypomania without intercurrent depressive symp-
3. Manic or mixed episode superimposed on delusional or
4. Unable to determine if bipolar disorder is primary, substance-
induced or related to a medical condition
ment in social, occupational, or other important areas of functioning.
The bipolar spectrum. There is a broad range of clinical presentations between the extremes of classic manic-depressive disorder (bipolar I disor- der) and strictly defined unipolar depression [major depressive disorder (MDD)] (65). To more precisely characterize the varied clinical presenta- tions, a number of authors have proposed classi- fication systems that identify other purported subtypes of bipolar disorder or invoke a relation- ship conveyed by the term ‘bipolar spectrum disorder’ (65–68). However, as noted in Table 2.2, the DSM-IV only formally recognizes a few categories of bipolar disorder, while also allowing for the expression of bipolar symptoms resulting from substance use or other medical disorder. As
the majority of clinical trials have been conducted in patients with bipolar I disorder, most of the recommendations made in this document apply to that patient group. Where data are available from patients with bipolar II disorder, they are reviewed and recommendations are made. How- ever, although few data are available, biphasic mood dysregulation, that may not meet the full threshold criteria for a bipolar disorder as per DSM-IV (Table 2.2), may benefit from mood- stabilizing therapies in conjunction with other treatments (69). None the less, clinicians should be cautious in interpreting literature citing ‘bipo- lar spectrum disorder’ because of the lack of agreement around its definition and the absence of specific treatment studies for these conditions.
Screening for and diagnosing bipolar disorder. Diag- nosing bipolar disorder can be a challenge. Delays from the onset of symptoms to the time of initial treatment for bipolar disorder of up to 20 years have been reported (40, 70, 71). An estimated 35–45% of patients with bipolar I disorder are misdiagnosed with unipolar depression (70, 72–74). One of the reasons for this is the fact that patients with bipolar disorder seek treatment in the depres- sive state two to three times more often than in the manic state (75).
The strategies shown in Table 2.3 can help to screen for bipolar disorder, which can then be diagnosed according to DSM-IV criteria (Table 2.2). Currently there is no ideal screening tool or diagnostic test for bipolar disorder; how- ever, the Mood Disorder Questionnaire (MDQ) (Table 2.4) may be a useful screening instrument. Endorsement of two or more symptoms by an individual should alert the physician to further explore potential manic/hypomanic symptoms in more detail. Patients seldom recognize hypomania as a problem, particularly when being questioned in an acute depression, as they may have concen- tration and memory difficulties that make it difficult to recall either hypomanic or even manic episodes. As such, several screening questions for both mania and hypomania should be asked, and if available, collateral history from family or friends should be obtained. In uncertain cases, prospective use of a mood diary can be very useful in identifying symptoms of a manic or hypomanic episode. The best way to confirm the diagnosis may be to assess the patient on those days when the patient rates symptoms in the mood diary in the hypomanic/manic range.
Screening for a family history of bipolar disorder is critical. A positive family history among first- degree relatives increases the likelihood of bipolar
Table 2.3. Interviewing for the potential for bipolar disorder
Who to screen?
Screen patients who present with depressive symptoms for a history of hypomanic or manic symptoms
Consider an underlying mood disorder in patients presenting with unexplained vague/non-specific somatic symptoms or reverse vegetative symptoms (e.g. hypersomnia and hyperphagia)
How to screen?
Listen to the patient’s unprompted presenting complaints Ask open-ended and non-leading general questions about the common symptoms of depression and mania
Ask questions about specific symptoms of depression and mania, including how long the symptoms have been present during the current episode, how long they lasted during prior episodes (if applicable), and whether they have caused problems in social relationships or work
Always ask about suicidal ideation
Ask about psychotic symptoms
Consider asking the patient to complete the Mood Disorder Questionnaire
Ask about a family history of bipolar disorder
Interview family or friends regarding prior episodes of mania or hypomania
If unclear, ask patients to do prospective mood ratings and assess when patients are rating symptoms in manic or hypo- manic range
Consider alternative diagnoses
General medical conditions that may produce similar symptoms
Alcohol and other substance abuse
Medications that may produce similar symptoms
II disorder by 8–18 times compared to those with no family history (76).
Comorbidities and mimics. Bipolar disorder is associated with an increased incidence of comor- bidity with substance abuse, anxiety disorders, and personality disorders (35, 78–80). Axis I or Axis II comorbidity may be associated with an earlier age at onset and a worse course of bipolar illness (35, 59).
Alternative causes of mood disorders, including general medical conditions, alcohol and substance abuse, medications that may produce similar symptoms and psychiatric disorders including schizophrenia and other psychoses, must be con- sidered in the differential diagnosis of depressive and manic syndromes (Table 2.5).
Chronic Disease Management: an integrated patient, provider, and systems model
Bipolar disorder is a chronic illness characterized by episodes of relapse/recurrence and periods of remission. As patients require a long-term, multi- disciplinary management plan, the Chronic Disease Management Model should be applied
(81, 82). The model, first proposed by Wagner (82), identifies the essential elements of a healthcare system for high-quality management of patients with chronic diseases (Table 2.6).
In patients with bipolar disorder, before addressing long-term strategies, stabilization of the acute episode, particularly those in the manic/hypomanic phase, is the first step in management. The first priority is to determine if patients are a danger to themselves or others, and whether they require hospitalization. For a patient who is no longer severely ill, the psycho- social approach should be modified to facilitate enhanced discussion and review of treatment options as a way of building patient confidence and responsibility in managing his or her own care.
The Chronic Disease Management Model, along with other models, has been integrated into a stepped care model specifically for bipolar disorder by Parikh and Kennedy (83). After initial pharmacotherapy and related clinical management as the first step, care should ideally be provided with a healthcare team that includes at least one other health professional in addition to the physician, typically a nurse who may provide detailed psychoeducation, additional monitoring, and support. One key example of monitoring would involve active outreach and follow up of patients known to be more severely ill, to ensure such individuals attend appoint- ments and follow recommendations. The third step involves the provision of robust psychoed- ucation, whose elements would include preparing the patient to become actively involved in self- management, identifying ways to collaborate most effectively with health providers, teaching key facts about bipolar disorder, teaching recog- nition of early signs of relapse, identifying a relapse drill, and learning a variety of key stress management techniques, including careful atten- tion to sleep regulation and avoidance of substance misuse. Involvement of family or key friends in part of the psychoeducation can be invaluable, particularly in creating a relapse drill. Effective relapse drills feature creating a docu- ment that lists early warning symptoms of relapse and specifies usual treatment responses, including self-management manoeuvres. This relapse drill document has the additional benefit of speeding and simplifying medical decision- making and reducing patient ambivalence about treatment, as the patient is the principal author of the document.
Under the stepped care approach, after initi- ating pharmacotherapy, identifying a treatment
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Table 2.4. Mood Disorder Questionnaire (MDQ) (77).
1. Has there ever been a period of time when you were not your usual self and…
…you felt so good or so hyper that other people thought you were not your normal self or you were so hyper that you got into trouble?
…you were so irritable that you shouted at people or started fights or arguments? …you felt much more self-confident than usual?
…you got much less sleep than usual and found you didn’t really miss it? …you were much more talkative or spoke faster than usual?
…thoughts raced through your head or you couldn’t slow your mind down?
…you were so easily distracted by things around you that you had trouble concentrating or staying on track?
…you had much more energy than usual?
…you were much more active or did many more things than usual?
…you were much more social or outgoing than usual, for example, you telephoned friends in the middle of the night?
…you were much more interested in sex than usual?
…you did things that were unusual for you or that other people might have thought were excessive, foolish, or risky?
…spending money got you or your family into trouble?
2. If you checked YES to more than one of the above, have several of these ever happened during the same
period of time? Please circle one response only.
3. How much of a problem did any of these cause you — like being unable to work: having family,money, or legal troubles: getting into arguments or fights? Please circle one response only.
No problem Minor problem Moderate problem Serious problem Reprinted with permission from the American Journal of Psychiatry. 2000, American Psychiatric Association
team (where available), and providing psychoed- ucation, the next steps involve tailoring the psychosocial treatments to the specific needs of the patient, as reviewed in detail below. How- ever, implicit in the first few steps of the stepped care model is that the physician should base treatment decisions on evidence-based guidelines, and that these guidelines should be explicitly revealed to the patient to enhance shared decis- ion-making. Other key recommendations for care drawn from the broader chronic care model include connecting the patient to other commu- nity resources to enhance support and autonomy. Community resources for bipolar disorder, as well as information on key treatment centres, reference texts, and websites, are listed at the end of this document.
Beyond regular monitoring and supportive care, there is evidence that psychoeducation and more formal psychotherapy can improve outcome when used in conjunction with maintenance pharmaco- therapy. Adjunctive psychosocial therapies should be considered early in the course of illness to improve medication adherence, identify prodromes of relapse, decrease residual symptoms (partic- ularly depressive) and suicidal behaviour, and help move patients towards a comprehensive functional recovery (84–90). A list of useful manuals descri- bing various methodologies can be found in Appendix 2. For consistency of scientific review, the major modalities are discussed in the context of available studies below; however, it is recommen-
Table 2.5 Differential diagnosis of bipolar disorder Diagnosisa
Major depressive disorder or dysthymic disorder
Mood disorder due to a general medical condition
Substance-induced mood disorder
Psychotic disorders (schizoaffective disorder, schizophrenia, delusional disorder)
Borderline personality disorder
Narcissistic personality disorder Antisocial personality disorder
Manic or hypomanic episodes probed for and not present
Episodes are judged to be a consequence of a medical condition such as
multiple sclerosis, stroke or hyperthyroidism. Onset or exacerbation of mood coincides with that of medical condition
Episodes are judged to be a consequence of a substance such as an illicit drug, a medication (stimulants, steroids, L-dopa, antidepressants), or toxin exposure. Episodes may be related to intoxication or withdrawal
Hypomanic symptoms do not meet the criteria for a manic episode, and depressive symptoms do not meet the criteria for a major depressive episode
Periods of psychotic symptoms in the absence of prominent mood symptoms. Consider onset, accompanying symptoms, previous course and family history
Instability of interpersonal relationships, self-image and mood, with marked impulsivity, and a central theme of intense abandonment fears. Early onset and a long-standing course. True euphoria and prolonged well-functioning intervals are extremely rare Grandiosity, need for admiration and lack of empathy of early onset. Grandiosity not associated with mood changes or functional impairments
Early onset of disregard for, and violation of, the rights of others, which does not occur only in the context of a manic episode
aNote many of these diagnoses frequently occur comorbidly with bipolar disorder.
Table 2.6. The Chronic Disease Management Model: elements of a healthcare system for effective care of patients with chronic disorders
Empower and prepare patients to manage their health and health care
Use effective self-management support strategies that include assessment, goal-setting, action planning, problem-solving and follow up
Promote clinical care that is consistent with scientific evidence and patient preferences
Embed evidence-based guidelines into daily clinical practice and share this and other information with patients to encourage their participation
Use proven provider education methods
Encourage patients to participate in effective community programmes Form partnerships with community organizations
Delivery system design
Provide clinical care and self-management support that patients understand and that fits with their cultural background Ensure regular follow up by the care team, with defined tasks for different team members
Provide clinical case management services for complex patients
Clinical information systems
Provide timely reminders for providers and patients
Facilitate individual patient care planning
Share information with patients and providers to coordinate care
Measure outcomes and use information to promote effective improvement strategies aimed at comprehensive system change Develop agreements that facilitate care coordination within and across organizations
CANMAT guidelines for bipolar disorder
ded that all patients first receive psychoeducation. Subsequently, only selected individuals would be recommended to pursue additional therapy such as cognitive-behavioural therapy (CBT) or interper- sonal therapy (IPT) based on specific clinical problems or characteristics, such as persistent symptoms, pervasive pessimism, or interpersonal deficits. Evidence for such a sequential approach has been provided by one randomized clinical trial (RCT) that has been submitted for publication (S. Parikh, personal communication).
Psychoeducation. Psychoeducation is focused on providing information on the disorder, its treat- ment, and the social and family consequences of the disorder. When added to pharmacotherapy, RCTs have shown that group psychoeducation significantly increased the time to depressive, manic, hypomanic, and mixed recurrences and reduced relapse rates (88, 91). Psychoeducation aimed at teaching patients to recognize prodromal symptoms of relapse was associated with improve- ments in time to first manic relapse, social func-
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tioning, and employment but had no effect on depressive relapse (92).
Cognitive-behavioural therapy. Here the focus is on cognitive restructuring and includes self-monitor- ing, strategies to deal with dysfunctional thoughts, and behavioural techniques to promote social functioning. Controlled trials comparing CBT to treatment as usual or wait-listed controls in bipolar patients have demonstrated increased functioning and adherence, and decreased relapses, mood fluctuations, need for medications, and hospitali- zations (93–95).
Interpersonal and social rhythm therapy (IPS- RT). Interpersonal and social rhythm therapy includes the traditional IPT focus on one of four problem areas (grief, interpersonal role transition, role dispute and interpersonal deficits) but extends into meticulous regulation of social and sleep rhythms. A large controlled trial demonstrated that therapy did not alter time to relapse but did have a significant impact on subsyndromal symp- toms; patients spent more time euthymic and less time depressed relative to intensive clinical man- agement (96, 97).
Family interventions. Family psychoeducational therapy is based on the premise that a hostile, critical or over-involved family atmosphere has a negative impact on relapse of bipolar disorder (98, 99). In RCTs, family-focused treatment was asso- ciated with fewer relapses and hospitalizations, and improvements in depressive symptoms and medi- cation adherence compared with individual ther- apy or a family crisis management intervention (100–102). However, a recommendation that there should be 21 sessions of family therapy is some- what impractical for most patients.
Putting recommendations into practice
A clinical case will be introduced in this section and the patient will be followed throughout these guidelines. The case will help demonstrate the evidence-based approach to case management throughout various phases of bipolar disorder.
Sara, 20 years old, is referred to you by her family practitioner for persistent symptoms of depression over the past several years, for which she has been taking an antidepressant ‘on-and-off.’ She explains that when she takes the antidepressant for a few weeks, she feels great, being so productive at work,
doing projects at home, and socializing with friends and family. When this happens she discontinues the antidepressant, but inevitably she slips back into depression and restarts the medication.
• What questions should you ask? • What is your diagnosis?
• What is your treatment plan?
Clinical management. Patients who present with depressive symptoms should be thoroughly ques- tioned about their medical and psychiatric history including a history of substance abuse. In partic- ular, all patients with depression should be specif- ically probed for prior episodes of mania or hypomania. In Sara’s case, her bouts of ‘feeling great’ triggered by antidepressant use suggest a hypomanic/manic switch, and a possible diagnosis of bipolar I or bipolar II disorder. On questioning, you learn that her ‘high’ periods have not been all positive. During these periods, she has an incredible amount of energy, gets very little sleep and her thoughts race; she often feels jumpy and cannot sit still at work. When things get too ‘out of control’ she usually calls in sick to work so she can do something physically active or go shopping. She has substantial debt from impulse purchases of things she admits she does not need. Her family and friends worry about her thrill-seeking behaviours. She has lost a few friends because of her irritability and ‘obnoxious behaviour’; she has engaged in sexual relationships with strangers during these periods, which she regrets. These episodes usually occur once or twice a year, lasting from a few days to a few weeks, and have occurred both on and off antidepressants. She denies using cocaine, but says she likes marijuana and occasionally ‘lets guys talk her into taking Ecstasy’ at parties because the ‘sex is more intense’. However, during her depression she feels ‘incredibly guilty and stupid’ about this.
You diagnose bipolar I disorder and recommend that she discontinue the antidepressant. You dis- cuss with Sara the need to first stabilize her condition and then put in place a long-term chronic disease management plan. The first steps are for her to understand the chronic nature of the disease and to recognize the negative impact of manic episodes both in terms of immediate and long-term consequences. You use an evidence- based approach to explain that relapse can become more frequent over time if the condition is left untreated and that there can be long-term changes in the brain. When viewing the overall picture, Sara agrees that she is having manic and depressive episodes and she accepts the diagnosis of bipolar disorder and agrees that long-term therapy is
necessary. After you explain the benefits and risks of the various mood-stabilizers, Sara agrees to take lithium.
You discuss with Sara the importance of self- management, and together you set a goal for the next 2 weeks for Sara to make a list of the signs of her manic and depressive relapses and she agrees to discontinue use of caffeine, alcohol and illicit sub- stances. She agrees that together you will develop a written management contract, and she identifies her mother as the best person to help her monitor her mood. You ask her to bring her mother to the next visit and encourage her to participate in a bipolar support programme. You provide her with infor- mation on the disorder and tell her that at her next visit you will introduce her to the other members of the healthcare team who will partici- pate in her care.
Section 3: Acute management of bipolar mania
Presentations of mania
Presentations can be either manic or mixed (dys- phoric) with or without psychotic features. Prior to initiating algorithmic treatment for mania, manic episode secondary to a general medical condition or substance use disorder (including antidepres- sant-associated mania) should be ruled out (103).
Mania. For a diagnosis of a manic episode, symptoms must be present for at least 1 week (or any time if hospitalization is required). Symptoms include a primary mood disturbance of persistently elevated, expansive, or irritable mood along with at least three of the following: inflated self-esteem or grandiosity, decreased need for sleep, pressure of speech, flight of ideas, distractibility, increased goal-directed activity or psychomotor agitation, and excessive involvement in pleasurable activities with a high potential for painful consequences (Table 2.2) (18). In patients with irritable mood as the primary mood disturbance, at least four of the above symptoms must be present to diagnose a manic episode.
Mania with psychotic features. If possible, specify if the psychotic features are mood-congruent (delusions/hallucinations where content is entirely consistent with typical manic themes) or mood- incongruent (delusions/hallucinations where con- tent does not involve typical manic themes, e.g. persecutory delusions, delusions of being con- trolled or thought insertion) (18). The presence of psychotic features and their congruency with the mood state may have prognostic implications.
Mixed states are a common presentation in an acutely manic patient and remain a significant treatment challenge. The criteria for both a manic and a major depressive episode (except for dur- ation) are met nearly every day for at least 1 week or for any duration if hospitalized (18).
Rapid cycling. About 20% of patients with bipolar disorder have a rapid cycling course with four or more mood episodes within 1 year (18). Episodes are demarcated by either partial or full remission for at least 2 months or a switch to an episode of opposite polarity (e.g. depressive to manic episode).
Terminology for pharmacotherapy
Although the term ‘mood-stabilizer’ is used fre- quently in the literature, there is no consensus on its definition. Several overlapping definitions and cri- teria have been proposed that include some combi- nation of: proven efficacy for the treatment of acute mania and depression, no propensity to induce an episode of opposite polarity or to destabilize the long-term course of the illness, and prophylactic efficacy (8, 17, 104, 105). To avoid confusion in these guidelines, generally accepted descriptive terms for medications according to their therapeutic class (e.g. antidepressants, anticonvulsants, antipsychotics) or the name of specific agents (e.g. lithium) will be used. For the sake of convenience we have used divalproex to refer to valproate, valpromide, valproic acid and divalproex sodium. In the case of ‘antipsychotic agents’ the term has been used to describe a group of medications that act across a broader therapeutic target, than just psychoses.
Emergency management of agitation
The acutely manic bipolar patient may present in an agitated state that acts as a barrier to therapy, interrupts the physician–patient alliance, and cre- ates a disruptive, even hazardous, environment. For all manic patients, the general principles of management of acute mania described in step 1 (see below) should be applied in combination with rapid effective pharmacotherapy.
Benzodiazepines, atypical antipsychotics, and conventional antipsychotics are the most com- monly prescribed medications in emergency set- tings. The choice of a single medication or a combination of medications is based on current and prior medication history, but the need for rapid control of agitation and aggressive behaviour, as well as a patient’s willingness or refusal to take medication may influence the choice of drug deliv- ery system (106, 107). This may include the use of
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drugs that are available in intramuscular formula- tions. Whenever possible, oral therapy should be offered first, as evidence suggests that oral agents can be as effective as intramuscular agents (108, 109). Intramuscular injections offer an alternative when oral therapy cannot be reliably administered.
Based on current efficacy and safety data, the atypical antipsychotics risperidone (level 2) (109), olanzapine (level 2) (110, 111), and quetiapine (level 3) (112) should be considered as a first choice in the treatment of acute agitation. In patients who refuse oral atypical antipsychotics, intramuscular olanza- pine, ziprasidone (113, 114) or a combination of an injectable typical antipsychotic and a benzodiazep- ine should be considered (level 2) (115–117). In general, benzodiazepines should not be used as monotherapy in patients with bipolar disorder. Benzodiazepines are useful adjuncts to sedate the acutely agitated manic patient with faster onset than anticonvulsants or lithium.
Pharmacological treatment of manic episodes
Lithium, divalproex sodium, atypical antipsychot- ics, carbamazepine, conventional antipsychotics and other agents, including benzodiazepines alone or in combination, have all been examined for their efficacy in the treatment of acute mania. These treatments have been evaluated using the criteria for strength of evidence (Tables 1.1 and 1.2) for their use and these are summarized in Tables 3.1 and 3.2.
Step 1: Review general principles and assess medi- cation status. When a patient presents in a manic state, certain general principles should be followed. The patient should be immediately assessed for risk of aggressive behaviour/violence to others, suicide, degree of insight and the ability to adhere to treatment. A physical examination with appropri- ate lab investigations should be conducted (see Section 8), but may be deferred until the patient is more cooperative. Based on the overall assessment the type of treatment setting (e.g. ambulatory or inpatient) should be established.
Antidepressants should be discontinued and steps taken to rule out factors that may be perpetuating manic symptoms, such as prescribed medication, illicit-drug use/abuse or an endocrine disorder. Substance abuse should be identified and treated. Patients should also be strongly encour- aged to discontinue using stimulants such as caffeine and alcohol and gradually discontinue nicotine. When patients are stabilized, behavioural and educational strategies should be applied (see Section 2). In order to direct subsequent therapeu- tic choices, current therapy should be assessed,
Table 3.1. Strength of evidence for monotherapy treatments of acute bipolar mania
Divalproex Carbamazepine Oxcarbazepine Lamotrigine Topiramate Gabapentin Tiagabine
Atypical antipsychotics Olanzapine Risperidone Quetiapine Ziprasidone Aripiprazole Clozapine
Other treatments Haloperidol Chlorpromazine Clonazepam Verapamil
ECT 1⁄4 electroconvulsive therapy.
Level of evidence 1
1 (ve) 1 (ve) 2 (ve) 3 (ve)
1 1 1 1 1 3
2 (ve) 3
Table 3.2. Strength of evidence for combination treatments of acute bipolar mania
Lithium/divalproex + Lithium/divalproex + Lithium/divalproex + Lithium/divalproex + Lithium/divalproex + Lithium/divalproex +
Lithium + divalproex
Lithium + carbamazepine Divalproex + carbamazepine Risperidone + carbamazepine Adjunctive gabapentin Adjunctive lamotrigine Adjunctive rTMS
Level of evidence
2 (ve) No data 1
risperidone olanzapine quetiapine ziprasidone aripiprazole haloperidol
rTMS 1⁄4 repetitive transcranial magnetic stimulation. including what medications the patient is taking
and at what dose.
Step 2: Initiate or optimize therapy and check adherence. In managing an acute manic episode, the decision to treat with monotherapy or a combi- nation of medications is influenced by current and prior medication use (Fig. 3.1), as well as patient factors that may influence prognosis or safety (106, 107). For untreated manic patients or those receiv- ing a medication other than a first-line agent, therapy should be initiated with one or more of the first-line agents: lithium, divalproex or an atypical antipsychotic (Table 3.3) (level 1). For patients who are uncontrolled on monotherapy with a first-line
Fig. 3.1. Treatment algorithm for acute mania. AAP 1⁄4 atypical antipsychotic; CBZ 1⁄4 carbamazepine; CAP 1⁄4 conventional anti- psychotic; DVP 1⁄4 divalproex; ECT 1⁄4 electroconvulsive therapy; Li 1⁄4 lithium; OXC 1⁄4 oxcarbazepine.
Table 3.3. Recommendations for pharmacological treatment of acute bipolar mania
conventional antipsychotics and anticonvulsant agents, with significant improvements occurring in about 50–70% of patients (103). Lithium has also been shown to be as effective as the atypical antipsychotics, olanzapine (119), risperidone (120) and quetiapine (121), and the conventional anti- psychotic, haloperidol (120).
Divalproex. In a meta-analysis, the efficacy of divalproex was superior to placebo and equivalent to lithium and carbamazepine in the treatment of mania (level 1) (122, 123). Clinically, divalproex sodium is preferred because it has fewer gastroin- testinal side effects compared with divalproex and valproic acid (103). In two studies examining the efficacy of divalproex compared with olanzapine in acute mania, one showed similar efficacy while the other showed statistically significant superior- ity of olanzapine (124, 125). A pooled analysis comparing an oral loading of divalproex to lithium or olanzapine showed no differences in early efficacy between these agents (126).
Atypical antipsychotics. Since 1997, substantial RCT data have emerged to support the efficacy of atypical antipsychotic monotherapy with olanza- pine, risperidone, quetiapine, ziprasidone and ari-
CANMAT guidelines for bipolar disorder
Step 1 Review general principles
assess medication status
Step 2 Initiate/optimize, check compliance
Step 3 Add-on or switch therapy
Step 4 Add-on or switch therapy
Step 5 Add-on novel or experimental agents
Not on medication or first line agent
Establish treatment setting
Rule out medical causes
D/C caffeine, alcohol and illicit substances Behavioural Strategies/rhythms, psychoeducation
On first line agent
Initiate Li, DVP, AAP, or 2 drug combination
Lithium or DVP
Add or switch to AAP
Add or switch to Li or DVP
Replace one or both agents with other first line agents
Consider CBZ (OXC) or CAP or clozapine or ECT
2 drug combination (Li or DVP + AAP)
Replace one or both agents with other first line agents
Consider adding levetiracetam, phenytoin, tamoxifen, mexilitine, omega-3-fatty acids, calcitonin
Second line Third line
Lithium, divalproex, olanzapine, risperidone, quetiapine, aripiprazole, ziprasidone, lithium or divalproex + risperidone, lithium or divalproex + quetiapine, lithium or divalproex + olanzapine
Carbamazepine, oxcarbazepine, ECT, lithium + divalproex
Haloperidol, chlorpromazine, lithium or divalproex + haloperidol, lithium + carbamazepine, clozapine
Monotherapy with gabapentin, topiramate, lamotrigine, verapamil, tiagabine, risperidone + carbamazepine
ECT 1⁄4 electroconvulsive therapy.
medication, the first option before adding or switch- ing therapies is to optimize the dose of current medication and to identify issues of non-adherence. Non-adherence to therapy is a frequent cause of recurrence of bipolar disorder, which is often associated with hospitalization or suicide (118).
Lithium. As in previous guidelines (103), lithium continues to be recommended as a first-line acute pharmacological treatment (level 1). Lithium is superior to placebo and comparable in efficacy to
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piprazole for the treatment of acute mania (level 1). Olanzapine monotherapy was more effective than placebo (127, 128) and at least comparable to divalproex (124, 125), lithium (119) and haloperidol (level 1) (129, 130). Risperidone monotherapy was more effective than placebo (131, 132) and as effective as lithium or haloperidol (level 1) (120, 131). Quetiapine monotherapy has demonstrated efficacy in two randomized placebo-controlled tri- als in patients with acute mania (level 1) (121, 133) and appears to have comparable efficacy to lithium (121) and haloperidol (133).
Both ziprasidone (level 1) (134, 135) and aripip- razole (level 1) were more effective than placebo (136, 137), and aripiprazole was as effective as haloperidol in the treatment of acute mania (138). When ziprasidone was used as an adjunct to lithium therapy, there were early benefits over placebo but these were not sustained over the 3 weeks of the study (139). As aripiprazole and ziprasidone are not currently available in Canada, recommendations for their use in mania are based largely on the reported efficacy data and adverse event profile of these agents.
Combination therapy. The combinations of lith- ium or divalproex with various atypical antipsych- otics [risperidone (140, 141), quetiapine (level 1) (142–144) or olanzapine (level 2) (145)] have demonstrated significant beneficial effects com- pared with lithium or divalproex monotherapy. These studies have shown that, on average, about 20% more patients will respond to combination therapy compared with mood-stabilizer mono- therapy; hence, combination therapy could be considered as a first-line option for some patients. To date, the efficacy of such combination therapies compared with atypical antipsychotic monothera- pies has not been reported.
Step 3: Add-on or switch therapy (alternate first-line therapies). If therapy with one of the first-line agents (lithium, divalproex or an atypical antipsy- chotic) at optimal doses is inadequate or not tolerated, the next step should involve switching to or adding-on an alternate first-line agent. Based on the efficacy and relative safety of first-line agents, the use of second- and third-line agents is only recommended after these classes of agents have been tried alone or in combination.
Step 4: Add-on or switch therapy (second- and third- line therapies)
Second-line options. In patients who are inad- equately responsive to first-line agents, second-line
choices would include other anticonvulsants such as carbamazepine and oxcarbazepine, the combi- nation of lithium plus divalproex, or electrocon- vulsive therapy (ECT). Although there are substantial data [reviewed by Kusumakar et al. (103)] demonstrating that carbamazepine has effic- acy similar to lithium and divalproex (level 1), safety and tolerability relegate it to a second-line option. Oxcarbazepine is a derivative of carb- amazepine that is reported to be better tolerated and has demonstrated efficacy in acute mania (level 2). However, trials were very small and likely underpowered to show differences between active comparators [reviewed by Yatham (2)].
The combination of lithium and divalproex has demonstrated efficacy and safety in uncontrolled trials (146–149). It is a widely used and reasonable option to treat acute mania based on the strong evidence of each agent as monotherapy (level 3).
It has been suggested that up to 80% of patients with acute mania will show marked clinical improvement with ECT (150). Unfortunately, there has been minimal research since the publication of the previous guidelines by this group in 1997 (103) to provide additional data on ECT in the treatment of mania. Therefore, it continues to be recommen- ded as a second-line therapy (level 3).
Third-line options. A variety of agents including the conventional antipsychotics, haloperidol, chlorpromazine or perphenazine in combination with lithium or divalproex (level 1), lithium plus carbamazepine (level 2) and clozapine (level 3) are recommended as third-line options for therapy.
In RCTs, the conventional antipsychotic, halop- eridol has demonstrated efficacy that is superior to placebo and comparable to divalproex (151), lithium (120) and atypical antipsychotics such as olanza- pine, risperidone, quetiapine and aripiprazole (level 1) (120, 129, 138, 152). Haloperidol has also dem- onstrated efficacy in combination with lithium or divalproex for the treatment of acute mania (level 1) (140, 153–155). However, side effects including extrapyramidal symptoms (EPS), acute dystonia and tardive dyskinesia limit the use of haloperidol (103). The combination of lithium and carbamaze- pine has demonstrated efficacy comparable to lith- ium plus haloperidol (level 2) (154); however, the limited data available, and the side effect profile of carbamazepine lead to a recommendation of the combination as a third-line option.
Although clozapine may have efficacy for acute mania, it should be reserved for treatment-resistant patients, based on the absence of double-blind RCTs in acute mania (156, 157) and concerns regarding its safety (level 3).
Step 5: Add-on novel or experimental agents.
Phenytoin (level 2) (158) and levetiracetam (level 3) (159–161) show some antimanic efficacy but should preferably only be used as add-on therap- ies in those patients who have shown partial refractoriness to all the standard treatments reviewed above. Similarly, there are reports of potential antimanic efficacy for tamoxifen (162, 163), mexiletine (164, 165), omega-3-fatty acids (166) and calcitonin (167, 168) but given the very limited data, these can only be recommended as add-on therapies after failure of all standard therapies.
Agents not recommended for the treatment of acute mania. In randomized controlled trials, gabapen- tin (level 2, negative) and topiramate (level 1, negative) failed to demonstrate antimanic efficacy (169–171). However, gabapentin may be useful in the treatment of patients with comorbid panic disorder or alcohol abuse (172), while topiramate may be useful in attenuating or reversing atypical antipsychotic-induced weight gain (171, 173). In open trials and case reports, tiagabine did not have antimanic efficacy and was associated with seizures and other side effects (level 3, negative) (174–176). Lamotrigine monotherapy or add-on therapy has not consistently shown antimanic effects that are superior to placebo in RCTs (level 1, negative) (2, 170, 177, 178), although it does play a role in the acute and maintenance treatment of bipolar depression (see Sections 4 and 5). There is little evidence of antimanic efficacy, and in some cases
evidence of inefficacy, for repetitive transcranial magnetic stimulation (rTMS) (level 2, negative) (179–181) and verapamil (level 2, negative) (182).
A meta-analysis concluded that the benzodia- zepine clonazepam is effective and safe in the treatment of acute mania, but results were incon- clusive for lorazepam (level 1) (183). However, because of concerns about benzodiazepine dependence, they are recommended as adjunctive therapy rather than as primary antimanic agents (103).
The combination of risperidone and carbamaze- pine should be avoided, as carbamazepine reduces the plasma concentration of risperidone by 40% resulting in decreased efficacy (141).
Clinical features that can help direct treatment choices
Lithium, divalproex and atypical antipsychotics, alone or in combination, are first-line treatments, but certain clinical features assist in making treatment choices for individual patients (see Table 3.4). Classical mania, elated mood in the absence of depressive symptoms or psychotic features, and a previous positive response to lithium are all predictors of a positive response to lithium treatment (103, 184, 185). Patients who display prominent depressive symptoms during mania and those with multiple prior mood episodes may respond better to divalproex (186–188). Rapid cycling and mixed mania are positive predictors of response to divalproex (103, 186, 187, 189), but generally predict poorer response to lithium (8,
Predictors of non-response
Mixed state (8, 103, 186, 194)
Rapid cycling (8, 103) Depression–mania–euthymia course (8, 103) Presence of depressive symptoms (184, 187) Multiple episodes (8)
No family history (8)
Comorbid personality disorders (189) More severe mania (189)
Rapid cycling (103, 197)
>10 year history of illness (197)
Table 3.4. Predictors of response Agent
Predictors of response
Elated mania (184, 185)
Previous response to lithium (184, 185) Mania–depression–euthymia course (103) No neurological impairment (184, 185)
No psychotic symptoms (184, 185)
No substance abuse (8, 184, 185)
Few episodes of illness (103, 184, 185) Rapid cycling (103, 187, 189, 195)
Mixed state (103, 186, 187, 189)
Multiple prior mood episodes (187, 188) Irritable-dysphonic subtype (196) Secondary mania (103)
Comorbid substance abuse (189)
Mixed state (103, 189)
Increased severity of acute mania (189)
No family history of mood disorders (189) Early age of onset (189)
Course dominated by manic episodes (189) Early age of onset (190)
No prior substance abuse (190)
No prior antipsychotic treatment (190) Rapid cycling (3, 127, 191)
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103). Patients with no family history and those with non-classical bipolar disorder, head injury or other neurological problems may respond to carb- amazepine (103, 189).
Predictors of a positive response to olanzapine include younger age at illness onset, no history of substance abuse and absence of prior antipsychotic exposure (190). There is some evidence to suggest that olanzapine may be effective in patients with rapid cycling as well as those with mixed states (3, 127, 185, 190–193). Atypical antipsychotics in general appear to be equally effective in patients with or without psychotic symptoms (3, 127, 128, 131, 132, 140, 141, 145, 190).
Combination therapy should be considered the treatment of choice for those with severe manic or mixed episodes which result in impairment in functioning, while monotherapy may be sufficient for those patients with less severe symptomatology.
Mania with psychotic features
About half of manic episodes are characterized by the presence of psychotic features (198). Psychotic symptoms in mania are frequently misdiagnosed as schizophrenia, especially during early episodes (199, 200). The idea that psychotic symptoms correlate with a more severe course of illness, worse prognosis and a greater risk of suicide remains largely unsupported by the evidence, and the absence of psychotic symptoms should not be viewed as a less severe mood state. However, mood-incongruent psychotic features do appear to be associated with more severe illness (201) and a poorer long-term prognosis than mood-congruent psychotic features (199, 202–204). Whether this influences response to specific treatments is not currently known.
Despite clinical impressions to the contrary, there is limited evidence to suggest that psychosis predicts a poorer response to monotherapy with a mood-stabilizer or an atypical antipsychotic ther- apy. One study reported a poorer response to lithium in patients with psychotic symptoms, unless it was given in combination with antipsych- otics (205), but this is not a consistent finding. In a review of RCTs, psychotic and classic mania responded similarly to lithium and divalproex (196). Similarly, treatment with an atypical anti- psychotic alone or in combination with lithium/ divalproex was equally effective in both patients with and without psychotic features (3, 127, 128, 131, 132, 140, 141, 145, 190). The efficacy of ECT in patients with mania was not influenced by the presence of delusions (206). There were no differ- ences in the efficacy of olanzapine in patients with
or without psychotic features, and olanzapine was as effective as divalproex in patients with psychotic features (124). It is likely that psychosis is a non- specific manifestation of mania that improves if the underlying mania improves (199).
The simultaneous presentation of manic and depressive symptoms presents significant treatment challenges. Data suggest that patients who are in a mixed state or rapid cycling are less likely to achieve remission and take longer to do so (207, 208). Suicide risk also appears to be higher in mixed mania compared with classic mania (209, 210).
Data also suggest that lithium is not as effective in mixed states as it is in classic mania (103, 186, 194, 207), while divalproex appears to be equally effective in both mixed episodes and pure mania (186, 211). Atypical antipsychotics alone or in combination with lithium or divalproex have shown conflicting results, but for the most part, appear to be as effective in patients with mixed episodes as in those with classic mania (3, 142, 185, 190, 193). Analysis of two RCTs showed that olanzapine had a significant effect on both manic and depressive symptoms in patients with mixed episodes (192). Carbamazepine also reduced depressive symptoms in patients with mixed epi- sodes (103, 212). Evidence also exists supporting the use of ECT in patients with mixed episodes (206, 213, 214).
Rapid cycling is reported in about 13–20% of patients with bipolar disorder, and more often in women than in men (195, 215, 216). The definition of four or more episodes per year is largely an arbitrary cut-off, and it is hypothesized that rapid cycling exists on a continuum of cycle lengths (195).
Hypothyroidism, antidepressants and substance abuse may contribute to rapid cycling (195, 215, 216). Thus, it is important to assess thyroid function, and reduce or stop antidepressants, as well as caffeine, nicotine, alcohol and illicit drugs in the presence of rapid cycling (103). Psychotropic agents should be discontinued gradually (103).
There are few controlled treatment trials in patients with rapid cycling. Acute manic episodes should not be treated in isolation in any patient with bipolar disorder, especially in those with rapid cycling. Therefore, appropriate pharmacotherapy should be selected primarily as a maintenance strategy (see Section 5). Lithium and carbamaze-
pine monotherapy appear to be less effective in patients with rapid cycling compared to those without (215, 217, 218). Monotherapy with div- alproex (195, 215) or olanzapine (128, 191) appears to be equally effective in patients with and without rapid cycling. The combination of lithium and divalproex has been shown to improve response rates (148, 195, 219). ECT may also prove effica- cious in selected cases (215).
Clinical questions and controversies
How long should a medication be tried before adding or switching therapies? Most (122, 128, 131, 132, 141, 142, 153, 220) but not all (127, 152) clinical trials in acute mania have demonstrated superior effects of the active treatment compared with placebo within the first 1–2 weeks. In studies where this did not occur (127, 152, 177), the starting dose of the medication was lower and/or dose titration was slower, so that it took a few days to reach adequate target doses. Given these observations, it is recommended that a pharmacotherapeutic regi- men be tried for at least 2 weeks at adequate doses before concluding that the patient is unlikely to respond (30% reduction in symptoms).
What is the role of psychosocial treatments in the acute management of mania? Pharmacotherapy is the foundation of treatment for an acute manic episode. However, all patients require some psy- choeducation, which should be undertaken once the patient–physician therapeutic alliance is estab- lished as discussed in step 1. Evidence suggests that a range of adjunctive psychological approaches offer some benefit during maintenance therapy (84, 86).
In patients successfully treated with a combination of a mood-stabilizer and an atypical antipsychotic, should one be discontinued and if so when? The prophylactic efficacy of lithium (221–229) is well established and there are some research data and a wealth of clinical experience supporting the utility of divalproex (219, 230, 231), however, this is not the case with atypical antipsychotics other than olanzapine (228, 231, 232). In an effort to minimize the side effect burden, it is prudent to minimize the number of medications whenever possible. How- ever, it is also important to recognize that mono- therapy may be insufficient to prevent relapses in many patients with bipolar I disorder. A patient’s prior history of mood stability on lithium or divalproex monotherapy should serve as a clinical guide as to whether monotherapy is adequate for that individual or combination therapy is required.
Two years after being diagnosed with bipolar disorder, Sara, now 22 years old, is brought to the emergency department (ED) in an acutely agitated state. During the past week, she has been out every night partying, coming home in the early hours of the morning and sleeping for just 2 or 3 h a night. She was well controlled on lithium for over a year but all of a sudden, she has become increasingly unstable. Sara’s mother asked her to see a doctor; she refused and she has become increasingly angry and physically aggressive towards her mother. When assessed in the ED she is fast talking and irritable, but denies having delusions or hallucinations.
• What is your immediate course of action? • What questions should you ask?
• What is your treatment plan?
Clinical management. You administer an atypical antipsychotic on an as needed basis in order to reduce her acute agitation, and after assessing the degree of danger to herself and others, she is admitted to hospital. When she becomes calmer, you attempt to interview her, asking in particular about adherence to her medication. She denies non-adherence to lithium, claiming that she has been taking her medication everyday. She also vehemently denies drug and alcohol use. Discus- sion with Sara’s mother belies this latter claim, and she says that although the number of pills in the bottle is decreasing she does not know whether Sara is actually taking them.
Assessments of thyroid status and lithium levels reveal no thyroid abnormalities and a lithium level of 0.2 mEq/L. Because she previously had a good response to lithium, you reinstate lithium. Over the course of the next 2 weeks, you see no improve- ment in her manic symptoms despite treatment adherence to lithium and serum lithium levels around 0.9 mEq/L. You decide to add an atypical antipsychotic at this stage and over the next few days, Sara becomes increasingly more rational and is able to discuss long-term management. She continues to insist that she had been taking lithium until confronted with the laboratory test results. She denies adverse effects but explains that she has read a lot of ‘bad things’ about lithium and because she had been well for more than a year she thought it would not be necessary for her to continue taking lithium on a regular basis.
You explain the proven benefits of lithium in preventing both depression and mania and pre- venting suicidal behaviour and hospitalizations. As she had a relapse of a manic episode because of her
CANMAT guidelines for bipolar disorder
Yatham et al.
poor adherence to lithium, you suggest that lithium remains a good choice to prevent her mood episodes. You also explain to her that continuing the atypical antipsychotic might provide additional benefit in preventing mood episodes. After discuss- ing the risks and benefits of combination therapy, she agrees to continue both drugs. You emphasize the need for her to take lithium even when she feels well and to see her psychiatrist regularly for follow up, and she agrees to do so.
Section 4: Acute management of bipolar depression
Epidemiology of bipolar depression
Although diagnosis of bipolar disorder is based on the presence of hypomania or mania, depressive symptoms and episodes are more frequent over the course of bipolar I disorder. Furthermore, bipolar I patients in treatment experience syndromal/subsyn- dromal depressive symptoms up to three times more commonly than that of syndromal/subsyndromal manic symptoms (233, 234). Depressive symptoms are even more problematic for bipolar II patients who spend up to 37 times more days experiencing depressive symptoms than hypomanic symptoms (235). More than 50% of bipolar patients experience depression as their index mood episode (236) and patients seek treatment in the depressive state two to three times more often than in the manic state (75).
The depressive phase of bipolar disorder is chronic in 20% of patients (208) and causes more disability and decreased quality of life than any other phase of the illness (42, 234, 235, 237). Even subsyndromal depressive symptoms are associated with functional impairment (42, 238, 239). In rapid cycling bipolar patients, depressive episodes have been found to be more refractory to treatment than hypomanic or manic episodes (240).
Suicidal acts are a major concern in patients with bipolar disorder (48, 52–54), and are associated with severe depressive and mixed phases of illness, higher depression scores, and a greater number of severe depressive episodes (48, 51).
Although pharmacotherapy is the cornerstone of management of bipolar disorder, there is an import- ant role for psychotherapy and psychoeducation. There are no large controlled trials examining the efficacy of psychosocial interventions in acute bipo- lar depression either alone or in combination with pharmacotherapy. The evidence to support psycho- social interventions has mainly come from mainten- ance trials, and most trials enrolled patients in a
euthymic or subsyndromal state. However, IPSRT and CBT have demonstrated efficacy in acute unipolar depression, and a pilot trial has shown that CBT had similar efficacy in acute bipolar and unipolar depression (241). Thus, there is some evidence that psychosocial interventions, in combi- nation with pharmacological treatments, can have a positive impact on depressive symptoms and reduce time spent depressed (84–89). Adjunctive psychoso- cial therapies should be considered early in the course of illness to improve medication adherence, identify prodromes of relapse, potentially decrease residual symptoms (particularly depressive) and help move patients towards a more comprehensive functional recovery (84). In addition, the use of psychotherapy that was tailored to bipolar disorder or intensive clinical management as adjuncts to lithium therapy were associated with significant reductions in suicidal behaviour in high-risk depressed patients with bipolar I disorder compared to prior treatment with lithium alone (90).
Pharmacological treatment of depressive episodes
Lithium, lamotrigine, atypical antipsychotics, div- alproex sodium, carbamazepine and other agents, including antidepressants in combination, have been examined for their efficacy in the treatment of acute bipolar depression. These treatments have been evaluated using the criteria for strength of evidence (Tables 1.1 and 1.2) for their use and these are summarized in Tables 4.1 and 4.2.
Step 1: Review general principles and assess medi- cation status. When a patient presents in a depressed state, certain general principles should
Table 4.1. Strength of evidence for monotherapy treatments of acute bipolar depression
Divalproex Carbamazepine Lamotrigine Gabapentin
Atypical antipsychotics Olanzapine Quetiapine Risperidone Aripiprazole Ziprasidone Clozapine
Other therapies ECT
ECT 1⁄4 electroconvulsive therapy.
Level of evidence 1
2 2 3 – – 3
Table 4.2. Strength of evidence for combination treatments of acute bipolar depression
ant to improve symptoms and prevent relapse (see Section 2). In order to direct subsequent therapeu- tic choices, current therapy should be assessed, including what medications the patient is taking and at what dose.
Step 2: Initiate or optimize therapy and check adherence. In managing an acute depressive epi- sode, the decision to choose monotherapy or combination therapy is based on current and prior medication use (Fig. 4.1), as well as patient factors that may influence prognosis or safety.
In the drug-free patient, therapy should be initi- ated with one or more of the first-line agents: lithium (level 1), lamotrigine (level 1), lithium or divalproex, plus a selective-serotonin reuptake inhibitor (SSRI) or bupropion (level 2), olanzapine plus an SSRI (level 2), or lithium plus divalproex (level 2) (Table 4.3). Given that quetiapine monotherapy has also shown efficacy in acute bipolar depression, it is possible that quetiapine plus an SSRI will be as effective as olanzapine plus an SSRI (level 3).
For patients who relapse into a depressive episode while on divalproex or atypical antipsy- chotic monotherapy, addition of an SSRI, bupro- pion, lamotrigine or lithium, or a switch to lamotrigine or lithium would be appropriate.
Lithium + divalproex
Lithium + lamotrigine
Lithium + carbamazepine
Lithium or divalproex + SSRI Lithium + tricyclic antidepressant Lithium or divalproex + bupropion Lithium + MAOI
Olanzapine + SSRI
Risperidone or quetiapine + SSRI Divalproex + lamotrigine
Lithium or divalproex + venlafaxine Adjunctive pramipexole
Adjunctive light therapy
Adjunctive omega-3-fatty acids
MAOI 1⁄4 monoamine oxidase inhibitor; tonin reuptake inhibitor.
Level of evidence
SSRI 1⁄4 selective-sero-
be followed (Fig. 4.1). The patient should be assessed for a risk of suicide/self-harm behaviour, ability to adhere to treatment plan, psychosocial support network and the ability to function. Based on these factors, a decision can be made as to whether the patient requires admission to hospital or can be safely managed in an outpatient setting. Behavioural and educational strategies are import-
CANMAT guidelines for bipolar disorder
Step 1 Review general principals
assess medication status
Step 2 Initiate/optimize, check compliance
Step 3 Add-on or switch therapy
Step 4 Add-on or switch therapy
Step 5 Add-on or switch therapy
LAM Li OLZ +SSRI
Li + DVP
On DVP or AAP
Add SSRI or BUP
or add/switch to LAM or Li
Not on medication
Add/switch to Li
or add QUE
Assess safety/functioning Behavioural strategies/rhythms, Psychoeducation
Add SSRI or add/switch to LAM
Switch SSRI or switch OLZ to QUE or Li
Replace one or both agents with alternate 1st or 2nd line agents
On first line agent
Li or DVP
+ SSRI or BUP
Switch to alternate SSRI or BUP
or switch Li or DVP to QUE or OLZ
Add SSRI or BUP
or add/switch to LAM
or add pramipexole or methylphenidate
Fig. 4.1. Treatment algorithm for the management of bipolar depression. AAP 1⁄4 atypical antipsychotic; BUP 1⁄4 bupropion; DVP 1⁄4 divalproex; ECT 1⁄4 electroconvulsive therapy; LAM 1⁄4 lamotrigine; Li 1⁄4 lithium; OLZ 1⁄4 olanzapine; QUE 1⁄4 quetiapine; SSRI 1⁄4 selective-serotonin reuptake inhibitor.
Yatham et al.
Table 4.3. Recommendations for pharmacological treatment of acute bipolar depression
However, this trial was small, and the dose of paroxetine in the combination group was lower than that in the monotherapy group. Both trials suggest that atypical antipsychotics might have antidepres- sant effects, but it is possible that clinically they are not robust; therefore, until further data are available, these agents are not recommended as first-line mono- therapy for the treatment of acute bipolar depression. Quetiapine has not been assessed in combination, but with evidence of efficacy as monotherapy; it is a recommended second-line choice (see below).
Lithium + SSRIs. The addition of an SSRI (paroxetine) to lithium or divalproex was as effect- ive as combining lithium and divalproex in improv- ing depressive symptoms, in a small RCT (level 2) (246). However, significantly more patients receiv- ing lithium plus divalproex discontinued therapy compared with those receiving either lithium or divalproex plus paroxetine. In a double-blind RCT of imipramine, paroxetine and placebo as adjunct to lithium, antidepressant response did not signifi- cantly differ from placebo for patients with high lithium levels, but both paroxetine and imipramine were superior to placebo for patients with low serum lithium levels (242). Thus, antidepressants may be useful as adjunctive therapy for bipolar depressed patients who cannot tolerate high serum lithium levels or who have depressive symptoms that are refractory to lithium (242).
Lithium + divalproex. The combination of lith- ium plus divalproex was as effective as lithium or divalproex plus an SSRI in improving depressive symptoms in a small RCT (level 2) (246).
Lithium or divalproex + bupropion. In a small RCT, bupropion and desipramine were equally effective when combined with lithium or divalproex in acute and maintenance treatment of bipolar disorder, but bupropion had a much lower manic switch rate (level 2) (247). Bupropion was also as effective as sertraline or venlafaxine when used as add-on therapy in acute and maintenance treat- ment of bipolar depression, but in this case, manic switch rates were significantly greater in the ven- lafaxine group (level 2) (248). There is additional uncontrolled evidence to support the role of bupropion in acute bipolar depression (249, 250).
Step 3: Add-on or switch therapy. If optimizing therapy or adding an SSRI, bupropion, lithium, or lamotrigine to an atypical antipsychotic or divalp- roex therapy is inadequate, therapeutic choices are governed largely by the medication the patient is currently taking (Fig. 4.1). These include adding or
Second line Third line
Lithium, lamotrigine, lithium or divalproex + SSRI, olanzapine + SSRI, lithium + divalproex, lithium or divalproex + bupropion
Quetiapine, quetiapine + SSRI Carbamazepine, olanzapine, divalproex, lithium + carbamazepine, lithium + pramipexole, lithium or divalproex + venlafaxine, lithium + MAOI, ECT, lithium or divalproex or AAP + TCA Monotherapy with gabapentin
AAP 1⁄4 atypical antipsychotic; ECT 1⁄4 electroconvulsive therapy; MAOI 1⁄4 monoamine oxidase inhibitor; SSRI 1⁄4 selective-sero- tonin reuptake inhibitor; TCA 1⁄4 tricyclic antidepressant.
For patients on lithium or lamotrigine, which have established antidepressant efficacy, the first option before adding or switching therapies is to optimize the dose of these medications.
Lithium. As in the previous Canadian guidelines (1997), lithium remains a recommended first-line therapy for acute bipolar depression, with response rates ranging from 64 to 100% (level 1) (87). In one RCT, there were no significant differences between treatments when lithium was used in combination with placebo, imipramine or paroxetine (242). The superiority of antidepressant add-on was only apparent in those that had serum levels below 0.8 mEq/L thus confirming that when lithium is dosed adequately, it has antidepressant efficacy in monotherapy.
Lamotrigine. Two RCTs have demonstrated the efficacy of lamotrigine for the acute treatment of bipolar depression (level 1) (170, 243). About 40–50% of patients responded, which was twice that seen in the placebo group. Further, lamotrig- ine therapy was not associated with increased risk of manic switch in bipolar depressed patients.
Atypical antipsychotics + SSRIs. In a large RCT, the combination of olanzapine plus fluoxetine was more effective than olanzapine alone or placebo, and olanzapine alone was more effective than placebo in the treatment of bipolar depression without an increase in the development of manic symptoms (level 2) (244). Unfortunately, this trial did not include a fluoxetine-alone treatment regimen, which raises the possibility that the olanzapine plus fluoxe- tine combination may be no more effective than fluoxetine alone. In a comparison of risperidone and paroxetine combined, risperidone alone and paroxe- tine alone, there were similar improvements in depressive symptoms in all treatment groups, with no added benefit to the combination (level 2) (245).
switching to alternate first-line agents or consider- ing second-line options. Quetiapine with or with- out an SSRI is recommended as an alternate or as add-on to first-line therapies.
Quetiapine. In a large RCT, quetiapine mono- therapy was significantly more effective than placebo for the treatment of bipolar depression (level 2) (251). The magnitude of antidepressant effect observed for both quetiapine doses used in the trial was similar to or greater than that reported with lamotrigine (170, 243) or antidepressants (252, 253) in other trials. However, given that this is the only trial available showing antidepressant efficacy of quetiapine, it is premature to recommend it as a first-line monothera- py until the findings are replicated. Quetiapine can be considered a second-line treatment as monotherapy or in combination with an SSRI.
Step 4: Add-on or switch therapy (alternate first- or second-line therapies). Where necessary, steps 2 and 3 should be repeated with further therapeutic choices being based on current medication. Because of the efficacy and relative safety of first- and second-line agents, the use of third-line agents is not recommended until these classes of agents have been tried alone or in combination.
Step 5: Add-on or switch therapy (third-line ther- apies). In patients who failed to respond to first- and second-line agents, third-line choices would include monotherapy or add-on therapy with olanzapine, divalproex or carbamazepine; combi- nation therapy with lithium or divalproex plus pramipexole or venlafaxine, lithium plus a mono- amine oxidase inhibitor (MAOI) or carbamazepine and lithium, divalproex or an atypical antipsychotic plus a TCA, as well as ECT.
Olanzapine monotherapy. Olanzapine mono- therapy demonstrated statistically significant, but clinically modest antidepressant effects (level 2) (244) and therefore, is a recommended third-line treatment.
Divalproex monotherapy. In two uncontrolled trials divalproex showed positive results, one in patients with rapid cycling (254), and the other in patients with bipolar II depression (255). At this time, more data are needed to support the use of divalproex in acute bipolar depression (level 3).
Carbamazepine monotherapy. Early, small dou- ble-blind trials showed that carbamazepine was more effective than placebo in depressed bipolar patients (level 2) (256, 257).
Lithium or divalproex + pramipexole. In two small RCTs, 60–70% of patients with bipolar I or II depression were responders to pramipexole when used as add-on to lithium or divalproex compared with 9–20% of patients treated with placebo (level 2) (258, 259).
Lithium or divalproex + venlafaxine. In a ran- domized controlled trial, venlfaxine plus a mood stabilizer was as effective as a mood stabilizer plus paroxetine (253). In a double-blind trial, there were no differences in efficacy between venlafaxine, sertraline or bupropion when added to a mood stabilizer in treating bipolar depression but manic switches were more common in the venlafaxine group (248).
Lithium + MAOI. In two RCTs, tranylcypro- mine was more effective than placebo or imipram- ine in the treatment of bipolar depression (level 2) (260–262). However, because of concerns regard- ing manic switch, MAOIs are recommended in combination with lithium. These agents are gener- ally held in reserve because of the recognized concerns about food and drug interactions. Two RCTs, one in a mixed population of bipolar and unipolar depression (263), and the other in bipolar depression (264), demonstrated that the efficacy of the reversible inhibitor of MAO-A (RIMA), moc- lobemide was similar to the tricyclic antidepressant (TCA), imipramine (level 2).
Lithium + carbamazepine. This combination is recommended as a third-line option based on evidence for each of the medications as mono- therapy and case reports suggesting that carb- amazepine plus lithium may be effective in lithium- resistant bipolar depressed patients (level 3) (87).
Lithium, divalproex or atypical antipsychotics + TCA. Imipramine was more effective than pla- cebo, but less effective than fluoxetine for bipolar depression (252). When added to lithium therapy, imipramine was as effective as paroxetine and was superior to placebo for patients with low serum lithium levels (242) but not for those with high levels (level 2). Although specific data are not available, the combinations of divalproex or an atypical antipsychotic with a TCA may also be effective (level 4). However, adverse event rates and rates of switch into mania have been reported to be substantially greater with TCAs compared with SSRIs, suggesting these agents be reserved for only those patients who are not responsive to first-, second- and other third-line options with lower switch rates (265–267).
CANMAT guidelines for bipolar disorder
Yatham et al.
ECT. Although controlled data are lacking, open studies and clinical experience suggest that ECT is a very effective treatment for acute bipolar depression. In open-label and retrospective studies, response rates ranged from 43 to 100%, and ECT was more effective than antidepressant therapy (level 3) (268). Given this, ECT can be considered earlier in patients with severe psychotic bipolar depression, those at risk of significant medical complications because of non-eating and drinking, and those with a past history of non-response to antidepressants or anti- depressant-induced rapid cycling.
Agents not recommended for the treatment of acute bipolar depression. Gabapentin (level 2, negative) and clozapine (level 3) have insufficient data to be recommended as monotherapy for the treatment of bipolar depression. The efficacy of gabapentin suggested by open trials was not borne out in a placebo-controlled RCT in a mixed population of patients with bipolar and unipolar depression (level 2) (170). Clozapine is not recommended for the treatment of acute bipolar depression, because of lack of data supporting antidepressant efficacy (269) and safety concerns (level 3).
Clinical features that can help direct treatment choices
No studies have systematically examined predic- tors of response to treatment in patients with bipolar depression. However, clinically there are some factors that can help direct treatment choices (87). It is important to consider a patient’s history of manic and depressive episodes. For patients with a history of rapid cycling or severe mania, strategies that do not include an antidepressant should be tried first, while for those with severe bipolar depression and a history of mild mania, the use of a combination that includes an antidepres- sant would be appropriate. When antidepressants are used, SSRIs and bupropion are preferred over TCAs and MAOIs. In patients with mild bipolar depression on maintenance therapy, CBT or psy- chosocial strategies may be considered before adding adjunctive medications. For patients with bipolar depression and psychotic features, ECT or a combination of an atypical antipsychotic plus an SSRI should be considered early in therapy.
Clinical questions and controversies
In patients successfully treated for a depressive episode with a mood-stabilizer plus an antidepres- sant, how long should the antidepressant be contin- ued? The risk-to-benefit ratio of the use of antidepressants as adjuncts to mood-stabilizers
continues to be an area of controversy. In a meta- analysis of 12 trials, antidepressants were more effective and overall did not induce more switching to mania than placebo (3.8% versus 4.7% with placebo) (267). However, the rate of switching for TCAs was 10% compared with 3.2% for all other antidepressants combined. Other reviews have also reported a higher switch rate with TCAs (265, 266).
An RCT including only the episodes of mania with some dysfunction reported a 12.6% rate of switching in the acute phase and a 17.9% rate over 1 year (270). In a double-controlled trial, hypoman- ic/manic switch rates were 14% during the first 10 weeks of the trial, and 33% over a 1-year maintenance phase (271). These data suggest that the longer the antidepressant is continued, the greater the risk of switch. However, it has also been reported that the rate of relapse into depression in patients who respond to and continue antidepres- sants was 35% compared with almost 70% in those who discontinued, with no increase in the rate of switching to mania in the group who continued (272). Data from double-blind, placebo-controlled trials in a large sample of patients for various antidepressant treatments are urgently needed to resolve this issue. In the meantime, for all bipolar I patients with the exception of those with highly recurrent bipolar I depressive episodes, we recom- mend that clinicians attempt to taper antidepres- sants within 6–8 weeks of remission of depressive symptoms and discontinue whenever possible.
Are there differences in manic switch rates between newer antidepressants? Results from two trials sug- gest a higher switch rate for venlafaxine compared with SSRIs and bupropion when used as add-on therapy in RCTs (253). In the first, the rate of switch was 13% with venlafaxine and 3% with paroxetine (253), and in the second a higher risk of manic switch was reported with venlafaxine (38%) compared with sertraline (10%) and bupropion (9%) (248, 270).
Sara, 25 years old, presents to her family physician (FP) with depression of 2 weeks duration. She moved to the city 3 months ago for a new job, and has felt lonely without her family and friends. During the interview, the FP discovers that she has at least a 5-year history of bipolar disorder and, up until now, had been stable on lithium for the past 3 years.
• Should he refer her to a specialist?
Clinical management. It is important to get Sara’s depression under control, but the FP is concerned
about prescribing antidepressants to a patient with bipolar disorder. Worried about manic switch, the FP decides to refer her to a psychiatrist in the new city for further management.
You are her new psychiatrist, and your assessment of Sara indicates that she is moderately depressed but has no psychotic features. Although Sara has suicidal thoughts, she has no plans to kill herself and is willing to enter into a contract regarding self- harm. She has no financial or other concerns, is not abusing any street drugs, and she has a good job, but she has little psychosocial support. She describes her past history of depressive episodes, her diagnosis of bipolar disorder at age 20, and her most recent manic episode 3 years ago. At that time she was treated with lithium and an atypical antipsychotic. She continued the atypical antipsychotic for 6 months but gained a lot of weight. As non-adherence to lithium probably played a role in her manic episode, she and her doctor decided that the atypical antipsychotic may not be necessary for maintenance if she adhered to the lithium regimen, which she says she has been doing faithfully.
You discuss with her a management plan that includes optimizing lithium therapy and helping her learn cognitive behavioural therapy (CBT) strategies to cope with her depression. Over the next 4 weeks, despite adequate serum lithium levels (0.9 mEq/L) and ongoing CBT, she shows little improvement in her symptoms.
You and Sara discuss possible next steps, inclu- ding (i) adding or switching to lamotrigine, (ii) adding an SSRI antidepressant or bupropion, or (iii) adding divalproex. She agrees to take lamot- rigine, which is initiated at 25 mg daily, increased to50 mgattheendofweek2,andto100 mgatthe end of week 4. She begins to have some sympto- matic improvement at week 3, with further improvement at week 5. However, she still has some depressive symptoms and you increase the dose of lamotrigine to 150 mg daily. At week 7, when you see Sara, she appears in good spirits and says she is feeling much better. You continue to be concerned with her lack of a support system, and provide her with information on local community support groups for people with bipolar disorders. You agree to continue to see her for maintenance treatment and at each visit you discuss treatment adherence and side effects of medications.
Section 5: Maintenance therapy for bipolar disorder
Need for long-term strategies
Estimated recurrence rates of 60–80% after discon- tinuation of lithium or antipsychotic therapy and
20–50% during ongoing therapy have been reported (225, 226, 228, 229, 232, 273–275) for bipolar disorder. In addition, a substantial proportion of patients with bipolar disorder, even those who undergo intense monitoring and treatment of acute episodes will experience considerable residual ill- ness-related morbidity. As a result, the long-term treatment goals include not only preventing suicidal behaviour and recurrence of syndromal depression and mania, but also improving subsyndromal symptoms, treatment adherence, quality of life, cognition and functional outcomes.
Comorbid substance abuse, mood-incongruent psychotic features and a family history of schizo- affective disorder with manic features are risk factors for recurrence (276). Data indicate that more previous episodes are associated with future episodes (277), decreased quality of life and func- tioning (278), poorer response to treatment (279) and longer hospitalization (280). It has also been suggested that cumulative structural changes in the brain (281) may be a consequence of multiple episodes and are associated with cognitive impair- ment (282–284). These consequences of multiple episodes argue in favour of initiating preventive therapy early, even after the first episode.
Several terms are used when discussing the long- term treatment of bipolar disorder. For example, ‘relapse’ and ‘recurrence’ refer to the return of symptoms, respectively, in the same or a new episode (285). However, there is little consensus on what that duration should be, and these episodes do not appear to differ in terms of how they respond to maintenance therapy. Therefore, these guidelines will use only the term recurrence to describe re-emerging episodes of mania or depression. Simi- larly, the terms ‘continuation’ and ‘maintenance’ have been used to define therapy during the early stable phase and the long-term prophylactic phase respectively (276, 285). Although there may be a higher probability of recurrence during the early period after an acute episode (285), these guidelines will refer to all prophylactic therapy after stabiliza- tion of acute manic or depressive episodes as maintenance therapy.
According to prospective data, one in three patients with bipolar disorder fails to take at least 30% of prescribed medication (286). In bipolar disorders, non-adherence to treatment has been identified as an important cause of recurrence (287) and is
CANMAT guidelines for bipolar disorder
Yatham et al.
Table 5.1. Factors negatively influencing treatment adherence (118)
Low education level
Lack of psychosocial support
Comorbid personality disorders Comorbid substance abuse Poor insight
Side effects of medications
Unfavourable personal attitudes towards treatment
Table 5.2. Characteristics of effective therapies that maximize adherence (118)
Managing side effects
Identifying and managing stressors
Addressing belief system and attitudes to illness
associated with higher rates of both hospitalization (288) and suicide (289). Recognizing the factors that have a negative impact on adherence to therapy might help target interventions towards patients at risk of discontinuation (Table 5.1) (118).
Among the methods to enhance treatment adherence, interventions that include both patient and family members, those that incorporate a good understanding of the disorder, the medications and their side effects, and those that are integrated into a long-term management plan can have beneficial effects [reviewed by Sajatovic et al. (118)] (Table 5.2). Interventions that include family only, without participation of the patient, do not appear to impact adherence (290). Psychotherapeutic interventions found to be effective in enhancing adherence include interpersonal group therapy, CBT, and patient and family psychoeducation (see below) (118).
Currently, limited data exist to predict which patients will respond to which medications. Even for the most investigated treatments, such data are from retrospective evaluations. As many first-line treatments of manic or depressive episodes have also been shown to have prophylactic efficacy, it is generally wise to continue the index medication used for the acute episode. For those bipolar patients who are currently not on treatment, the
essential starting point would be a careful history including details of clinical course, response (or lack thereof) to previously used medications and family history. Other variables should also be considered: the predominant polarity of the illness so far and whether the most recent episode was manic or depressive are particularly relevant. Because the depressive pole predominates in most bipolar patients (233, 291) and suicidal behaviour is over represented in this population (44–54), careful consideration should first be given to prescribing lithium, both on the strength of evidence for its role in bipolar prophylaxis and also because of its antisuicidal effects (60–63). Furthermore, as suicidal behaviour is more common when patients are experiencing syndromal/subsyndromal depressive episodes (48, 53), it is recommended that depressive symptoms be treated aggressively with appropriate first-, and where necessary, second-line treatments.
Although pharmacotherapy is the cornerstone of management of bipolar disorder, adjunctive psy- chotherapy or psychoeducation should be provided early in the course of illness to improve medication adherence, identify prodromes of recurrence, impart coping strategies to decrease residual symp- toms and suicidal behaviour, and help move patients towards a more comprehensive functional recovery (84–96, 100–102, 292, 293).
The importance of follow up cannot be over emphasized, as it is crucial in enhancing patient adherence, detecting early symptoms of recurrence and monitoring side effects.
Psychoeducation (level 2). Psychoeducation should emphasize the importance of lifestyle regularity and healthy habits, early detection of prodromal signs and treatment adherence (88). In two RCTs, group psychoeducation added to pharmacotherapy delayed the time to recurrence, irrespective of the nature of the prior episode and reduced hospital- izations over a 2-year follow up (88, 91). In a third trial, psychoeducation aimed at teaching patients to recognize prodromal symptoms of recurrence was associated with prolongation of time to first manic recurrence, as well as improved social functioning and employment, but had no effect on depressive recurrence (92).
A significant reduction in suicidal behaviour in high-risk patients with bipolar I disorder has been demonstrated when patients were treated with adjunctive bipolar focused psychotherapy in a very supportive clinical environment (90), or in a specialized programme during lithium therapy (60, 63, 294). Group psychoeducation has also
been reported to improve quality of life and functioning in bipolar patients (293).
Cognitive-behavioural therapy (level 2). Controlled trials have demonstrated decreased recurrences, mood fluctuations, need for medications and hospitalizations, and increased functioning and treatment adherence with the use of concurrent CBT and mood-stabilizers compared to treatment as usual or wait-listed controls (93–95). In one study the benefits of CBT were clinically significant in those that had six or fewer episodes but not in those with more than six episodes (295).
Family therapy (level 2). Family-focused treat- ment in combination with pharmacotherapy has also been shown to reduce recurrences and hospit- alizations and also improve depressive symptoms and medication adherence to a greater extent than individual therapy or a family crisis management intervention (100–102).
Interpersonal and social rhythm therapy (level 2).
Interpersonal and social rhythm therapy, a modi- fied form of interpersonal psychotherapy, focuses on four problem areas (grief, interpersonal role transition, role dispute and interpersonal deficits) with the objective of identifying interpersonal problems and providing therapy to stabilize social rhythms. Although a large controlled trial failed to demonstrate that IPSRT prolonged time to recur- rence better than intensive clinical management (96), subsequent analysis showed that IPSRT did have a significant impact on subsyndromal symp- toms, and patients spent more time euthymic and less time depressed (97).
Pharmacological treatments for maintenance therapy
The evidence base for effective maintenance ther- apies is most comprehensive for lithium, lamotrig- ine, olanzapine, and to a lesser degree for divalproex. Some data are also available for carbamazepine and for combination therapies. To date, there are no long-term RCT data for other atypical antipsychotics including risperidone and quetiapine, or other anticonvulsants including oxcarbazepine, topiramate and gabapentin. Main- tenance treatments evaluated on strength of evidence for their use (Tables 1.1 and 1.2) are summarized in Tables 5.3 and 5.4.
First line. Lithium, lamotrigine, divalproex and olanzapine have the most data to support their use as first-line therapies for the maintenance treat- ment of bipolar disorder (Table 5.5).
Table 5.3. Strength of evidence for efficacy of maintenance monotherapy for bipolar mania
CANMAT guidelines for bipolar disorder
Carbamazepine Gabapentin Topiramate Oxcarbazepine
Atypical antipsychotic Olanzapine Aripiprazole Risperidone Quetiapine Clozapine
Other treatments ECT
ECT 1⁄4 electroconvulsive therapy.
Level of evidence 1
Depression: 1 Mania: 2
Mania: 2 3
Table 5.4. Strength of evidence for efficacy of maintenance combination therapy for bipolar mania
Lithium + divalproex Lithium + carbamazepine
Level of evidence
Lithium or divalproex Lithium or divalproex Lithium or divalproex Lithium or divalproex Lithium + TCA
Lithium + SSRI
Lithium or divalproex Lithium or divalproex Adjunctive phenytoin Adjunctive gabapentin Adjunctive topiramate Lithium or divalproex + ECT Lithium + flupenthixol
ECT 1⁄4 electroconvulsive therapy;
reuptake inhibitor; TCA 1⁄4 tricyclic antidepressant.
2 (ve) 3
disorder First line
Lithium, lamotrigine monotherapy
(mainly for those with mild manias), divalproex, olanzapine
Carbamazepine, lithium + divalproex, lithium + carbamazepine, lithium or divalproex + olanzapine, aripiprazole, risperidone, quetiapine, ziprasidone, lithium + risperidone or quetiapine, lithium + lamotrigine or an
SSRI or bupropion
Adjunctive phenytoin, clozapine, ECT, topiramate, gabapentin, omega-3-fatty acids, oxcarbazepine
Adjunctive flupenthixol, monotherapy with gabapentin, topiramate, antidepressants
+ olanzapine + risperidone + quetiapine + clozapine
+ omega-3-fatty acids
SSRI 1⁄4 selective-serotonin Table 5.5. Recommendations for maintenance pharmacotherapy of bipolar
ECT 1⁄4 electroconvulsive therapy; SSRI 1⁄4 selective-serotonin reuptake inhibitor.
Yatham et al.
Lithium. There is good evidence to support lith- ium monotherapy in the maintenance treatment of bipolar disorder from meta-analyses (221–223) and RCTs (224–229) (level 1). A meta-analysis of studies conducted prior to 1990 suggested that the magni- tude of prophylactic benefit with lithium is greater for the prevention of manic episodes than for depressive episodes (45). This was confirmed in recent RCTs that showed clear benefit in preventing mania but not depression (225, 229). Lithium has also been shown to have antisuicidal properties (60–63).
Rapid discontinuation of lithium is followed by a high rate of recurrence in bipolar patients even after good response and a lengthy illness-free period (273). If lithium is discontinued, it should be done gradually, as abrupt discontinuation appears to be associated with a higher rate of recurrence (296, 297).
Lamotrigine. Three RCTs have demonstrated the efficacy of lamotrigine for the prevention of recurrence of bipolar disorder in patients with most recent episode manic, most recent episode depressed or rapid cycling patients (level 1) (225, 229, 275). Lamotrigine has demonstrated efficacy that was superior to placebo in prolonging time to intervention for any episode and for depressive episodes, but not for manic episodes. Hence, lamotrigine should not be used as a monotherapy for bipolar patients if prevention of recurrence of mania is a major objective. Lamotrigine appears to be beneficial in those with bipolar II disorder with rapid cycling (275), and in such cases, lamotrigine monotherapy is appropriate.
Divalproex. Although one RCT failed to demon- strate that divalproex was superior to placebo in preventing recurrence of bipolar episodes (298), in three other RCTs divalproex was as effective as lithium (219, 230) or olanzapine (231) in the prevention of recurrence. In the placebo-controlled trial, neither lithium nor divalproex showed superi- ority on the primary efficacy measure (298). How- ever, a sub-analysis showed that divalproex was superior to placebo in severely ill bipolar patients, and was associated with a longer time to discon- tinuation for depression. The fact that two double- blind studies (219, 231), and an open controlled study (230), showed equivalency of divalproex and active comparators, together with the wealth of experience and good tolerability of this medication, led to the conclusion that divalproex should be considered as a first-line treatment option (level 2).
Olanzapine. Olanzapine treatment delayed recurrence in bipolar disorder, significantly re-
duced rates of both manic and depressive episodes compared with placebo (232) and was found to be as effective as both divalproex (231) or lithium (228) in prolonging remission (level 2).
Carbamazepine. There are no large-scale, dou- ble-blind, placebo-controlled trials examining the efficacy of carbamazepine in the maintenance treatment of bipolar disorder. However, most, but not all, studies have shown that carbamazepine has similar efficacy to that of lithium (197, 224, 299, 300) and might provide better prophylactic efficacy than lithium in patients with non-classical presentations of bipolar mania (e.g. mood-incon- gruent features, comorbidities and bipolar II dis- order) (level 2) (300).
Other atypical antipsychotics. Aripiprazole sig- nificantly prolonged the time to recurrence, and significantly decreased the number of mood episodes compared with placebo in a 6-month RCT (level 2) (301). However, a sub-analysis showed that aripip- razole was superior to placebo in preventing mania but not depression. Therefore, at present, it is recommended as a second-line treatment for bipolar patients with predominantly manic episodes.
There are no double-blind RCTs examining the long-term efficacy of risperidone, quetiapine or ziprasidone for bipolar disorder. Open-label data suggest that risperidone may be effective in sus- taining improvement of bipolar disorder when used in combination with lithium/divalproex (level 3) (302–305) or topiramate (level 3) (306). Quetiapine alone or as add-on to mood-stabilizers (level 3) (307, 308) and ziprasidone monotherapy have also reported long-term improvements in open-label trials (level 3) (309).
Because aripiprazole and ziprasidone are not currently available in Canada, and the guidelines group has only limited clinical experience with these agents, recommendations for their use as maintenance treatments are based largely on the reported efficacy data and adverse event profile of these agents.
Combination therapy. Combination therapy is an important option for patients who have failed adequate trials of first-line monotherapy. However, there are no systematic comparisons of switching to alternate monotherapy versus using a combina- tion of treatments, and there is little evidence to recommend one combination over another. Com- binations that have demonstrated some efficacy include: lithium plus divalproex (level 2) (310, 311)
or carbamazepine (level 2) (197); as well as lithium or divalproex plus olanzapine (level 2) (312) or risperidone (level 3) (302–304). No data are avail- able on lithium plus lamotrigine, but this combi- nation is recommended based on the proven prophylactic efficacy of the two medications as monotherapies.
Clozapine. Adjunctive treatment with clozapine was significantly better than treatment as usual in a small RCT of 12 months duration (level 3) (269). In addition, evidence from the schizophrenia literature demonstrating that clozapine has antisuicidal prop- erties suggests a role for this agent in some patients with bipolar disorder (313).
ECT. Evidence from case series suggests that maintenance ECT (usually adjunctive to medica- tion) is effective in reducing hospitalizations in bipolar disorder (level 3) (314). However, a review of data concluded that ECT had an acute but not a long-term beneficial effect on suicidality in patients with mood disorders (315).
Other agents. Open-label and preliminary data support the use of adjunctive oxcarbazepine (level 3) (316, 317) or phenytoin (level 3) (318). Open trials have also suggested the efficacy of topiramate as add-on to mood-stabilizers (level 3) (319, 320) or atypical antipsychotics (level 3) (306, 321). Ongoing, adjunctive gabapentin was effective for some patients who had responded to this agent acutely, but 30% of patients experienced a loss of efficacy over time (level 3) (322). In a 4-month, RCT, omega-3-fatty acids prolonged the time in remission compared with placebo (level 2) (323).
Benzodiazepines. A systematic evaluation of benzodiazepines as prophylactic agents in bipolar disorder has not yet been conducted (276), but issues such as dependence, rebound anxiety, mem- ory impairment and discontinuation syndrome argue against their long-term use (324). The absence of prophylactic efficacy and attendant risks associated with long-term use support the gradual titration of these agents to either discon- tinuation or to the lowest effective dose for essential symptomatic management (276).
Antidepressant monotherapy. Although antide- pressants have efficacy in acute depressive episodes, a review of seven RCTs of antidepressants (pre-
dominantly TCAs) as monotherapy or adjunctive treatment concluded that they were ineffective in the prevention of future episodes (325). In a seminal maintenance study reported in 1973, manic episodes occurred in 12% of patients on lithium, 33% of patients on placebo, and 66% of patients on imipramine monotherapy (326). In another study of 1 year duration, 50% of patients rand- omized to desipramine as add-on to mood-stabi- lizers experienced a manic switch compared with only 11% of patients randomized to bupropion add-on treatment (247). These data clearly suggest that TCAs destabilize the course of bipolar disor- der whether used in monotherapy or in combina- tion with lithium or divalproex.
No double-blind, placebo-controlled trials have examined the efficacy of SSRI monotherapy for the maintenance treatment of bipolar disorder. How- ever, in a 1-year clinical trial comparing lithium, divalproex and placebo, in which patients received SSRIs for breakthrough-depressive episodes, a significantly greater proportion of patients discon- tinued the study in the SSRI plus placebo group compared with the SSRI plus divalproex group (327). Therefore, SSRI monotherapy is also not recommended for maintenance treatment of bipo- lar disorder.
Other treatments. Flupenthixol does not appear to have prophylactic efficacy in patients with bipolar disorder (level 2, negative) (328, 329). Perphenazine in combination with a mood-stabil- izer was not superior to mood-stabilizer alone, and in fact had led to increased incidence of depressive episodes in bipolar disorder (330). Agents such as gabapentin, topiramate and calcium channel blockers have been investigated for use in bipolar disorder, but insufficient data exist to recommend their use as monotherapy.
Clinical features that can help direct treatment choices
Psychoeducational interventions are an essential part of long-term management of bipolar disorder for all patients. Lithium has the best evidence of prophylactic efficacy in bipolar disorder, prevent- ing both manic and depressive episodes and having important antisuicidal effects. Olanzapine, divalp- roex and lamotrigine have proven long-term bene- fits, with olanzapine and divalproex perhaps being more suitable for patients with manic recurrences, while the efficacy of lamotrigine appears to be mainly in the prevention of depressive recurrences. Lamotrigine should not be used as monotherapy in patients with a history of severe or frequent manic episodes.
CANMAT guidelines for bipolar disorder
Yatham et al.
Predictors of response to maintenance treatment have been investigated to a varying degree for different medications. While there are more and better data for predictors of response to lithium (331), the data for other maintenance treatments are limited. Lithium can be considered the treatment of choice in patients with typical bipolar disorder, an episodic clinical course, low rates of psychiatric comorbidity, and those who have a family history of lithium-responsive bipolar disorder.
For patients with rapid cycling, lithium, lamot- rigine and divalproex have demonstrated efficacy, but it is likely that most patients will require a combination of treatments. The atypical antipsych- otics have demonstrated equal efficacy in patients with and without rapid cycling in acute studies, and likely would be useful add-on therapies in long-term management.
Few patients manage a lifetime of bipolar disorder with monotherapy. Most require short- or long-term combination therapy with lithium, divalproex, atypical antipsychotics, antidepres- sants, lamotrigine and/or ECT. Serum levels of medication and other monitoring of bodily systems should be conducted as clinically indicated, but no less than once every 6 months (see Section 8).
Bipolar disorder with rapid cycling
Rapid cycling, which occurs in approximately 20% of patients with bipolar disorder (216, 217, 332), is associated with greater severity of illness on a number of clinical measures (333).
First line. As shown in Table 5.6, lithium, lamot- rigine and divalproex are recommended first-line therapies for the long-term management of pati- ents with bipolar disorder and rapid cycling.
Lithium. Although rapid cycling has been repor- ted to be associated with a poorer response to lithium therapy (334), a meta-analysis of long-term treatment found that rapid cycling was associated with a poorer response to all treatments evaluated (level 2) (332).
Table 5.6. Pharmacological maintenance treatment of bipolar disorder with rapid cycling
In a placebo-controlled RCT, patients on lith- ium experienced numerically, but not significantly lower rates of recurrence (level 2) (335). In the first of two trials against active comparators, lithium was as effective as carbamazepine but less effective than a combination of the two drugs (197). In the second trial, patients with rapid cycling who had a persistent response to the combination of lithium or divalproex were randomized to monotherapy with one of the agents (219). There were no significant differences in rates of recurrence of depression or mania/hypomania in patients treated with lithium or divalproex.
Based on overall prophylactic and antisuicidal effects in patients with bipolar I disorder, lithium is recommended as a first-line therapy, but it is likely that patients with rapid cycling will require a com- bination of treatments for maintenance therapy.
Lamotrigine. In a 6-month placebo-controlled RCT there were no significant differences in the primary end point of time to additional interven- tions between lamotrigine and placebo. However, there was a significantly lower rate of recurrence in the lamotrigine group (59%) compared with the placebo group (74%) (level 2) (275). The difference in recurrence rates was not significant for patients with bipolar I, but was significant for patients with bipolar II (54% versus 82% with lamotrigine versus placebo). Therefore, lamotrigine may be useful in monotherapy for patients with bipolar II and rapid cycling, but combination with lithium or divalproex may be required in patients with bipolar I.
Divalproex. As discussed above there were no significant differences in recurrence rates in patients with rapid cycling treated with lithium or divalproex (level 2) (219). Rates of recurrence into mood episodes with divalproex and lithium were: 50% versus 56% overall, 29% versus 34% into depression, and 22% versus 19% into hypomania/ mania, respectively. However, median survival in the trial was longer on divalproex compared with lithium. Evidence from open case series provides additional support for the use of divalproex in rapid cycling bipolar disorder (334, 336).
Lithium + divalproex. Although no long-term
data are available, the combination of lithium and divalproex has been used effectively to stabilize patients with rapid cycling (level 4) (219).
Lithium + carbamazepine. In an RCT compar- ing the prophylactic efficacy of lithium, carbamaze-
First line Second line
Lithium, lamotrigine, divalproex
Lithium + divalproex, lithium + carbamazepine
Lithium or divalproex + topiramate, olanzapine, quetiapine, risperidone, clozapine, oxcarbazepine, levothyroxine Antidepressants
pine and their combination, the sub-group of patients with a past history of rapid cycling did poorly on either monotherapy but significantly better on the combination (level 2) (197).
Lithium or divalproex + topiramate. Open-label add-on topiramate demonstrated some efficacy in patients with rapid-cycling (level 3) (319).
Atypical antipsychotics. In acute treatment of mania, monotherapy with olanzapine (128, 191) or aripiprazole (337) appears to be equally effective in patients with and without rapid cycling. Risperidone was shown to effectively decrease the number of affective episodes in a series of 10 patients with rapid cycling followed for 6 months (level 3) (338). A case series of patients with rapid cycling receiving quetia- pine as adjunctive therapy for up to 1 year reported that patients had early improvements in manic and depressive symptoms, but that 70% of patients dropped out, including 27% for lack of efficacy and 7% for depression or mixed episodes (level 3) (308). In a series of patients treated with clozapine as adjunct to mood-stabilizers, more than 80% showed at least some improvement over the 1-year study (level 3) (339). Clozapine was more effective in non-rapid cyclers than in those with rapid cycling. However, long-term safety concerns limit the use of clozapine (291).
Some data suggest a relationship between hypo- thyroidism and current but not lifetime rapid cycling, suggesting that thyroid dysfunction may contribute to mood destabilization (195, 216). This is supported by evidence from open trials that levothyroxine enhances maintenance therapy in some patients with rapid cycling (level 3) (340– 345). Levothyroxine may be useful in combination with other agents in patients who are refractory to other treatments (346). In addition, some data suggest that bipolar II patients who became rapid cyclers as a result of lithium failure might benefit from thyroid augmentation in selected cases (195). However, studies have found no difference in thyroid hormone levels in those with versus those without rapid cycling (347, 348).
Bipolar disorder with mixed episodes
Although there have been relatively few studies to assess the role of various medications in the main- tenance management of patients with mixed epi- sodes, it is likely that these patients will require combination therapy to best address both depressive and manic symptoms. Two RCTs provide support- ive evidence for olanzapine in this population.
Patients with a mixed index episode randomized to olanzapine maintenance therapy had significantly lower recurrence rates (59%) compared with those assigned to placebo (91%) over a 1-year follow up (level 2) (349). In a comparison of olanzapine and divalproex in which almost half of the patients had a history of mixed episodes, a lower rate of recurrence of mixed episodes was reported with olanzapine (1 of 14 episodes) than divalproex (3 of 13 episodes) (231).
In a sub-group of recently manic or hypomanic patients who were randomized to lithium, lamot- rigine or placebo in an RCT, recurrence of mixed episodes was numerically greater with lamotrigine (4 of 28 episodes) or placebo (6 of 49 episodes) than with lithium (2 of 10 episodes) (level 3) (229).
There is also preliminary support from a post hoc analysis of an RCT that carbamazepine (212) and from an open trial that oxcarbazepine (317) may be effective in patients with mixed episodes (level 3).
Clinical questions and controversies
Should maintenance pharmacotherapy be discontin- ued, and if so, when? Maintenance pharmacotherapy is recommended for all patients with bipolar dis- order who have had at least one moderately severe manic episode. For patients who refuse maintenance therapy, psychosocial strategies should include a clear discussion of risks and benefits associated with maintenance therapy. In those who refuse, the effective acute-phase dosages should be continued for at least 3–6 months. Attempts to simplify the medication regime should not be made until several weeks of stability have passed, and if a medication is discontinued, it should be tapered slowly, usually by no more than 25% per week (350). Medications should be reinstated promptly if symptoms recur.
Discontinuation of lithium appears to be fol- lowed by a high rate of recurrence in patients with bipolar disorder, even after a prolonged period of well-being (273, 296, 297). Rates of recurrence during the first 40 weeks after lithium discontinu- ation were much higher (58%) than in the year before treatment was discontinued (21%) (274).
Benzodiazepines, if used, must be weaned gradu- ally. If an antidepressant has been used to treat an acute depressive episode, it should be continued at the same dose for 1–3 months following symptom resolution. Although this is a subject of much debate, generally this will mean discontinuing antidepressants after 3–6 months of use.
It may be appropriate to discontinue one or more maintenance pharmacotherapies before or during pregnancy or the postpartum period in some cases.
CANMAT guidelines for bipolar disorder
Yatham et al.
When is it appropriate to use lamotrigine in combi- nation with lithium, divalproex or an atypical antipsychotic? Although lithium has demonstrated efficacy for the prevention of both manic and depressive episodes, it is better at preventing manic episodes. Similarly, divalproex and the atypical antipsychotic olanzapine have demonstrated pro- phylactic efficacy, and it is likely that the magni- tude of benefit is greater against manic episodes. The prophylactic efficacy of lamotrigine, on the other hand, is greater for the prevention of depressive episodes. Although the use of lamotrig- ine in combination has not been studied, it may be useful for patients whose manias are well con- trolled on lithium, divalproex or an atypical antipsychotic, but are having depressive relapses.
In addition, there is little concern regarding the safety of combining lithium or atypical antipsych- otics with lamotrigine. However, caution should be exercised when combining lamotrigine and divalp- roex, because divalproex doubles the serum levels of lamotrigine (351), and rapid up-titration of lamotrigine in those that are on divalproex can increase the risk of skin rash and Stevens–Johnson syndrome (352–354). Carbamazepine can reduce the levels of lamotrigine by up to half, and thus potentially decrease its efficacy (355).
Sara, 29 years old, has at least a 9-year history of bipolar disorder. She has recently returned to your clinic after living in another city for 4 years. During the past 2 years, the pressure of her job and the lack of family support have contributed to poor eating and sleeping habits; she has taken up smoking, and has been suffering from increasing mood instability: she has had at least four signi- ficant mood episodes in the past year. She stopped taking lamotrigine 3 years ago but continued to take lithium on an irregular basis. She lost her job because of some bizarre behaviour and frequent absenteeism when she felt ‘so depressed that she couldn’t get out of bed’. Since moving home with her parents, she says she would like to ‘get well and rebuild her life’.
Sara has developed a rapid cycling course and is currently in a mixed state, describing bouts of anxiety, crying and irritability occurring in the same day with racing thoughts, increased energy and agitation. At the same time, she has no motivation, feels hopeless and has thoughts about suicide. She has multiple stressors in her life including no job, nicotine dependence and the need to regain her family’s trust. She feels that her family ‘blames’ her for being in this state.
• What is your immediate course of action? • What questions should you ask?
• What is your treatment plan?
Clinical management. Bipolar disorder is a chronic condition with frequent recurrences, in some cases despite maintenance treatment with one or more medications. It is important to first re-establish a therapeutic alliance with Sara and re-emphasize the chronic nature of her illness. Thinking about normal biorhythms, you first explain to her the importance of a regular routine and adherence to medication. Thyroid hormones are normal but lithium levels are low at 0.44 mEq/L. She recalls taking lamotrigine to help her depression a few years ago. She had a good response but discontin- ued when the prescription ran out. She also attended five or six weekly sessions of group therapy, which she felt helped but they took up too much time, so she stopped attending.
You assess her suicide risk; although she thinks it would not matter if she did not wake up tomorrow, she does not have any plans to harm herself and has made no past attempts. You discuss a management plan that includes optimizing pharmacotherapy and meeting family members to enhance psychosocial support. Over the next 3 weeks, despite optimizing lithium therapy (serum lithium level is now 0.84) and ongoing psychosocial support, she shows little improvement in her symptoms.
You discuss a number of treatment options with Sara including: (i) adding or switching to divalp- roex, (ii) adding lamotrigine or (iii) adding olanza- pine. You review the risks and benefits of each strategy. Based on the discussion she decides to take divalproex in addition to lithium. Within 2 weeks she begins to have some symptomatic improvement, which continues over the next few weeks. After 4 weeks on the combined treatment, Sara appears in good spirits and says she is feeling much more stable. You ask her to make a list of the signs and symptoms of the onset of a depressive and a manic episode and ask her to bring her mother to the next appointment. Together, the three of you make a contract regarding what steps should be taken if Sara shows any of the identified signs of recurrence of an episode.
Section 6: Special populations
Issues in the management of bipolar disorder in women
Pregnancy, lactation and the use of oral contracep- tives are just some of the issues that complicate the management of bipolar disorder in women. As 50%
Table 6.1. Planning for pregnancy
Counselling for all women of child-bearing age
Document birth control method (357)
Discuss risks of medication exposure during pregnancy Enquire about pregnancy plans
Emphasize need for pre-pregnancy consultation
Discuss effects of medications on OC efficacy
Carbamazepine and topiramate decrease levels of OCs (358)
OCs decrease lamotrigine levels by 49% and lamotrigine could potentially decrease contraceptive efficacy (359)
No known OC interactions with divalproex, lithium, gabapentin
or atypical psychotics (360) Pre-pregnancy counselling
Provide prenatal counselling at least 3 months before preg- nancy
Discuss risks of medications during pregnancy, risk to child and mother of antenatal recurrences, and genetic trans- mission (361)
Develop management plans including treatment of recur- rence during and after pregnancy (362)
Consider a pregnancy contract Medication use
Prior to conception, consider that conventional antipsychotics and risperidone increase prolactin and may decrease fertility (363)
Stable patients may be able to discontinue one or more medications before attempting to conceive and during first trimester (364–366)
Assess response to gradual pregravid tapering of medication If medication is required, use monotherapy at minimally effective doses, if possible (361, 363)
Assess patient’s risk of recurrence and avoid medication during pregnancy especially during first trimester, if possible (361)
of pregnancies are unplanned (356), it is important that women with bipolar disorder receive education early in the course of illness about the effects of mood stabilizing and other medications on contra- ceptive effectiveness, as well as the need to plan medication management during pregnancy and the postpartum period (Table 6.1). It is recommended that the physician and patient enter into a preg- nancy contract, which includes an explanation of the risks (teratogenic effects) and benefits (preven- tion of recurrence) of medication to the patient and the fetus before and during pregnancy. In case of recurrence, the contract will offer provisions for agreed-on treatments for specified symptoms depending on the trimester of pregnancy.
Management of acute depressive and manic episodes during pregnancy. Little data are available on the use of medications for the acute management of depression or mania in pregnant women with bipolar disorder. Treatment of breakthrough epi- sodes should follow the guidelines for all patients (see Sections 3 and 4), with additional considera- tions about teratogenicity of medications (Table 6.2), as well as the risks of untreated episodes to both the mother and the child. When possible, mild-to-moderate episodes should be managed using psychosocial approaches during the first trimester to minimize the risk of teratog- enicity.
CANMAT guidelines for bipolar disorder
OC 1⁄4 oral contraceptive.
Table 6.2. Medications and teratogenicity
Base rate: no drugs
Lithium (357, 361, D 367–369)
Divalproex D (361, 362, 370)
Carbamazepine D (361, 362, 370–375)
Lamotrigine (361, C 376, 377)
Gabapentin (360, 361) C Topiramate (360, 361) C
Olanzapine (362, 378) C Risperidone (360, 361) C Quetiapine (360) C Ziprasidone (360) C Clozapine (362, 379) B
Overall risk of major congenital malformations in humans: reported events
4–12%: Ebstein’s anomaly (tricuspid valve malformation) (0.1%, risk 20 times higher
than general population), polyhydramnios, premature delivery, floppy baby
syndrome, thyroid abnormalities, perinatal mortality, diabetes insipidus
11%: spina bifida and neural tube defects, fetal anticonvulsant syndrome, cardiovascular defects, cerebral haemorrhage, developmental delay, intrauterine growth retardation, coagulopathies
5.7%: spina bifida and neural tube defects, fetal anticonvulsant syndrome,
coagulopathies, cerebral haemorrhage, craniofacial defects, fingernail hypoplasia, developmental delay. Increased risk when administered with divalproex
2.9%: pregnancy registry (n 1⁄4 414 monotherapy exposures) showed no
increased risk of teratogenicity; 12.5% rate in combination with divalproex.
Teratogenic effects reported in animals
No data: fetotoxic effects in rodents
No data: craniofacial and skeletal anomalies, decreased fetal weight in animals;
reports hypospadias in male infants
No data: pregnancy registry (n 1⁄4 96 exposures) showed no increased risk of teratogenicity No data: one case report of agenesis of corpus callosum; fetotoxic in animals
No data: developmental toxicity, possible teratogenic effects in animals
Not available: no evidence of increased risk of teratogenicity
US Food and Drug Administration’s use-in-pregnancy ratings: A 1⁄4 controlled studies show no risk; B 1⁄4 no evidence of risk in humans; C 1⁄4 risk cannot be ruled out (human data lacking; animal studies positive or not done); D 1⁄4 positive evidence of risk (benefit may outweigh risk), X 1⁄4 contraindicated in pregnancy (360).
Yatham et al.
Table 6.3. Maintenance pharmacotherapy during pregnancy
Gabapentin Topiramate Olanzapine Risperidone Quetiapine Ziprasidone Clozapine
Recommendations for use in pregnancy
52% recurrence rate after discontinuation, lower with gradual withdrawal (274) Avoid during first trimester if possible (362)
Recommendations for lithium use (367):
Mild stable: gradual (>2 weeks) withdrawal pre-pregnancy and plan for pregnancy without maintenance treatment if appropriate
Severe, moderate risk recurrence: consider risks and benefits; if possible avoid at least during first trimester if clinically appropriate
Severe, high risk of recurrence: maintain lithium if patient is agreeable, counsel on risk of teratogenicity Serum levels may be lowered by pregnancy, regularly monitor (357)
Avoid during pregnancy and/or first trimester, if possible (362)
Decrease risk by using <1000 mg/day (serum levels <70 lg/mL) in three or more divided doses (370, 387) Monitor divalproex levels (361)
Vitamin K-12 supplementation in last month of pregnancy and to neonate (361, 388) Folate supplementation while attempting conception and during first trimester (375) Avoid during pregnancy and/or first trimester if possible (362)
Use as monotherapy if necessary, in divided doses (361)
Folate supplementation while attempting conception and during first trimester (375)
Vitamin K-12 supplementation in last month of pregnancy (361, 375)
Women started after conception are at higher risk of serious side effects (agranulocytosis, hepatic failure, Stevens–Johnson syndrome) (389)
Caution during pregnancy (32)
Folate supplementation should be encouraged in all women of childbearing age (390)
Careful dose management required during pregnancy and early postpartum as significant increase
in clearance during pregnancy (391, 392)
Caution during pregnancy (32)
Caution during pregnancy (32)
Should be used during pregnancy only if benefit justifies the potential risk (360)
Caution during pregnancy (32)
No data; caution during pregnancy
No data; caution during pregnancy
Should be used during pregnancy only if clearly needed (360)
Potential agranulocytosis warrants white blood cell counts in neonates
Maintenance therapy during pregnancy. There are conflicting data on the effect of pregnancy on recurrence of bipolar mood episodes: some studies show a protective effect, while others do not (274, 364, 365, 380, 381). In general, medications should be avoided or used as monotherapy in minimally effective doses, especially during the first trimester; however, this is not feasible for all patients (Table 6.3) (361). Risks and benefits of continuing medication during pregnancy should be based on severity and past response to treatment (362). Patients may require higher doses of some agents because of various physiological increases including plasma volume in the second and early part of third trimester, hepatic activity and renal clearance rates. However, lower doses may be required during the last few weeks before delivery (382, 383). Each pregnancy should be closely monitored and appro- priate screening tests (e.g. fetal ultrasound, a- fetoprotein levels) should be performed (362).
As is the case for the acute treatment of break- through episodes, the choice of maintenance medi- cation should be influenced by teratogenic potential (Table 6.2). If possible, avoid lithium, divalproex and carbamazepine, as these agents incur some
teratogenic risk, particularly when used in combi- nation (32). In situations where patients warrant treatment with a mood-stabilizer, lithium is pre- ferred over the anticonvulsants as the absolute risk of Ebstein anomaly is only 0.1%. Lamotrigine may be considered, particularly in patients who primar- ily suffer depressive relapses, as data from a large pregnancy registry suggest no increased teratoge- nicity (376). Atypical antipsychotics may also be reasonable choices, however, with the exception of data on olanzapine and clozapine suggesting no increased teratogenic risk, data on the atypical antipsychotics are limited (362, 378, 379). Reports of gestational diabetes with atypical antipsychotics should also be considered (379, 384, 385).
Electroconvulsive therapy may be considered as alternative during pregnancy in cases of psychotic decompensation or suicidal ideation (32). The procedure is relatively safe if special precautions are taken (386), and there are no indications of teratogenesis (357).
Management of bipolar disorder during the postpar- tum period. The high risk of postpartum recur- rence (about 50%) after discontinuing lithium
Table 6.4. Factors associated with increased risk of postpartum recurrence of bipolar disorder or puerperal psychosis
Postpartum mood episode in first pregnancy (365) Depression during pregnancy (365) Sleep-deprivation (397)
Euphoria after delivery (398)
during pregnancy suggests the need for prophylac- tic therapy (274, 393). In addition, women with bipolar disorder have a significantly increased risk of postpartum psychosis (394). Certain factors have been associated with a higher risk of post- partum psychosis and recurrent episodes of bipolar disorder during the postpartum period (Table 6.4). Little data are available on postpartum prophy- laxis. However, lithium has been found to reduce the rate of recurrence from nearly 50% to about 10% (393, 395, 396). While prophylaxis is recom- mended, particularly for women at risk, the impli- cations of selected treatments on breastfeeding need to be considered (Table 6.5).
Women should be educated on the potential risks and benefits of taking medication while breastfeed- ing, including recognition of the signs of infant drug toxicity (362). Most medications used for the treatment of bipolar disorder are excreted in breast milk (Table 6.5). Because of the potential for higher concentration of medication in colostrum, a 1- to 2- day washout (without breastfeeding) is recommen- ded if medication was taken during pregnancy (362). Medication should be taken after breastfeed- ing to help minimize the risk of exposure (375). The use of hind milk and supplementing breast milk with formula feedings can also be considered.
Although data are limited, the American Acad- emy of Pediatrics (AAP) and other groups have made some recommendations on the use of medica-
tions for bipolar disorder while breastfeeding (32, 362, 363, 375, 379, 399). The infant’s clinical status and blood levels should be monitored if there are potential risks. Lithium should be used with caution, which includes monitoring for complete blood count (CBC), hypotonia, lethargy and cyanosis in infants. Divalproex and carbamazepine are considered com- patible with breastfeeding, with monitoring of liver enzymes, CBC, and platelets to rule out hepatotox- icity and haematological toxicity, as necessary. Benzodiazepines, SSRIs, conventional antipsychot- ics, clozapine and lamotrigine are classified by the AAP as drugs for which the effect on nursing infants is unknown but may be of concern (375).
There are little or no data on the use of topiramate or gabapentin, and, as these agents are not well proven for the treatment of bipolar disorder, they are not recommended during breast- feeding. There are little data on atypical antipsych- otics and the manufacturers do not recommend their use while breastfeeding (379).
Sara, 33 years old, has at least a 13-year history of bipolar disorder. She has been stable for the last 2 years on a combination of lithium and divalproex. She is planning to be married this month, and has come to you to discuss whether she will be able to have children. She is concerned about the effects of medications during pregnancy and breastfeeding, as well as the effect of bipolar disorder on her ability to raise children.
• What is your immediate course of action? • What questions should you ask?
• What is your treatment plan?
CANMAT guidelines for bipolar disorder
Table 6.5. Medications and breastfeeding
Ratio of milk/maternal
Ratio of infant/ maternal serum (%)
5–200 0–40 6–65
Lithium (32, 362, 363)
Divalproex (32, 362, 363)
Carbamazepine (32, 362, 363)
Lamotrigine (390, 400–402)
Olanzapine (379, 403, 404)
Risperidone (379, 405, 406) Quetiapine (362, 379, 407)
Clozapine (361, 379, 385, 408) N/A 1⁄4 not available.
serum (%) 24–72 <1–10
Related adverse effects
T-wave changes on ECG, cyanosis, lethargy, heart murmur, hypotonia, hypothyroidism Thrombocytopenia, anaemia
Hepatotoxicity reported in young children
Hepatic dysfunction, hyperexcitability, seizure-like activity, drowsiness, poor feeding
No associated events in infants
Life-threatening rash reported in children
Jaundice, sedation, cardiomegaly, shaking, lethargy, protruding tongue, rash, diarrhoea, poor sleep
N/A, four patients, no adverse effects reported
N/A, one patient, mean 13 lg/L quetiapine in milk,
no adverse effects reported
Sedation, decreased suckling, restlessness, irritability, seizures, cardiovascular instability
Yatham et al.
Clinical management. Your first concern is whe- ther Sara has been using birth control, and she says she has being using oral contraceptives for the past 6 months. You assure her that her concerns are real but that with careful planning and close follow up she should be able to have a family. There is a risk of her offspring having bipolar disorder and many medications are not recommended during pregnancy. You enquire about her pregnancy plans and she states that because of her and her fiance ́ ’s older ages, they plan to have children within the next year or two. Her current medications should not interfere with the efficacy of her birth control, so you recommend that at least 3 months before she plans to become pregnant they meet again.
Sara returns to your office 1 year later, and expresses her intention to start trying to become pregnant and her desire to discontinue medication. You discuss with her the risks and benefits of prophylaxis with mood-stabilizers while trying to conceive and during pregnancy versus no medica- tion, the treatment of acute episodes during and after pregnancy, and the need for a pregnancy contract. Balancing the risk to the fetus (teratog- enicity), and the risk to Sara herself (recurrence of mood episodes), together you decide to gradually discontinue one of her medications and see if she remains stable. Over the course of the next month, she lowers the dose of divalproex weekly, and discontinues without any incident. She insists on discontinuing lithium, and you agree that if she can remain stable that is the ideal situation during the first trimester of pregnancy. She gradually discon- tinues lithium over the next 6 weeks and together you write a pregnancy contract describing her symptoms of depression and mania and what treatments she authorizes during pregnancy and the postpartum period.
Sara returns monthly, and 4 months later, declares that she is 1 month pregnant and has had no manic symptoms, but has been feeling a little tired and depressed. She feels strongly that she would like to continue medication free for the first trimester and so you continue to monitor her closely. Over the next 6 weeks, you can see that she is becoming increasingly depressed. Her husband has now come in with her, and supports you in encouraging her to resume a medication regimen.
You discuss with Sara and her husband the risk of not treating her depression versus the risk of teratogenicity of medications. As lamotrigine is associated with a low risk of teratogenicity, and adverse effects during breastfeeding, it is decided that this may be the best option for her at the present time. During titration over the next 6 weeks, her depression improves and she agrees
to continue through the postpartum period. You caution her about the risk factors for recurrence during the postpartum period and recommend that she have her mother stay with her to ensure she does not become sleep deprived.
Issues in the management of bipolar disorder in children and adolescents
The child psychiatric workgroup on bipolar disor- der has recently published guidelines for treatment of children and adolescents with this condition (409) and the reader is referred to this document for more details on this topic. Therefore, in the following section, we will provide only a very brief overview of some of the issues in this population.
Presentation and diagnosis. Approximately 53–66% of bipolar patients experience their first episode during childhood and adolescence, with a peak age of onset between 15 and 19 years of age (36, 37). About 20–30% of children who are diagnosed with MDD go on to have manic episodes (410–412). Mood disorders, including bipolar disorders, are among the most important risk factors for youth suicidal behaviour (413, 414); the earlier the onset of bipolar disorder, the greater the likelihood of suicide attempts (37).
The diagnosis of childhood bipolar disorder remains challenging, in part because of high rates of comorbidity with other common childhood disorders, and the fact that manic symptoms are frequently preceded by depressive or dysphoric- irritable symptoms. In addition, although diagno- sis is based on the same DSM-IV criteria used to diagnose adults (18), children with mania frequently present with atypical symptoms (Table 6.6) (45, 415–420). Half of the children who manifest mood lability and sleep disturbance early in life, meet all DSM-IV criteria except episode-duration requirements (418). These atyp- ical and complicated presentations have led to under diagnosis of bipolar disorder in teenagers (421) and misdiagnosis as schizophrenia (422–424).
Table 6.6. Presentation of mania in paediatric patients with bipolar disorder (45, 415–419)
Erratic, not persistent, changes in mood, level of psychomotor agitation, and mental excitement
Irritability, belligerence, and mixed state features more common than euphoria
Reckless behaviours: school failure, fighting, dangerous play, inappropriate sexualized activity
Psychotic symptoms, mood-incongruent hallucinations, paranoia, marked thought disorder
Severe deterioration in behaviour
A diagnosis of bipolar disorder should be consid- ered for any youth with a marked deterioration in functioning associated with either mood or psy- chotic symptoms (425).
Risk factors for bipolar disorder in children. Risk factors predictive of mania include a depressive episode characterized by rapid onset, psychomotor retardation and psychotic features, a family history of affective disorders, especially bipolar disorder, and a history of psychomotor agitation or antide- pressant-induced mania or hypomania (410, 412, 419).
Children who have a parent diagnosed with bipolar disorder display increased risks of bipolar disorder and other affective, anxiety and beha- vioural disorders, or substance abuse (426–428). In these offspring, the prodromal symptoms of child- hood bipolar disorder may be more subtle presen- tations of mood regulation difficulties (428). A prospective study of the offspring of bipolar parents who were responsive and non-responsive to lithium treatment suggested that response to lithium may be inherited (429).
Comorbidities and mimics. Comorbid disorders further complicate both the diagnosis and course of early-onset bipolar disorder. Childhood bipolar disorder displays significant symptomatic overlap or comorbidity with attention deficit hyperactivity disorder (ADHD), MDD, dysthymia, anxiety and conduct disorders (422, 430–436). An estimated 88% of bipolar children had another psychiatric disorder and 76% demonstrated a comorbid anxi- ety disorder (437). In one study, 91% of children with current or past mania also met criteria for ADHD (430), which has been associated with a poorer response to therapy (438). High rates of substance abuse and cigarette smoking have also been noted in some samples (422, 423, 432, 439).
A diagnosis of early-onset bipolar disorder requires specific differentiation from ADHD and conduct disorder, due to symptomatic over- lap (Table 6.7) (435, 440–442). Diagnostic tools
Table 6.7. Differential diagnosis of early-onset bipolar disorder and ADHD (447, 448)
True euphoria, decreased need for sleep and hypersexuality are uncommon in ADHD but common in bipolar disorder
Onset of symptoms including inattention typically >7 years of age in bipolar disorder but earlier in ADHD
Family history of bipolar disorder more common in those with bipolar disorder whereas disruptive disorders such as
conduct disorder are more common in those with ADHD Periods of normal functioning may be seen in those with bipolar disorder but rare in those with ADHD
ADHD 1⁄4 attention deficit hyperactivity disorder.
including the Mania Rating Scale (443) and sub- scales on the Child Behaviour Checklist have demonstrated some benefit in distinguishing be- tween children with mania and those with ADHD (444, 445). Parental reports have been shown to be more useful in facilitating a differential diagnosis of bipolar disorder in children than either teacher or adolescent self-reports (446).
Acute and maintenance treatment of paediatric bipolar disorder. The early course of bipolar dis- order in adolescents is often chronic and refractory to treatment, while the long-term prognosis ap- pears similar to that of adults (422–424, 449). Although available data are limited, and have methodological issues, the results of both RCTs and open clinical trials suggest that adolescent- onset bipolar disorder will likely respond to the same agents as adult-onset bipolar disorder (450). Like adult bipolar disorder, childhood-onset bipo- lar disorder has a chronic course with a high rate of recurrence and evidence suggests that prophylactic therapy is needed (451, 452).
Informed consent (addressing the rationale for treatment, as well as the potential risks and benefits of the therapy) should be obtained from the child or adolescent’s legal guardian, and the patient’s consent or assent should be obtained.
Lithium. As expected, there is more evidence evaluating the effectiveness of lithium than other agents. A placebo-controlled RCT in adolescents with bipolar disorders and comorbid substance abuse showed that acute treatment with lithium was effective in both disorders (level 2) (453). Open trials have also suggested that lithium is effective for acute treatment of children and adolescents with manic or mixed episodes (level 3) (454, 455). Lithium was effective in combination with other agents in a retrospective study (level 4) (456).
When lithium was used for the prevention of recurrence in a small RCT, there was no significant difference in recurrence rates compared with pla- cebo, due to an unexpectedly high rate of recur- rence in the lithium group (52.6%) (level 2, negative) (457). Naturalistic data suggest a rate of recurrence of 28% among patients on adequate doses of lithium (level 4) (456).
Data suggest that response rates with lithium are lower in patients with comorbid ADHD (level 4) (438). However, mood stabilization appears to be a prerequisite for successful treatment of ADHD in children with bipolar disorder (458).
Divalproex. In prospective, open trials, divalp- roex was effective for the treatment of children and
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adolescents with bipolar disorder (455, 459), with response rates numerically, but not statistically, superior to lithium and carbamazepine (455) (level 3). Long-term treatment with divalproex has been associated with improved outcomes in the treatment of children and adolescents with bipolar disorder (level 4) (460).
Atypical antipsychotics. In an RCT, the combi- nation of quetiapine and divalproex was signifi- cantly more effective than divalproex alone in the treatment of acute mania in adolescents with bipolar disorder (level 2) (142).
Open-label prospective and retrospective data suggest that either risperidone or olanzapine alone, or in combination with mood-stabilizers, may be effective in treating children and adolescents with bipolar disorder (level 3 and 4) (461–464).
Antidepressants. In general, antidepressant mo- notherapy is not recommended for the treatment of bipolar disorder (see Section 4). In addition, recent meta-analyses and Food and Drug Administration (FDA) position papers (465–468) demonstrate an excess risk of suicidality with SSRIs in children and adolescents with depression. A Statement for the Canadian Psychiatric Association on antidepres- sant prescribing for depression estimated one to three excess cases of suicidality for every 100 patients treated with an SSRI other than fluoxe- tine, which carried a lower risk (469). Although most of the data gathered to prepare these recom- mendations come from studies of MDD, the general recommendations of this statement would be appropriate when antidepressants are used in patients with bipolar depression. Discussion with the patient and family of potential side effects that may affect suicidality such as anxiety, agitation, hypomania and activation syndrome is recommen- ded, and early reassessment (weekly for the first month) after initiation of therapy should take place (469).
ECT. Data on the use of ECT in adolescents and children come mainly from case series (level 3) (470). While there are concerns regarding possible adverse effects on the maturing nervous system, several follow-up studies have not found evidence of long-term cognitive impairment in adolescents treated with ECT (471, 472). The American Acad- emy of Child Adolescent Psychiatry (473) stated that ECT may be an effective treatment for adolescents with severe mood disorders and other Axis I psychiatric disorders. They recommended that ECT be considered when there is a lack of response to two or more trials of pharmacotherapy
or when the severity of symptoms precludes waiting for a response to pharmacological treat- ment.
Psychoeducation. Preliminary data suggest bene- fits from adjunctive group psychoeducation for families of children with mood disorders and child- and family-focused CBT (474–476).
Issues in the management of bipolar disorder in older patients
Presentation and course. Population-based surveys indicate that bipolar disorder becomes less com- mon with age, with a prevalence of 0.1–0.5% among individuals 65 and older (28, 74, 477, 478). Bipolar disorder is a life-long illness, and in older adults bipolar depression accounts for 8–10% of psychiatric admissions and is frequently associ- ated with neurological factors (479–483). Older adults also appear to have a higher prevalence of mixed episodes (480, 484) and a lower treatment response (484). Bipolar disorder of late-onset has a lower association with family history (484–487) and occurs more frequently in women than in men (483). Long-term studies indicate that bipolar disorder neither ‘burns out’ in old age nor follows a progressively deteriorating course (483, 488, 489).
The high risk of suicide in older people and in patients with bipolar disorder appears to be additive. However, results from a long-term survey indicate that the highest risk for completed suicide occurs during the first 7–12 years post-onset and in those under age 35 (490), suggesting that older patients with early-onset bipolar disorder may belong to a survivor cohort (483).
Comorbidity. The lifetime rate of substance abuse in those over 60 was 20–30%, significantly lower than that in mixed age populations (61%) (31, 483). Although anxiety disorders are frequent comorbidities, no data were found examining the rate of these psychiatric disorders in older patients with bipolar disorder.
The prevalence of neurological illness in older adults with bipolar disorder was 23% in a review of eight studies (483). The prevalence of neurological illness is reportedly higher in patients with bipolar disorder than in those with unipolar depression (36% versus 8%) (491). Bipolar disorder may be frequently complicated by or secondary to demen- tia in older patients (483, 492–494). Silent cerebral infarctions are more common in patients with late- onset manic symptoms versus patients with early- onset affective disorder (495).
Other medical comorbidities in older adults with bipolar disorder are extremely common (483). In a survey of psychiatric admissions, 20% of elderly bipolar patients had seven or more comorbid medical diagnoses (496). Rates of diabetes were significantly elevated in older bipolar patients compared to either a mixed-age bipolar population (497) or the general population (498).
Treatment of bipolar disorder in older adults.
Surprisingly, there do not appear to have been any RCTs initiated exclusively in elderly bipolar patients to evaluate treatment outcomes (483). However, data suggest that acute treatment can improve cognitive performance in geriatric bipolar patients (479).
Acute treatment of mania. In open trials, 66% of older patients treated with lithium improved over- all (494, 499–501). Renal clearance of lithium decreases with age, and the elimination half-life in older patients is twice that in younger pati- ents (502). Renal disease, cardiac insufficiency, decreased body fat and use of concurrent medica- tions can increase lithium concentrations and decrease clearance (502–504). Based on retrospec- tive data, 59% of patients improved with divalp- roex therapy (500, 505–508). Increases in plasma concentrations of divalproex have been reported with ageing (509, 510) and with the concurrent use of aspirin (511). Few data are available on the efficacy of atypical antipsychotics in elderly bipolar patients. Two small open trials reported a positive response to clozapine in older mania patients (512, 513). Age-associated increases in serum concentra- tions have been reported with risperidone (514) and clozapine (515).
Acute treatment of bipolar depression. Lamot- rigine was effective as an add-on to lithium or divalproex, in a small open study, with three of five geriatric patients with bipolar depression respond- ing (516). In an RCT involving adult patients (age 21–71 years) with acute bipolar depression, the combination of paroxetine and lithium was more effective than lithium alone in those with low serum levels, with age having no impact on response (242). If antidepressants are used in older patients, SSRIs and bupropion are preferred over tricyclics, as they have a lower reported risk of switching to mania, which can also occur in older patients (517, 518).
Maintenance treatment. No RCT data are avail- able on maintenance treatment of bipolar disorder in elderly patients. Naturalistic studies in mixed-
age samples suggest a poorer response to lithium in older versus younger patients (499, 519–521). Factors that alter acute treatment outcomes may also influence long-term outcomes in these pati- ents, but data are limited (522). Given the paucity of data on maintenance treatment of bipolar disorder in older patients, treatment choices should be informed by the safety and tolerability profiles of these medications in older patients.
Neurological side effects, ranging from mild tremor to disabling delirium, are reported in about 30% of patients treated with lithium (494, 501, 519, 523, 524). Almost 60% of older patients receiving lithium maintenance therapy experienced electro- cardiographic abnormalities (525). Over 30% received thyroxine replacement or had elevated thyroid-stimulating hormone levels (526). Side effects such as polyuria and polydipsia, weight gain and oedema are reported in about 30–45% of older patients taking lithium (520, 527).
Neurological side effects, including sedation, tremor and gait disturbance, have been observed in up to 13% of elderly patients with bipolar disorder taking divalproex (505–508). Lamotrigine was well tolerated in elderly patients with seizures after stroke (528–530). Carbamazepine has been associated with bradycardia and atrioventricular conduction delays (531).
Some atypical agents such as clozapine, olanza- pine and quetiapine can cause somnolence, but effects on cognition have not been studied in elderly patients. Atypical antipsychotic agents have demonstrated a lower tendency for acute motor side effects compared with conventional antipsych- otics and some may also be associated with lower rate of tardive dyskinesia (532–535). Antipsychotic treatment can prolong the QT interval (QTc), particularly in patients with pre-existing conduc- tion abnormalities (536). The clinical significance of QTc prolongation by ziprasidone is not known (537). Antipsychotic agents, especially low-potency conventional antipsychotics and olanzapine, have anticholinergic effects that can contribute to tachy- cardia, constipation and urinary hesitancy/obstruc- tion, as well as cognitive impairment.
Antidepressants can cause sedation in older patients (522). SSRI treatment has been associated with neuromotor side effects, bradycardia and hyponatremia in older patients.
Factors that influence treatment response. Lith ium remains one of the treatments of choice for mania. Comorbid medical conditions and sub- stance abuse have been shown to predict a poorer response to treatment overall and to lithium specifically (494, 538). A retrospective report sug-
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gested that lithium had a better therapeutic effect than divalproex in elderly patients with classic but not mixed manic states (500). Divalproex is a rational alternative to lithium in manic elderly patients, particularly in patients who develop deterioration of cognitive performance during lithium treatment. More data are needed to deter- mine the role of atypical antipsychotics in older patients with mania. Lamotrigine may be useful for bipolar depression in older patients.
Issues in the management of bipolar disorder in patients with comorbid conditions
Epidemiology. Patients with bipolar disorders fre- quently present with comorbid substance abuse, anxiety and other psychiatric disorders, and phys- ical illnesses. There is an estimated sevenfold higher risk of drug and alcohol abuse compared to the general population, with higher rates in women versus men, and in bipolar I versus bipolar II (539–541). Patients with comorbid bipolar and substance abuse disorders are four times as likely to have other comorbid Axis I disorders than the general population (542).
Current and lifetime Axis I comorbidities are common in patients with bipolar I and II disorders (539). The risk of anxiety disorder is estimated to be 35-fold higher than that in the general popula- tion (539), including a higher risk of generalized anxiety disorder (GAD), simple phobia, social phobia, panic disorder and post-traumatic stress disorder (PTSD) (35, 539). During their lifetime, 65–90% of patients with bipolar I disorder will have a comorbid anxiety disorder (35, 539). The lifetime prevalence of personality disorders is estimated to be between 30 and 50% among patients with bipolar disorder (78, 543–546) com- pared with 9% in community samples (547).
Patients with bipolar disorder experience more physical illness than the general population, inclu- ding higher rates of type 2 diabetes and cardiovas- cular disease (498, 548, 549). Mortality from cardiovascular disease is almost twofold higher than that seen in the general population (550–553). Higher rates of migraine and other pain syndromes have also been reported in patients with bipolar disorder compared with the general population (554, 555).
Comorbidity can have a significant negative impact on diagnosis, severity, suicidality, treatment adherence and response, as well as functional outcomes in bipolar disorder (40, 70, 171).
Treatment of bipolar disorder and comorbid condi- tions. There are no large, double-blind, placebo-
controlled trials examining the efficacy of any pharmacotherapy in bipolar patients with comor- bidity. Given the lack of efficacy data in this patient sub-population, we will briefly review open- label studies and studies that have examined the efficacy of various agents in conditions that com- monly co-occur with bipolar disorder.
Substance abuse disorders. In patients with bipolar disorder, comorbid substance abuse was associated with lower rates of remission (556) and more psychiatric hospitalizations (79, 542).
The anticonvulsants lamotrigine, divalproex, carbamazepine and gabapentin, as well as the atypical antipsychotic quetiapine, have been eval- uated in the management of patients with bipolar disorder and comorbid substance abuse.
In patients with bipolar disorder and comorbid cocaine dependence, open-label lamotrigine treat- ment resulted in statistically significant improve- ments in mood and drug cravings but did not significantly decrease drug use (level 3) (557). In a retrospective chart review, remission rates were higher in bipolar patients with a history of sub- stance abuse who had received divalproex or carbamazepine versus lithium monotherapy (level 4) (556). The presence of alcohol abuse was associated with a positive response to open-label adjunctive gabapentin treatment in patients with bipolar disorder (level 3) (172). Open-label adjunctive quetiapine treatment demonstrated significant improvements in mania and depres- sion scores, and drug cravings in patients with bipolar disorder and cocaine dependence (level 3) (558).
Divalproex, carbamazepine and topiramate have shown efficacy in patients with substance abuse disorders, but have not been evaluated in patients with both bipolar disorder and comorbid substance abuse disorders. In an RCT, divalproex reduced the symptoms of alcohol withdrawal faster than a benzodiazepine (level 2) (559). Carbamazepine demonstrated efficacy equal to lorazepam in decreasing the symptoms of alcohol withdrawal (560). Patients treated with topiramate demonstra- ted significantly less alcohol consumption and cravings compared with placebo in the treatment of alcohol dependence (561).
Anxiety disorders. Comorbid anxiety disorders are associated with more complicated bipolar illness, including higher rates of suicidality (80, 562–564), higher rates of cycle acceleration, in- creased severity of episodes (35, 564, 565), more frequent depressive episodes (80, 565) and poorer overall functional outcome (565–567).
The anticonvulsants topiramate and gabapentin have shown some benefits in the management of patients with bipolar disorder and anxiety disor- ders. In a small retrospective review of bipolar patients with comorbid psychiatric conditions, 73% of patients treated with topiramate experi- enced a significant improvement in their comorbid conditions (level 4) (568). Open-label adjunctive gabapentin has been shown to improve residual depressive symptoms, irritability, social withdrawal and anxiety in patients with refractory bipolar disorder (level 3) (172, 569).
Other therapies used for bipolar disorder inclu- ding atypical antipsychotics, antidepressants and benzodiazepines have been shown to reduce anxiety symptoms, although specific data are not available in patients with both bipolar disorder and comorbid anxiety disorders. When used as add-on to antidepressant therapy in refractory patients atypical antipsychotics, including olanza- pine, quetiapine and risperidone, have demonstra- ted efficacy in obsessive compulsive disorder (OCD) (570–573), PTSD (574–578) and GAD (171, 579, 580). Antidepressants including SSRIs and TCAs have demonstrated efficacy in social anxiety disorder (581, 582), PTSD (583–585), OCD (586) and panic disorder (587). Some benzodiazepines (588), antidepressants (589–591) and gabapentin (592) have demonstrated efficacy in GAD.
Personality disorders. Bipolar patients with co- morbid personality disorders are reported to have poorer treatment outcomes (545, 593–596), a higher number of currently prescribed psychiatric medications (546) and poorer medication adher- ence (287).
The anticonvulsants divalproex and lamotrigi- ne, as well as adjunctive psychoeducation, have shown some benefits in the management of patients with bipolar disorder and comorbid personality disorders. In contrast, data suggest that lithium prophylaxis is less effective in bipolar patients with comorbid personality disorders compared to those with bipolar disorder alone (level 4) (597, 598). In a small, placebo-controlled RCT, divalproex demonstrated efficacy in the treatment of women with bipolar II disorder and borderline personality disorder, significantly diminishing interpersonal sensitivity and anger/ hostility, as well as overall aggression (level 2) (599). A retrospective analysis of two studies, in which 40% of bipolar patients met criteria for borderline personality disorder, found that bor- derline personality disorder responded to lamot- rigine (level 4) (600). Similarly, subanalysis of an
RCT suggested that psychoeducation might be a useful intervention for bipolar patients with comorbid personality disorders (level 3) (601).
Although olanzapine was significantly more effective than placebo in patients with personality disorders (602, 603), its benefit remains to be established in patients with both bipolar disorder and comorbid personality disorders.
Section 7: Bipolar II disorder: acute and maintenance management
Bipolar II disorder is characterized by recurrent episodes of major depression and hypomania. The prevalence rates vary from 0.5 to 6.4% of the general population, depending on the criteria employed (20, 22, 28, 29, 604). However, evi- dence-based recommendations presented in these guidelines are based on DSM-IV criteria for bipolar II disorder.
Conceptually, bipolar II disorder can be viewed along a continuum from unipolar depression to bipolar I disorder, with intermediate differences in course of illness, gender ratio, family history and possibly treatment response (605–608).
Hypomania, the defining feature of bipolar II disorder, is often missed leading to the under diagnosis of this condition (609). As a result, it can take up to 12 years before patients are appropri- ately diagnosed with bipolar II or bipolar spectrum disorder, compared with 7 years for bipolar I disorder and 3.3 years for unipolar depression (72, 610).
However, bipolar II disorder can be reliably diagnosed when experienced psychiatrists use a careful, structured interview, in conjunction with collateral history from friends or family (610, 611). The MDQ is a simple self-report questionnaire which has moderate sensitivity and specificity in screening for past hypomania of undetermined duration (77, 612, 613).
By definition, hypomania, unlike mania, is not severe enough to cause marked functional impair- ment; thus, many patients will not intuitively recognize such states as part of an illness. Thus, it cannot be over-emphasized that detection of bipolar II disorder can be greatly improved by involving families and friends where possible in the evaluation of patients with mood disorders (68, 72, 610). It is also important to emphasize that the diagnosis requires an unequivocal change in mood and behaviour that is observable by others – a requirement that should limit over diagnosis.
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Differential diagnosis of bipolar II disorder
The majority of patients with an eventual diag- nosis of bipolar II disorder have a prior diagno- sis of unipolar depression (MDD) (610). In some cases, this is because the illness has not yet declared itself, but often a careful screening for hypomania has not occurred (610). Bipolar II disorder and highly recurrent depression are closely related (610). Bipolar II disorder appears to be associated with a significant risk of suicide (614–617). Patients with a diagnosis of bipolar II disorder are more likely to have demonstrated an earlier age of onset, have a family history of bipolar II, and will experience higher rates of recurrence, anxiety disorders and substance abuse compared to patients with MDD (76, 609, 610, 618, 619). In addition, atypical depressive symp- toms such as mood reactivity, increased appetite, carbohydrate cravings, over-eating, weight gain, oversleeping, extreme fatigue and interpersonal sensitivity occur more frequently in bipolar II depression (609, 620–622).
Bipolar II disorder and borderline personality disorder also share components of mood dysregu- lation and impulsivity as well as a history of instability in relationships (623). However, they differ in the quality, degree and duration of mood episodes, the degree of mood lability, the episodic pattern of troublesome behaviours (624), onset (625) and family history (45).
In contrast, specific cyclothymic or hyperthymic temperaments and cyclothymic disorder may clus- ter in families with bipolar disorder and in some cases are antecedents of a frank bipolar I or II disorder (615). These chronic conditions more often mimic the symptoms of hypomania and often, atypical episode of MDD, similar to those in bipolar II but of milder degree and without obvious dysfunction. In some cases, they can be productive or functionally enhancing (626).
It is important to emphasize that bipolar II is not simply a milder form of bipolar I disorder; it is associated with significant rates of rapid cycling and suicide and a comparable degree of psychoso- cial impairment as seen with bipolar I disorder (29, 217, 617, 627).
Management of bipolar II disorder
Other recent guidelines for the management of bipolar disorder have chosen not to include recom- mendations for the treatment of bipolar II disorder (9, 14, 17). However, we believe that the growing recognition of this disorder makes the need for a review of current, albeit limited data, important for
physicians who are faced with an increasing number of such patients in their practice.
Acute management of hypomania
Untreated hypomania may be associated with major financial, legal and psychosocial problems, without ever commanding medical attention (30), yet virtually no studies have been carried out to assess effective treatments. The only study specific to the management of acute hypomania is an open- label study of risperidone that demonstrated acute benefit within 1 week (level 3) (304). Treatment approaches for acute hypomania otherwise have typically mimicked those for manic episodes.
Acute management of bipolar II depression
Acute management of depression is a major focus in the management of bipolar II disorder. To date, most studies have evaluated the effectiveness of antidepressants and anticonvulsants (Table 7.1), which are evaluated on the strength of the evidence (Tables 1.1 and 1.2). However, because of the paucity of evidence that is derived specifically for bipolar II disorder trials, it is necessary to combine evidence and expert opinion to formulate treat- ment recommendations (Table 7.2).
There is inadequate evidence to support any treatments as first-line therapy for the management of acute bipolar II depression; therefore, it is neces- sary to consider second-line options (Table 7.2).
Table 7.1. Strength of evidence for monotherapy treatments of acute bipolar II depression
Divalproex Lamotrigine Gabapentin
Atypical antipsychotics Olanzapine Risperidone Quetiapine Ziprasidone Aripiprazole Clozapine
Antidepressants Fluoxetine Venlafaxine Tranylcypromine
Lithium or divalproex + pramipexole Lithium or divalproex + SSRI
Lithium or divalproex + topiramate Atypical antipsychotic + antidepressant
SSRI 1⁄4 selective-serotonin reuptake inhibitor.
Level of evidence 3
No data No data 2 (ve) No data No data No data
3 3 2
2 3 3 4
Table 7.2. Recommendations for pharmacological treatment of acute bipolar II depression
evidence would suggest that these agents should be used only in combination with an antidepressant for patients with acute bipolar II depression.
Antidepressants. The use of antidepressant mono- therapy in bipolar II depression is a highly contro- versial area. Two RCTs support the use of the MAOI, tranylcypromine, in ‘anergic bipolar depres- sion.’ In the first RCT, tranylcypromine mono- therapy was superior to placebo in 59 patients with anergic depression, of which 19 had DSM-III- defined bipolar II depression (260). No separate analysis was reported for this sub-group. A second RCT found that tranylcypromine monotherapy was more effective than imipramine in bipolar II depres- sion, and that patients with bipolar II had less risk of treatment-emergent mood swings than those with bipolar I (262). Safety concerns regarding food and drug interactions result in downgrading the recom- mendation for MAOIs to second-line use. Surpris- ingly there are very few reports involving the SSRIs in bipolar II depression. A small RCT, showing that the addition of an SSRI (paroxetine) to lithium or divalproex was as effective as combining lithium and divalproex in improving depressive symptoms, included 16 bipolar II patients in a sample of 27, but no separate analysis of these patients was conducted (level 3) (246).
Open-label data and post-hoc analysis of an RCT suggest that fluoxetine monotherapy is safe and effective for the short-term treatment of bipolar II depression with a relatively low manic switch rate (level 3) (631, 632). Preliminary open- label data also suggest that short-term venlafaxine monotherapy may be a relatively safe and effective antidepressant treatment in patients with bipolar II depression (level 3) (633, 634). However, in an RCT including both patients with bipolar I and bipolar II disorder, the switch rate was numerically greater with venlafaxine compared to paroxetine (253).
Although there is some evidence that the risk of hypomanic switch or cycle acceleration with anti- depressants may be less in bipolar II patients (631, 635, 636), this has not been consistently reported (637–639). Antidepressants may also induce mixed symptoms, in particular agitation, irritability, rapid thoughts and distractibility, though these are not always recognized (621, 640, 641). Several of the acute trials of antidepressant monotherapy suggested ‘agitation’ may occur, but had no specific assessment of either hypomanic or mixed symptoms (262, 631–634).
If bipolar II disorder is conceptualized on a continuum of unipolar and bipolar I disorder, then it is possible that some patients will do well on monotherapy with SSRIs or other newer antide-
First line Second line
Lithium, lamotrigine, lithium or divalproex + antidepressants, lithium + divalproex, atypical antipsychotics + antidepressants Switch to alternate antidepressant
See text on antidepressants for recommendations regarding antidepressant monotherapy
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Lithium. Data on the acute antidepressant effects of lithium in bipolar II disorder are embedded in studies of both bipolar I disorder and recurrent unipolar depression. These studies show moderate acute antidepressant effects for lithium, but with- out separate analysis of bipolar II depression (level 3) (605, 628, 629).
Anticonvulsants. In an open trial, divalproex was effective in bipolar II depressed patients, with a trend towards a higher rate of response in naive patients compared to those who had received previous medications (level 3) (255). In a small RCT, involving women with comorbid bipolar II disorder and borderline personality disorder, divalproex significantly decreased irritability, an- ger and impulsive aggressiveness, but not depres- sive symptoms on the Symptom Check List-90 (599).
In an RCT comparing lamotrigine, placebo and gabapentin, including 14 patients with bipolar II and 11 with bipolar I, overall lamotrigine was more effective than placebo (level 3) (170). In an RCT that included eight patients with bipolar II depression, lamotrigine as add-on to the antide- pressant fluoxetine, demonstrated some efficacy compared with placebo on measures of global improvement, but not on measures of depression (630).
Atypical antipsychotics. Again limited data are available on the use of atypical antipsychotics in patients with bipolar II depression. Quetiapine monotherapy was significantly more effective than placebo for the treatment of acute depression in a large RCT involving patients with bipolar I and II disorders (251). The effect size in the bipolar I sample was very large (0.88 and 0.73 on 600 and 300 mg, respectively), but was small in the bipolar II sample (0.22 and 0.16, respectively) (level 2, negative) (251). The recent trial of olanzapine and olanzapine-fluoxetine in bipolar depression exclu- ded patients with bipolar II disorder (244).
Thus, available data suggest little antidepressant benefits of atypical antipsychotics alone. Current
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pressants, whilst others will not. If antidepressant monotherapy is being considered, then a careful longitudinal history should be taken, noting prior consequences of hypomanic episodes, history of any prior antidepressant-induced worsening, sta- bility of bipolar II diagnosis and family history of bipolar I illness. Similarly, the patient must be made aware of the risks, educated to detect hypomania, mania, rapid-cycling and mixed mood, and must be monitored accordingly.
Although evidence is lacking, clinical consensus supports the use of mood-stabilizers in combina- tion with antidepressants in bipolar II depression, and the cautious consideration of antidepressant monotherapy in a subset of what is likely a heterogeneous group.
Other agents. There is limited support for the role of dopamine agonists. Pramipexole as add-on to lithium or divalproex had significant antidepres- sant effects in patients with bipolar II depression, in a small RCT (level 2) (259). A chart review also suggested that pramipexole and ropinirole were useful adjunctive treatments for drug-resistant bipolar II depression (level 4) (642).
Open data suggested that adjunctive gabapentin was effective in 30–55% of patients, including some with bipolar II disorder (level 3) (643, 644). Similarly, in an open trial, adjunctive topiramate was useful in treating bipolar II disorder, with good response rates over 12 weeks in patients presenting with either hypomania or depression (645).
Maintenance therapy for bipolar II disorder
It has been reported that patients with bipolar II disorder in treatment spend 37 times more days experiencing depressive symptoms than hypomanic symptoms (235). Therefore, the focus of long-term therapy for patients with bipolar II disorder is on aggressive prevention of depressive episodes. The data for lithium, anticonvulsants and antidepres- sants have been rated on the strength of the evidence (Table 7.3) according to the preset criteria (Tables 1.1 and 1.2). However, because of the scarcity of trials, specifically in patients with bipolar II disorder, it is necessary to combine evidence and expert opinion to formulate treat- ment recommendations (Table 7.4).
First line. In most situations, patients will continue the acute treatment regimen, and some will require additional pharmacotherapy. There is evidence for the efficacy of lithium and lamotrigine for the maintenance of bipolar II disorder.
Table 7.3. Strength of evidence for maintenance treatments of bipolar II disorder
Divalproex Lamotrigine Carbamazepine Gabapentin
Atypical antipsychotics Adjunctive risperidone
Antidepressants Fluoxetine Imipramine
Lithium + imipramine
Lithium + SSRI, venlafaxine or bupropion ECT
Level of evidence 2
3 2 3 4
2 (ve) 4
ECT 1⁄4 electroconvulsive reuptake inhibitor.
SSRI 1⁄4 selective-serotonin
Table 7.4. Recommendations for maintenance treatment of acute bipolar II disorder
First line Second line
Divalproex, lithium or divalproex or atypical antipsychotic + antidepressant, combination of two of: lithium, lamotrigine, divalproex or atypical antipsychotic Carbamazepine, atypical antipsychotic, ECT
ECT 1⁄4 electroconvulsive therapy.
Lithium. The prophylactic benefit of lithium in patients with bipolar II disorder has been replicated in three small RCTs (level 2) (646– 648), however, in one trial the prophylactic benefit of lithium was less clear in bipolar II patients than in bipolar I patients (647), while in another, only the reduction in depressive episodes was statisti- cally significant (646). Long-term observational data suggest that lithium maintenance has superior benefits in bipolar II patients, who experience significantly fewer episodes per year, and signifi- cantly less time ill, compared to the time prior to initiation of lithium therapy (608, 627).
Lamotrigine. In a large, 6-month RCT, there were no significant differences between lamotrigine and placebo in terms of time to additional therapy for bipolar I and II rapid cycling patients (level 2, negative) (275). However, significantly more pati- ents treated with lamotrigine compared to placebo were stable without recurrence at 6 months among patients with bipolar II disorder (46% versus 18%) (level 2). Open-label data also support the adjunc- tive use of lamotrigine in bipolar II patients for prevention of depressive symptoms (649, 650).
Divalproex. Divalproex has been evaluated as a maintenance therapy in rapid cycling bipolar II patients and in women with bipolar II and comor- bid borderline personality disorder (336, 599). Divalproex did not significantly decrease depressive symptoms compared with placebo in a small RCT involving women with bipolar II disorder and comorbid borderline personality disorder. How- ever, attrition was high with only 11 patients remaining in the study at 6 months (599). In a small open trial over 3 years, divalproex was effective in reducing mood episodes in patients with bipolar II disorder and rapid cycling (level 3) (336).
Lithium or divalproex or atypical antipsychotic + antidepressant. Lithium and divalproex, as well as the atypical antipsychotic, olanzapine, have proven benefit in preventing bipolar I depression (see Section 5), and as antidepressants have, by defini- tion, antidepressant effects, the combination might be appropriate. However, an RCT comparing lithium, imipramine, lithium plus imipramine, or placebo, found that lithium was effective in pre- venting depressive relapse among patients with bipolar II, but imipramine, either alone or in combination with lithium, provided no additional benefit (level 2, negative) (648).
Carbamazepine. In a large well-conducted RCT, carbamazepine had similar prophylactic efficacy to lithium over 2.5 years in a subset of patients with bipolar II disorder or bipolar disorder NOS, with a trend favouring carbamazepine. This was in con- trast to the bipolar I group where lithium was superior to carbamazepine (level 3) (300).
Atypical antipsychotics. Risperidone, either alone or in combination with mood-stabilizers, was protective against hypomanic recurrences in patients with bipolar II disorder during a 6-month, open trial (level 3) (304).
Antidepressants. In an early prospective trial examining the incidence of hypomania in 230 patients with recurrent depression treated with imipramine, the sub-sample of 33 bipolar II patients had a similar rate of switch (2.5%) in both the acute and continuation phase as the unipolar group, perhaps reflecting the close relationship between recurrent unipolar depression and bipolar II disorder (651). In a post-hoc analysis of the bipolar II sample in a placebo-controlled trial,
fluoxetine monotherapy was as effective for bipolar II depression as it was for unipolar depression (level 3) (632). Similarly, fluoxetine monotherapy was effective in 10 of 13 patients with bipolar II disorder over 10 or more months (652). In contrast, imipr- amine was ineffective in preventing depressive relapse in an RCT comparing lithium, imipramine, the combination and placebo (648).
The addition of bupropion to lithium and/or levothyroxine in a very small case series of six bipolar II patients with treatment-refractory rapid cycling was associated with significant improve- ments that were sustained over an average of 2 years of continued treatment (level 4) (653).
ECT. Based on retrospective chart review, ECT was as effective in patients with bipolar I (n 1⁄4 25) and bipolar II (n 1⁄4 41) as it was in unipolar depression, with more rapid clinical improvement and fewer treatments required in the bipolar sample (level 4) (654).
Clinical questions and controversies
How can I differentiate bipolar II disorder from borderline personality disorder? There are substan- tial phenomenological overlaps between these two disorders. As the duration requirement for hypoma- nia in bipolar II has been shortened, it is even more difficult to distinguish between bipolar II and bor- derline personality disorder. Beyond affective insta- bility, patients with bipolar II disorder have, at times, impulsivity, risk-taking, substance abuse, suicide attempts, unstable relationships and unstable work histories if untreated (623). However, a careful phenomenological, developmental and longitudinal history, in conjunction with family history, will help differentiate the two (Table 7.5) (655). While the first step is to attempt to establish one of these diagnoses, it is also recognized that the two conditions may be comorbid, particularly if an early cyclothymic tem- perament preceded the onset of bipolar II (78, 656).
George is a 21-year-old university student who appeared at a walk-in clinic complaining of depres- sion and extreme tiredness. He says he has no desire to socialize with friends as he is always exhausted. He spends much of each day in bed sleeping. He says he has been snacking a lot on junk food and has gained about 3 kg (7 lbs) in the past 3 weeks. He recalls being very depressed, even suicidal, about a year ago, and says that the antidepressant he was given made him feel ‘always too good’. Since then he has experienced frequent ‘peaks and valleys’ but his
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Table 7.5. Relative differences between bipolar II and borderline personality disorder (18, 623–625, 655, 657)
Bipolar II disorder
Onset in teens or early 20s
Observable, unequivocal change in prevailing mood Spontaneous mood changes
Mood changes last days to months
Euthymic, dysphoric, anxious and elated mood shifts Irritable mood shifts may occur with use of antidepressants Ego-dystonic
Episodic impulsivity and risk-taking
Binge-eating as part of atypical depressive episodes only Episodic suicide attempts related to depressive episodes
Endorse ‘depressed mood’ as descriptor
Decreased need for sleep
Racing thoughts random and associated with elation or antidepressant-induced mixed mood
Family history of bipolar I or II or recurrent depression Adverse developmental history less likely
Good response to mood-stabilizers
depression has not been as bad as it is now. He is not sure which medication it was, but would appreciate a prescription for something similar. On questioning, he admits to suicidal ideation, but no plan at the present time. The family practitioner has concerns about some of the atypical features of his depression, his suicidal ideation, and his description of ‘feeling great’ on antidepressants, and refers him to you.
• What is your first course of action? • What questions should you ask?
• What is your treatment plan?
Clinical management. Before prescribing treatment for George, it is important to determine whether he is suffering from unipolar or bipolar depression. You specifically probe for the presence of manic or hypomanic symptoms. He admits there are times when he requires little sleep and is very outgoing; he is also very productive during these periods and says ‘there is no down side to them’. On review of family history, he reports his mother had episodes of depression when he was younger but there is no history of bipolar disorder. You explain to him that he may be having hypomanic episodes as well as depression and you ask him to come back with a family member or a friend for a second visit. George presents to your office a few days later with his girlfriend of 2 years. He continues to be depressed. During discussions with him and his girlfriend, it becomes clear that George has experi- enced three to four episodes of hypomania in the last year, associated with intrusive and embarras- sing behaviour as well as an uncharacteristically high sex drive. He is, however, much more
Borderline personality disorder
No defined onset
Most often not observable
Mood changes precipitated by internal or external events
Mood changes may last for hours, or at most a day
Euthymic, dysphoric, anxious and angry mood shifts but
elated mood is rare
Chronic impulsivity and risk-taking
Binge-eating not uncommon
Recurrent suicidal gestures associated with both depression and internal/external precipitants
Endorse ‘emptiness’ as descriptor
‘Too on edge’ to sleep
Racing thoughts anxious in content and associated with anxiety
Family history negative for bipolar I, II and recurrent depression Adverse developmental history more likely
Good response to dialectical behaviour therapy
frequently depressed. Furthermore, his girlfriend, in conversation with his mother, discovers that she also experienced hypomanic episodes, which did not settle until her doctor prescribed her lithium. You provide George with information on bipolar disorder, and discuss with him a course of action that includes long-term treatment with either lithium or lamotrigine, and the risks and benefits of each strategy. George is reluctant to give up what he says are his most productive, sociable periods. However, you explain to him the hazards associated with untreated mood episodes including the high risk of suicide and the likelihood of spending more time depressed than hypomanic. George agrees to start lithium. He begins to have some symptomatic improvement over the next few weeks. After 2 months of lithium therapy, George says he feels much more stable and would like to continue the lithium therapy for the time being.
Section 8: Safety and monitoring
Medical evaluation of new patients
Ideally, complete medical and baseline laboratory investigations should be performed before initi- ation of pharmacological treatment for bipolar disorder. However, if an acute clinical situation precludes immediate evaluation, assessments should be performed as soon as possible. Patients with bipolar disorder should be regularly monit- ored for weight changes and adverse effects of medication including extrapyramidal symptoms (EPS), and women should be assessed for poly- cystic ovary syndrome (PCOS).
Table 8.1. Baseline laboratory investigations in patients with bipolar disor- der
Fasting lipid profile (TC, vLDL, LDL, HDL, TG) Platelets
Prothrombin time and partial thromboplastin time Urinanalysis
Urine toxicology for substance use
24-h creatinine clearance (if history of renal disease) Thyroid stimulating hormone
Electrocardiogram (>40 years or if indicated) Pregnancy test (if relevant)
CBC 1⁄4 complete blood count; HDL 1⁄4 high density lipoprotein; LDL 1⁄4 low density lipoprotein; TC 1⁄4 total cholesterol; TG 1⁄4 triglyceride; vLDL 1⁄4 very low density lipoprotein.
Laboratory investigations. The laboratory investi- gations shown in Table 8.1 should be performed at baseline. Data suggest that there is no need to do blood counts and liver function tests frequently (658, 659). These investigations should be repeated about 4 weeks after commencement of treatment, and every 3–6 months thereafter. Closer monitor- ing, however, is required in children younger than 10, seniors, medically ill patients and patients on more than one medication. Clinical symptoms and signs of haematological, hepatic, cardiovascular and neurological dysfunction are particularly valu- able in predicting or timing investigations and remedial treatment (658, 659). During lithium maintenance therapy, thyroid and renal function tests should be assessed annually.
Monitoring medication serum levels
Regular monitoring of serum medication levels is required for patients on lithium or divalproex, particularly in patients who are non-adherent. The target serum lithium levels are 0.8–1.1 mmol/L and divalproex levels are 400–700 mmol/L. Serum lev- els should be repeated at the trough point (approxi- mately 12 h after the last dose). For lithium, serum levels should be obtained about 5 days after the most recent dose titration, for divalproex about 3–5 days after the most recent dose titration. Common practice is to establish two consecutive serum levels in the therapeutic range during the acute phase. Thereafter, serum levels should be repeated every 3–6 months unless the clinical situ- ation warrants otherwise. If patients are receiving concomitant carbamazepine or other inducers of
hepatic enzymes, it may be necessary to monitor serum levels of risperidone and other psychotropic agents to ensure that the efficacy is not compro- mised because of lower serum levels.
Safety and tolerability of pharmacotherapy for bipolar disorder
Weight gain. Weight gain and obesity are common in patients with bipolar disorder and appear to be associated with both patient and treatment factors (660). Weight gain is perceived by patients to be the most distressing of all side effects (661, 662), and thus, frequently contributes to non-adherence with treatment. Many agents currently used in the treatment of bipolar disorder are associated with some degree of weight gain.
Lithium is associated with a mean gain of 0.7–2.4 kg over 12 weeks of therapy (121, 228), and the amount of weight gained increases with increasing duration of therapy (663). In a compar- ison study, there was a significantly higher incidence of weight gain with divalproex (21%) compared with placebo (7%) (298). There was also a higher incidence of weight gain with lithium (13%), but this was not significantly different from placebo.
Weight gain appears to occur, to some degree, with all atypical antipsychotics, but to a greater extent with clozapine and olanzapine (533, 664, 665). Over 47 weeks of follow up, mean weight gain was significantly greater with olanzapine (2.8 kg) compared with divalproex (1.2 kg) (231). Weight gain does not appear to be a significant issue with lamotrigine or carbamazepine.
Gastrointestinal symptoms. Nausea, vomiting and diarrhoea are commonly reported with lithium and divalproex, occurring in about 35–45% of patients (122, 298). However, divalproex is significantly better tolerated than valproic acid, and preferen- tially prescribed (666). Gastrointestinal side effects may be common with lithium when it is first initiated or if doses are increased rapidly (667). Gradual dose titration, taking lithium with food, and the use of slow-release preparations may reduce nausea (17, 668).
Renal toxicity. Lithium has been associated with several symptomatic renal conditions, including diabetes insipidus, nephrotic syndrome and renal failure (220). It is estimated that polyuria occurs in up to 20% of patients. About 30% of lithium- treated patients will experience an episode of lithium intoxication, which may lead to decreased glomerular filtration rate. Deteriorating renal function has been associated with higher plasma
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lithium levels, concurrent medication, somatic illness, and age rather than time on lithium (669). Overall, there is minimal evidence that most patients are at risk for progressive renal failure but plasma creatinine concentrations should be measured at least annually in those on lithium therapy (220).
Haematological side effects. Dose-related hepatic and haematological effects have been reported with anticonvulsants (670, 671). Leucopenia has been reported during the first 3 months of treatment in about 12% of children and 7% of adults who received carbamazepine (670). In one study, the rate of leucopenia was five times higher with carbamazepine than with divalproex (672). How- ever, a large survey found that the overall rate of blood dyscrasias was not different for carbamaze- pine, phenobarbital, phenytoin or divalproex (671). Leucopenia is generally reversible with dose reduc- tion or discontinuation of carbamazepine (670, 672). Rapidly developing bone marrow suppres- sion resulting from hypersensitivity can also occur with carbamazepine. The risk of blood dyscrasias increases with age, being two to four times higher in older patients (671, 673).
In a large survey of 122 562 patients, most of the changes in white blood cell counts, which were rated as probably or definitely drug-induced, were attributed to clozapine (0.18% of patients), carb- amazepine (0.14%) and perazine (0.09%) (674). In patients on newer atypical antipsychotics, neu- tropenia rated as probably or definitely drug- related in only five patients during treatment with olanzapine and in one case with risperidone. Incidences of haematological changes for antide- pressants were much lower (about 0.01%).
Analysis of post-marketing surveillance data showed that clozapine and remoxipride had the highest risks of haemopoietic reactions followed by the phenothiazine derivatives, thioridazine and chlorpromazine. All patients started on clozapine should have a baseline haematological profile and be enrolled in the clozapine monitoring pro- gramme that requires weekly or biweekly monit- oring of haematological parameters. There was no evidence of an increased risk with haloperidol, pimozide, sulpiride or risperidone (675).
Cardiovascular side effects. In a comparison of clozapine, olanzapine, quetiapine, risperidone, haloperidol and thioridazine, QTc interval was prolonged to some degree by all agents, but only thioridazine prolonged QTc interval 75 ms, and only ziprasidone and thioridazine prolonged QTc interval 60 ms (676, 677). An increased risk of
abnormal QTc >456 ms has been associated with age over 65 years, TCAs, thioridazine, droperidol and high antipsychotic dose (678). Abnormal QT dispersion or T-wave abnormalities were not sig- nificantly associated with antipsychotic treatment, but were associated with lithium therapy (678). Almost 60% of older patients receiving lithium maintenance therapy experienced electrocardio- graphic abnormalities (525).
Endocrine side effects. Lithium maintenance ther- apy increases the risk of hypothyroidism, which has been associated with an increased risk of affective episodes, rapid cycling and more severe depressive episodes in some studies (216, 679). Over 30% of older patients receiving lithium maintenance therapy required thyroxine replace- ment or had elevated thyroid-stimulating hormone levels (526). Routine screening of thyroid function is recommended during lithium treatment.
Evidence has suggested a risk of PCOS with the use of divalproex; however, this information is mainly derived from patients with epilepsy, which in itself has been associated with a high incidence of PCOS. In a small open-label study in women with bipolar disorder, divalproex was associated with higher rates of menstrual abnormalities and biochemical evidence of hyperandrogenism com- pared with lithium (680). In another small study, 100% of lithium-treated, and 60% of divalproex- treated patients reported some type of menstrual dysfunction, which had preceded the diagnosis of bipolar disorder in some cases; however, PCOS- like changes were not seen in women receiving divalproex or lithium (681).
Cognitive impairment. While patients commonly attribute lithium non-adherence to difficulties with memory (45), evidence of a negative effect is weak (284). When cognitive function was assessed in medication-free, carbamazepine-treated, and lith- ium-treated patients with bipolar disorder, no signi- ficant differences in attention, concentration, visuomotor function or memory were observed across the three groups when compared with non- bipolar control subjects (682). Other data have suggested a slowing of motor speed, and perhaps mild memory deficits with lithium therapy (683, 684). These effects of lithium may, however, be related to clinical or subclinical hypothyroidism (685, 686). Dosage reduction or substitution with divalproex may help reduce cognitive deficits (17, 687).
Lamotrigine and gabapentin appear to have benign cognitive profiles, while topiramate may cause cognitive impairment, especially when dos- age is rapidly titrated (688).
Atypical antipsychotics have well demonstrated cognitive benefits in patients with schizophrenia (284). Preliminary data suggest improvements in measures of cognitive performance with risperi- done and olanzapine in patients with bipolar disorder (284, 689, 690).
Sedation. Divalproex and gabapentin have been associated with sedative effects, whereas lamotrig- ine appears less likely to cause sedation (691). Patients taking divalproex are more likely to feel sedated than are those taking lithium (692). The atypical antipsychotics are associated with sedation in 30–50% of patients compared to 8–13% with placebo (127, 128, 132, 134, 140), and 21–29% with divalproex (124, 125). Amongst atypical antipsych- otics, quetiapine, clozapine and olanzapine cause more sedation than ziprasidone, risperidone or aripiprazole.
Neurological side effects including extrapyramidal symptoms. Approximately 10–18% of patients tak- ing lithium (121, 145, 693, 694) and 10–15% of patients taking divalproex experience tremor (145, 695). Tremor may be reduced by decreasing medica- tion dose and by using sustained release formula- tions (279, 696, 697). Conventional antipsychotics, particularly the high potency drugs, are often asso- ciated with EPS (698), but atypical antipsychotics have a much lower rate of EPS comparable in most studies to that seen with placebo (533, 699). The incidence of EPS is dose related with risperidone with higher doses (i.e. 4 mg or higher) causing more EPS.
Dermatological reactions. Early clinical experience with lamotrigine was associated with a risk of non- serious rash of approximately 10%, and of serious rash, such as toxic epidermal necrolysis and Stevens-Johnson syndrome of 0.3–1% (352, 360). Concomitant divalproex administration and rapid dose escalation increase the risk of rash (352, 354, 700, 701). With decreases in the recommended starting dose to 25 mg, and following a gradual titration, with 25 mg increments weekly, the risk of serious rash may be as low as 1 in 5000 (353). Patients treated with lamotrigine should be informed about these concerns and told to contact their physician immediately should a rash occur; lamotrigine should be discontinued if a serious rash is suspected.
Divalproex and carbamazepine have been asso- ciated with increased risk of rash and Stevens- Johnson syndrome, primarily within the first 8 weeks of therapy (389). In a case-controlled study, the relative risk of Stevens-Johnson syn- drome and toxic epidermal necrolysis among
carbamazepine users was 25 and among valproic acid users was 24 (valproic acid data based on four cases, all of whom were using other associated drugs) compared with non-users of these medica- tions (389). Lithium may be associated with the development of severe treatment-resistant pustular acne that only resolves with lithium discontinu- ation (702).
Hyperglycaemia and type 2 diabetes. Reports of increased prevalence of diabetes with the use of atypical antipsychotics have prompted the FDA to ask manufacturers to add a warning statement describing the increased risk of hyperglycaemia and diabetes in patients taking these medications. Patients with bipolar disorder appear to be at higher risk of developing hyperglycaemia and type 2 diabetes compared with the general population (498). The risk is further increased with atypical antipsychotics compared to conventional anti- psychotics (703–707). The risk may be higher with clozapine and olanzapine but definitive prospective data are unavailable. While much of the risk may be related to weight gain, some individuals develop type 2 diabetes during treatment with atypical antipsychotics without measurable weight gain (708).
Product labelling for atypical antipsychotics now recommends that patients with existing diabetes be monitored regularly for worsening of glucose control, and those with risk factors for diabetes (e.g. obesity, family history of diabetes) undergo fasting blood glucose testing at the beginning of treatment and periodically thereafter. All patients on atypical antipsychotics should be monitored for symptoms of hyperglycaemia including polydipsia, polyuria, polyphagia and weakness; if identified, patients should undergo fasting blood glucose testing, discontinuation of the atypical antipsy- chotic if possible, and initiation of anti-diabetic treatment if necessary.
Dyslipidaemia. Much of the data on the effects of atypical antipsychotics on lipid parameters come from retrospective, cohort studies in patients with schizophrenia. Studies suggest significantly greater increases in lipid levels with olanzapine than risperidone (709, 710). Olanzapine was associated with nearly a fivefold increase in the risk of developing hyperlipidaemia compared with no antipsychotic exposure, and more than a threefold increase compared with those receiving conven- tional antipsychotics (710). Increases in triglyceride levels of about 40% have been reported with olanzapine over 3–4 months of therapy (711, 712). In a 47-week, RCT, there was a significantly
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greater increase in cholesterol level with olanzapine compared with divalproex, but no significant difference in the incidence of treatment-emergent hypercholesterolaemia (231). In RCTs in patients with schizophrenia, treatment with olanzapine increased total cholesterol and LDL-C levels, while ziprasidone significantly decreased these measures (713). The rate of hypertriglyceridaemia was also significantly increased with olanzapine compared with ziprasidone (714). Small increases in choles- terol and triglycerides have been reported with quetiapine (715). Lipid profiles should be monit- ored and appropriate lipid-lowering medications prescribed as needed.
Mortality in Elderly with behavioural problems
There are no reports of increased risk of mortality with atypical antipsychotics in the treatment of patients with bipolar disorder. However, the FDA recently issued a public advisory black box warning on the increased risk of mortality with atypical antipsychotics in the treatment of elderly patients with dementia. The FDA opinion was based on a meta-analysis involving 5106 elderly patients with dementia treated with aripiprazole, olanzpaine, quetiapine and risperidone. The public advisory, however, also covered other atypicals including ziprasidone and clozapine. The FDA also said that the preponderance of deaths (30 days hazard ratio of 1.7) were related to cardiovascular and infectious (pneumonia) adverse events. Although the data are limited, FDA indicated that, in its opinion, typical antipsychotics carried a similar risk and that the FDA is conducting an analysis of this currently. The pathophysiological mechanism was not identified for this increased risk of mortality (FDA, April 11, 2005).
Key resources for bipolar disorder
Bauer M, McBride L. Structured Group Psycho- therapy for Bipolar Disorder, 2nd edn. New York: Springer, 2003. This is the best manual, very detailed, and is available in French and English. Phase I describes a six-session psychoeducational intervention that has been used extensively in studies and in clinical practice.
Sperry, L. Psychopharmacology and Psychother- apy: Strategies for Maximizing Outcomes. New York: Brunner/Mazel, 1995. Useful for basic principles.
Miklowitz DJ, Goldstein MJ. Bipolar Disorder: A Family Focussed Treatment Approach. New
York: The Guildford Press, 1997. Includes family psychoeducation, but goes far beyond into family therapy.
Cognitive therapy for bipolar disorder manuals Basco MR, Rush, AJ. Cognitive-Behavioral Ther- apy for Bipolar Disorder. New York: Guildford Press, 1996. This was the first manual of this type; useful but perhaps too specific and now dated on medication aspects. Good session guidance.
Lam DH, Jones Sh, Hayward P, Bright JA. Cognitive Therapy for Bipolar Disorder. Chichester: Wiley, 1999. Widely regarded as the most used in clinical studies and very specific.
Newman CF, Leahy RL, Beck AT, Reilly- Harrington NA, Gyulai L. Bipolar Disorder: A Cognitive Therapy Approach. Washington, DC: American Psychological Association, 2001. More philosphical, less directive, less practical, but still good.
Key books for patients
Greenberger D, Padesky CA. Mind Over Mood: A Cognitive Therapy treatment Manual for Clients. New York: Guilford, 1995.
Mondimore FM. Bipolar Disorder – A Guide for Patients and Families. Baltimore, MD: John Hop- kins University Press, 1999.
Duke P, Hochman G. A Brilliant Madness. New York: Bantam Books, 1993.
Jamison KR. An Unquiet Mind: A Memoir of Mood and Madness. New York: Random House, 1995.
Copeland ME. Living Without Depression and Manic Depression: A Workbook for Maintaining Mood Stability. Oakland, CA: New Harbinger, 1994.
Torrey EF, Knable MB. Surviving Manic Depres- sion: A Manual on Bipolar Disorder for Patients, Families and Providers. New York: Basic, 2002.
Miklowitz DJ. The Bipolar Disorder Survival Guide. New York: Guildford, 2002.
Key web resources
Canadian Mental Health Association http:// http://www.cmha.ca
Centre for Addiction and Mental Health http:// http://www.camh.net/
Canadian Network for Mood and Anxiety Treatments http://www.canmat.org
Depression and Bipolar Support Alliance (USA) http://www.dbsalliance.org/
Mood Disorders Society of Canada http:// http://www.mooddisorderscanada.ca/
National Institute of Mental Health (USA) http://www.nimh.nih.gov/
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