In the June 2016 issue of the Canadian Journal of Diagnosis entitled, “What Kind of Depression Are You Treating? Diagnosing and Treating Bipolar Depression,” Dr. Roger McIntyre and his colleagues highlighted the importance of differentiating bipolar from unipolar depression. The failure to correctly identify the presence of a bipolar diathesis has a tremendous impact on long-term patient functioning and quality of life. However, treatment selection also has the potential to positively or negatively influence short-term and long-term quality of life. Once a diagnosis has been confirmed and a treatment plan has been formulated, clinicians should strive to avoid the potential cascade of negative physical health outcomes associated with some treatments. While many medications effectively treat the symptoms of mania and/or depression, they may also induce adverse effects that add to the burden of illness—particularly weight gain and metabolic syndrome. It is crucial that prescribers, in the midst of making acute treatment decisions, consider the long-term implications of their choices. This should include the physical health impact of medications, in addition to the efficacy and prophylactic benefits. Essentially, we must treat the mind while respecting the body.
Diagnostic Challenges
Bipolar disorder is commonly misdiagnosed, sometimes for decades,1,2 for a myriad of reasons.3,4 Most often, bipolar patients present to their healthcare provider during a depressive episode,5 which in cross-section often appears identical to uni-polar depression.5 A long-term study found that patients with bipolar I disorder were symptomatic for nearly one-half of the time throughout 13 years of follow-up. On average, those patients spent about 30% of their time depressed, while they were manic or hypomanic less than 10% of the time.6 A similar 13-year study of bipolar II patients found they were symptomatic for more than half the time, with depressive symptoms 54% of the time and hypomania only 1.3% of the study period.7
When patients with bipolar disorder are depressed, some do not recall or lack insight regarding their past manic or hypomanic episodes. Family history, which is helpful in establishing a bipolar diagnosis, is often murky, perhaps because the term “bipolar” has only recently been added to the lay lexicon. Patients often do not recognize that a family member might have a bipolar diagnosis, so clinicians must seek out a family story “suggestive” of bipolar disorder. This might include a family history of chronic depression and/or anxiety, suicide, substance abuse, “nervous breakdowns,” institutionalization, or marked family dysfunction or chaos.
Gathering collateral history is an essential element of making a bipolar diagnosis, particularly if a patient lacks insight regarding the severity of their illness. Lack of an adequate collateral history is sometimes due to the absence of an appropriate, accurate historian, but clinicians should seek out and encourage collateral historians.
Comorbidity is highly prevalent in bipolar disorder, further obscuring diagnostic clarity. Close to 90% of bipolar patients have a comorbid psychiatric disorder,8 and more than 50% have a medical comorbidity.9 The most common psychiatric comorbidities include: anxiety disorders (77%), behavioural disorders (54%) and substance use disorder (52%). The 2011 World Mental Health Survey8 found that while 20% of patients with unipolar depression have three or more psychiatric comorbidities, the rate was more than 60% for patients with bipolar disorder. The presence of comorbid mental illnesses often lead to more severe, sometimes treatment-resistant, symptoms, greater functional impairment, non-compliance and a heightened risk of suicide.10-13
Bipolar spectrum disorders (I, II and not otherwise specified [NOS]) are chronic, functionally impairing illnesses that affect about 4.5% of the population and have a profound impact on quality of life.14,15 When considering neuropsychiatric illnesses, the global disease burden associated with bipolar disorder, measured by productive time lost among working age adults, ranks second only to major depression.16 This statistic is not surprising, given the hefty toll of suicide associated with bipolar disorder. One-quarter of completed suicides may be related to bipolar disorder,17 which is associated with a 20-30 times greater suicide risk compared to the general population.18 Making the correct diagnosis as early as possible and developing an individualized treatment plan that includes effective, tolerable treatments and considers long-term adherence, should improve functional outcomes and maintain the best possible quality of life for patients. Characterizing the type of bipolar presentation, which is an important element of treatment selection, will further inform an effective clinical management plan that can minimize harms to the body without compromising treatment for the mind.
Treatment Selection Factors
There are many considerations when choosing a treatment for an acutely ill patient with bipolar disorder. These include patient/illness-specific, treatment-specific, and prescriber-specific factors. Clinicians must balance these sometimes competing factors when formulating a management plan that best suits their patient’s needs, both in the short term and long term.
Patient/illness-specific factors generally focus on current symptomatology, but clinicians should also consider how the patient has experienced their illness historically. When treating a first episode of illness, family history might provide valuable information and inform treatment choices. As well, the presenting symptoms of bipolar disorder may provide clues about the future course of illness. Most patients with bipolar disorder first present with depressive symptoms during their teen years, which may be preceded by or occur coincident with marked anxiety symptoms.19 If the first symptoms of bipolar disorder are mania or hypomania, this might foretell a more severe course of illness. Likewise, an earlier age of onset,20,21 the presence of rapid cycling,22 mixed features23 or comorbid conditions (e.g., attention deficit hyperactivity disorder [ADHD], substance abuse, a physical illness) might portend a more severe and difficult-to-treat illness.
For a patient with multiple previous episodes, issues like insight, likelihood of compliance, willingness to follow safety protocols, willingness to consider new treatment options, previous response to treatment, severity of past episodes, and suicidality must be considered. Additionally, the quality of social support, functional limitations (e.g., ability to maintain employment or stay in school), and engagement with care providers are essential considerations. Most importantly, a patient’s preferences are paramount.
A myriad of treatment-specific factors must also be considered when treating a patient with bipolar disorder. While most pharmacological treatments have empirical evidence for efficacy, studies do not provide information about the needs of individual patients. Thus, clinicians must employ a “trial and error” approach, which may be highly frustrating and disheartening for patients. Patients might lose faith in the process if an effective and tolerable treatment remains elusive for too long. Side effects are a major reason for non-compliance, particularly metabolic issues, excessive sedation, and sexual dysfunction. Drug-drug interactions must be considered if a patient is prescribed medications for other conditions. Ease of use (e.g., once daily dosing, depot drug delivery), cost and availability round out the extensive list of considerations.
Less often discussed are factors related to the treating clinician or care team. Prescriber knowledge and comfort is at the core of all pharmacological decisions. Some may prescribe based on habit rather than basing their decisions on an individual’s unique needs and preferences. Others may be hesitant to prescribe new treatment options, which may offer superior tolerability, perhaps due to lack of familiarity or confidence. Combination treatments for bipolar disorder are appropriate and increasingly employed because they often confer an additive benefit,24,25 yet some clinicians are reluctant to combine treatments, which may hamper symptomatic remission and full functional recovery. Many prescribers feel limited by sometimes-ill-informed provincial regulatory bodies, which may prevent clinicians from appropriately prescribing necessary, compassionate, sometimes life-saving treatments. An example is the apprehension some clinicians experience when prescribing benzodiazepines to bipolar patients for anxiety, agitation and sleep.
Hospital-based mental health providers are often under pressure to discharge patients as quickly as possible, leading to acute treatment choices that might have significant side effects, like weight gain or excessive sedation. When patients are discharged on these medications, their community healthcare provider may be loath to change acutely effective medication, fearful of provoking a relapse. Yet, they are then left to support and encourage a frustrated, disgruntled patient who hates their medication and will likely become non-compliant. Finally, an important barrier to adequate treatment is lack of access, particularly in remote areas where psychiatric support is limited.
Clinicians can challenge their usual practice, whether related to treatment selection or the development of treatment goals, by reviewing clinical trial evidence, gathering knowledge regarding approved drug indications, following published guidelines and engaging with colleagues to consider emerging practise experience. Critical goals of bipolar treatment are long-term mood stability and prophylaxis,26 and must take physical health outcomes into account. With the abundance of evidence available to highlight the negative impact of chronic, undertreated or untreated bipolar illness, it is imperative clinicians consider long-term management from the outset of treatment.2 With the length of untreated illness correlated with cognitive impairment, unemployment, poverty, social conflict and worsening overall physical health outcomes, early, effective, tolerable treatment that can safely and effectively transition from acute to long-term illness stability is the Holy Grail of bipolar management.
Historically, bipolar treatment has largely focused on the management of mania, perhaps due to the tremendous health and safety impact of mood elevation. The majority of Health Canada and Food and Drug Administration (FDA) approved medications for bipolar disorder are for the treatment of mania, a medical emergency that requires a rapid assessment of insight and safety and urgent medical intervention. However, recently, there has been a greater emphasis on the management of the depression pole, likely due to the preponderance of time most patients spend depressed,6,7 as well as the mortality associated with bipolar-related suicide.17,18
Perhaps because bipolar treatment has largely focused on managing or preventing mood elevation, clinicians have historically taken a short-term view of bipolar management. In their haste to rapidly control manic symptoms, clinicians sometimes fail to consider the long-term impact of their acute treatment choices. Additionally, patients, whether due to poor insight, lack of social support or a paucity of psychoeducation, rarely push clinicians to consider their long-term wellbeing when treatment is initiated.
Choice of Treatment
There is compelling scientific evidence regarding the efficacy of lithium, divalproex, and atypical antipsychotics (AAPs) for the treatment of mania.27,28 While lithium and valproate continue to be considered first-line treatment options for bipolar mania, some patients preferentially respond to one treatment or the other. Lithium responders tend to have a family history of bipolar disorder and experience classic euphoric mania. For patients who lack a bipolar family history, experience rapid cycling, mixed features, or substance abuse, valproate may be a better choice.27,28
The value of lithium for bipolar depression, as well as its robust long-term prophylactic benefits, has been established.29 Treating depression with valproate does not have similar clinical or empirical support. For some patients, lithium is a challenging medication to take in the long-term. Aside from its narrow therapeutic index, requiring blood levels to ensure efficacy while preventing toxicity, it is also a dangerous drug in the hands of a suicidal patient and has many side effects some patients find intolerable.30 Neither lithium nor valproate are officially indicated by Health Canada or the FDA for bipolar depression. The most recent Canadian bipolar guidelines, published in 2013 by the Canadian Network for Mood and Anxiety Treatments (CANMAT), recommend lithium as first-line therapy for bipolar depression. In the U.S., the Florida Best Practice Guidelines (published in the Journal of Clinical Psychiatry in 2015) suggest a second-line rating for lithium in the treatment of bipolar depression. Until the Canadian guidelines are updated, American recommendations can be a useful tool for helping physicians make informed treatment selection decisions for their patients (within the scope of Health Canada approved agents).
Because patients with bipolar disorder spend most of their symptomatic time in a depressed state, it is imperative that clinicians consider the long-term implications to the whole body when choosing an agent for the treatment of bipolar mania or depression. The adverse effects of medication may be tolerable in the short term, but can add a significant burden to patients if prescribed for long periods of time.
The 2013 CANMAT guidelines recommend lamotrigine as first-line therapy for the acute treatment of bipolar I depression and for maintenance therapy, and as second-line therapy for bipolar II depression. The Florida Best Practice Guidelines rate lamotrigine as a second-line agent based on efficacy. The number needed to treat (NNT) for lamotrigine response, when compared to placebo, is 12 (8-41); the number needed to harm (NNH) is much more favorable.31,32 Aside from the 1/1,000 risk of a serious rash,33 lamotrigine has a tolerability profile superior to AAPs, lithium and valproate. However, the double-digit NNT does not compare favorably to AAPs, lithium or valproate. So despite a NNH that is 3-times higher than the NNT, the favorable benefit/harm ratio is offset by inadequate efficacy. Lamotrigine’s use is also limited for some patients because it is not an effective acute or preventive treatment for mania or hypomania.
In 2011, the Lancet published a systematic review, including 68 randomized controlled trials (16,073 participants), that found that antipsychotic drugs were “strikingly” more effective than mood stabilisers in the management of acute mania.34 Similarly, another meta-analysis of 38 studies involving 10,800 patients demonstrated responses to various antipsychotics were somewhat greater or more rapid than lithium, valproate or carbamazepine in acute mania.35
As a class, AAPs offer several important advantages over conventional antipsychotic agents. Arguably, the reduction in movement disorders has the strongest evidence,36,37 although a reduction of negative symptoms and an improved sense of well-being are also commonly described by patients.38,39 Most AAPs, through their impact on a variety of receptors, also improve depression and anxiety symptoms, as well as conferring mood stabilizing, anti-manic and antipsychotic effects.40 In contrast, many typical antipsychotics, while very useful in the treatment of acute mania, lack good maintenance data and may provoke depression. Because of their breadth of potential symptom amelioration and well-established evidence for short-term and long-term efficacy, AAPs have become first-line choices for bipolar disorder, whether the first presentation is mood elevation or depression. There is also evidence for the value of employing a combination of an AAP and either lithium or valproate, which may improve overall efficacy by 20% compared to either drug alone.41-46
Unfortunately, many AAPs are burdened with tolerability issues to varying degrees—not all are the same.47 The AAPs that have strong empirical evidence for efficacy in acute bipolar depression, including quetiapine, lurasidone and olanzapine (plus fluoxetine), may not be well tolerated by all patients.48,49 Patients with bipolar disorder have an increased risk of metabolic disorders, the cause of which is multifactorial and includes the impact of the underlying disease state, lifestyle factors, and treatment factors.50-54 The metabolic risks associated with olanzapine, and to a somewhat lesser degree with quetiapine, are an added burden for a population that already has an increased risk for cardiometabolic disorders.55 The presence of metabolic syndrome is associated with a more complex bipolar presentation, less favourable response to treatment, and adverse course and outcome. The significant risk of weight gain in bipolar patients is negatively associated with cognitive function56 and highly associated with treatment non-compliance.57 Compared to unipolar depression, bipolar depression is associated with twice the risk of endocrine, cardiovascular, and cerebrovascular morbidity and mortality.58
Fortunately, there have been important advancements regarding metabolic side effect burden with some of the newer AAPs.59 While their classification suggests homogeneity, AAPs have heterogeneous safety and tolerability profiles. The most recently available AAPs, aripiprazole, lurasidone, asenapine and ziprasidone, have more favorable metabolic profiles (Table 1).60 Of the group that has demonstrated efficacy in bipolar depression, lurasidone’s tolerability, when compared to quetiapine and olanzapine, may be associated with greater compliance due to a generally positive tolerability profile.61-63
Numbers Need to Treat and Numbers Needed to Harm
Examining NNT compared to NNH amongst AAPs approved to treat bipolar depression can be a helpful approach when selecting one treatment over another. A low NNT is desired, accompanied by a high NNH. A comparative table of approved AAPs and their respective NNTs and NNHs are shown in Table 2.47
The Florida Best Practice Guidelines64 recommend lurasidone monotherapy or lurasidone prescribed in combination with lithium or valproate as first-line treatment for bipolar I depression. Lurasidone monotherapy, when compared with placebo, had a NNT for response of 5 (4-8) and a NNH for akathisia of 15 (10-33),60 demonstrating that lurasidone monotherapy is efficacious and more likely to yield benefit (response) than harm (akathisia). When compared with placebo, lurasidone prescribed in conjunction with lithium or valproate, had a NNT for response of 7 (4-24) and an NNH for nausea of 16 (95% confidence interval was not significant),61 suggesting this combination is more likely to yield benefit (response) than harm (nausea). Thus, lurasidone, whether prescribed alone or as adjunctive therapy, has a favorable benefit/harm ratio.
Quetiapine, both as monotherapy and in combination with lithium and valproate, is also recommended first-line treatment by the Florida Best Practice Guidelines and as first-line monotherapy by the 2013 CANMAT guidelines,65 for both bipolar I and II depression. Quetiapine has comparable efficacy to lurasidone as monotherapy, with a NNT for response when compared to placebo of 6 (5-9). However, its NNH for sedation and somnolence is 5 (4-5).46,66 While the efficacy of olanzapine with fluoxetine is well established, it is considered second-line treatment in the Florida Best Practice Guidelines and the CANMAT guidelines due to weight and metabolic side effects. When compared to placebo, olanzapine plus fluoxetine has a NNT for response of 4 (3-8) and a NNH of 6 (4-10) for ≥ 7% weight gain.48 Consequently, while both quetiapine and the combination of olanzapine and fluoxetine have single-digit NNTs, when compared to placebo, they also have single-digit NNHs. While this demonstrates clinical efficacy, they are just as likely to cause side effects that some patients might find intolerable.
Summary
While it is essential to rapidly and effectively treat acute mania, long-term mood stability and prophylaxis are critical considerations. Though effectiveness is a core component of treatment choice, so too is tolerability. Negative health issues associated with some agents, particularly related to weight gain and metabolic syndrome, not only impact patient quality of life but also contribute to the burden of disease by compounding the symptoms of depression. For optimal treatment outcomes, both in the short term and the long term, therapy for bipolar disorder should be selected for the individual patient to maximize efficacy and minimize negative consequences to overall physical health. Clinicians support the best short-term and long-term quality of life for their patients with bipolar disorder when they treat the mind and also respect the body.
Development of this article was funded by Sunovion Pharmaceuticals Canada Inc. The author had complete editorial independence in the development of this article and is responsible for its accuracy and completeness. Editorial assistance was provided by STA HealthCare Communications.
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