Practical Applications of New Research in Bipolar Disorder

Bipolar disorder is a leading cause of disability worldwide,1 and the lifetime prevalence of this condition is about 1% in community populations.2 This activity presents highlights from 4 presentations given at the 2011 International Conference on Bipolar Disorder (ICBD), a conference dedicated to sharing research results and clinical experience to help clinicians improve the lives of those with bipolar disorder.

Supported by an educational grant from Bristol-Myers Squibb.

Paul King, MD (Series Editor)

Medical Director, Parkwood Behavioral Health System, Olive Branch, Mississippi

Bipolar disorder is a leading cause of disability worldwide,1 and the lifetime prevalence of this condition is about 1% in community populations.2 This activity presents highlights from 4 presentations given at the 2011 International Conference on Bipolar Disorder (ICBD), a conference dedicated to sharing research results and clinical experience to help clinicians improve the lives of those with bipolar disorder.

Medical Lifestyle Management: Theory and Interventions

Patients with bipolar disorder and metabolic syndrome have more manic and depressive episodes, longer duration of depressive episodes, more psychiatric hospitalizations and suicide attempts, higher medical costs, and greater symptom severity and functional impairment.3 Despite the high prevalence, burden, and dire consequences of metabolic disorders in bipolar disorder, these conditions remain underrecognized and undertreated.

Cardiometabolic conditions. Most deaths in bipolar disorder occur from natural causes, with the most frequent being cardiovascular mortality.4 In fact, patients with bipolar disorder are likely to have cardiovascular disease 5 times as often and almost 15 years earlier than their healthy counterparts.5 Even in pediatric bipolar disorder, youths have excessive obesity, hypertension, and diabetes, as well as an increased metabolic sensitivity to mood stabilizers.6 Even though cardiometabolic conditions are common and can be fatal, many mental health care providers do not implement guideline-concordant care with respect to medical monitoring (AV 1).7

The risk for cardiometabolic conditions is increased in mood disorders for several reasons, and patients with bipolar disorder often have multiple risk factors. Medical factors, such as inflammation, genetics, poor circulation, diabetes, and hormonal dysregulation, as well as modifiable lifestyle factors, such as being overweight or obese, smoking, and having poor dietary and exercise habits, substantially contribute to cardiovascular risk.8–11 Medications to treat bipolar disorder can also contribute to an increased risk of cardiovascular disease and metabolic disorders.

When clinicians provide comprehensive care, patients with bipolar disorder experience not only improvement in mental and physical status, but also a reduction in risk of cardiovascular events, more attention from healthcare providers, an improved quality of life, and a greater satisfaction with care.12,13 Implementing a bipolar disorder medical care model such as that provided by Kilbourne et al14 establishes a framework for physicians to provide quality, comprehensive care.

Health benefits of sleep. Sleep disturbance is a cardinal symptom of bipolar disorder and leads to inadequate recovery and relapse risk.15 Patients with mania have a decreased need for sleep, while those with depression often have insomnia or hypersomnia.16 As with cardiovascular disease, obesity, poor diet, and lack of exercise negatively impact sleep hygiene.11,17,18 To improve sleep for patients with bipolar disorder, the presenters stated that clinicians can combine principles from CBT for insomnia, interpersonal and social rhythms therapy, and chronotherapy.19–21

Real-time interventions. Bipolar disorder has a tremendous medical illness burden and high mortality rates associated with poor lifestyle choices, including smoking, substance use, and obesity. The presenters stated that, from the outset of treatment, clinicians should be aware of these common health risks in patients with bipolar disorder and implement interventions to effectively address them.

Unfortunately, many barriers exist that impede successful smoking cessation, including a lack of provider buy-in and insurance reimbursement, long-standing attitudes about smoking in the mentally ill, and the lack of awareness of available resources. Additionally, barriers to successful behavioral changes to reduce cardiac risks include misconceptions about medical treatments, lack of integrated mental and medical health care, and lack of treatment by nonspecialty physicians. Also, in a misguided effort to promote a good quality of life, caregivers and family members may resist healthful interventions and enable their loved ones to continue unhealthy behaviors.

To overcome these barriers and help patients lead healthy lifestyles, the presenters recommended that clinicians systematically identify risk factors, educate patients about the hazardous effects of an unhealthy lifestyle, and implement interventions to promote healthy behaviors such as quitting smoking, eating healthy foods, and managing weight gain. Further, motivational interviewing, CBT, and pharmacotherapy are specific therapies that can aid patients in leading healthier lives.

For clinical use. Integrated management of psychiatric and medical care is necessary to help ensure optimal outcomes for patients. Based on the presentations, the following recommendations were made for clinicians to use in their practice:

  • Screen patients with bipolar disorder for metabolic abnormalities, including diabetes, dyslipidemia, and hypertension
  • Complete a risk/benefit assessment of treatment for each patient and then tailor appropriate therapies to that patient
  • Educate patients about bipolar disorder and the common co-occurrence of medical illnesses
  • Systematically identify risk factors and address unhealthy behaviors, including poor sleep hygiene, smoking, poor diet, and lack of exercise

Bipolar Disorder and the DSM

The DSM is currently being updated, and the fifth edition is slated to be published in 2013. In revising the current DSM criteria, the goals were to:

  • Clearly differentiate between psychiatric disorders to be as useful as possible to clinicians during assessment and treatment
  • Be evidence-based and provide a foundation for future research
  • Consider comorbidities that may affect treatment
  • Be easy to use, clinically applicable, and valid across disciplines
  • Preserve the continuity achieved with the other versions of the DSM while having no a priori limitations on the degree of change

When proposing new disorders or retiring disorders, the work groups have been charged to articulate the reasons and present supporting evidence for the change, as well as consider the need for the category, the disorder’s relationship with other DSM disorders, and available treatments for the disorder.

Mixed episodes. To meet the DSM-IV criteria for a mixed episode, both the manic episode and the depressive episode criteria must be met nearly every day for at least 1 week.2 The mood disturbance must cause impairment and must not be due to a substance or medical condition. These restrictive criteria do not reflect the current use of the term “mixed,” which can cause confusion and inaccuracy, and using these criteria results in a lack of suicide risk awareness, inappropriate treatment, and unsuccessful identification of the likelihood of progression from unipolar to bipolar disorder.

To be more consistent with clinical use as well as in the literature, the DSM-5 Mood Disorders Work Group is revising the mixed episode criteria. Using a mixed episode “specifier” allows for subthreshold symptoms of one pole to be present during a full episode of the opposite pole; this criteria could be used for both unipolar and bipolar disorders (AV 2).22 Validators of the proposed mixed specifier criteria include having a family history of mixed states, early illness onset, multiple episodes, suicidality, comorbidities, traumatic brain injuries, poor treatment outcomes, mood instability, and progressing from unipolar to bipolar disorder.

Hypomanic episodes. To meet the DSM-IV criteria for a hypomanic episode, criterion A currently states that a patient must have “a distinct period of persistently elevated, expansive, or irritable mood, lasting throughout at least 4 days, that is clearly different from the usual nondepressed mood.”2(p368) When reviewing this criterion, the presenters recommended the addition of “activity or energy.” Although inferred in the current criteria, inserting this language reinforces that increased activity and energy is a cardinal symptom of mania and hypomania.

The presenters also examined the arbitrary 4-day duration ascribed for a hypomanic episode, a critical definition for bipolar II disorder and bipolar spectrum disorders, which has been a major point of contention. Although some patients have hypomania that lasts fewer than 4 days, decreasing the 4-day duration criterion would substantially increase the number of people with bipolar II disorder, and the literature simply does not support this change at this time. So, those who do not meet criterion A for hypomania typically fall into the catchall diagnostic category of bipolar disorder NOS. The problem with this diagnostic entity is that subcategories are not defined, coded, or trackable. To improve the NOS specificity for each diagnostic group, the presenters recommended adding the subcategories “subsyndromal,” “other specified,” and “unspecified due to insufficient information.” Subsyndromal hypomania, then, would include “short duration” of 2 to 4 days and “insufficient symptoms” qualifiers.

The international BRIDGE study23 used a bipolar specifier (ie, adapted DSM-IV criterion A to allow for increased activity for mania and hypomania, and no minimum duration for hypomania) to assess the occurrence of bipolar disorder in MDD. Of 5,635 patients diagnosed with MDD, 16% met the criteria for bipolar disorder. When the specifier was used, 47% met the criteria for bipolar disorder (AV 3). Patients with bipolar I disorder had higher recurrence rates, suicidality, psychosis, hospitalizations, and family history of mania, while those with bipolar II disorder had higher rates of comorbid psychiatric disorders. The specifier criteria was more sensitive than DSM-IV criteria regarding validators and provided the opportunity for earlier and more accurate diagnoses.

Changing the NOS category will impact classification codes and insurance billing, targets for drug development, and clinicians’ understanding of the bipolar spectrum as well as research opportunities in bipolar disorder. The rest of the criteria for a hypomanic episode would remain unchanged.

Current Status of Child and Adolescent Bipolar Disorder

Diagnosis. Bipolar disorder is prevalent in youth and commonly has an early age at onset.24,25 Having bipolar disorder adversely affects the normal development of children and substantially increases the risk of suicide, substance use, and psychosocial problems. Further, young patients who have elevated mania, which often results in poor functioning, severe mood symptoms, disruptive behavior, and anxiety, often do not meet the diagnostic criteria for bipolar disorder or receive a bipolar disorder NOS diagnosis.26

The presenters noted that diagnosing pediatric bipolar disorder is difficult due to varying clinical presentations, developmental problems, and symptom overlap with other disorders (AV 4). Further, even defining the disorder for this population can prove problematic, eg, irritability versus elation, acute versus chronic course, rapid cycling, and narrow versus broad criteria. The rates of bipolar diagnoses are rising, particularly in the United States, which may be due to the use of a broader definition of the disorder, including NOS.27 In the longitudinal course, children with bipolar disorder have worse prognoses, more subsyndromal recurrences, and more mood variation within episodes than adults.28 Further, almost half of youth with bipolar disorder NOS are likely to convert to bipolar I or bipolar II disorder, and a fourth of those with bipolar II disorder are likely to convert to bipolar I disorder.28 A main predictor of developing bipolar disorder is having a family history of the condition.29

Treatment. Several therapies are available to effectively manage bipolar disorder in children and adolescents. Concerning pharmacotherapy for young patients with bipolar disorder, divalproex was not shown to be superior over placebo for acute mania30 and SGAs were more effective than mood stabilizers for acute manic and mixed episodes.31,32 However, youth are sensitive to metabolic adverse events associated with some SGAs, including weight gain and increased triglycerides and cholesterol.33 Overall, long-term placebo-controlled studies are needed to further assess medication efficacy in this population.

For psychotherapy, multifamily psychoeducational psychotherapy plus treatment as usual has been shown to improve mood for children with mood disorders, including those with bipolar spectrum disorders.34 Additionally, family-focused therapy has helped to reduce depressive and manic symptoms in adolescents through moderating parental expressed emotion.35

Debates in Bipolar Disorder: Antidepressants Are Ineffective for Bipolar Depression

Antidepressants continue to be the most commonly prescribed class of psychotropic medications.36 Even in bipolar disorder, antidepressants are prescribed twice as often as mood stabilizers (AV 5).37 Although not recommended as a first-line treatment, the presenters stated that antidepressant agents can have both benefits and harms when treating bipolar depression; however, evidence of antidepressant efficacy in bipolar disorder is limited.

Benefit. One benefit may include response to treatment in acute and maintenance phases, although the evidence is not overwhelming. In the short-term treatment of bipolar depression, one meta-analysis38 found that, in addition to mood stabilizers or atypical antipsychotics, antidepressants were more effective than placebo, while another meta-analysis39 found a small but insignificant difference favoring antidepressants; both reported that antidepressants did not increase the risk of manic switch. The presenters noted that almost all efficacy studies on antidepressants present positive results, but upon further analysis by the FDA, only about half of those studies are actually positive.40

In studies41,42 of the long-term treatment of bipolar depression, antidepressants either alone or with a mood stabilizer did not substantially prevent depressive relapse or increase a manic switch, reinforcing that mood stabilizers are the mainstay of prophylactic maintenance treatment. However, in those who achieve remission with an adjunctive antidepressant, the longer the antidepressant is continued, the less likely it is to lead to a depressive relapse.43 On the other hand, patients with rapid-cycling may have worse outcomes when continuing antidepressants. Other types of depression that have poor antidepressant response include mixed depression, neurotic depression, melancholia, and mixed or melancholic bipolar depression.

Harms. Harms of antidepressants in bipolar disorder include inducing a switch to acute mania, mood destabilization, and suicide risk. Regarding a switch to mania, antidepressants have not been shown to clearly increase this risk,38,39,44 although switching may be more common in bipolar I than in bipolar II disorder.45,46 Also, using antidepressants over the long term may lead to treatment refractory bipolar disorder and mood destabilization, particularly with TCAs, which contribute to rapid cycling.42 For suicidality, factors such as illness severity and chronicity and age must be considered, and patients on antidepressant treatment should always be monitored for suicidal thoughts and behaviors.47,48

For clinical use. Based on the evidence presented, recommended antidepressant strategies are that clinicians should:

  • Use mood stabilizers as first-line treatment, except for patients who have suicidality or severe melancholia
  • Avoid antidepressants for depressive mixed states or rapid cycling
  • Be more cautious when using antidepressants in bipolar I than in bipolar II disorder
  • Use SRIs before TCAs and MAOIs, and administer at half the dosage used for MDD
  • Taper antidepressant treatment after remission has been achieved for 2 months


ADHD =  attention-deficit/hyperactivity disorder; BRIDGE = Bipolar Disorders: Improving Diagnosis, Guidance, and Education; CBT = cognitive-behavioral therapy; DSM-IV = Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; FDA = US Food and Drug Administration; MDD = major depressive disorder; MAOI = monoamine oxidase inhibitor; NOS = not otherwise specified; ODD = oppositional defiant disorder; SGA = second-generation antipsychotic, SRI = serotonin reuptake inhibitor; TCA = tricyclic antidepressant



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