Long-Term Treatment of Bipolar Disorder in Adults

Roger S. McIntyre, MD, FRCPC

Departments of Psychiatry and Pharmacology, University of Toronto, and the Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, Ontario, Canada

Bipolar disorder is a chronic, multidimensional syndrome that is currently listed as one of the top 10 leading causes of disability amongst adults (ie, aged 15–44 years).1 The typical age at onset is between 17 and 21 years,2 and the estimated prevalence in adults is 1.0% for bipolar I disorder, 1.1% for bipolar II disorder, and 2.4% for subthreshold bipolar disorder.3 Depressive symptoms tend to dominate the illness presentation and are approximately 3.5 times more frequent than manic/hypomanic symptoms in bipolar I disorder4 and 38.5 times more frequent in bipolar II disorder.5 Additionally, patients with bipolar disorder are at a high risk for suicidal ideation; the estimated lifetime rate of suicide is between 10% and 15%, roughly 20-fold greater than that of the general population.6

Impact of Bipolar Disorder

Bipolar disorder is a progressive illness wherein each episode that a patient has substantially increases the risk that another episode will occur. Moreover, subsequent episodes are often more severe, have a complex presentation, have a longer duration, and are less responsive to conventional treatment strategies. It is hypothesized that the disturbances in mood regulation, affective processing, behavior, and cognition in the bipolar population are subserved by alterations in the discrete brain regions and circuits implicated in the pathophysiology of this condition.7

The biphasic and episodic nature of bipolar disorder substantially contributes to its negative impact on patients’ quality of life as well as their physical, social, and occupational well-being. For example, the National Comorbidity Survey Replication8 found that bipolar disorder was associated with an average of 65.5 lost workdays per worker per year (AV 1AV 1)—a performance gap estimated to cost $14.1 billion in lost productivity per year in the United States. Compared with MDD, patients with bipolar disorder exhibited considerably more functional impairment due to experiencing more persistent and more severe depressive episodes. Much of the workforce impairment associated with bipolar disorder may be a result of insufficient long-term management of the condition. Effective control can help reduce the burden of the illness on patients as well as reduce its overall costs.

Common Comorbidities and Health Risks in Bipolar Disorder

Patients with bipolar disorder often have co-occurring conditions including psychiatric comorbidities, such as anxiety, substance use, and personality disorders, and medical comorbidities, such as pain disorders, obesity, and cardiovascular disease.9 Unfortunately, several psychotropic medications prescribed to treat bipolar disorder, particularly atypical antipsychotics, may increase the risk of developing certain medical illnesses, such as those associated with metabolic syndrome. Characteristics comprising metabolic syndrome include excess abdominal weight, dyslipidemia, dysglycemia, and hypertension, a combination that compounds the risk for diabetes, stroke, and cardiovascular disease, which is purportedly the most frequent cause of death for patients with bipolar disorder.10

A community survey11 on mental health and well-being found that individuals with a mood disorder were significantly more likely to be obese than the general population (P < .05), and that antipsychotics were the only specified medication significantly associated with obesity (P < .05). Similarly, a review12 reported that the prevalence of diabetes may be 3 times higher in people with bipolar disorder than in the general population. And, another survey13 showed that bipolar patients were significantly more likely to have cardiovascular disease and hypertension than those with MDD or healthy controls (P < .0001). Overall, the rates of metabolic syndrome are considerably higher in those with bipolar disorder than in the general population (up to 56% vs 22%, respectively).14–16

Although the recommendation in psychiatric care is to regularly assess patients’ physical health, including their waist circumference, weight, BMI, and lipid and glucose levels, more clinicians still need to implement this strategy in clinical practice. The UNITE survey,17 which included 1,300 patients with bipolar disorder who primarily saw psychiatrists, indicated that many patients reported not having received screening or monitoring for medical risk factors and disorders (AV 2AV 2). To provide comprehensive care, clinicians must be able to recognize illnesses concurrent with bipolar disorder, which in turn should guide individualized treatment decisions as well as chronic disease management plans. Thus, clinicians should assess patients with bipolar disorder for medical problems, particularly those associated with metabolic syndrome, at baseline and throughout treatment and address each health risk appropriately.


Long-Term Pharmacotherapy for Bipolar Disorder

When treating bipolar disorder, keep in mind the chronic course of the illness and choose medications that will not only stabilize patients in the acute phase but also transition them into the maintenance phase of therapy. Generally, the treatment strategy that helps a patient achieve remission will also help to sustain remission and prevent relapse. Yet, despite this general principle, patients with bipolar disorder often have high rates of medication discontinuation early in the treatment course. Further, finding the most effective acute treatment may require trial and error. For example, the EMBLEM study18 indicated that, during 12 weeks of treatment for acute mania, 54% of patients had at least 1 medication switch, 62% of whom had multiple switches, demonstrating the complexity of treatment for bipolar disorder. Clinicians reported that the most common reasons for switching medications included perceived inefficacy, intolerability, and patient request, signaling an exigent need for better knowledge of the evidence base, comprehensive patient evaluations, and individualized treatment tailoring.

When making evidence-based medication choices for bipolar disorder, clinicians can select from several FDA-approved agents for the treatment of acute manic and depressive episodes as well as for maintenance therapy, a majority of which are atypical antipsychotics approved in the 2000s. Agents approved for use as maintenance monotherapy include lamotrigine, lithium, aripiprazole, risperidone LAI, and olanzapine, and agents approved for use as adjunctive maintenance therapy include risperidone LAI, quetiapine, and ziprasidone. The treatments differ in efficacy for preventing mania and depression and in causing adverse events. Because no one therapy has proven to be a panacea for bipolar disorder, combination treatment is often used.18

Mood stabilizers. Lamotrigine is generally well tolerated and has a minimal tendency to cause weight gain, diabetes, metabolic abnormalities, EPS, and cognitive impairment. Similarly, lithium is generally well tolerated; however, clinicians should be cautious of lithium toxicity when prescribing higher dosages. A pooled analysis19 of two 18-month trials showed that monotherapy with lithium or lamotrigine was superior to placebo for time to intervention for any mood episode; lamotrigine was more effective in reducing risk for depressive relapse while lithium was more effective in reducing risk for manic relapse.

Atypical antipsychotics. Atypical antipsychotics have differing propensities to cause certain metabolic and neurologic side effects (AV 3AV 3),20 with which clinicians should become familiar in order to make informed treatment decisions. Concerning efficacy, several studies have examined each atypical antipsychotic in treating bipolar disorder.

Keck et al21 reported that aripiprazole monotherapy significantly delayed the time to relapse for manic (P = .005), but not depressive, episodes over 100 weeks of treatment. Likewise, the time to recurrence for manic (P < .001), but not depressive, relapse was significantly longer with risperidone LAI monotherapy than with placebo during 2 years of treatment.22 Olanzapine monotherapy significantly prolonged the time to relapse for both manic and depressive episodes (P < .001) in maintenance treatment lasting up to 48 weeks.23

In the EMBOLDEN study,24 adjunctive quetiapine with lithium or divalproex significantly reduced the risk of manic or depressive relapse (P < .0001) in the continuation phase of treatment. Similarly, ziprasidone, used in addition to a mood stabilizer, produced a significantly longer time to intervention for a mood episode than placebo (P = .0104) over the 6-month study period.25

Adjunctive antidepressants. Although antidepressants are not approved to treat bipolar disorder, they are often prescribed for patients with this condition, not only during acute therapy but over the long term as well. Altshuler et al26 found that patients with bipolar depression who were successfully treated with a mood stabilizer and an adjunctive antidepressant had a longer time until depressive relapse if they continued the antidepressant. So, even though antidepressants are not the recommended first-line treatment for patients with bipolar disorder, these agents may be appropriate adjuvant medications for certain patient subpopulations. If patients are already taking an adjunctive antidepressant and the illness is stabilized, then they should continue that same regimen. Because antidepressants may disrupt glucose homeostasis, which is associated with diabetes,27 clinicians should regularly assess patients for signs of this condition.

Psychotherapy for Bipolar Disorder

Several psychotherapies are available to use in combination with pharmacotherapy for bipolar disorder. These include manual-based psychosocial interventions, such as cognitive-behavioral therapy and interpersonal therapy, as well as group psychoeducation and family psychotherapy, to name a few. Benefits of psychotherapy include higher recovery rates and shorter times to recovery than medication treatment alone provides.28 Although the therapies have differing modalities, each is generally effective, and research is currently underway to determine if one therapy is more effective in a symptom domain of bipolar disorder than another.

For Clinical Use


  • When selecting treatment for bipolar disorder, anticipate a chronic course of illness
  • Regularly assess bipolar patients for psychiatric and medical comorbidities, particularly for metabolic abnormalities when prescribing psychotropic medications
  • Become familiar with the evidence base and side effect profiles for medications used to treat bipolar disorder
  • Communicate with patients, especially about tolerability concerns, and involve them in the treatment decision-making process
  • Implement adjunctive psychotherapy to improve patients’ overall outcomes


Drug Names

aripiprazole (Abilify), asenapine (Saphris), clozapine (Clozaril, FazaClo, and others), lamotrigine (Lamictal and others), lithium (Lithobid and others), olanzapine (Zyprexa), quetiapine (Seroquel), risperidone (Risperdal and others), ziprasidone (Geodon)


BMI = body mass index,EMBLEM = European Mania in Bipolar Longitudinal Evaluation of Medication,EMBOLDEN = Efficacy of Monotherapy Seroquel in BipOLar DEpressioN,EPS = extrapyramidal symptoms,FDA = US Food and Drug Administration,LAI = long-acting injectable,MDD = major depressive disorder,UNITE = Understanding Patients’ Needs, Interactions, Treatment, and Expectations

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