A pharmacist’s guide to managing bipolar disorder

Bipolar disorder is a chronic mental health condition that afflicts roughly 1%–2% of Canadians at some point in their lives.1,2 It is characterized by cycling between periods of elevated mood (mania or hypomania) and periods of depressive mood (depression). Bipolar disorder is often highly debilitating, leading to significant distress and impairment in daily functioning.2,3 With many pharmacological treatment options available, pharmacists are often faced with complex medication regimens. This guide provides a brief overview of the management of bipolar disorder, along with some clinical pearls to help pharmacists navigate the diverse range of pharmacological treatments available. Etiology/pathophysiology Bipolar manic episodes are generally characterized by a persistent period of elevated or irritable mood, grandiosity, hypertalkativeness, flight of ideas (jumping rapidly between ideas and thoughts), a decreased need for sleep, and general increase in energy or goal-directed activities. When this period lasts longer than one week, it is categorized as a manic episode. In severe manic episodes, a person can experience symptoms of psychosis. Hypomanic episodes are defined as periods of four days or more of the same symptoms at a lower intensity, but these episodes do not result in hospitalization, or cause significant impairment or psychosis.4 Bipolar depressive episodes are similar to unipolar depressive episodes seen in major depressive disorder, with a persistent period of depressed mood, anhedonia (inability to feel pleasure), sleep difficulties, changes in weight and appetite, fatigue, changes in psychomotor activity, and potential suicidal ideation and/or attempts. A period of two weeks or more of these symptoms can be defined as a major depressive episode.4 For patients, depressive episodes are often more impairing than manic episodes, and can represent two-thirds of the time they are unwell.2,5,6 Further details on bipolar manic, hypomanic and depressive episodes are available in the Diagnostic and Statistical Manual, Fifth Edition (DSM-5).4 In the absence of mania or depression, a patient is said to be euthymic. One of the main goals of bipolar disorder treatment is to achieve and maintain euthymia. The etiology of bipolar disorder remains unclear. Genetics are known to play a strong role, with a 9% risk if someone has a first-degree relative with bipolar disorder, and risks as high as 40%–80% in identical twin pairs.7,8 The age of onset of bipolar disorder is generally in late adolescence or early adulthood, with an average age of onset of 25 years. Later age of onset, while possible, should be investigated for alternate causes.2 Diagnosis Bipolar disorder can broadly be categorized into bipolar I disorder and bipolar II disorder. According to the DSM-5, a diagnosis of bipolar I disorder requires the presence of one or more manic episodes, while a diagnosis of bipolar II disorder requires the presence of one or more hypomanic and one or more major depressive episodes. All mood episodes should be thoroughly investigated to rule out other potential causes, such as the effects of substances and/or other medical conditions.4 Differential diagnosis includes major depressive disorder, anxiety disorders, substance use disorders, psychotic disorders, attention-deficit/hyperactivity disorder and personality disorders.2,4 Many of these conditions can often present as comorbidities with bipolar disorder. Management Management of bipolar disorder relies largely on pharmacotherapy. Nevertheless, some evidence has found adjunctive psychosocial interventions, such as psychoeducation and cognitive behavioural therapy (CBT), to be helpful in acute depressive episodes and maintenance treatment.2 There is currently no evidence for nonpharmacological interventions in acute mania.2 Pharmacological management of bipolar disorder is broadly categorized into the three phases of the condition: mania, depression and maintenance. The Canadian Network for Mood and Anxiety Treatments (CANMAT) offers detailed guidelines on management of each phase.2 Unfortunately, most high-quality evidence focuses on the treatment of bipolar I disorder. As such, most guideline recommendations are largely limited to bipolar I disorder, and subsequently that is the focus of this article. Table 1 (see below for download link) 2,9-22 summarizes first-line medications for bipolar disorder, with information on dosing, significant side effects and drug interactions. Mania First-line treatments for acute mania include the mood stabilizers lithium and divalproex, along with atypical antipsychotics (see Box 1).2 These first-line agents have similar efficacy, with the choice largely based on side effect profile and patient preference.2 Combination therapy with a mood stabilizer plus an atypical antipsychotic has been found to be more efficacious than monotherapy in mania treatment, but the choice to use combination therapy needs to be carefully balanced against the higher risks of side effects.2,23-25 Depression Compared to acute mania, treatment options for acute depression are more limited. First-line agents include the mood stabilizers lithium and lamotrigine, and the atypical antipsychotics quetiapine and lurasidone (Box 2).2 Conflicting evidence on the efficacy of antidepressants, combined with their significant risk of inducing mania, limits their use in bipolar depression.2,26 Antidepressant monotherapy should never be used.2 When an informed decision is made to use adjunctive antidepressants, a selective serotonin reuptake inhibitor (SSRI) or bupropion is preferred due to their lower risks of inducing mania when compared to serotonin–norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants.27-29 Maintenance The vast majority of patients with bipolar disorder will require maintenance treatment to maintain remission and prevent subsequent acute mood episodes.2 Evidence shows that discontinuation of treatment during the maintenance phase, whether intentionally or through patient nonadherence, significantly increases relapse rates.2,29-31 Generally, the agent used in treatment of the acute mood episode should be continued in the maintenance phase, with the key exception of antidepressants used for bipolar depression.2 Thus, when choosing among treatment options in acute mania or depression, it is often prudent to select an agent that also carries evidence as a first-line maintenance treatment (see Box 3).2 Pharmacist’s role Bipolar disorder is a chronic condition that requires life-long therapy in most patients in order to prevent relapses.2 Unfortunately, medication adherence is often a significant challenge.2,32 Pharmacists can play a key role in providing psychoeducation to patients, especially on the importance of medication adherence in the treatment and prevention of acute mood episodes. The many potential side effects of treatment are often cause for concern for patients. Pharmacists can assist patients in weighing the risks and benefits of treatment, and collaborate with physicians in the selection of treatment options that may carry a lower side effect burden and align with patient goals. One motivational interviewing strategy is to reflect with patients on the many significant and life-altering consequences that can accompany acute mood episodes, and the benefits of treatment in minimizing these episodes, despite potential medication side effects. Pharmacists can also reassure patients and ease their anxiety through regular side effect monitoring, and offering management strategies if side effects do occur. Special emphasis should be placed on regular metabolic monitoring with atypical antipsychotics, particularly with quetiapine and olanzapine.2 As front-line healthcare providers who interact with patients regularly, pharmacists are also uniquely positioned to monitor for changes in mood symptoms, and advise patients to follow up with their physicians, or urgently seek emergency care where appropriate. Therapeutic drug monitoring (TDM) plays a significant role in the success and safety of lithium and divalproex/valproic acid treatment. Pharmacists should play a leading role in TDM and advocate for access to patient lab values, where possible, in order to advise on safe and effective use of lithium and divalproex/valproic acid. For patients receiving lithium, thyroid and renal function, along with calcium, should be checked every six months at a minimum.2 Hepatic function should be checked at three- to six-month intervals for divalproex/valproic acid.2 Divalproex/valproic acid’s teratogenicity risks must also be discussed with patients, and pharmacists must ensure female patients of reproductive potential are maintained on adequate contraception throughout therapy.12 Drug interactions are also of importance, especially with medications such as lithium and lamotrigine, where interactions can lead to potentially fatal consequences. Prescribers may often not be completely aware of the patient’s other medications. It is therefore important for pharmacists to identify these interactions, and promptly notify and offer management strategies to the patient and prescriber. Clinical pearls for pharmacists Lithium and divalproex/valproic acid TDM should be performed using post-dose trough levels at 12 hours, after at least five days of therapy to ensure steady state.2 Always check the timing of TDM when faced with unexpectedly low or high levels. Once-daily lithium and divalproex dosing is commonly used in practice to aid patient adherence. The relatively-long half-lives of these agents generally allow for adequate levels throughout the day.9,11-13 Lithium is considered the ‘gold-standard’ for treatment of bipolar I disorder, with first-line recommendations across all three phrases of the condition.2 Always educate patients on the signs and symptoms of lithium toxicity (see Table 1), and advise them to seek immediate medical attention if experiencing signs and symptoms of toxicity. Emphasize the importance of adequate hydration while on lithium, especially if the patient plans to be active (e.g., sports, long hikes). Similarly, highlight the importance of the patient maintaining stable salt and caffeine intake throughout lithium therapy. Ensure female patients of reproductive potential on divalproex/valproic acid are educated on its teratogenicity risks, and maintained on at least one nonbarrier form of contraception (preferably two complementary forms) throughout treatment.12 The teratogenicity risks of all bipolar treatments should be thoroughly assessed and benefits vs. risks carefully weighed in collaboration with patients and prescribers. Closely follow lamotrigine’s dosage titration schedule as outlined in the product monograph, with special attention paid to drug interactions and patient adherence. There are significant risks of potentially fatal Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TENS) if the dose is titrated too quickly or if a patient is resumed on a full dose inadvertently after a significant period of nonadherence.14 Lamotrigine rechallenge after a benign rash/dermatological side effect is possible, but requires specialist guidance and a very slow and careful dosage titration schedule.34 Be mindful of the need for renal impairment dose adjustments for paliperidone, risperidone and lurasidone.18-20 Olanzapine is an effective option with level 1 efficacy data in acute mania and for maintenance, and level 2 evidence in acute depression as the olanzapine–fluoxetine combination. Its significant side effect profile places it as a second-line agent in the CANMAT guidelines.2 Cariprazine recently became available for use in Canada. It has efficacy data for both bipolar mania and depression,2,35,36 but further clinical experience is required. Currently, it is not covered by most public formularies, so cost remains an issue. Aripiprazole, paliperidone and risperidone offer long-acting injection (LAI) formulations for patient convenience and adherence. Asenapine’s sublingual administration (which specifies no food/drink for 10 minutes after dosing) and twice-daily rather than once-daily dosing often makes adherence challenging compared to other atypical antipsychotic options. Be mindful of medications that can exacerbate acute mood episodes, including stimulants, systemic corticosteroids and antidepressants.2 Collaborate with patients and prescribers on weighing the benefits vs. risks of continuing these medications. Electrocardiogram QT-monitoring should ideally be performed prior to the prescribing of a psychotropic medication, with repeat monitoring as required based on changes in patient risk factors (e.g., interacting medications, electrolyte disturbances) or if the patient experiences any cardiovascular signs and symptoms.2,37 Summary Bipolar disorder is a debilitating, chronic mental health condition. Management relies mainly on pharmacological agents, to treat and prevent acute mood episodes. Specific pharmacological treatments are recommended for each phase of the condition, each with its own unique efficacy and safety profile. Despite the availability of many novel agents, the mood stabilizer lithium continues to be recognized as the ‘gold standard’ given its efficacy across the acute mania, depression and maintenance phases. Pharmacists play an important role in helping patients manage their complex pharmacological regimens. This includes providing psychoeducation on the importance of adherence to treatment; side effect counselling, monitoring and management; identifying significant drug interactions; and performing TDM for lithium and divalproex/valproic acid. Sunny Wang (sunny.wang@camh.ca) is a clinical pharmacist with the Centre for Addiction and Mental Health (CAMH) in Toronto, ON. With diverse experience in mental health and substance use disorders, Sunny has been working as a clinician and educator at CAMH and with the Leslie Dan Faculty of Pharmacy at the University of Toronto. The author thanks Patrick Wong, clinical pharmacist at CAMH for his critical review of this manuscript. References: McDonald KC, Bulloch AGM, Duffy A, et al. Prevalence of bipolar I and II disorder in Canada. Can J Psychiatry 2015; 60(3):151-6. Canadian Network for Mood and Anxiety Treatments (CANMAT). 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A pharmacist’s guide to managing bipolar disorder

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