US Pharm. 2011;36(11):HS17-HS24.
Bipolar disorder is characterized by pathologic variations in mood, with periods of mania, hypomania, psychosis, and depression. The two most common types, bipolar I and bipolar II, differ in the presentation of mood variations. The course of bipolar II is less well studied and less understood than bipolar I disorder. Patients with bipolar I disorder have episodes of full mania alternating with episodes of major depression,1,2 whereas patients with bipolar II disorder pre-sent with one or more episodes of major depression with at least one hypomanic episode.1 Bipolar II can also manifest itself as a mixed state, which is the presence of both depressive and mood elevated symptoms simultaneously.3 Patients with bipolar II disorder display fewer manic symptoms than those with bipolar I disorder; both conditions may have an equivalent impact on quality of life and may also be associated with increased suicide risk.3 Patients may also present with rapid-cycling bipolar disorder, which consists of at least four discrete episodes of mania or depression in a single year, demarcated by clear periods of remission or by switches to episodes of opposite polarity.4
The criteria for mania and hypomania are outlined in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR).4
Bipolar II disorder shares some similarities with bipolar I disorder (FIGURE 1). Approximately 60% to 70% of the hypomanic episodes that occur in patients with bipolar II disorder occur immediately before or after a major depressive episode, with characteristic patterns that are unique to each individual.4 As with bipolar I disorder, the interval between episodes seems to decrease with age, though approximately 5% to 15% of patients experience rapid cycling.4 The more episodes a patient experiences, the poorer the prognosis. Fortunately, the majority of patients return to a normal functional level between episodes, yet 15% of patients continue to experience mood lability between episodes.4 Some evidence has shown that sleep-wake cycle disturbances can precipitate or exacerbate a hypomanic or depressive episode. If a patient experiences a manic episode, an episode of psychosis, or a mixed episode, the diagnosis changes to bipolar I disorder.
Epidemiology
The prevalence of bipolar II disorder (1.1%) is slightly higher than the prevalence of bipolar I disorder (1%) in adults in the United States.3,5 The true prevalence of bipolar disorder is uncertain because the diagnosis is likely to be missed, especially when patients are seen with depression and not specifically questioned about symptoms that may suggest prior episodes of mania or hypomania.3 Bipolar II disorder is more common in women, whereas bipolar I affects men and women equally.3 The age of onset of bipolar II is generally between 15 and 30 years of age, with less common new diagnoses made in childhood and in adults over the age of 65 years.3
Pathophysiology
The search for genetic candidates has been the subject of considerable study, although no single gene has been identified.3 Some studies suggest a role for the tryptophan hydroxylase 2 (TPH2) gene, which is an enzyme in the synthetic pathway for serotonin.3 In addition, genomic studies have suggested an association with the CACNA1C gene, which codes for a subunit of calcium channels. This gene is involved in channel gating, supporting the use of lithium, which in turn results in the down-regulation of calcium channel subunits.3 There have also been studies that have revealed abnormalities of the corpus callosum, amygdala, dopamine D4 receptor genotype, and dopamine transporter gene SLC6A3, and decreased protein kinase in platelets.5
Other central nervous system (CNS) neurotransmitters involved in activity modification include serotonin, dopamine, norepinephrine, acetylcholine, gamma-aminobutyric acid (GABA), and glutamate.6 The basis for most pharmacotherapy is aimed at regulating these neurotransmitters to restore normal mood and cognition.5 Other nonpharmacologic ways to regulate these neurotransmitters may include meditation, deep relaxation, and exercise, which increase endogenous opioid and nicotinic receptor function.5
Evaluation and Assessment
Many psychiatric conditions may mimic and sometimes coexist with bipolar II disorder. These include schizophrenia, schizoaffective disorder, posttraumatic stress disorder, substance abuse (e.g., alcohol, cocaine, or amphetamines), and personality disorders. Manic episodes can also occur in some medical conditions, such as thyrotoxicosis, partial complex seizures, systemic lupus erythematosus, cerebrovascular accidents, HIV infection, tertiary syphilis, and other CNS insults (i.e., steroid-induced mood symptoms or encephalopathy).3 For these reasons, it is prudent to carefully assess and evaluate patients holistically who present with these variations in mood. Physical examination, with particular focus on neurologic and endocrine systems, signs of substance abuse, symptoms of trauma to the CNS, and laboratory testing (including thyroid testing, CBC, blood chemistries, and urine toxicology testing), should be conducted to rule out other etiologies of mood disorders.3
Conducting a mental status examination (MSE) is also an essential component of evaluating mental health. The MSE is used to assess the patient’s general appearance and demeanor, speech, movement, and interpersonal relatedness with the examiner and others.5 The MSE addresses: 1) mood and cognitive abilities; 2) issues of safety, by exploring suicidal or homicidal ideation; 3) subtle forms of psychosis, such as paranoia or delusional states; 4) overt psychosis; and 5) the patient’s insight and judgment, which is integrated into the evaluation of the global mental state of the patient at that moment. Though a limitation of this examination is its subjectivity, it is essential in the diagnosis and management of bipolar II disorder.5
Treatment and Management
Prior to beginning treatment, patients should be clinically assessed for their safety and presenting symptoms. Patients who present with acute manic episodes should be assessed for their risk of suicide, aggressiveness, and potential for violence to others.1 Antidepressants, nicotine, and alcohol should be discontinued, and any substance abuse issues addressed. Other psychosocial problems should be evaluated in the patient.
Treatment of elevated mood syndromes is based upon what has been established for bipolar I disorder, even though bipolar II disorder is more prevalent. Most published studies have focused upon bipolar I patients with mania, and few studies have focused on the treatment of hypomania.1
Mania and Hypomania
The goal of treatment is full remission of the elevated mood syndrome, with caution not to have unrealistic goals set for the patient.1 Drug classes commonly used to induce remission in patients with acute mania, mixed states, or moderate-to-severe hypomania include lithium, anticonvulsants, antipsychotics, and benzodiazepines (TABLE 1).1 Most treatment modalities are afforded 2 weeks to determine efficacy; studies show that if a patient does not remit within 2 weeks, an alternative agent may be used. If a patient demonstrates partial remission, clinicians may choose to augment therapy with another drug to get the most benefit and then reevaluate the patient’s response.1
Many drugs are effective as monotherapy for treating acute mania, mixed states, and moderate-to-severe hypomania. First-line medications include aripiprazole, carbamazepine, haloperidol, lithium, quetiapine, olanzapine, risperidone, valproate or divalproex, and ziprasidone. Several meta-analyses have shown that the aforementioned drugs used as monotherapy may allow for significant improvement on the mania rating scale and response compared with placebo, and have also shown similar efficacy across these first-line medications.1,7-9
Depression
For bipolar depression, all antidepressants should be discontinued; monotherapy with an antidepressant is not recommended in order to prevent precipitation of manic or hypomanic episodes.1,10 The likelihood of this switch to hypomania, however, is less in patients with bipolar II disorder as compared with those with bipolar I. The first-line pharmacologic treatment for bipolar depression is either lithium or lamotrigine, or, as an alternative for more severely ill patients, lithium can be given with an antidepressant.10 If patients on treatment suffer a breakthrough depressive episode, the dose of the therapy should be optimized before adding other agents. If dosing optimization is not sufficient, lamotrigine, bupropion, or paroxetine may be added.10 Alternative treatment modalities may include other selective serotonin reuptake inhibitors (SSRIs), venlafaxine, or a monoamine oxidase inhibitor (MAOI).
Rapid Cycling
If the patient experiences rapid cycling, the individual should be evaluated for underlying conditions, such as alcohol abuse or hypothyroidism, which may contribute to cycling.10 Certain medications, particularly antidepressants, may also precipitate cycling and should be tapered down. Patients who experience cycling should be managed with lithium, valproate, or lamotrigine.
Pharmacologic Therapy
Lithium
Lithium has been around for several decades and is approved by the FDA for treatment of mania and for treatment and prophylaxis of bipolar disorder. There have been more controlled trials demonstrating the efficacy of lithium monotherapy for the treatment of acute mania (including patients with psychosis) than for any other medication.11 Lithium has also shown efficacy for bipolar depression and preventing suicidality.12,13
Lithium causes a number of biochemical and biological effects, although the exact mechanism for mood stabilization remains unknown.13 A review of 32 trials shows that lithium is the only mood stabilizer that has lowered the suicide rate in patients with bipolar disorder.14 Lithium has also been shown to mitigate relapse of bipolar disorder from 61% to 40%, and it prevents more manic episodes when compared with depressive episodes.15
Dosing and Monitoring: The starting dose of lithium is usually 300 mg two to three times daily (start with smaller doses in the elderly, e.g., 150 mg twice daily), which should be increased by 300 to 600 mg every 1 to 5 days based upon response, tolerability, and body mass index.1 The target dose is usually 900 to 1,800 mg daily in divided doses. Lithium has a narrow therapeutic index (0.8-1.2 meq/L); serum lithium levels should be checked at a minimum of every 6 months in stable patients, or more frequently if clinical status changes. Lithium levels should be checked 5 days after dosages are adjusted—once the drug reaches steady state concentration. Optimal serum maintenance levels may vary from patient to patient.16,17 In patients with renal impairment or thyroid disorder, serum lithium levels should be checked every 2 to 3 months in the first 6 months of treatment and every 6 to 12 months thereafter, or more frequently if clinical status changes.
Side Effects: The most common acute side effects include nausea, tremor, polyuria and thirst, weight gain, loose stools, and cognitive impairment.12,18,19 Any exacerbation of these side effects may indicate lithium toxicity and should be addressed. Long-term adverse effects of lithium include nephropathy, hypothyroidism, goiter, and possibly cardiac rhythm disturbances, especially in patients with pre-existing cardiac disease.1,5
Anticonvulsants
Anticonvulsants are used in the treatment of bipolar II disorder because they: 1) decrease brain excitation; 2) enhance inhibition by blocking low-voltage sodium-gated channels; 3) lower glutamate and other excitatory amino acids; and 4) potentiate the levels of GABA. Anticonvulsants that are used in bipolar disorder include valproate or divalproex, lamotrigine, and carbamazepine. The agent of choice depends on patient preference, tolerability, presentation and severity of symptoms, and the drug’s side-effect profile.20,21
Valproate and Divalproex: Valproate has demonstrated efficacy for bipolar disorder in several clinical trials,20 with an FDA indication for acute manic episodes. Valproate use should be limited to nonpregnant patients due to its tendency to cause neural tube defects in the fetus.22,23
Dosing and Monitoring: The starting dose is 750 mg daily in divided doses, and should be titrated upward to desired clinical effect. The goal is to reach therapeutic serum levels (50-125 mcg/mL), which generally occurs around 1,500 to 2,500 mg per day in divided doses.18,24 Valproate levels should be checked every 6 to 12 months in stable patients, or more frequently if clinically warranted.25
Side Effects: Common side effects include weight gain, vomiting, hair loss, easy bruising, and tremor. Divalproex may be used rather than valproate to decrease gastrointestinal discomfort. Hepatic failure, thrombocytopenia, and possible pancreatitis may occur with prolonged use; therefore, liver function, platelets, amylase, and lipase should be monitored every 6 to 12 months while the patient is on therapy, especially if symptoms of any of these effects arise.2,26,27
Lamotrigine: Lamotrigine has been shown to be more beneficial in patients affected by bipolar I disorder and in those who experience manic episodes than in bipolar II patients with hypomania.20,21 It has also been demonstrated in some clinical trials to be effective in bipolar II rapid cycling and as an adjunct in patients with bipolar depression.28 In a single blind comparison of lithium and lamotrigine monotherapy for the treatment of bipolar II depression, there was significant improvement of depressive symptoms from baseline in both groups, with no significant difference between the two groups.29
Dosing and Monitoring: The starting dose is 25 mg daily for 2 weeks, 50 mg daily for 2 weeks, then titrated up by 50 mg weekly as clinically indicated, up to 200 mg daily.30 If used in combination with valproate, the dose of lamotri-gine should be reduced by 50%, as these two agents are metabolized primarily via glucuronide conjugation and may compete for the same site of metabolism. In addition, valproate inhibits p-glycoprotein, which decreases the metabolism of lamotrigine.30
Side Effects: Side effects include rash and nausea, with more life-threatening adverse effects including Stevens-Johnson syndrome and toxic epidermal necrolysis.
Carbamazepine: Carbamazepine may have some efficacy in managing bipolar II disorder; however, more studies have been conducted with carbamazepine in the management of bipolar I manic and depressive episodes.20
Dosing and Monitoring: The starting dose of carbamazepine is 100 to 200 mg once or twice daily, which should be increased by 200 mg per day every 1 to 4 days. The dose may be increased based on severity of symptoms and patient tolerance. The optimal dose is 800 to 1,000 mg per day in divided doses.18,31 Caution should be exercised when using carbamazepine with other medications metabolized via the CYP450 system, as it may induce the metabolism of other drugs as well as its own metabolism. This justifies the slow increase in dose as therapy continues.2,26,27
Side Effects: Side effects include nausea, vomiting, diarrhea, hyponatremia, rash, pruritus, leukopenia, fluid retention, and neurotoxicity, which may manifest as drowsiness, dizziness, and changes in vision, lethargy, and headache. Carbamazepine has also been associated with Stevens-Johnson syndrome and toxic epidermal necrolysis, which is more common in patients who have the HLA-B*1502 allele, seen prevalently in South Asian populations.32-34
Antipsychotics
Some first- and second-generation antipsychotics have demonstrated efficacy in patients with mania, moderate-to-severe hypomania, and mixed states either as monotherapy or in combination with lithium, valproate, or carbamazepine.7-9,35-39 Haloperidol has been widely used for mania and mixed states, more so for patients with bipolar I than for bipolar II.40,41 Olanzapine has been used as a first-line agent as monotherapy or adjunct therapy because it has been shown to be effective for acute mania, depressive episodes, and maintenance of patients with bipolar I disorder.1,42 Aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone are each similarly efficacious in treating acute mania, moderate-to-severe hypomania, and mixed states.7,8,35-37
The biggest concern with the use of atypical antipsychotics is their tendency to cause metabolic syndrome, which is characterized by weight gain, glucose intolerance, diabetes mellitus, and hyperlipidemia.1 Metabolic syndrome is more pronounced with olanzapine, risperidone, and quetiapine when compared with aripiprazole and ziprasidone. Patients taking these drugs should be regularly monitored for weight, waist circumference, blood pressure, and serum glucose and lipid levels.1 Extrapyramidal side effects are more common with first-generation antipsychotics, aripiprazole, ziprasidone, and risperidone compared with olanzapine or quetiapine.1 Refer to Table 1 for dosing and side effects.
Antidepressants
Few studies have shown promise for use of antidepressants in managing depressive symptoms in bipolar II disorder. A small prospective study (88 patients) has shown that fluoxetine monotherapy may be an effective short-term treatment (up to 14 weeks) of bipolar II major depressive episode with a relatively low rate of syndromal hypomanic episodes.43 Another randomized, double-blind, placebo-substituted trial compared long-term (50 weeks) fluoxetine, lithium monotherapy, and placebo.44 Lithium and fluoxetine both showed superiority to placebo. Results suggested fluoxetine monotherapy may provide relapse-prevention benefit relative to lithium monotherapy after recovery from bipolar II major depressive episode without an increase in hypomanic mood conversion episodes.44 Refer to Table 1 for dosing and side effects.
The Role of the Pharmacist
The pharmacist plays a tremendous role in optimizing care for patients with bipolar II disorder. To clinical pharmacists, obtaining an accurate and complete medication history is very important in determining the appropriate therapy, or even identifying underlying medication-related causes of disease cycling. The pharmacist can be a viable component in providing appropriate dosing strategies, reviewing therapeutic regimens for drug interactions, instituting clinical monitoring parameters, and identifying signs and symptoms of medication toxicity. Clinical pharmacists can also provide the patient with discharge counseling. Educating this population on appropriate administration times, possible adverse reactions, and potential drug interactions can increase medication adherence and reduce future hospitalizations.
As an easily accessible resource, community pharmacists are also key players in providing optimal care to patients with bipolar II disorder. Not all institutions employ the services of a pharmacist for discharge counseling, and in this instance outpatient counseling through community pharmacists is very important in increasing medication compliance and adherence. Community pharmacists may also provide information about ways to identify early signs and symptoms of mania or depression so as to help patients seek medical help sooner.
Conclusion
Bipolar II disorder is characterized by hypomanic episodes alternating with major depressive episodes without mania or psychosis. It is less debilitating than bipolar I disorder, yet it still has significant morbidity and mortality if left untreated. There are few studies that focus on treatment of bipolar II alone. The literature shows lithium to be the mainstay of therapy to stabilize mood, along with anticonvulsants (e.g., valproate, lamotrigine, or carba-mazepine) as adjunct therapy. More research and clinical trials are warranted.
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