Philip G. Janicak, MD

This activity offers CE credits for:
1. Physicians (CME)
2. Other

This article reviews DSM-5 changes to symptom criteria for bipolar disorder. The primary focus is on treatment of bipolar depression and cyclothymic disorder.

At the end of this CE activity, participants should be able to:

• Identify the 4 FDA-approved medications for bipolar depression

• Identify FDA-approved medication for maintenance therapy of depression in bipolar disorder

• Distinguish which antidepressants to avoid to minimize the risk of mood destabilization

This continuing medical education activity is intended for psychiatrists, psychologists, primary care physicians, physician assistants, nurse practitioners, and other health care professionals who seek to improve their care for patients with mental health disorders.

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. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

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Philip G. Janicak, MD, reports that he has received grant support from, and is on the speakers bureau for, Neuronetics Inc, Sunovion, and Ortho-McNeil/Janssen; he is also a consultant for Neuronetics Inc.

Joseph Esposito, MS, MD, has no disclosures to report.

Michael Gilin, MD, (peer/content reviewer) reports that he is on the speakers bureau for Otsuka.

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, we focused on the diagnosis and pharmacological management of mania and hypomania.

 Here, we consider the diagnosis and management of the depressed phase of bipolar disorder and cyclothymic disorder. We also review the increasing support for various psychotherapies to enhance the overall benefits of treatment and consider future directions in terms of improving diagnosis and developing novel treatment strategies.

It is difficult to distinguish MDD from bipolar depression early in the course of illness. Many bipolar patients will initially present with one or more depressive episodes before experiencing mania or hypomania. This can delay proper diagnosis and appropriate treatment, worsen the long-term prognosis, and increase the cost of treatment.

Several demographic and clinical characteristics may help differentiate the 2 disorders. Factors such as a family history of bipolar disorder; earlier onset of illness; a seasonal component to mood changes; mixed episode presentations (ie, also experience 3 or more criteria for mania/hypomania [

]); mood reactivity; psychotic features; reverse neurovegetative symptoms, such as hypersomnia and increased appetite; a history of suicide attempts; and antidepressant “misadventures,” such as mood switches, may indicate a greater likelihood of bipolar depression. More recent findings suggest that statistical models may further help delineate MDD from bipolar depression. For example, one study using a probabilistic model found that younger depressed individuals with psychomotor retardation, psychosis, or mixed features had an increased risk of bipolar disorder.

The irony in treating bipolar I and II disorders is that depression is much more prevalent than mania or hypomania, but there is far less evidence from controlled trials to guide its management. Bipolar depression is associated with high morbidity and mortality; it is often chronic, persisting in refractory or subsyndromal forms; and it increases the risk of suicide. While the existing evidence is limited and at times inconsistent, it indicates benefit for acute management with the combination of olanzapine-fluoxetine, quetiapine monotherapy, or lurasidone as a monotherapy or an adjunct to lithium or valproate (

). These 3 FDA-approved acute bipolar depression therapies appear to have similar efficacy profiles, but they differ substantially in terms of tolerability.

A recent summary calculated the likelihood to help or harm, which considers the ratio of the number needed to treat and the number needed to harm for the olanzapine-fluoxetine combination, quetiapine, and lurasidone.

 Although the overall results supported lurasidone, multiple factors may shift the balance in favor of olanzapine-fluoxetine or quetiapine (eg, good response with acceptable tolerability, extensive clinical experience, better maintenance data, lower cost).

Lamotrigine shows benefit for maintenance management, particularly in preventing depressive episodes, and is FDA-approved for this indication. Other treatment strategies commonly used but with less evidence to support their use include lithium, valproate, carbamazepine, antidepressants, and ECT.

 illustrates the treatment strategy for acute bipolar depression.

The FDA initially approved the combination of olanzapine plus fluoxetine as the first treatment for adults with acute bipolar depression. This indication is supported by a systematic review and meta-analysis of controlled trials (N = 1330) showing that olanzapine-fluoxetine improved responses compared with olanzapine monotherapy and placebo.

 As a result, this combination is often considered a first-line treatment for moderate to severe episodes.

The positive results from a randomized, double-blind, placebo-controlled trial (N = 255) with olanzapine-fluoxetine (6/25 to 12/50 mg/d) in children and adolescents with bipolar I depression supported an additional FDA approval for patients aged 10 to 17 years.

 An important concern, however, is the risk of weight gain and related metabolic complications associated with ongoing treatment, particularly in younger patients.

Some data support olanzapine monotherapy for acute bipolar depression, although the drug is not approved for this indication. Two placebo-controlled studies (N = 1214) demonstrated that olanzapine was effective for bipolar I depression, regardless of the presence of concurrent manic symptoms, and that melancholic features might predict a better outcome with this agent.

In a double-blind placebo-controlled study (N = 68) olanzapine monotherapy was superior to placebo in treating bipolar I depression but was associated with significant metabolic adverse effects.

 Finally, results from a 12-month naturalistic observational study (N = 51) showed that olanzapine monotherapy was superior to lamotrigine in preventing bipolar depression relapses.

Substantial evidence from controlled trials supports the role of quetiapine in bipolar depression as either a monotherapy or in combination with lithium or valproate. Statistical superiority for quetiapine monotherapy or combination therapy (300 or 600 mg/d) over placebo for acute bipolar I or II depression was reported in a systematic review and meta-analysis (11 randomized clinical trials [RCTs]; N = 3488).

 Quetiapine had a lower switch rate into mania/hypomania than placebo but a higher incidence of adverse effects such as extrapyramidal symptoms, sedation, increased appetite, and weight gain. Two of these studies involved pediatric populations; however, the data were insufficient to support its use in this age group.

In an analysis of 2 randomized controlled maintenance trials (N = 1326), quetiapine combined with either lithium or valproate was superior to placebo in bipolar I patients in preventing a recurrence of either mania or depression.

 Another analysis from 2 placebo-controlled maintenance trials (N = 584) with quetiapine monotherapy in bipolar I and II depressed patients showed similar results.

 These outcomes, however, should be tempered by the potential for cardiometabolic risks with longer-term exposure.

This is the most recent agent to receive FDA approval for acute bipolar I depression as both a monotherapy and in combination with lithium or valproate.

 Its purported mechanism(s) of antidepressant action include serotonin (5-HT)-1A agonism; and 5-HT2A and norepinephrine alpha-1 antagonism.

 The data also indicate comparable benefit in mixed episodes.

 Note that its adverse-effect profile indicates minimal risk of weight gain, dyslipidemia, or electrocardiographic abnormalities. The most common adverse effects associated with lurasidone were mild to moderate and included gastrointestinal disturbances, extrapyramidal symptoms, akathisia, and somnolence.

Certain anticonvulsants have demonstrated a role in treating acute depressive episodes, as well as preventing relapse in stabilized bipolar patients.

Valproate has consistent, albeit limited support for acute management of bipolar depression. One meta-analysis of 4 RCTs (N = 142) found valproate superior to placebo in reducing depressive symptoms, and the proportion of patients who achieved at least a 50% improvement in symptoms; tolerability was similar to that of placebo.

 Despite the small sample sizes, which preclude a more definitive conclusion about this agent’s usefulness in treating bipolar depression, it is a first- or second-line treatment recommendation as monotherapy or adjunctive therapy.

While there are preliminary encouraging results, this agent requires further study, particularly in light of its adverse-effect and drug-interaction profiles, which are more problematic than existing alternatives.

The mechanism of action for this agent in the context of treating bipolar disorder appears to involve modulation of glutamate, particularly at cortical projections to the ventral striatal-limbic areas. This may be related to its inhibition of voltage-sensitive Na+ channels, blockade of calcium channels, and weak 5-HT3 receptor inhibition.

The half-life of lamotrigine is 15 to 30 hours but may be accelerated by enzyme induction with agents such as carbamazepine, phenytoin, and estrogen or prolonged (ie, 30 to 90 hours) by agents such as valproate and sertraline. The latter scenario requires a lower lamotrigine starting dose (12.5 mg) and a slower titration schedule to reduce the risk of serious skin reactions (eg, Stevens-Johnson syndrome). Elimination occurs through glucuronidation and subsequent renal excretion (90%).

Overall, the safety and tolerability profile of lamotrigine compares favorably to that of alternative therapies for bipolar depression. The most common adverse effects associated with lamotrigine are headache, nausea, and mild rash. More severe skin reactions are the most important potential serious risk, estimated to occur in fewer than 0.2% of cases.

 This complication can be minimized by an initial low dose (eg, 25 mg/d) and slow titration schedule (eg, increase every 2 weeks) over several weeks.

While the results for acute management are inconsistent, there is evidence for a potential role (usually in combination with other mood stabilizers) in more severe depressive episodes in bipolar I and II.

 These studies involved comparisons to or combinations with agents such as placebo, lithium, valproate, citalopram, gabapentin, risperidone, and the olanzapine-fluoxetine combination. Typical daily dosing ranged from 50 to 200 mg, but the necessity to titrate slowly limits the usefulness of lamotrigine in more severe acute episodes. As noted, if combined with valproate, the lamotrigine dose should be half the recommended amount and the titration schedule slower.

In contrast to the trial data for acute management, there is more consistent evidence for its role in preventing a mood relapse, particularly into depression. Two 18-month, placebo-controlled studies (N = 638) assessed the benefit of lamotrigine or lithium maintenance therapy compared with placebo in bipolar I patients (either recently manic/hypomanic or depressed) initially stabilized with open-label lamotrigine.

 In each trial, both active drugs were superior to placebo in prolonging time to intervention for any mood episode; lamotrigine was superior to placebo in time to intervention for a depressive episode; and lithium (but not lamotrigine) was superior to placebo in time to intervention for manic, hypomanic, or mixed episodes. In terms of safety and tolerability, no serious rashes occurred and lamotrigine’s overall adverse-effect profile was similar to placebo in these trials.

Although lithium is often used to treat acute bipolar depression either alone or as an adjunct with other mood-stabilizing strategies (eg, lithium plus lamotrigine), the evidence to support this approach is presently inadequate. However, an open-label, proof of concept trial (N = 31) found that with lithium monotherapy, lower serum levels (< 0.5 mEq/L) were as effective as higher levels (> 0.5 mEq/L) in achieving robust remission rates (ie, 62%). Moreover, lower levels were better tolerated.

 A potential advantage is lithium’s anti-suicidal properties that may be further enhanced by concurrent use of various adjuncts such as psychoeducation, bright light therapy, and sleep deprivation.

Most guidelines for the long-term management of bipolar depression recommend lithium as first-line maintenance therapy. Since early studies of lithium do not meet present-day criteria for adequacy, this is primarily based on more recent placebo-controlled trials in which lithium was used as an active comparator (eg, lamotrigine, quetiapine). Two meta-analyses that included data from these trials concluded that lithium was superior to placebo in preventing both manic and depressive episodes for up to 2 years.

 The data came from lithium non-enriched samples, making this finding even more noteworthy; however, this finding must be weighed against the potential renal complications associated with prolonged lithium exposure.

While antidepressants are frequently used in clinical practice, there are limited data to support their short-term benefit in bipolar depressed or mixed episodes. Indeed, in a report of their meta-analysis, Sidor and Macqueen

 concluded that although antidepressant augmentation was generally safe, relative to placebo it did not improve response or remission rates more than mood stabilizers alone. Furthermore, there is concern that these agents may worsen the course of illness (eg, promote mood switches or cycle acceleration). Thus, their role for treatment of bipolar depression is controversial and yet to be resolved. Given these circumstances, reasonable recommendations include:

• Avoid antidepressants when possible for the treatment of acute depression; particularly in bipolar I patients, those with mixed episodes, rapid cyclers, and patients with comorbid substance abuse/dependence

• If antidepressants are used, it should only be after better-supported approaches (eg, olanzapine-fluoxetine, or quetiapine, or lurasidone) prove insufficient and then, only in combination with a mood stabilizer

• To minimize the risk of mood switches, bupropion or SSRIs (eg, paroxetine, sertraline) may be preferable to TCAs, tetracyclics, or dual-acting agents (eg, venlafaxine)

• Consider ECT (and possibly transcranial magnetic stimulation [TMS]) in more severe episodes of depression, when there are insufficient benefits from medications or medication intolerance

• After a patient is stabilized, frequently reassess the need to continue the antidepressant in lieu of maintenance with a mood stabilizer(s) only

While there is far less evidence regarding the diagnosis and management of cyclothymic disorder, this is a prevalent, often underdiagnosed, and highly impairing condition. This disorder involves mild to moderate fluctuations in mood, thinking, and activity for at least 2 years (1 year in children or adolescents) that do not meet full criteria for a major depression or hypomania (

). In addition, there is often a family history of bipolar disorder. Theories on the basis of these cyclical “subsyndromal” mood swings range from characterological, with individuals seen as temperamental or unreliable; a prodromal phase prior to the development of bipolar disorder (particularly bipolar II) with a greater propensity to rapid cycling and greater reactivity to environmental factors; or a distinct clinical phenotype along a continuum of bipolar spectrum disorders.

In the context of treating cyclothymic disorder, recommendations and concerns about mood destabilization with antidepressants parallel those for bipolar disorder, particularly type II. The existing literature, however, more equally considers pharmacological (eg, lithium, anticonvulsants, quetiapine) and psychotherapeutic approaches (eg, cognitive behavioral therapy [CBT], mindfulness-based cognitive therapy, psychosocial, psychoeducational) for at least acute treatment. There are no FDA-approved medications with an indication for cyclothymic disorder.

Paralleling the experience with other major disorders such as schizophrenia, environmental factors substantially contribute to the long-term course and prognosis of bipolar disorder. In this context, various adjunctive psychotherapeutic interventions can help enhance acute response, decrease the risk of relapse or recurrence, improve functionality, and facilitate recovery. While more extensively studied for MDD, there is growing evidence supporting adjunctive psychotherapy (eg, psychoeducation, CBT, family-focused therapy, interpersonal and social rhythm therapy) for bipolar disorder. The goals for these approaches are to:

• Facilitate appropriate interventions with early signs of a pending relapse

• Reduce psychosocial stressors and family conflict

• Regulate social and circadian rhythms

To accomplish this successfully, it is crucial to achieve an effective working alliance with patients and their families early in the course of treatment.

During an acute manic or mixed episode, the role for various psychotherapeutic interventions is limited. Thus, there is much more information regarding psychotherapy in mildly ill patients as part of a maintenance strategy that focuses on the management of depressive symptoms in the context of bipolar disorder. However, psychotherapy may help patients and their families better manage mania.

A recent functional MRI study compared 12 patients (ages 13 to 17) with mood dysregulation who were also at familial risk for bipolar disorder with 12 healthy controls.

 After 4 months of psychotherapy, the investigators observed a normalization of brain frontal executive control regions in the patient group that correlated with improvement in their manic symptoms. Another study utilized a collaborative care model that included group psychoeducation to enhance bipolar patients’ self-management skills.

 This approach improved long-term clinical outcomes, particularly in reducing the duration of manic episodes.

Most psychotherapy studies, however, involve more chronic patients who were euthymic or mildly ill and focused on management of residual subsyndromal symptoms and prevention of relapse or recurrence. Acutely symptomatic patients were usually in a depressed phase, since acutely ill manic patients are more difficult to engage. In one study, stabilized bipolar I (n = 115) or bipolar II (n = 45) patients were assessed for up to 72 weeks while receiving standard pharmacotherapy and manualized, evidence-based psychosocial treatment (ie, CBT or psychoeducation).

 The data showed that 65% remained euthymic over this period. Those who became symptomatic primarily experienced subsyndromal depression with relapses averaging every 7.5 months. The researchers concluded that these patients had an improved course of illness compared with the results of earlier trials that assessed the long-term, natural history of this illness.

These results are consistent with data from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) that followed 293 depressed bipolar patients randomized to an intensive psychosocial intervention (ie, 30 sessions of CBT, family-focused therapy, or interpersonal and social rhythm therapy) or 3 sessions of psychoeducation.

 Patients were also receiving standard pharmacotherapy, including antidepressants for some. At the end of the 6-month acute treatment phase, the intensive psychosocial group was 15% more likely to have achieved symptom remission.

Ideally, therapies should be based on a clear understanding of underlying pathoetiology. Unfortunately, as in other areas of psychiatry, this is not the case. Thus, our theories often “work back” from the purported mechanisms of drug actions to help decipher the disease’s origins. Increasingly, however, work in several areas (eg, genetics, neuroimaging, the immune system, biological rhythms) is providing a better understanding of bipolar disorder and offers the hope for new and more effective treatment approaches.

The increased risk of inflammatory processes in bipolar disorder may explain its higher comorbidity with various medical disorders (eg, cardiovascular disease, diabetes). This leads to consideration of a dysfunctional immune system and what role the observed elevations in pro-inflammatory cytokines play in the development and neuroprogression of bipolar disorder. For example, they may be used as markers for this disorder, as well as potential targets for novel treatments.

Indicators of increased oxidative stress are also found in bipolar patients. A recent meta-analysis reported that markers of stress such as lipid peroxidation, DNA/RNA damage, and nitric oxide were significantly increased in bipolar patients compared with controls.

 This finding may indicate that there is a potential role for antioxidant therapies; however, more research is needed.

Disruptions in biological rhythms (eg, sleep-wake cycle, seasonality of symptoms) are common in bipolar disorder and may play an important role in its pathophysiology. In particular, it has been postulated that an abnormally shifted or arrhythmic circadian system is common in bipolar disorder. Abnormal sleep patterns are even seen in bipolar patients with symptom remission. Support for this hypothesis also comes from studies demonstrating the therapeutic potential for chronotherapies such as sleep deprivation, bright light therapy, and CBT for insomnia.

The role of dopamine in the pathology of bipolar disorder is supported in part by the number of agents that act at its receptors and have approved indications for this illness, as well as the impact of this neurotransmitter on mood and reward systems. Recently, cariprazine, a partial agonist at the D2 and D3 receptors, demonstrated efficacy for the treatment of bipolar mood symptoms, which raises the question of whether other dopamine agonists could serve as adjuncts for the treatment of bipolar disorder.

Another hypothesis is based on the potential contributions of the glutamate excitatory neurotransmitter system to the pathophysiology of bipolar disorder. A meta-analysis of MRI spectroscopy studies found that the levels of glutamine (the precursor to glutamate) were elevated in bipolar patients.

 Further support involves the study of gene variants and their possible contribution to bipolar susceptibility. In this context, the 

 gene encodes the excitatory amino acid transporter 2, which is responsible for clearing glutamate from the synaptic cleft. Certain variations in this gene are associated with both schizophrenia and bipolar disorder, perhaps increasing susceptibility to them.

One potential therapeutic application is the use of the glutamate 

-methyl-D-aspartate (NMDA) ionotropic receptor antagonist, memantine. A recent 3-year naturalistic study (N = 30) showed that when used as an augmentation strategy in patients with treatment-resistant bipolar I or II disorder, memantine (20 to 30 mg/d) provided substantial long-term benefits.

Data from MDD and bipolar depression trials show a short-term, rapid and robust antidepressant, anxiolytic, and anti-suicidal effect with a single intravenous infusion of ketamine (eg, 0.5 mg/kg), a more potent NMDA receptor antagonist.

 While this strategy holds the promise of a more rapidly effective antidepressant effect, it presently remains investigational and requires more data regarding both the mid-term and long-term benefits, as well as the potential for adverse effects (eg, psychotomimetic reactions; abuse potential).

When algorithm-based pharmacological strategies prove insufficient, ECT can be beneficial. Although an effective therapy for more severe episodes of mania and depression in the context of bipolar disorder, there are several disadvantages to consider in terms of an overall risk-to-benefit evaluation. These include its limited availability in many areas, cognitive disruption, high relapse rates, a negative public image, and cost. Therefore, alternative therapeutic and neuromodulation strategies are being considered. For example, preliminary data support the use of adjunctive TMS in bipolar depressed patients for acute and maintenance purposes.

 Studies with vagus nerve stimulation and deep brain stimulation have also shown initial promise.

Important questions to be addressed in future studies include the value of introducing psychotherapy early in the course of illness; clarifying which components of the various therapies are most helpful; determining which patients are more likely to benefit from a specific approach; and the potential role of alternate psychotherapeutic approaches such as mindfulness-based cognitive therapy, systematic care management, and cognitive or functional remediation. Given that only a small proportion of patients presently utilize psychotherapy, strategies to increase its use are necessary.

Articles

This article reviews DSM-5 changes to symptom criteria for bipolar disorder with a focus on treatment of bipolar depression and cyclothymic disorder.

Update on Bipolar Disorder, Part 2: Bipolar Depression and Cyclothymic Disorder

All other clinicians either will receive a CME Attendance Certificate or may choose any of the types of CE credit being offered.

This article reviews DSM-5 changes to symptom criteria for bipolar disorder. The primary focus is on the diagnosis and treatment of mania and hypomania.

• Understand the various bipolar specifiers

• Identify bipolar diagnostic categories

• Identify FDA-approved indications for pharmacologic management of bipolar mania

• Distinguish which intervention (pharmacotherapy or psychotherapy) is best for each patient

Note to Nurse Practitioners and Physician Assistants: 

AANPCP and AAPA accept certificates of participation for educational activities certified for 

Faculty of this CME/CE activity may include discussion of products or de­vices that are not currently labeled for use by the FDA. The faculty have been informed of their responsibility to disclose to the audience if they will be discussing off-label or investigational uses (any uses not approved by the FDA) of products or devices. CME Outfitters, LLC, and the faculty do not endorse the use of any product outside of the FDA-labeled indications. Medical professionals should not utilize the procedures, products, or diagnosis techniques discussed during this activity without evaluation of their patient for contraindications or dangers of use.

In this 2-part article, we consider bipolar disorder symptom manifestations in light of the changes in DSM-5. We review the management of acute mania and hypomania, as well as subsequent maintenance strategies. Throughout, we also consider the implications of course specifiers (eg, rapid cycling, mixed or psychotic features) for altering treatment approaches (

) we will discuss the management of bipolar depression and cyclothymic disorder, the role of psychotherapy, and future directions.

The lifetime prevalence of bipolar disorder is estimated to be 1.6%.

 This illness typically begins early in life and is characterized by acute exacerbations of mania, hypomania, and depression; a chronic, recurrent course with substantial interepisodic morbidity; an increase in other psychiatric (eg, substance abuse) and medical (eg, cardiovascular disease) comorbidities; and a heightened risk for suicide. As a result, bipolar disorder negatively affects functioning in multiple spheres of activity, health status, and quality of life.

A manic episode experienced even once in a lifetime qualifies for a diagnosis of bipolar I disorder. While these patients may experience hypomanic and major depressive episodes as well, these are not required criteria. Despite this, depression typically is the more predominant mood disturbance.

A diagnosis of bipolar II disorder requires both a hypomanic and a major depressive episode. It is important to emphasize that bipolar II is not a less severe form of bipolar I, but rather a distinct disease process that can be just as detrimental to psychosocial functioning, particularly in the depressive phase. While patients with bipolar I and bipolar II disorder may experience major depressive episodes and hypomania, bipolar II patients never experience mania.

Bipolar disorder usually presents as discrete episodes. Thus, mania and hypomania often occur with a relatively sudden and recognizable change in behavior clearly out of character from the patient’s baseline mood state. While mania and hypomania share many of the same symptoms, a key difference is severity (

). True mania must be present for at least 1 week with associated increases in energy or activity and marked functional impairment that results in a substantial loss of social and occupational functioning. Psychotic features may also be present in more severe episodes and often require hospitalization. Alternatively, hypomania should last at least 4 days with symptoms that are not as severe as mania in terms of social or occupational impairment. Psychotic features are never present in bipolar II patients, and hospitalization is a specific exclusion criterion. Per DSM-5, if either mania or hypomania presents with at least 3 criteria for a depressive episode, they would warrant a mixed specifier designation as well.

Clarifying whether there has been a manic or hypomanic episode may be difficult. This is in part because patients may not consider hypomania or mild mania to be problematic. Clinicians need to carefully explore for possible past episodes, using collateral sources of information whenever possible. Screening instruments such as the Mood Disorders Questionnaire and the prospective Life Chart Method are also helpful.

Cyclothymic disorder is characterized by at least 2 years (1 year in children and adolescents) of periodic hypomanic and depressive symptoms that are distinct from each other. Neither mood phase, however, ever meets the full criteria for a hypomanic or depressive episode. During this time, there are no periods of normal mood that last more than 2 months. These mood disturbances should also lead to problems in social or occupational functioning.

Bipolar disorder can be difficult to distinguish from other psychiatric conditions because there is often substantial symptomatic overlap. Acute schizophrenia can mimic a more severe episode of mania and requires careful attention to the patient’s psychiatric history to help clarify the diagnosis. While similar symptoms may occur in both disorders, schizophrenia more commonly presents with hallucinations and fixed delusions.

Schizoaffective disorder is distinguished from acute mania with psychosis by a period of psychotic symptoms that lasts at least 2 weeks in the absence of significant mood symptoms. Over the long-term course of schizoaffective disorder, however, there should be a substantial proportion of time (> 50%) when mood symptoms are present.

MDD and bipolar depression are often clinically indistinguishable. MDD, however, involves only depressive episodes, whereas bipolar depression requires a history of mania or hypomania. Obtaining a thorough personal and family history, including premorbid functioning, may help clarify the diagnosis.

Other disorders (eg, ADHD, conduct disorder, stimulant use) may also include certain symptoms of hypomania or mania and, to further complicate the diagnosis, often occur as comorbidities with bipolar disorder. Various substances, medications, and medical conditions can mimic the symptoms of bipolar disorder and have their own specific diagnostic categories. For example, manic or hypomanic symptoms due to the effects of cocaine would not be given a bipolar diagnosis unless the symptoms persisted well after the drug’s effects subsided.

 lists and briefly describes DSM-5 categories for bipolar disorder.

Management of bipolar mania and hypomania

Several reviews, professional guidelines, pragmatic studies, and treatment algorithms serve as the basis for our suggested treatment approaches. The strategies recommended in these publications are based primarily on the strength of evidence from placebo- and/or active comparator-controlled trials involving various medications or psychotherapeutic approaches. In some cases, however, there is a lack of such data and information of lesser strength forms the basis for recommendations. In particular, guidelines for the management of certain patient subgroups (eg, rapid cyclers) are often based on results from fewer and less well-controlled trials. One additional caveat is that the preponderance of evidence derived from controlled trials is industry sponsored.

Manic patients who present with severe agitation or aggression may require immediate pharmacologic intervention to prevent harm to themselves and others. Second-generation antipsychotics are generally preferred over first-generation (typical) agents because of their lower short-term adverse effect burden. Benzodiazepines may also be used as adjuncts to quickly calm an agitated patient, to reduce the amount of antipsychotic required, or to prevent withdrawal symptoms when alcohol or other substances are involved.

When possible, oral formulations should be offered initially and acute parenteral formulations reserved for those unwilling or unable to tolerate oral therapy.

 Alternatively, the combination of lower doses of haloperidol (eg, 2 to 5 mg) and lorazepam (eg, 2 mg) may be used either orally or parenterally. A recent study indicated that successful remission of postpartum psychotic mania may require combined treatment with lithium, an antipsychotic, and a benzodiazepine.

 In more emergent situations such as manic delirium, ECT can be life-saving.

Once the safety of the patient and others is assured, attention turns to resolution of an acute episode (

). If the patient is currently taking an antidepressant, it should be discontinued (preferably by taper rather than by abrupt cessation) to prevent persistent manic symptoms and a greater risk for relapse.

Most published strategies to manage acute, mild to moderate manic or mixed episodes (and to a lesser extent hypomania) recommend lithium, valproate, or a second-generation antipsychotic as first-line monotherapies. Of note, recent evidence supports lithium’s potential neuroprotective properties and lower non-suicide mortality risk compared with anticonvulsants.

 In patients with more severe symptoms, associated psychosis, or schizoaffective disorder, a second-generation antipsychotic alone or in combination with other mood stabilizers plus a benzodiazepine are usually recommended (eg, lithium or valproate plus an antipsychotic). Second-generation antipsychotics are usually preferred to first-generation antipsychotics to minimize adverse effects, particularly neuromotor; or to lithium, valproate, or carba­mazepine during pregnancy. With insufficient benefit, clozapine as monotherapy or augmentation therapy may also be an alternative.

 Finally, ECT alone or combined with an atypical antipsychotic can control episodes of psychotic mania and severe refractory episodes, and constitutes a safer alternative during pregnancy.

Lithium and valproate appear to be comparably effective in treating pure manic episodes, while valproate may be more effective for mixed or rapid cycling presentations.

 Carbamazepine with or without an antipsychotic is usually recommended as second-line therapy because it is limited by its adverse effect profile and the risk of significant interactions with other psychotropic and nonpsychotropic medications.

 In this context, oxcarbazepine-a structurally similar analog of carbamazepine-may be an alternative based on promising but limited data from preliminary studies, primarily because of its lower adverse effect profile and fewer drug interactions.

Once the initial target dose or blood level is achieved, medication adjustments may be considered within 1 to 2 weeks if there is insufficient improvement. When feasible, dose adjustments of the initial medication(s) should be attempted before the addition of another medication to minimize adverse effects, drug interactions, and unnecessarily complicated treatment regimens-all of which may exacerbate adherence problems. At times, however, the combination of lithium plus valproate will more effectively control acute symptoms. This strategy is usually done in a sequential fashion rather starting both medications simultaneously.

The agent(s) used to successfully control a manic episode are typically continued for maintenance purposes. Thus, the most commonly recommended treatments mirror those used for acute management and include lithium, valproate, and second-generation antipsychotics. In addition, risperidone long-acting injectable formulation (alone or in combination with lithium or valproate) may be considered for patients with a history of poor oral absorption or inadequate adherence. At times, combined treatments may enhance efficacy but often at the cost of a greater adverse effect burden. In this context, the results of the BALANCE study indicate that lithium alone is more likely to prevent relapse than valproate alone.

 However, it is unclear whether lithium alone is as effective in preventing relapse as the combination of lithium and valproate. In addition, psychotherapy to address residual mood symptoms and comorbid conditions such as substance use disorders is critical to achieving and maintaining a successful outcome.

In the absence of persistent psychosis, adjunctive antipsychotics used for acute control may be slowly tapered after a reasonable period of mood stability is achieved. If benzodiazepines are used for acute stabilization, they should also be slowly discontinued when symptoms are resolved. Maintenance ECT may be continued after a successful acute treatment course at the lowest possible frequency, if symptoms are not adequately controlled with medication(s) and psychotherapy.

Maintenance treatment should be continued for at least 6 to 12 months after complete remission of a manic episode before assessing the need for ongoing treatment. Given the high relapse rates with discontinuation, however, it is generally recommended that maintenance therapy continue indefinitely. If lithium is discontinued, it should be done by a slow taper over several weeks to decrease the risk of relapse.

While lithium’s exact mechanism of action is unknown, its ability to modulate various aspects of brain chemistry is consistent with many current models of the pathogenesis of bipolar disorder. Lithium exerts multiple biochemical effects at a variety of targets owing to its relatively simple nature. Because of its similarity to other cations (eg, Na

), lithium can alter ion channels and pumps in cell membranes. It is also implicated in the modulation of neurotransmitters and neuropeptides such as lithium-induced decreases in beta-adrenergic receptor number, beta-adrenergic activity through inhibition of thyroid hormone, dopamine receptor supersensitivity, and glutamate-mediated calcium signaling; and increases in serotonin release.

In addition, lithium interacts with G-protein and second messenger systems leading to downstream effects on DNA transcription, which may serve to explain its long-term therapeutic effects. Neuroprotective properties such as increasing neuronal viability in the context of glutamate cytotoxicity and the expression of brain-derived neurotrophic factor are also associated with sustained lithium treatment.

Lithium is rapidly absorbed in the gastrointestinal tract, is not protein bound, and distributes throughout total body water with peak serum concentrations at 1 to 2 hours after administration (4 to 5 hours for slow-release preparations). It has no metabolites and is almost entirely excreted by the kidneys. Its typical half-life in a healthy adult is about 24 hours, and steady-state serum levels are usually achieved in 4 to 5 days.

Lithium is usually started at 300 mg, 2 or 3 times daily, and gradually increased 300 to 600 mg every 1 to 5 days based on response to treatment, blood levels, and tolerability. Optimal dosing generally falls between 900 and 1900 mg daily to achieve a target serum concentration of 0.8 to 1.2 mEq/L. If dose adjustments are made, a lithium trough (10 to 12 hours after the last dose) level should be drawn 5 to 7 days after the change to properly reflect the new steady-state concentration.

Lithium is contraindicated in patients with significant renal impairment, dehydration, and low sodium levels, because these states increase the likelihood of acute toxicity. Lithium should also be avoided in patients with significant cardiovascular disease because of its impact on the heart’s conduction system.

Lithium is associated with a number of adverse effects even at therapeutic levels. Nausea is most commonly managed by encouraging food intake with each dose or the use of extended-release formulations. Tremor, which can also be an early sign of toxicity, may be managed by dividing doses and avoiding exacerbating factors such as anxiety, stress, and caffeine. Weight gain, loose stools, and cognitive impairment can also occur and may require dose adjustment. Renal function should be assessed once or twice a year because lithium may cause impairment with long-term use. Lithium also affects the thyroid and parathyroid glands, reducing thyroid hormone release and increasing parathyroid hormone activity.

In the context of pregnancy, lithium is listed as a category D drug owing to the risk of cardiac defects such as Ebstein’s anomaly. During pregnancy (particularly the first trimester), the developing fetus should be closely monitored for cardiac defects. Doses will need adjustment, particularly near parturition and postpartum because of changes in metabolism and fluid volumes. When neonates are breastfed while their mother is taking lithium, they should be assessed for lethargy, as well as growth and feeding problems.

As with lithium, the mechanism of action for valproate as a mood stabilizer is not fully understood. Two actions that may be relevant include blockade of voltage-dependent sodium ion receptor channels and enhancement of gamma-aminobutyric acid activity by increasing its synthesis and release.

Valproate is well absorbed with greater than 80% bioavailability after oral administration and may be administered after meals because food delays absorption, lessening adverse effects. It is highly protein bound and remains mainly in the extracellular fluid. Peak serum levels occur between 1 and 4 hours after administration, and half-life ranges between 6 and 16 hours. Valproate is metabolized by the liver and excreted through the kidneys.

Valproate is usually started at a dose of 250 mg, 2 or 3 times daily, and titrated every few days until a dose of 1500 to 2500 mg/d is reached. Valproate can also be orally loaded at 20 to 30 mg/kg daily to more rapidly achieve therapeutic levels. Optimal therapeutic plasma levels of valproate generally fall between 50 and 125 µg/mL and should be checked 2 to 5 days after a dose increase, 12 hours after the last dose.

Valproate can cause nausea, vomiting, hair loss, easy bruising, and tremor. Valproate-associated weight gain and insulin resistance can lead to metabolic syndrome. More rarely, it may cause liver toxicity, elevations in ammonium levels, pancreatitis, thrombocytopenia, and coagulation problems. It is contraindicated in persons with liver disease and those with mitochondrial disorders. Liver function tests should be performed before starting treatment and repeated during the first few months if indicated.

In the context of pregnancy, valproate is listed as a category D drug because of a 9% risk of development of major malformations.

 Women of child-bearing age should use adequate contraceptive methods while taking valproate and should receive folic acid. If pregnancy does occur, the patient should be switched to an alternative treatment and the fetus monitored for cardiac anomalies. Valproate also carries an increased risk of polycystic ovary syndrome, which is particularly relevant in women of childbearing age.

The hypothetical mechanism of action of carbamazepine in bipolar disorder may relate to its binding of sodium ion channels, enhancing the inactivated state and blocking the propagation of rapid action potentials. It is absorbed slowly, with peak serum levels occurring 6 to 8 hours after administration and a bioavailability of 85%, and is metabolized in the liver by cytochrome P450 (CYP450) 3A4. Its half-life during the initial stages of treatment ranges from 25 to 65 hours, but may decrease to 12 to 17 hours after several weeks owing to autoinduction. For this reason, serum levels should be measured at 3, 6, and 9 weeks after starting treatment.

Oxcarbazepine is usually fully absorbed and not affected by food with peak serum concentrations achieved 4 to 6 hours after administration and a half-life of 8 to 12 hours. Oxcarbazepine also undergoes hepatic metabolism but is less likely to induce liver enzymes than carbamazepine.

Carbamazepine is usually started at an oral dose of 400 to 600 mg daily with dose increases of 200 mg every 3 to 5 days until a clinical effect is achieved or adverse effects become intolerable. Although target serum levels for patients with epilepsy typically range from 4 to 12 µg/mL, clinical response and tolerability should take priority over levels in those with bipolar disorder. Starting doses of oxcarbazepine are generally 300 to 600 mg daily, which can be increased by up to 600 mg per day weekly with a range of 300 to 3000 mg daily.

Common adverse effects of carbamazepine include nausea, vomiting, headache, diarrhea, hyponatremia (possibly higher risk with oxcarbazepine), rash, pruritus, fluid retention, and low testosterone in males. More serious effects include Stevens-Johnson syndrome, agranulocytosis, and aplastic anemia, which often present within the first few months of treatment. Carbamazepine can lead to multiple clinically relevant drug interactions, primarily through CYP450 3A4 induction. Pharmacogenetic testing (eg, HLA-B*1502, HLA-A*31:01) can prevent carbamazepine-induced hypersensitivity reactions (ie, Stevens-Johnson syndrome) in certain ethnic groups (eg, Han Chinese, Europeans).

In the context of pregnancy, carbamazepine is labeled as a category D drug owing to an increased risk of spina bifida, craniofacial defects, cardiovascular malformations, developmental delays, and hypospadias. Women of childbearing age should use adequate contraceptive methods while taking carbamazepine and should receive folic acid. While carbamazepine enters the breast milk as its active metabolite and is detected in the serum of breastfed infants, it is generally thought to be safe. However, mothers are encouraged to discontinue breastfeeding if the neonate begins to experience related adverse events (eg, transient hepatic dysfunction).

Oxcarbazepine is a category C drug found to cause adverse effects in animal studies, but with no specific malformations identified in humans. It is also transferred to newborns in small amounts through breast milk.

First-generation antipsychotics preceded the availability of lithium in the US by almost 20 years and were the mainstay of medication treatment for bipolar disorder during this period. Indeed, chlorpromazine still has an FDA-approved indication for this disorder. With the advent of lithium, however, the primary role of antipsychotics was to serve as adjunctive therapy for more severe episodes. With extended experience, lithium was found insufficiently effective and/or poorly tolerated in a substantial proportion of patients with bipolar disorder. This ushered in a series of studies with anticonvulsant agents and second-generation antipsychotics to ascertain their potential as alternative mood stabilizers. Theories on the mechanism of action of second-generation antipsychotics focus on their multiple neuroreceptor effects, particularly related to the dopamine and serotonin systems.

A series of controlled trials considered olanzapine as either monotherapy or adjunctive therapy for bipolar disorder, particularly for acute mania. The consistently positive results with olanzapine led to studies with other second-generation antipsychotics. While the most common adverse effects of antipsychotics include neuromotor, sedative, hormonal, and metabolic complications, they vary substantially among the different agents. For example, haloperidol and risperidone can increase the risk of acute extrapyramidal side effects and hyperprolactinemia, while agents such as olanzapine and quetia­pine may be more likely to cause sedation, weight gain, and related cardiometabolic effects. 

 lists the agents approved by the FDA for acute and maintenance treatment of mania and hypomania; phases of the illness for which antipsychotics have approved indication(s) as either monotherapy or adjunctive therapy; their usual dosing ranges; and other clinically relevant considerations.

The defining characteristic of bipolar disorder is the presence of mania or hypomania. Bipolar I disorder is primarily distinguished from bipolar II disorder by meeting the criteria for a full manic episode. Conversely, bipolar II disorder must meet criteria for both a hypomanic and a depressed episode. Cyclothymic disorder consists of more chronic mood disturbances that do not meet the full criteria for hypomania, mania, or depression.

Treatment approaches depend on the illness phase and symptom severity. Mania, hypomania, and mixed episodes can be managed initially with 1 of 3 strategies: lithium, valproate, or a second-generation antipsychotic either as monotherapy or in various combinations. Short-term use of antipsychotics and/or benzodiazepines may also address associated symptoms (eg, agitation, psychosis, drug or alcohol withdrawal) during an acute exacerbation. Successful maintenance strategies usually require a combination of pharmacologic and psychotherapeutic approaches customized to meet the needs of a given patient.

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