Treatment for bipolar disorder with psychotic features

Approach Considerations

Always evaluate patients with mania, hypomania, or mixed episode, and those with bipolar depression, for suicidality, acute or chronic psychosis, or other unstable or dangerous conditions. [3]

The treatment of bipolar disorder, or manic-depressive illness (MDI), is directly related to the phase of the episode (ie, depression or mania) and the severity of that phase. For example, a person who is extremely depressed and exhibits suicidal behavior requires inpatient treatment. In contrast, an individual with a moderate depression who still can work would be treated as an outpatient. Fortunately, most patients recover from the first manic episode, but their course beyond that is variable. [75]

It is important to determine whether current medications may be causing the patient’s manic, hypomanic, or mixed manic episode. In such patients, discontinue antidepressants or other mania-inducing agents. However, antidepressants known to have associated discontinuation syndromes should be tapered over several weeks. [3]

Evaluate and closely monitor patients with bipolar depression for the risk for mood destabilization or switching to mania and for the presence of emergent symptoms following initiation of pharmacotherapy for a depressive episode. [3] Initiate an antipsychotic agent in patients with bipolar depression with psychotic features, and consider psychosocial interventions (eg, psychoeducation; psychotherapy strategies such as cognitive behavioral therapy [CBT], interpersonal and social rhythm therapy [IPSRT], family focused therapy; chronic care model-based interventions).

The patient’s response to treatment may depend on the number of previous episodes of bipolar disorder. In a report that analyzed pooled data, the importance of early intervention was demonstrated with better treatment responses in individuals who had earlier stages of illness. [76] Bipolar patients who experienced fewer previous mania episodes (1-5) displayed a twofold increase in the treatment response rate to olanzapine relative to those who had already experienced more than 5 previous episodes. [76] In patients with depression, the response rates were also significantly higher in patients with fewer episodes, although the findings were only for 2 of the measured responses. In the maintenance studies, groups with fewer previous episodes (1-5 or 6-10) experienced a 40-60% reduction in the risk of relapse to either mania or depression compared to the group that had more than 10 previous episodes. [76]

If the patient is in a short-term inpatient care unit and has not made significant progress, reevaluate the management strategy. Transfer to a long-term inpatient care unit might also be considered. If the patient is in a depressed or manic phase and is not responding to medications, transfer the patient to a facility where electroconvulsive therapy (ECT) can be administered. Additionally, consultation with a psychiatric colleague or a psychopharmacologist is always appropriate if the patient does not respond to conventional treatment and medication.

All patients with bipolar disorder need outpatient monitoring for both medications and psychotherapy. In addition, these individuals need education regarding their condition. The schedule must be regular, with great flexibility if they need extra sessions.

The 2010 Veterans Administration/Department of Defense (VA/DoD) clinical practice guideline for management of bipolar disorder recommends reassessing patients who start treatment for acute bipolar mania, hypomania, or mixed episodes every 1-2 weeks for at least 6 weeks. [3] Patients with severe mania who are not hospitalized should be reassessed every 2-5 days until symptoms improve. An absence of any significant symptoms of mania or depression for 2 months should be considered to be full remission and assessment of symptoms should then be continued periodically to monitor for relapse. [3]

Evaluate the patient’s response to treatment with the same standardized tool at follow-up visits, after changes in therapy, and with periodic assessments until complete remission has been reached. [3] The Center for Quality Assessment and Improvement in Mental Health (CQAIMH) provides assessment and screening tools for bipolar disorder and suicide at: http://www.cqaimh.org/stable.html.

No surgical care is indicated for bipolar disorder. Historically, treatment was attempted with psychosurgical procedures, such as prefrontal lobotomy. However, lobotomy is no longer used in the clinical care of patients with bipolar disorder.

Indications for Inpatient Management

Patients diagnosed with bipolar mania or depression and severe symptoms must be referred for urgent/emergent mental health intervention. [3] The indications for inpatient treatment in a person with bipolar disorder, or manic-depressive illness (MDI), include the following:

• Danger to self

• Danger to others

• Delirium

• Marked psychotic symptoms

• Total inability to function

• Total loss of control (eg, excessive spending, undertaking a dangerous trip)

• Medical conditions that warrant medication monitoring (eg, substance withdrawal/intoxication)

Patients with a possible diagnosis of bipolar depression must also be referred for urgent/emergent mental health intervention if they present with serious delusion, visual/auditory hallucinations, confusion, catatonic behavior, extreme negativism/mutism, and/or inappropriate affect of a bizarre or odd quality. [3]

A patient with bipolar disorder, especially one in a depressive episode, may present with a significant risk for suicide, especially those with an early onset of symptoms. [77] Serious suicide attempts and specific ideation with plans constitute clear evidence of the need for constant observation and preventive protection; consider referring these individuals to mental health specialty care. [3] Occasionally, depression is so profound that the person cannot function at all; thus, the danger to the person may come from other aspects of the disease. For example, a person in extreme mania who foregoes sleep or food may be in a state of serious exhaustion. Leaving such a person alone would be dangerous and not therapeutic.

Goldstein and associates followed the mental health of 413 youths diagnosed with bipolar disorders and found that 76 (18%) attempted suicide at least once within 5 years of study; of these youths, 31 (8% of the overall group and 41% of those who attempted suicide) made many attempts. [77] The investigators concluded that bipolar disorder with early onset is associated with high suicide attempt rates. Therefore, the patient’s severity of depression at presentation and their family history of depression must be considered when evaluating youths with bipolar disorder and their suicide risk. [77]

Patients with bipolar disorder can also become a threat to others. For example, a patient experiencing a severe depression believed the world was so bleak that she planned to kill her children to spare them from the world’s misery.

Sometimes, patient’s behaviors are totally out of control, which is a particular concern during a manic episode. In this situation, patients’ behaviors are so beyond limits that they destroy their career and can be harmful to those around them. For example, a delusional patient having a manic episode believed everyone was against him; he searched for a rifle in order to defend himself and to “get them” before they “got” him.

Some patients with bipolar disorder have other medical conditions for which medication monitoring is warranted. For example, patients with certain cardiac conditions should be in a medical environment where the effects of the psychotropic medications can be monitored and observed closely.

In the clearest case of the bipolar/depressed phase, the patient is suicidal and homicidal in a few situations (this can result in homicide followed by suicide). In these scenarios, institutioinal commitment is in order and indicated. In other situations, the depression has led to an inability of the patient to work, eat, and function; hospitalization is also indicated in these cases.

In the situation of a patient in the bipolar/manic phase, although the patient does not show clear and dramatic evidence of homicide or suicide, a pattern of very poor judgment and impairment emerges. Because of their behavior during the manic phase, the person often does major damage to their finances, career, and position in the community. This type of self-destructive mania calls for containment with good documentation and family support.

Considerations for Partial Hospitalization or Day Treatment

In general, patients with bipolar disorder, or manic-depressive illness (MDI), who are candidates for partial hospitalization or day treatment experience severe symptoms but have some level of control and a stable living environment. For example, a patient with severe depression who has thoughts of suicide but no plans to act upon them and who has a high degree of motivation can get well when given a great deal of interpersonal support, especially during the day, and with the help of a very involved and supportive family. The family needs to be home every night and should be very concerned with the patient’s care.

Partial hospitalization also offers a bridge to return to work. Returning directly to work is often difficult for patients with severe symptoms, and partial hospitalization provides support and interpersonal relationships.

Considerations of Outpatient Treatment

Outpatient treatment for patients with bipolar disorder, or manic-depressive illness (MDI), has 4 major goals, as follows:

1. Look at areas of stress and find ways to handle them: The stresses can stem from family or work, but if they accumulate, they propel the person into mania or depression; this is a form of psychotherapy

2. Monitor and support the medication: Medications make an incredible difference, and the key is to obtain the benefits while avoiding adverse effects; patients are ambivalent about their medications—although they recognize that the drugs help and prevent hospitalizations, they also resent that they need them; the goal is to address their feelings and allow them to continue with the medications

3. Develop and maintain the therapeutic alliance: This is one of the many reasons for the practitioner to deal with the patient’s ambivalence about the medications; over time, the strength of the alliance helps keep the patient’s symptoms at a minimum and helps the patient remain in the community

4. Provide education (see Patient Education): The clinician must help educate both the patient and the family about bipolar illness; patients and families need to be aware of the dangers of substance abuse, the situations that would lead to relapse, and the essential role of medications; support groups for patients and families are of tremendous importance

Psychotherapy helps patients with bipolar disorder but does not cure the disorder by itself. When Schottle and colleagues looked at psychotherapy for patients, family, and caregivers, they found that although results were heterogeneous, most studies demonstrated relevant positive results in regard to decreased relapse rates, improved quality of life, increased functioning, or more favorable symptom improvement. [4]

Somatic health issues in individuals with bipolar disorder are ubiquitous, underrecognized, and suboptimally treated. [78] Therefore, practitioners must pay attention to patient’s medical conditions, including cardiovascular concerns, diabetes, endocrine problems, infections, urinary complications, and electrolyte imbalances. In view of the possible medical complications, medical follow-up is important. Persons with bipolar disorder often have difficulty obtaining primary physician care. [79]

Patients with chronic medical illnesses and depression should be treated with a comprehensive approach involving the patient, the family, the support team, the physician, other professionals, and community resources. Such models, called Collaborative Chronic Care Models (CCMs), have been developed to improve outcomes in chronically ill patients treated in the primary care setting who also suffer from depression. CCMs were defined a priori as interventions with at least 3 of the 6 components of the Improving Chronic Illness Care initiative, as follows:

• Patient self-management support

• Clinical information systems

• Delivery system redesign

• Decision support

• Organizational support

• Community resource linkages

When Woltmann et al examined this approach in patients with bipolar disorder, they concluded that CCMs can improve both mental and physical outcomes for patients with mental disorders across a wide range of care settings. [80] CCMs also provide a robust clinical and policy framework for the integration of care. The review included 78 articles, yielding 161 analyses from 57 trials. [80]

Pharmacologic Therapy

Appropriate medication depends on the stage of the bipolar disorder, or manic-depressive illness (MDI), the patient is experiencing. Thus, a number of drugs are indicated for an acute manic episode, primarily the antipsychotic agents, valproate, and benzodiazepines (eg, lorazepam, clonazepam). The choice of agent depends on the presence of symptoms such as psychotic symptoms, agitation, aggression, and sleep disturbance. (See the list of medications for bipolar disorder in Table 1, below.) For patients with bipolar disorder in the depressed phase, the Medscape Reference article Depression provides antidepressant guidelines.

Table 1. FDA-Approved Bipolar Treatment Regimens (Open Table in a new window)

Bauer and colleagues have suggested 2 approaches to treatment options in bipolar patients. [82] First, in a patient with bipolar depression who is not currently being treated with a mood-stabilizing agent (de novo depression, first or subsequent episode), options include quetiapine or olanzapine, with carbamazepine and lamotrigine as alternatives. [82] Antidepressants are options for short-term use, but it remains controversial as to whether it is better to administer them in combination with mood-stabilizing agents or as monotherapy. Second, if the patient is already optimally treated with a mood-stabilizing agent (appropriate dose, good compliance) such as lithium, an option would be lamotrigine. No evidence suggests additional benefit from antidepressants if a patient is already being treated with a mood stabilizer, but this often tried in practice. [82]

One cautionary note of interest: Post and colleagues found that the more different antidepressant trials the patient with bipolar disorder has received, the less responsive they become to treatment. [83]

Inhaled loxapine (Adasuve) is the first noninjectable therapy approved by the FDA to treat acute agitation associated with schizophrenia and bipolar disorder type I (BPI). The FDA approval was based on 2 phase III studies of 658 individuals; statistically significant reductions in agitation were apparent starting 10 minutes following administration compared with placebo, and these effects were sustained at 2 hours. [84, 85]

Severe mania or mixed episodes

Combined therapy with an antipsychotic agent and another antimanic medication is recommended for patients with severe mania or mixed episodes, with or without psychotic features. [3] Thus, lithium, a drug commonly used for prophylaxis and treatment of manic episodes, or valproate may be used in combination with antipsychotic agents (eg, severe mania: olanzapine, quetiapine, aripiprazole, risperidone, or possibly ziprasidone; severe mixed episode: aripiprazole, olanzapine, risperidone, haloperidol or possibly quetiapine or ziprasidone). [3]

Despite the serious side effects associated with clozapine, the Veterans Administration/Department of Defense (VA/DoD) suggest this drug may be added to existing medications if it was successfully used previously for severe mania or mixed episodes or if other antipsychotic agents are unsuccessful. [3]

Reevaluate nonhospitalized patients being treated for severe mania or mixed episodes every 2-5 days until symptomatic improvement, and adjust medication dosages and regimens as needed. [3] The therapeutic range of lithium is a serum trough concentration between 0.6-1.2 mEq/L; for valproate, 50-125 mcg/mL; and for carbamazepine, 4-12 mcg/mL. If the patient’s serum concentrations of their medication fall below the therapeutic range, adjust the drug’s dose to the maximum range. For medications without known therapeutic plasma concentrations, increase the dose until symptomatic improvement, patient intolerance, or the manufacturer’s maximum dose limits have been reached. [3]

Mania/hypomania or mixed episodes

Initiate lithium, valproate, carbamazepine, aripiprazole, olanzapine, quetiapine, risperidone, or ziprasidone in patients with mania. [3] In patients with mixed episodes, initiate therapy with valproate, carbamazepine, aripiprazole, olanzapine, risperidone, or ziprasidone. Consider clozapine, haloperidol, or oxcarbazepine in patients with mania or mixed episodes, and consider lithium or quetiapine in those with mixed episodes. [3]

Researchers have demonstrated a link between a locus on chromosome 21 and patient response to lithium. The study found that a single locus of four linked SNPs on chromosome 21 met genome-wide significance criteria for association with lithium response. Carriers of the SNPs had significantly lower rates of disease relapse than carriers of the alternate alleles. [86]

It is not recommended that topiramate, lamotrigine, and gabapentin be used to treat patients with mania or mixed episodes. [3]

Bipolar depression

The American Psychiatric Association's (APA) 2005 guideline watch for the treatment of patients with bipolar disorder noted that medications having the strongest evidence for efficacy for the acute treatment of depression in BPI are the olanzapine-fluoxetine combination, quetiapine, and lamotrigine. [59] Furthermore, there is some evidence that pramipexole may be helpful as an adjunctive agent, although only modest evidence exists for the efficacy of an antidepressant with adjunctive mood stabilizer. Antidepressants in the absence of a mood stabilizer are not recommended by the APA for BPI patients. [59]

Monotherapy

The VA/DoD considers first-line monotherapy in adult patients with bipolar depression to include quetiapine, lamotrigine, or lithium. [3] Cautiously consider olanzapine monotherapy due to its adverse effects. Second-line pharmacotherapy includes the combination of olanzapine/fluoxetine owing to its side-effect profile of weight gain, diabetes risk, and hypertriglyceridemia. [3]

Although the VA/DoD found insufficient evidence for or against the use of valproate, carbamazepine, topiramate, risperidone, ziprasidone, or clozapine for managing bipolar depression, it did advise against aripiprazole monotherapy in patients with acute bipolar depression, except in cases in which there was [3] : (1) a previous good response during depression without a switch to mania or (2) a history of treatment of refractory depression.

A post hoc analysis of older adults (aged >55 years) showed lurasidone was significantly more effective than placebo as monotherapy. Adjunctive therapy with lurasidone was not associated with significant improvement. Both monotherapy and adjunctive therapy with lurasidone were safe and well tolerated in this older adult population. [87]  

Lumateperone monotherapy demonstrated statistically significant improvements in depression associated with bipolar I or II disorder over placebo for the change from baseline in the Montgomery-Asberg Depression Rating scale (MADRS) total score at week 6. [136]

Combination therapy

In patients whose bipolar depression is unresponsive to monotherapy, consider the combination of lithium with lamotrigine. [3] Alternatively, consider short-term augmentation of antidepressant agents with a selective serotonin reuptake inhibitor (SSRI), serotonin norepinephrine reuptake inhibitor (SNRI), bupropion, and monoamine oxidase inhibitor (MAOI); patients using this treatment strategy must be closely monitored for triggering of manic symptoms. [3]

As in severe mania or severe mixed episodes, consider adding clozapine for augmentation, and closely monitor the patient for metabolic or other adverse effects. [3] Because of the known complications involved with clozapine, it is recommended that a psychiatric consultation be initiated.

The VA/DoD found insufficient evidence for or against the use of augmentation with aripiprazole, olanzapine, risperidone, haloperidol, oxcarbazepine, topiramate, ziprasidone, valproate, or carbamazepine in bipolar depression. [3] However, the VA/DoD advised against the use of gabapentin and tricyclic antidepressant agents (TCAs) for monotherapy or augmentation in patients with acute bipolar depression, except in cases in which there was [3] : (1) a previous good response during depression without a switch to mania or (2) a history of treatment of refractory depression.

Use of lumateperone as adjunctive therapy with lithium or valproate demonstrated statistically significant improvements for depression associated with bipolar I or II disorder compared with placebo for the change from baseline in the MADRS total score at week 6. [136]

Dosing or medication adjustments

Switch to another effective treatment for patient intolerance to side effects. For patients that switch into mania or hypomania or enter a mixed manic state, follow the recommendations discussed above in Mania/hypomania or mixed episodes.

Reevaluate patients every 1-2 weeks for a minimum of 6 weeks. As noted earlier, the therapeutic range of lithium is a serum trough concentration between 0.6-1.2 mEq/L; for valproate, 50-125 mcg/mL; and for carbamazepine, 4-12 mcg/mL. [3] If the patient’s serum concentrations of their medication fall below the therapeutic range, adjust the drug’s dose to the maximum range. For medications without known therapeutic plasma concentrations, increase the dose until symptomatic improvement, patient intolerance, or the manufacturer’s maximum dose limits have been reached. [3]

In patients with a partial treatment response (no response 2-4 weeks after initiation of an adequate medication dose), consider augmenting the medication with additional agents as discussed under Combination therapy,discontinuing the current drug (tapered withdrawal with monitoring for antidepressant syndrome and mood destabilization) and switching to another effective agent, or electroconvulsive therapy (ECT) if multiple trials of switching medications/augmentation strategies have been unsuccessful. [3]

Other considerations

A study by Bauer et al suggested that lithium may also have a neuroprotective role. [88] However, this agent is also associated with increased risk of reduced urinary concentrating ability, hypothyroidism, hyperparathyroidism, and weight gain. The consistent finding of a high prevalence of hyperparathyroidism should prompt physicians to check patient calcium concentrations before and during treatment. Lithium is not associated with a significant reduction in renal function in most patients, and the risk of end-stage renal failure is low. [89]

Atypical antipsychotics are increasingly being used for the treatment of both acute mania and mood stabilization. The broad range of antidepressants and ECT are used for an acute depressive episode (i.e. major depression). However, ECT may also be considered for patients with severe mania or treatment-resistant mania, those who prefer ECT, and pregnant women with severe mania. [3] Ansari and Osser developed a very useful algorithm for the Harvard South Shore Program to treat a bipolar patient in a depressed phase through “an organized, sequential, and evidence-supported approach.” [90] Finally, another set of medications is chosen for the maintenance and preventive phases of treatment.

Diazgranados and colleagues reported that for patients with treatment-resistant bipolar depression, impressive and swift antidepressant effects occurred when a single intravenous (IV) dose of the N -methyl-D -aspartate (NMDA) antagonist ketamine was administered. [91] Increasingly, the role of glutamate in mood disorders is being researched, and experimental evidence shows that the NMDA receptor antagonist ketamine may be helpful in short-term treatment of depression, even in the context of bipolar disorder. However, it is important to note that the benefit of such treatment disappeared after 4 days.

Although antidepressant medications are most often prescribed for patients with bipolar disorder who are experiencing an acute depression, a study found that antidepressants were not statistically superior to placebo or other current standard treatment for bipolar depression. [92]

Clinical experiences have shown that patients with bipolar disorder have fewer episodes of mania and depression when treated with mood-stabilizing drugs. [93] These medications not only serve to stabilize the patient’s mood, as the name implies, they can also dampen extremes of mania or depression. Kessing et al found that, in general, lithium was superior to valproate. [94]

Atypical antipsychotics (including ziprasidone, quetiapine, risperidone, aripiprazole, olanzapine, and asenapine) are also now frequently used to stabilize acute mania—or even to treat bipolar depression in some cases.

In the treatment of depression associated with bipolar disorder type II, Swartz and associates reported that 95% of relevant trials were published later than 2005. [95] They noted compelling evidence for the efficacy of quetiapine and preliminary support for the efficacy of lithium, antidepressants, and pramipexole. However, mixed support was noted for lamotrigine. [95]

Maintenance

The role of mood stabilizers and antipsychotic medications in maintaining patients with bipolar disorder is well documented, [96] as is the use of long-acting antipsychotics to help with the maintenance phase. The APA’s 2005 guideline watch for the treatment of patients with bipolar disorder considered both lamotrigine and lithium to have substantial utility in the maintenance treatment of patients with bipolar disorder. [59]

Popovic et al suggested the use of a Polarity Index to guide the choice of maintenance therapy in bipolar patients. [97] Based on results from randomized, placebo-controlled trials, the investigators indicated that this index may provide a measure of the relative preventive antimanic versus antidepressive efficacy of drugs that are used to treat bipolar disorder. [97] They defined a Polarity Index value greater than 1.0 as having a relative greater antimanic prophylactic efficacy, whereas a value less than 1.0 would have a relative greater antidepressive efficacy. The following are this study’s polarity indices results for maintenance drugs in bipolar disorder [97] :

• Risperidone: 12.09

• Aripiprazole: 4.38

• Ziprasidone: 3.91

• Olanzapine: 2.98

• Lithium: 1.39

• Quetiapine: 1.14

• Lamotrigine: 0.40

Note that Popovic et al indicated the respective polarity indices for valproate and oxcarbazepine were potentially unreliable owing to the failure of their maintenance trials. [97]

There have been concerns that ziprasidone may have adverse effects on body weight, fasting lipids, and fasting glucose. When Pappadopulos et al looked at a comprehensive set of analyses of metabolic alternations in patients on this medication, they found no significant differences between the ziprasidone and placebo groups in levels of fasting triglycerides, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, or glucose in the controlled studies. [98]

In July 2017, the FDA approved aripiprazole extended-release injectable suspension (Abilify Maintena) for maintenance monotherapy of bipolar I disorder (BP-I) in adults. Approval was based on a 52-week, Phase 3, double-blind, placebo-controlled, randomized withdrawal study that enrolled patients experiencing a manic episode at screening and met the DSM-IV-TR criteria for BP-I. The primary endpoint showed once monthly aripiprazole IM significantly delayed recurrence time of any mood episode in adults having a manic episode at screening compared with placebo (P < 0.0001). Significant differences were observed between treatment arms in delaying time to recurrence of both manic and mixed episodes. No substantial differences, however, were seen for depressive mood episodes. [99]

According to a multiple treatments meta-analysis of treatments for acute mania, the most efficacious treatments are haloperidol, risperidone, and olanzapine, significantly outperforming primary mood stabilizers and other antipsychotic medications. [100] In several randomized, double-blind, controlled studies, olanzapine monotherapy was significantly more effective in treating manic or mixed episodes than haloperidol [101] or divalproex monotherapy. [102] The adjunctive use of olanzapine with divalproex or lithium, [103] or of risperidone with divalproex or lithium, was also significantly more effective than divalproex or lithium alone. [104, 105]

As outlined in the APA’s 2002 clinical practice guideline, [106] benzodiazepines have sedative effects, which may make them useful adjunctive medications until antimanic medications take effect. With the increased risk of substance use disorder in patients with bipolar disorder, long-term use of benzodiazepines is generally discouraged.  Additionally, the guideline stated that manic symptoms may be treated with chlorpromazine, which was deemed superior to placebo in a randomized trial and was deemed comparable to lithium (for controlling manic and psychotic symptoms) in acute treatment comparison trials.

Children and adolescents who have bipolar disorder are particularly challenging to treat, and their discussion is beyond the scope of this article (see the Medscape Reference article Pediatric Bipolar Affective Disorder). However, Hamrin and Iennaco developed guidelines and recommendations for medications and management approaches after an extensive literature review using research findings on medication effectiveness in this population. [107]

There is evidence that risperidone may be the best first-line treatment for childhood mania, as shown in a randomized controlled trial with patients aged 6 to 15 years with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, (DSM-IV-TR) diagnosis of BPI (manic or mixed phase). [108] Specifically, risperidone was significantly more effective than lithium or divalproex sodium for the initial treatment of childhood mania; however, use of risperidone had the potential for serious metabolic side effects. [108]

Caution in polyantipsychotic therapy in bipolar disorder

In August 2010, the FDA announced that lamotrigine carries a risk of aseptic meningitis. [109]

In a study that sought to evaluate the safety and tolerability of second-generation antipsychotic (SGA) polytherapy compared with monotherapy in patients with bipolar disorder receiving open naturalistic treatment in the 22-site Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), Brooks et al concluded that although polytherapy was fairly common in bipolar disorder, it was also associated with increased side effects (eg, dry mouth, sexual dysfunction, and constipation) and increased health service use (almost threefold) but not with improved clinical status or function. [110] Therefore, polytherapy in bipolar disorder may incur important disadvantages without clear benefit, warranting careful consideration before undertaking such interventions. [110]

Electroconvulsive Therapy

Electroconvulsive therapy (ECT) is useful in a number of instances in patients with bipolar disorder, or manic-depressive illness (MDI), such as the following [3] :

• When rapid, definitive medical/psychiatric treatment is needed

• When the risks of ECT are less than that of other treatments

• When the bipolar disorder is refractory to an adequate trial with other treatment strategies

• When the patient prefers this treatment modality

Often, the severity of the patient’s symptoms, the lack of response to medications, or the presence of contraindications to certain medications necessitates the use of ECT. This treatment modality has proven to be highly effective in the treatment of acute mania.

The 2010 Department of Veterans Affairs/Department of Defense (VA/DoD) clinical practice guideline for management of bipolar disorder indicates ECT is the primary therapy in bipolar disorder patients that present with psychotic symptoms, catatonia, severe suicidality, food refusal leading to nutritional compromise, or who have a history of previous positive response to ECT. [3] Indeed, in a review of 50 years’ experience with ECT for acute manic episodes, data from early literature revealed that 313 of 400 patients with acute mania who received ECT showed significant clinical improvement. [111]

Dietary and Activity Measures

Unless the patient with bipolar disorder, or manic-depressive illness (MDI), is on monoamine oxidase inhibitors (MAOIs), no special diet is required. Patients should be advised not to make significant changes in their salt intake, because increased salt intake may lead to reduced serum lithium levels and reduced efficacy, and reduced intake may lead to increased levels and toxicity.

Although a meta-analysis by Starris et al found strong evidence that bipolar depressive symptoms may be improved by adjunctive use of omega-3, omega-3 does not improve bipolar mania. [112]

Patients in the depressed phase are encouraged to exercise. These individuals should try to develop a regular daily schedule of major activities, especially times of going to bed and waking up. Propose a regular exercise schedule for all patients, especially those with bipolar disorder. Both the exercise and the regular schedule are keys to surviving this illness. However, increases in exercise level, with increased perspiration, can lead to increased serum lithium levels and lithium toxicity.

Complications

The main complications of bipolar disorder, or manic-depressive illness (MDI), are suicide, homicide, and addictions.

Previously or currently suicidal patients remain at risk for suicide. Patients emerging from a depression are thought to be at an increased risk for suicide. The risk of self-destructive behavior and death is lifelong. Hong et al’s study demonstrated a genetic link between bipolar disorder and suicidal behavior, especially in white individuals. [113] According to a more recent study, men with bipolar disorder are at higher risk for suicide. [114]

The European Mania in Bipolar Longitudinal Evaluation of Medication (EMBLEM) study, a 2-year prospective, observational study, suggested the following characteristics found in patients with bipolar disorder who are suicidal may help identify subjects at risk for suicidal behavior [115] :

• Female sex

• A history of alcohol abuse

• A history of substance abuse

• Young age at first treatment for a mood episode

• Longer disease duration

• Greater depressive symptom severity (5-item Hamilton Depression Rating Scale [HAMD-5] total score)

• Current benzodiazepine use

• Higher overall symptom severity (Clinical Global Impression-Bipolar Disorder [CGI-BP]: mania and overall score)

• Poor compliance

Homicidal patients, often in the manic phase, can be very demanding and grandiose. In this context, they are angered if others do not immediately comply with their wishes, and they can turn dramatically violent. In addition, these individuals can become homicidal by acting on delusions.

Individuals with bipolar disorder are at risk for an addiction. This creates the problem of a dual diagnosis and, therefore, complicates treatment.

One area of major concern is the relationship between violent crime and bipolar disorder. This danger is particularly present and prominent with patients who have a substance abuse problem. [116] Although some persons with bipolar disorder may become violent, clinicians must be vigilant when treating patients with the dual diagnosis of substance abuse.

Quality of life (QOL) has been an important way to look at the effects of mental illness. Bipolar disorder type I (BPI) results in diminished quality of life as measured by health utility and QOL and utility-based health-related quality of life. The QOL losses in patients with BPI were less than those in persons with schizophrenia. The patients with depression sustained the greatest loss in QOL. [117]

In a study by Fiedorowicz et al, hypomania symptoms were frequently associated with progression to bipolar disorder, even when symptoms were low intensity; however, most patients did not have hypomania symptoms at baseline. [118] The study concluded that monitoring for progression to bipolar disorder is necessary in patients with long-term major depressive disorder.

Some of the most challenging situations involve children and adolescents with severe emotional lability. Often, psychiatrists have applied the bipolar diagnosis to this group. Leibenluft reviewed this situation and concluded that children have increasingly been diagnosed with bipolar disorder. [119] In some cases, the criteria were clearly met, whereas other cases were less clear.

Severe mood dysregulation is a syndrome formulated to describe the symptoms of children who do not clearly meet the criteria for bipolar disorder. Leibenluft’s findings revealed that nonepisodic irritability in youths is common and is associated with an elevated risk for anxiety and unipolar depressive disorders (not bipolar disorders) in adulthood. In fact, data suggest that children and adolescents with severe mood dysregulation have lower familiar rates of bipolar disorder than children and adolescents with bipolar disorder.

Prevention and Long-Term Monitoring

Prevention is the key to the long-term treatment of bipolar disorders, or manic-depressive illness (MDI), as follows:

• First, use medications such as lithium serve as mood stabilizers

• Second, psychoeducation is instituted for the patient and the patient’s family; it is critical that the patient and the patient’s family understand and recognize the importance of medication compliance and the early signs of mania and depression

Regardless of the pharmacologic regimen chosen in individual patients with acute bipolar mania, hypomania, or mixed episodes, and those with bipolar depression, reevaluate for treatment response every 1-2 weeks for a minimum of 6 weeks. [3] Continue to monitor these individuals for the following situations [3] :

• Depressive symptoms (or changes in), suicidal/homicide ideation

• Neurovegetative symptoms

• New-onset/change in psychotic symptoms or manic/hypomanic symptoms

• Illicit substance use

• Medication side effects and compliance

• Medical stability

• Significant psychosocial changes

Reevaluate all patients for treatment response at 4-8 weeks, after each change in treatment, and periodically until full remission is achieved. [3] Full remission is defined in patients with mania as the absence of significant mania symptoms for 2 months; in patients with mixed episode, it is the absence of significant mania or depression symptoms for 2 months; and in those with bipolar depression, it is the absence of significant depressive symptoms for 2 months.

Treat adult patients who have had an acute manic episode for a minimum of 6 months after the initial episode is controlled; encourage these individuals—as well as those who have had more than 1 manic episode or with 1 manic and 1 depressive episode, or 3 or more depressive episodes—to continue on lifelong prophylactic pharmacotherapy. [3] Following full remission of the depressive episode, consider withdrawing antidepressant treatment after 4-6 months. Discontinuation should consist of a gradual taper over a minimum 2-4–week period, unless medically contraindicated. [3]

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Author

Stephen Soreff, MD President of Education Initiatives, Nottingham, NH; Faculty, Boston University, Boston, MA and Daniel Webster College, Nashua, NH

Stephen Soreff, MD is a member of the following medical societies: ACMHA: The College for Behavioral Health Leadership

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

Glen L Xiong, MD Associate Clinical Professor, Department of Psychiatry and Behavioral Sciences, Department of Internal Medicine, University of California, Davis, School of Medicine; Medical Director, Sacramento County Mental Health Treatment Center

Glen L Xiong, MD is a member of the following medical societies: AMDA - The Society for Post-Acute and Long-Term Care Medicine, American College of Physicians, American Psychiatric Association, Central California Psychiatric Society

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: SafelyYou, Blue Cross Blue Shield, Included Health<br/>book co-editor for: Wolter Kluwer, American Psychiatric Publishing Inc.

Additional Contributors

Acknowledgements

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

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