Bipolar affective disorder, or manic-depressive illness (MDI), is a common, severe, and persistent mental illness. This condition is a serious lifelong struggle and challenge.
Signs and symptoms
Bipolar affective disorder is characterized by periods of deep, prolonged, and profound depression that alternate with periods of an excessively elevated or irritable mood known as mania.
Manic episodes are feature at least 1 week of profound mood disturbance, characterized by elation, irritability, or expansiveness (referred to as gateway criteria). At least 3 of the following symptoms must also be present[2] :
- Grandiosity
- Diminished need for sleep
- Excessive talking or pressured speech
- Racing thoughts or flight of ideas
- Clear evidence of distractibility
- Increased level of goal-focused activity at home, at work, or sexually
- Excessive pleasurable activities, often with painful consequences
Hypomanic episodes are characterized by an elevated, expansive, or irritable mood of at least 4 consecutive days’ duration. At least 3 of the following symptoms are also present :
- Grandiosity or inflated self-esteem
- Diminished need for sleep
- Pressured speech
- Racing thoughts or flight of ideas
- Clear evidence of distractibility
- Increased level of goal-focused activity at home, at work, or sexually
- Engaging in activities with a high potential for painful consequences
Major depressive episodes are characterized as, for the same 2 weeks, the person experiences 5 or more of the following symptoms, with at least 1 of the symptoms being either a depressed mood or characterized by a loss of pleasure or interest :
- Depressed mood
- Markedly diminished pleasure or interest in nearly all activities
- Significant weight loss or gain or significant loss or increase in appetite
- Hypersomnia or insomnia
- Psychomotor retardation or agitation
- Loss of energy or fatigue
- Feelings of worthlessness or excessive guilt
- Decreased concentration ability or marked indecisiveness
- Preoccupation with death or suicide; patient has a plan or has attempted suicide
See Clinical Presentation for more detail.
Diagnosis
Examination of patients with suspected bipolar affective disorder includes evaluation using the Mental Status Examination as well as assessment of the following:
- Appearance
- Affect/mood
- Thought content
- Perception
- Suicide/self-destruction
- Homicide/violence/aggression
- Judgment/insight
- Cognition
- Physical health
Testing
Although bipolar disorder is diagnosed based on the patient’s history and clinical course, laboratory studies may be necessary to rule out other potential causes of the patient’s signs and symptoms as well as to have baseline results before administering certain medications.
Laboratory tests that may be helpful include the following:
- CBC count
- ESR levels
- Fasting glucose levels
- Electrolyte levels
- Protein levels
- Thyroid hormone levels
- Creatinine and blood urea nitrogen levels
- Liver and lipid panel
- Substance and alcohol screening
Depending on the patient’s presentation, other laboratory tests may be indicated, which may include the following:
- Urinary copper levels
- Antinuclear antibody testing
- HIV testing
- VDRL testing
Electrocardiography is important in elderly patients and before antidepressant therapy. Electroencephalography and/or MRI may be appropriate for selected patients.
See Workup for more detail.
Management
The treatment of bipolar affective disorder is directly related to the phase of the episode (ie, depression or mania) and the severity of that phase, and it may involve a combination of psychotherapy and medication. 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.
Pharmacotherapy
Medications used to manage patients with bipolar disorder include the following:
- Benzodiazepines (eg, lorazepam, clonazepam)
- Antimanic agents (eg, lithium)
- Anticonvulsants (eg, carbamazepine, valproate sodium, valproic acid, divalproex sodium, lamotrigine, topiramate)
- First-generation antipsychotics (eg, inhaled loxapine, haloperidol)
- Second-generation antipsychotics (eg, asenapine, ziprasidone, quetiapine, risperidone, aripiprazole, olanzapine, olanzapine and fluoxetine, clozapine, paliperidone)
- Phenothiazine antipsychotics (eg, chlorpromazine)
- Dopamine agonists (eg, pramipexole)
Nonpharmacotherapy
Psychotherapy may help to decrease relapse rates, improve quality of life, and/or increase functioning, or more favorable symptom improvement.[4]
Electroconvulsive therapy may be useful in selected patients with bipolar disorder.
Pharmacologic Therapy
Appropriate medication depends on the stage of the bipolar affective 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 affective 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)
| Generic Name | Trade Name | Manic | Mixed | Maintenance | Depression |
| Valproate | Depakote | X | |||
| Carbamazepine extended release | Equetro | X | X | ||
| Lamotrigine | Lamictal | X | |||
| Lithium | X | X | |||
| Aripiprazole | Abilify | X | X | X | |
| Ziprasidone | Geodon | X | X | ||
| Risperidone | Risperdal | X | X | ||
| Asenapine | Saphris | X | X | ||
| Quetiapine | Seroquel | X | X | ||
| Chlorpromazine | Thorazine | X | |||
| Olanzapine | Zyprexa | X | X | X | |
| Olanzapine/fluoxetine combination | Symbyax | X | |||
| FDA = United States Food and Drug Administration. Source: Gutman DA, Nemeroff C.Medscape Education. Atypical antipsychotics in bipolar disorder.Available at:http://www.medscape.org/viewarticle/554128. Accessed: June 27, 2007.[79] | |||||
Bauer and colleagues have suggested 2 approaches to treatment options in bipolar patients. 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. 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.
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.
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.
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. 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).
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.
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]
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.[53] 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.[53]
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.
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.
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.[84] 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.[85]
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 (ie, 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.”[86] 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.[87] 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.[88]
Clinical experiences have shown that patients with bipolar disorder have fewer episodes of mania and depression when treated with mood-stabilizing drugs.[89]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.[90]
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.[91]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.[91]
Maintenance
The role of mood stabilizers and antipsychotic medications in maintaining patients with bipolar disorder is well documented,[92] 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.[53]
Popovic et al suggested the use of a Polarity Index to guide the choice of maintenance therapy in bipolar patients.[93] 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.[93] 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[93] :
- 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.[93]
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.[94]
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.[95] In several randomized, double-blind, controlled studies, olanzapine monotherapy was significantly more effective in treating manic or mixed episodes than haloperidol[96] or divalproex monotherapy.[97] The adjunctive use of olanzapine with divalproex or lithium,[98] or of risperidone with divalproex or lithium, was also significantly more effective than divalproex or lithium alone.[99, 100]
As outlined in the APA’s 2002 clinical practice guideline,[101] benzodiazepines have sedative effects, which may make them useful adjunctive medications until antimanic medications take effect. 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.[102]
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).[103] 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.[103]
Caution in polyantipsychotic therapy in bipolar disorder
In August 2010, the FDA announced that lamotrigine carries a risk of aseptic meningitis.[104]
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.[105] Therefore, polytherapy in bipolar disorder may incur important disadvantages without clear benefit, warranting careful consideration before undertaking such interventions.
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