Bipolar Disorder

Bipolar disorder (BPD) is characterized by chronic, recurrent, disabling mood symptoms further complicated by high rates
of suicide, substance use, comorbid psychiatric disorders, and mortality. All contribute to the lower life expectancy seen in this condition. The US lifetime prevalence rate of bipolar I disorder is estimated to be 1.3%. When bipolar II and other more subtle forms of the illness (e.g., cyclothymic disorder) are included, the prevalence rate may be as high as 3.7%. There is an equal distribution among ethnic groups and between men and women. The onset of this disorder is usually before the age of 20 peaking between the ages of 15 to 19, but a definitive diagnosis is often delayed by several years. BPD produces substantial disability and functional impairment in work, leisure, and interpersonal activities, both during and between mood episodes.

Mania/hypomania, depression, or their combination (i.e., mixed states) are the primary mood symptoms. Bipolar I disorder includes full mania and full depression, whereas bipolar II disorder involves hypomania and full depression. Associated symptoms of mania/hypomania may include hyperactivity, pressured speech, flight of ideas, inflated self-esteem, decreased need for sleep, distractibility, and excessive involvement in activities that have a high potential for painful consequences. The course of illness can vary from only a few episodes to a more virulent pattern characterized by multiple episodes over short periods of time (e.g., rapid cycling that involves four or more episodes per year). Of note, depression is often the heralding symptom and patients usually experience more time depressed than manic/hypomanic over the course of their illness. More severe episodes can present with psychotic features and impulsive destructive behavior. For example, the suicide rate for BPD is approximately 10% in untreated patients and approximately 25% attempt suicide at some point. The risk for suicide is greatest during a depressed or mixed symptom episode.

DIFFERENTIAL DIAGNOSIS

BPD is often mistaken for other conditions (e.g., unipolar depression, schizophrenia, attention deficit hyperactivity disorder [ADHD]). This can substantially delay accurate diagnosis and implementation of appropriate treatment. Further, other comorbid conditions are common (e.g., substance abuse) and can also impede proper diagnosis.

Secondary mania can be precipitated by a variety of medical conditions (e.g., hyperthyroidism, complex partial seizures), medications (e.g., steroids, tricyclic antidepressants), or drug intoxication/withdrawal (e.g., amphetamines, cocaine).

Substance and alcohol abuse or dependence frequently co-occur, can mimic mood symptoms seen in BPD, make accurate diagnosis more difficult, worsen the long-term course, and compromise otherwise effective treatments.

Other comorbid conditions frequently associated with BPD include obsessive compulsive disorder, panic disorder, bulimia nervosa, impulse control disorder, ADHD, conduct disorder, and certain personality disorders.

NEUROBIOLOGY

As with many psychiatric disorders, the cause of this condition involves both biological predisposition and environmental influences. Several hypotheses have been proposed including abnormalities in:

Neurotransmission (e.g., norepinephrine, serotonin)
Second messenger systems (e.g., phosphoinositide cycle)
Biological rhythms (e.g., sleep-wake cycle)
Neuroanatomy
Neurophysiology (e.g., kindling phenomenon)
Immune function

From a genetic perspective, family studies establish a pattern of aggregation; linkage studies identify specific genomic regions associated with the disorder; and twin studies estimate concordance rates to be 14% for dizygotic twins and 57% for monozygotic twins. The absence of 100% concordance rate in monozygotic twins, however, indicates an important role
for environmental factors. Therefore, a genetic-environmental interaction has been proposed in which a number of small susceptibility genes establish a gradient of liability that may trigger BPD in the context of various stressors. Of note, linkage studies report a number of genomic regions that may represent susceptibility loci for both BPD and schizophrenia. This is consistent with several clinical characteristics that these two disorders have in common.

TREATMENT OF BIPOLAR DISORDER

The optimal treatment of BPD requires early identification, medication, psychotherapy, and attention to concurrent psychiatric and medical disorders. Therefore, the management of BPD is complicated and must encompass effective treatments to minimize the frequency and severity of acute episodes, ensure long-term mood stabilization, and minimize the risk for suicide. In addition, education of patients and their families is crucial to long-term success. Although medication is clearly the necessary first step, various psychotherapeutic interventions (e.g., interpersonal social rhythm therapy [IPSRT], cognitive behavioral therapy [CBT], family focused therapy [FFT], or psychoeducation) may substantially enhance the beneficial effects of mood stabilizers.

Pharmacotherapy for Bipolar Disorder

In keeping with the multiple symptoms of BPD, several classes of psychotropics are used including:

Mood stabilizers
Antipsychotics
Antidepressants
Antianxiety/sedative-hypnotics

The ideal mood stabilizer should control symptoms of acute mania and depression, stabilizemood long-term, decrease suicidal propensity, minimize switches from one mood state to another, and not worsen the course of illness (e.g., induce rapid cycling). The ideal approach is a single-drug therapy, usually combined with psychotherapy. Table 8-1 lists the most common medications
used to treat BPD and Table 8-2 lists their most common adverse effects.

TABLE 8-1 Medications for Treatment of Bipolar Disorder

*Class/Generic Name*	*Trade Name (Indication)*	*Usual Daily Dosage (mg/d)*
Cation
Lithonate, others	Lithium (A, M)	600-2,700
Antiepileptic
Depakote	Divalproex (A)	750-2,500
Lamictal	Lamotrigine (M)	50-400
Equetro	Carbamazepine ER (A)	400-1600
Antipsychotic
Thorazine	Chlorpromazine (A)	300-900
Zyprexa	Olanzapine (A, M, ADJ)	10-20
Risperdal	Risperidone (A, ADJ)	2-6
Seroquel	Quetiapine (A, AD, ADJ)	300-800
Abilify	Aripiprazole (A, M)	10-30
Geodon	Ziprasidone (A)	80-160
Antipsychotic plus antidepressant
Symbyax	OLZ/FLU (AD)	6 or 12 (OLZ)
		25 or 50 (FLU)
A, acute mania; M, maintenance therapy; ADJ, adjunct; AD, acute depression; OLZ, olanzapine; FLU, fluoxetine.
(Adapted from Janicak et al. Principles and Practice of Psychopharmacotherapy, 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2006.)

For bipolar mania, if one or two adequate trials with a classic mood stabilizer (e.g., lithium or divalproex sodium) are insufficient, then various drug combinations are usually attempted (e.g., lithium plus divalproex sodium). The second-generation antipsychotics (SGAs) (e.g., olanzapine, risperidone, quetiapine, ziprasidone, and aripiprazole) have all demonstrated antimanic
properties separate from their antipsychotic effects. Therefore, they are an alternate strategy either as monotherapy or in combination with other agents.

TABLE 8-2 Common adverse effects with mood stabilizers

*Drug*	*Weight Gain*	*Central Nervous System*	*EPS*	*Derm*	*Qtc*	*HEM*
Cation
Lithium	++	+++	0	++	0	+
^aAntiepileptic
Divalproex DR, ER	++	++	0	+	0	+
Lamotrigine	±	+	0	+++	0	±
Carbamazepine ER	±	+++	0	+++	0	++
Antipsychotic
Olanzapine	+++	++	+	+	0	0
Risperidone	++	+	++	+	0	0
Quetiapine	++	++	0	+	0	0
Ziprasidone	±	+	+	+	±	0
Aripiprazole	±	+	+	+	0	0
Paliperidone ER	++	+	++	+	±	0
Clozapine	+++	+	0	+	0	+++
^aFood and Drug Administration (FDA) recently issued warning of possible increased suicidal risk with antiepileptic drugs (AEDs), particularly in patients with epilepsy.
DR, delayed release; ER, extended release; EPS, extrapyramidal side effects; QTc, corrected QT interval; Derm, dermatological; Hem, hematological; +, mild; ++, moderate; +++, substantial; 0, none; ±, Possible issue conflicting data.
(Adapted from Strakowski SM, DelBelloMP, Adler CM. Comparative efficacy and tolerability of drug treatments for bipolar disorder. CNS Drugs. 2001;15(9):701-718; Strakowski SM, DelBello MP, Adler CM, et al. Atypical antipsychotics in the treatment of bipolar disorder [Review]. Exp Op Pharmacother. 2003;4(5):751-760.)