Mood Disorders— Bipolar Disorder

Donald M. Hilty MD

Martin H. Leamon MD

Elizabeth N. Gutierrez MD

Donald R. Ebersole MD

Russell F. Lim MD

A 35-year-old man presents to the outpatient clinic with the following request: “I want to be checked for high blood pressure.” During the interview, the patient states, “I was on fluoxetine a few years ago and my wife thinks I need something to take the edge off.” Currently he is not feeling depressed, but his wife encouraged him to discuss his episodic irritability at this visit. These episodes appear in waves of weeks, several times per year. He mentioned that his wife took him to the emergency room for a prior “episode.”

CLINICAL HIGHLIGHTS

The “building blocks” for both bipolar spectrum disorders include depressive, hypomanic, manic, and mixed episodes. Patients with bipolar disorder I must have had at least one manic or mixed episode and those with bipolar II must have had at least one depressive and one hypomanic episode. The principle difference between a manic and a hypomanic episode is that the former must result in significant social or occupational dysfunction or need for psychiatric admission.
Most patients with bipolar disorder present with depression, so it is important to screen for bipolar disorder in all patients who present with depressive symptoms.
The classic presentation of bipolar mania may be absent in many patients. There is a delay in an accurate diagnosis of bipolar disorder that averages about 8 years after the initial presentation to a mental health professional.
Up to 30% of depressed and anxious patients who present to primary care settings may have an underlying bipolar disorder.
Bipolar disorder is a chronic disease with an episodic, relapsing-remitting condition that requires long-term treatment.
Bipolar disorder occurs frequently with substance use disorders and attention deficit hyperactivity disorder (ADHD).
The contemporary treatment of bipolar acute manic or mixed states involves the use of combination therapy with a mood stabilizer and a second-generation antipsychotic (SGA).
Treatment options for bipolar depression include lamotrigine, lithium, quetiapine, and an antidepressant combined with a mood stabilizer or SGA. As a general rule, antidepressants should not be used as monotherapy to treat a bipolar spectrum disorder.

Clinical Significance

Establishing an accurate diagnosis and appropriate treatment plan for patients with bipolar disorder in the primary medical setting is challenging (1). The lifetime prevalence of bipolar I and bipolar II disorders has been estimated to be 1.0% and 0.8%, respectively (2). Bipolar disorder is a significant source of morbidity and mortality. The World Health Organization (WHO) found bipolar disorder to be the world’s sixth leading cause of disability (adjusted life years) for people aged 15 to 44 years. As many as 25% to 50% of bipolar patients attempt suicide during their lifetime and about 15% of inadequately treated bipolar patients die by suicide. Additionally, up to 30% of depressed and anxious patients who present to primary care settings may have an underlying bipolar disorder (3, 4). Therefore, health service utilization rates for patients with bipolar disorder are increasing and many patients are presenting to their primary care providers for treatment.

Diagnosis

The diagnosis of bipolar disorder is often difficult due to its fluctuating course and variable presentation. Patients usually present in a depressed state rather than a manic state. Furthermore, they may not accurately recall previous manic episodes. A misdiagnosis of bipolar depression as unipolar or major depressive disorder can lead to ineffective and possibly adverse treatment outcomes. The National Depressive and Manic-Depressive Association survey of bipolar members showed an average delay of 8 years between the first presentation to mental health professionals and correct diagnosis.

The “building blocks” for both bipolar spectrum disorders include manic, hypomanic, mixed, and depressive episodes. The Diagnostic and Statistical Manual of Mental Disorders, 4th ed., text revision (DSM-IV-TR), defines a manic episode as “a distinct period of abnormally and persistently elevated, expansive, or irritable mood, lasting at least 1 week, or any duration if hospitalization is necessary” (5). During this period of mood disturbance, other manic symptoms also have to be present (Table 3.1). More importantly, the mood disturbance should be sufficiently severe to cause impairment in functioning. The criteria for a hypomanic episode are the same for a manic episode, except the duration of the mood disturbance is at least 4 days rather than 1 week, and the disturbance causes less impairment in functioning without the need for psychiatric hospitalization. A mixed episode is defined as a period lasting 1 week when the criteria for both a depressive episode and a manic episode are simultaneously met. During this week, the individual may experience mood fluctuation between depression, irritability, unexplained agitation, and euphoria. A depressive episode is defined as the presence of either a depressed mood or loss of interest in pleasurable activities for at least 2 weeks. Four other symptoms (e.g., sleep disturbance, weight changes, decreased energy and concentration, guilty thoughts, psychomotor changes, and suicidal ideation) must also be present during this same time period.

The diagnosis of bipolar I disorder is made with the presence (or history) of at least one manic or mixed episode. The diagnosis of bipolar II disorder is indicated with the presence (or history) of at least one major depressive and one hypomanic episode. It is important to remember that most bipolar patients spend more time in depressed episodes than manic episodes, but the presence of one or more hypomanic or manic episodes changes the diagnosis from unipolar (i.e., major depressive disorder) to bipolar disorder.

Table 3.1 DSM-IV-TR Criteria for a Manic Episode

A.	A distinct period of abnormally and persistently elevated, expansive, or irritable mood, lasting at least 1 week (or any duration if hospitalization is necessary)
B.	During the period of mood disturbance, three (or more) of the following symptoms have persisted (four if the mood is only irritable) and have been present to a significant degree:
	1.	Inflated self-esteem or grandiosity
	2.	Decreased need for sleep
	3.	More talkative than usual or pressure to keep talking
	4.	Flight of ideas or subjective experience that thoughts are racing
	5.	Distractibility
	6.	Increase in goal-directed activity or psychomotor agitation
	7.	Excessive involvement in pleasurable activities that have a high potential for painful consequences
From Diagnosis and Statistical Manual of Mental Disorders. 4th ed., text revision. Washington DC: American Psychiatric Association; 2002.

Table 3.2 Screening Questions for Manic and Hypomanic Episodes

1.	“Have you ever felt the complete opposite of depressed, where friends and family were worried about you because you were too happy?”
2.	“Have you ever had excessive amounts of energy running through your body, to the point where you did not need to sleep for days?”
	•	“How long did these symptoms last?”
	•	“During these periods, did you feel like your thoughts were going really fast and it was hard to focus?”
	•	“During these periods, did people comment that you were talking really fast?”
	•	“During these periods, did you ever make impulsive decisions that you regretted later (e.g., spending too much money or being sexually promiscuous)?”
	•	“During any of these periods, did your behaviors get you into trouble at work, at home, or with the law, or cause you to end up in the hospital?”
	•	“During these periods, were you using any alcohol or substances?”

PATIENT ASSESSMENT

For patients who do not clearly present in a manic episode, it can be challenging to elicit the history of a previous manic episode. Some sample interview questions designed to increase recognition of a prior manic or hypomanic episode are presented in Table 3.2. Grouping several symptoms together and specifically asking whether they occurred simultaneously can be more revealing when establishing a manic or hypomanic episode. When patients report that their mood episodes last for only a few minutes or hours or less than a day, the differential diagnosis may include a rapid-cycling bipolar disorder, malingering, and personality disorders. Rapid-cycling bipolar disorder occurs infrequently and is defined by the presence of four or more discrete mood (depressive or manic) episodes within 12 months.

The Mood Disorder Questionnaire (MDQ) is a validated, self- or clinician-administered questionnaire that takes about 5 minutes to complete and consists of 17 questions (6) (Figure 3.1). The first section contains 13 questions with yes or no answers about possible symptoms. The second section asks whether the symptoms occurred simultaneously, whereas the other questions assess severity, family history, and past diagnosis. A positive screen consists of seven or more affirmative answers to item 1, an affirmative answer to item 2, and at least a “moderate or serious” problem for section 3. The MDQ can identify 7 of 10 patients with bipolar disorder and eliminates 9 of 10 without it. The MDQ has also been validated in the general medical population (7).

In addition to screening for depression and mania, a sleep history should be obtained. Patients with mania or hypomania often report chronic insomnia or episodes of decreased need for sleep. On examination, patients with mania often present with rapid, pressured speech that may be difficult to interrupt. They may be highly distractible or fidgety and have a hard time focusing on the interview. Racing thoughts may explicitly manifest as a flight of ideas (when the interview jumps from one topic to the next) or looseness of association (when multiple disconnected topics are discussed). The content of their thoughts may

be grandiose or delusional and themes of exaggerated power and achievement are often present.

Figure 3.1. The mood disorder questionnaire (6). (© 2000 by American Psychiatric Publishing, Inc. Reprinted with permission. This instrument is designed for screening purposes only and is not to be used as a diagnostic tool.)

A review of medical conditions, past psychiatric history, substance use, and current medications are indicated, as well as a physical examination and basic laboratory studies (e.g., thyroid function tests and urine toxicology). Collateral information from significant others, family members, and friends should be obtained whenever possible to remedy any recall errors.

Differential Diagnosis

Manic or depressive symptoms can be indicators of general medical, substance use, mood, or psychotic disorders (Table 3.3). The general approach is to rule out treatable general medical conditions, to identify substance-induced disorders, and then to differentiate among the mood and psychotic disorders. General medical conditions that may mimic manic or depressive symptoms include neurologic, infectious, immunologic, metabolic, and endocrine disorders.

Acute intoxication with stimulants such as methamphetamine or cocaine can mimic a manic episode, whereas withdrawal from these substances can mimic a depressive episode. Chronic use of any substance can also induce chronic mood changes that can be difficult to
distinguish from a primary mood disorder. Therefore, it is important to inquire about the existence of any mood disturbances during periods of sobriety.

Table 3.3 Medications and Medical Conditions Associated with Mood Disturbances

Medications
•	Antidepressants
•	Corticosteroids
•	Dopamine agonists
•	Isoniazid
•	Interferon
•	Opioids
•	Sedatives-hypnotics
•	Stimulants
•	Sympathomimetics
General Medical Conditions
•	Adrenal disorders
•	CNS infections (e.g., HIV, herpes, syphilis)
•	Brain tumor
•	Huntington disease
•	Multiple sclerosis
•	Parkinson disease
•	Porphyria
•	Seizure disorder
•	Stroke
•	Systemic lupus erythematosus
•	Thyroid disorder
•	Traumatic brain injury
•	Vasculitis
•	Vitamin B₁₂ deficiency
•	Wilson disease
Substance Conditions Intoxication
•	Alcohol
•	Amphetamines
•	Cocaine
•	Caffeine
•	Phencyclidine
•	Hallucinogens
Withdrawal
•	Alcohol
•	Barbiturates
•	Benzodiazepines
Other Psychiatric Conditions
•	Schizoaffective disorder
•	Schizophrenia
•	Major depressive disorder
•	Attention deficit hyperactivity disorder
•	Borderline personality disorder
•	Narcissistic personality disorder
CNS, central nervous system; HIV, human immunodeficiency virus.

Among psychiatric disorders, bipolar depression must be distinguished from major depression (by the absence of manic or hypomanic episodes) and less severe forms of depression including adjustment disorder, and dysthymia. Acute manic or mixed episodes may also present with psychotic symptoms, often making it difficult to distinguish from a primary psychotic disorder such as schizophrenia. Psychosis from a manic episode tends to be more grandiose and less bizarre or disorganized than the psychosis related to schizophrenia. Some patients meet the criteria of schizophrenia and a mood disorder (either bipolar disorder or major depressive disorders) and are diagnosed with schizoaffective disorder, depressive or bipolar type. In these patients, the psychosis persists even when the mood symptoms are absent (Figure 3.2).

Other psychiatric disorders may contain symptoms that overlap with bipolar disorder, making the differential diagnosis even more complex. These symptoms include hyperactivity, distractibility, and the impulsivity seen with ADHD and mood lability and impulsivity seen with borderline and cluster B personality disorders (8). Usually, ADHD and personality disorders have a more consistent and chronic course with a preadolescent onset whereas bipolar disorder has an episodic relapsing-remitting course with symptom-free periods in between episodes. In practice, bipolar disorder is often difficult to distinguish from ADHD or borderline personality disorder. These conditions are often highly comorbid and therefore the same patient may have bipolar disorder and ADHD or borderline personality disorder.

Biopsychosocial Treatment

TREATMENT PRINCIPLES

The principles of bipolar disorder management are outlined in Table 3.4 (9). In general, pharmacotherapy is a key component for the treatment of bipolar disorder. The number of medications with Food and Drug Administration (FDA) indications for both bipolar mania and depression has expanded rapidly over the last decade. Nevertheless, a strong, trusting therapeutic relationship is fundamental for enhancing adherence to treatment, detecting recurrence of illness, and addressing psychosocial stressors. Patients require ongoing education regarding the illness, treatment options, medication side effects, and impact of the illness on family and friends, employment, and finances. When needed, families often provide support, living arrangements, and input on treatment adherence. National organizations also offer significant education and social support (see Practical Resources).

PHARMACOTHERAPY

The American Psychiatric Association (APA) treatment guideline for bipolar disorder provides an evidence-based and detailed overview of
the treatment for bipolar disorder (10). Manic episodes frequently require psychiatric hospitalization. For acute bipolar mania, a mood stabilizer (except lamotrigine) is generally indicated in combination with an SGA (11). SGAs have FDA approval for acute bipolar manic and mixed episodes (Table 3.5). For bipolar depression, lamotrigine, lithium, quetiapine, and an antidepressant combined with a mood stabilizer or an SGA are possible options. There is currently no FDA-approved medication
specifically for the treatment of bipolar II disorder, per se. The hypomania of bipolar II may be treated with a mood stabilizer and/or an SGA. The approach to the treatment of depression is similar for both bipolar I and bipolar II disorders. Antidepressants should be used with caution in patients with bipolar disorder (particularly when used as monotherapy) because it carries a small but unpredictable risk of inducing mania and agitation (12).

Figure 3.2. Diagnostic algorithm for bipolar disorders. (Adapted with permission from Diagnosis and Statistical Manual of Mental Disorders. 4th ed., text revision. Washington DC: American Psychiatric Association; 2002: Appendix A.)

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