Brian L. Crabtree and Martha J. Faulkner
LEARNING OBJECTIVES
Upon completion of the chapter, the reader will be able to:
1. Explain the pathophysiologic mechanisms underlying bipolar disorder.
2. Recognize the symptoms of a manic episode and depressive episode in patients with bipolar disorder.
3. Identify common comorbidities of bipolar disorder.
4. Recognize the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria for bipolar disorder as well as the subtypes of bipolar I disorder, bipolar II disorder, and cyclothymic disorder.
5. List the desired therapeutic outcomes for patients with bipolar disorder.
6. Explain the use of drugs as first-line therapy in bipolar disorder, including appropriate dosing, expected therapeutic effects, potential adverse effects, and important drug–drug interactions.
7. Recommend individualized drug therapy for acute treatment and relapse prevention based on patient-specific data.
8. Recommend monitoring methods for assessment of therapeutic and adverse effects of drugs used in the treatment of bipolar disorder.
9. Recommend treatment approaches for special populations of patients with bipolar disorder, including pediatric patients, geriatric patients, and pregnant patients.
10. Educate patients with bipolar disorder about their illness, drug therapy required for effective treatment, and the importance of adherence.
KEY CONCEPTS
Patients presenting with depressive or elevated mood features and a history of abnormal or unusual mood swings should be assessed for bipolar disorder.
The diagnosis of bipolar disorder is made based on clinical presentation, a careful diagnostic interview, and review of the history. There are no laboratory examinations, brain imaging studies, or other procedures that confirm the diagnosis.
Goals of treatment are to reduce symptoms, induce remission, prevent relapse, improve patient functioning, and minimize adverse effects of drug therapy.
Psychotherapy improves functional outcomes and may help treat or prevent mood episodes.
The primary treatment modality for manic episodes is mood stabilizing agents, often combined with antipsychotic drugs.
The primary treatment for depressive episodes in bipolar disorder is mood stabilizing agents or certain antipsychotic drugs, sometimes combined with antidepressant drugs.
The primary treatment for relapse prevention is mood stabilizing agents, often combined with antipsychotic drugs.
Education of the patient regarding benefits and risks of drug therapy and the importance of adherence to treatment must be integrated into pharmacologic management.
INTRODUCTION
Bipolar disorder is a mood disorder characterized by one or more episodes of mania or hypomania, often with a history of one or more major depressive episodes.1 It is a chronic illness with a course characterized by relapses and improvements or remissions. Mood episodes can be manic, depressed, or mixed. They can be separated by long periods of stability or can cycle rapidly. They occur with or without psychosis. Disability and other consequences (i.e., increased risk of suicide) of bipolar disorder can be devastating to patients. Correct diagnosis and treatment are essential as early as possible in the course of the illness to prevent complications and maximize response to treatment.
Patient Encounter, Part 1
MW, a 43-year-old Caucasian female, is a married mother of two boys and is moderately obese. She is dressed in a short skirt, low-cut blouse, heavy makeup, and is somewhat disheveled. Motorically, she is mildly agitated, speaking rapidly, has fair eye contact, and appears tired and anxious.
Chief complaint: “I am about to get fired from my job, and I can’t seem to get any sleep.”
What diagnoses are suggested by this patient’s presentation?
What additional information is needed to clarify the diagnosis?
EPIDEMIOLOGY AND ETIOLOGY
Epidemiology
Bipolar disorders have been categorized into bipolar I disorder, bipolar II disorder, and bipolar disorder not otherwise specified (NOS). Bipolar I disorder is characterized by one or more manic or mixed mood episodes. Bipolar II disorder is characterized by one or more major depressive episodes and at least one hypomanic episode. Hypomania is an abnormally and persistently elevated, expansive, or irritable mood, but not of sufficient severity to cause significant impairment in social or occupational function and does not require hospitalization. The lifetime prevalence of bipolar I disorder is estimated to be between 0.3% and 2.4%. The lifetime prevalence of bipolar II disorder ranges from 0.2% to 5%. When including the bipolar spectrum, the lifetime prevalence is between 3% and 6.5%.1
Bipolar I disorder affects men and women equally. Bipolar II is more common in women. Rapid cycling and mixed mood episodes occur more often in women. In all, 78% to 85% of individuals with bipolar disorder report having another Diagnostic and Statistical Manual, Fourth Edition, Text Revision (DSM-IV-TR) diagnosis during their lifetime. The most common comorbid conditions include anxiety, substance abuse, and eating disorders.2
The mean age of onset of bipolar disorder is 20, although onset may occur in early childhood to the mid-40s.1 If the onset of symptoms occurs after age 60, the condition is probably secondary to medical causes. Early onset of bipolar disorder is associated with greater comorbidities, more mood episodes, a greater proportion of days depressed, and greater lifetime risk of suicide attempts, compared to bipolar disorder with a later onset. Substance abuse and anxiety disorders are more common in patients with an early onset. Patients with bipolar disorder also have higher rates of suicidal thinking, suicide attempts, and completed suicides.
Etiology
The precise etiology of bipolar disorder is unknown. Thought to be genetically based, bipolar disorder is influenced by a variety of factors that may enhance gene expression. These include trauma, environmental factors, anatomical abnormalities, exposure to chemicals or drugs, and others.3–5 Neurochemical abnormalities in bipolar disorder may be caused by these factors, discussed further in the pathophysiology section.
PATHOPHYSIOLOGY
Neurochemical
The pathophysiology of bipolar disorder remains incompletely understood. Imaging techniques such as positron emission tomography (PET) scans and functional MRI (fMRI) are being used to elucidate the cause. Research in the 1970s focused on neurotransmitters such as norepinephrine (NE), dopamine (DA), and serotonin. One hypothesis was that bipolar disorder is caused by an imbalance of cholinergic and catecholaminergic neuronal activity. Serotonin (5-HT) has been suggested to modulate catecholamine activity. Dysregulation of this relationship could cause a mood disturbance.6 An early theory was that elevation of NE and DA caused mania, and a reduction caused depression, but this theory is now considered overly simplistic.3 Other neurotransmitters are involved and interact with multiple neurochemical and neuroanatomic mechanisms and pathways. The pathophysiology of bipolar disorder has also been hypothesized from the mechanisms of action of lithium and other mood stabilizers. Lithium, valproate, and carbamazepine all have similar effects on neuronal growth that are reversible by inositol, supporting the hypothesis that bipolar disorder is related to inositol disturbance.7 Evidence has shown that brain-derived neurotrophic factor (BDNF) may also play a role in bipolar disorder. Serum BDNF is low in mania and improves with response to treatment.8
Genetic
Results of family and twin studies suggest a genetic basis for bipolar disorder.4 The lifetime risk of bipolar disorder in relatives of a bipolar patient is 40% to 70% for a monozygotic twin and 5% to 10% for another first-degree relative.
CLINICAL PRESENTATION AND DIAGNOSIS
Diagnosis of Bipolar Disorder
Bipolar disorder can be conceptualized as a continuum or spectrum of mood disorders.9 They include four subtypes: bipolar I (periods of major depressive, manic, and/or mixed episodes); bipolar II (periods of major depression and hypomania); cyclothymic disorder (periods of hypomanic episodes and depressive episodes that do not meet all criteria for diagnosis of a major depressive episode), and bipolar disorder NOS. The defining feature of bipolar disorders is one or more manic or hypomanic episodes in addition to depressive episodes that are not caused by a medical condition, substance abuse, or other psychiatric disorder.1
Patient Encounter, Part 2: Medical History, Physical Exam, Laboratory Exam
The interview reveals the following additional information about MW.
PMH: Para 2, gravida 2.
Hx: STD (unspecified) as a teen and in her 20s, but has been monogamous since last marriage at 34 years of age. She states, “It has not always been easy to stay with my husband.” She feels sexually attracted to many men.
Past Psychiatric Hx: Hospitalized at age 15 for physical aggression toward parents, suicidality, and running away. Does not remember if she was placed on medication or if she was given a diagnosis. Admits history of sleep disturbance that alternates between hyposomnia and hypersomnia and moodiness, when she shifts from feeling “on top of the world” to very depressed, “like I’m a nobody.”
FH: Father was an alcoholic and died at 55 years of age of cirrhosis. Mother is alive, has an anxiety disorder and emphysema. Brother was incarcerated for attempted murder and drug trafficking. Sister has an anxiety disorder and self-medicates with marijuana.
SH: Obtained general education diploma (GED). Smokes two packs of cigarettes per day (PPD). Multiple jobs and two previous marriages. Currently works as a salesperson in an auto parts store. Lives with husband who is a mechanic and two elementary school-aged sons.
SA Hx: In late teens into mid-20s, heavy abuse of stimulants, barbiturates, and alcohol. Currently smokes marijuana three times per week and states “it calms me down and helps me sleep.” Occasionally drinks beer on weekends.
Meds: Antacids as needed for heartburn, ibuprofen as needed for headache
ROS: (+) increased energy, irritability and anger outbursts, racing thoughts, decreased need for sleep; (-) heart palpitations, weight loss, nausea, vomiting, diarrhea
PE:
VS: BP 130/88, P 88, RR 20, T 37.0°C (98.6°F)
HEENT: Neck supple, thyroid smooth, symmetrical, nontender, moveable
CV: RRR, normal S1, S2; no murmurs, rubs, gallops, or heaves
Abd: Soft, nontender, nondistended; (+) bowel sounds, no hepatosplenomegaly
Labs: Within normal limits (WNL) except + tetrahydro-cannabinol (THC)
Considering this additional information, what is the most likely diagnosis?
What are the key pieces of information leading you to this conclusion?
Initial and subsequent episodes of bipolar disorder are mostly depressive.10 Studies that followed patients with bipolar disorder over an average of about 13 years show that bipolar I patients spend about 32% of weeks with depressive symptoms compared to 9% of weeks with manic or hypomanic symptoms.11 Patients with bipolar II disorder spend 50% of weeks symptomatic for depression and only 1% with hypomanic symptoms.12 Because patients may present with depression and spend more time with symptoms of depression than mood elevation, bipolar disorder is often misdiagnosed or underdiagnosed. It is helpful to utilize a screening tool such as the mood disorder questionnaire.13
DSM-IV-TR criteria for the diagnosis of bipolar disorder are summarized in Table 39–1.
Bipolar I Disorder
The diagnosis of bipolar I disorder requires at least one episode of mania, for at least 1 week or longer, with a persistently elevated, expansive, or irritable mood with related symptoms of decreased need for sleep, excessive energy, racing thoughts, a propensity to be involved in high-risk activities, and excessive talkativeness.1 Bipolar I depression can be misdiagnosed as major depressive disorder (MDD); therefore, it is essential to rule out past episodes of hypomania or mania. If bipolar depression is mistaken for MDD and the patient is treated with antidepressants, this can precipitate a manic episode or induce rapid cycling of depression and mania.
Bipolar II Disorder
The distinguishing feature of bipolar II disorder is depression with past hypomanic episodes that often are not recalled by the individual as being unusual. Irritability and anger episodes are also common. There cannot have been a prior full-manic episode.1,14
Cyclothymic Disorder
Cyclothymic disorder is a chronic mood disturbance generally lasting at least 2 years (1 year in children and adolescents) and characterized by mood swings including periods of hypomania and depressive symptoms. Hypomanic symptoms include inflated self-esteem or grandiosity (nondelu-sional), decreased need for sleep, pressure of speech, flight of ideas (FOI), distractibility, and increased involvement in goal-directed activities, not causing severe impairment in social or occupational functioning or requiring hospi-talization. Psychotic features are not found in cyclothymic disorder.1
Clinical Presentation and Diagnosis
General
The patient may present in a hypomanic, manic, depressed, or mixed state and may or may not be in acute distress.
Symptoms
Mood and Affect:
• Mood elevation
• Expansive mood
• Irritable mood
• Depression
• Hopelessness
• Suicidality
Physical/Behavioral:
• Agitation
• Impulsivity
• Aggression
• Rapid, pressured speech
• Decreased need for sleep
• Insomnia (sometimes for days or weeks)
• Hypersexuality
• Increased physical energy
• Inflated self-esteem, boasting, grandiosity
• Heightened interest in pleasurable activities with high risk of negative consequences (spending sprees, promiscuity, etc.)
• Fatigue
• Hypersomnia
Thought Processes, Content, and Perceptions:
• Racing thoughts, FOI, distractibility
• Delusions of grandeur, ideas of reference, persecution, wealth, religion
• Psychosocial
• Substance use
• Disrupted relationships
• Job loss
Laboratory and Other Diagnostic Assessments
There are no objective laboratory tests or procedures to diagnose bipolar disorder, but such testing can be done to rule out other medical diagnoses.
• Urinalysis, urine toxicology, thyroid function, and white blood cell count in the elderly to rule out urinary tract infection
• Mood disorder questionnaire, completed by the patient, asks about common symptoms of bipolar disorder, problems caused by the symptoms, and family history in a “yes” or “no” answer format. It is then scored by the clinician.
Suicidality risk is increased in the presence of:
• Substance abuse
• Prior suicide attempts and lethality of attempts
• Access to a means of suicide
• Command hallucinations/psychosis
• Severe anxiety
• Family history of attempted or completed suicide
Compiled from Refs. 1, 3, 4.
Suicide
Patients with bipolar disorder have a high risk of suicide. Factors that increase that risk are early age at disease onset, high number of depressive episodes, comorbid alcohol abuse, personal history of antidepressant-induced mania, and family history of suicidal behavior.15 In those with bipolar disorder, one of five suicide attempts is fatal, in contrast to one of 10 to one of 20 in the general population.
Differential Diagnosis
Schizophrenia and bipolar disorder share certain symptoms, including psychosis in some patients. The prominence of mood symptoms and the history of mood episodes distinguish bipolar disorder and schizophrenia. In addition, the psychosis of schizophrenia occurs in the absence of prominent mood symptoms.
Personality disorders are inflexible and maladaptive patterns of behavior that deviate markedly from expectations of society beginning in adolescence or early adulthood.1 Personality disorders and bipolar disorder may be comorbid, and patients with personality disorders may have mood symptoms. The two diagnoses are distinguished by the predominance of mood symptoms and the episodic course of bipolar disorder, in contrast to the stability and persistence of the behavioral patterns of personality disorders.
Delirium is characterized by a disturbance of consciousness and a change in cognition that develops over a short period of time, usually hours or days. The course can fluctuate over the course of the day, usually worsening in the evening. Underlying medical problems such as urinary tract infections in the elderly, substance abuse, or withdrawal symptoms in adults may precipitate delirium.1
Dementia is the loss of function in multiple cognitive domains that occurs over a longer period of time, usually months to years. Diagnostic features include memory impairment and at least one of the following: aphasia (deterioration of speech), apraxia (impaired ability to execute motor activities despite intact motor abilities, sensory function, and comprehension of the required task), agnosia (failure to recognize or identify objects despite intact sensory function), or disturbances in executive functioning.1
Table 39–1 Evaluation and Diagnostic Criteria of Mood Episodes
Patient Encounter, Part 3: Creating a Care Plan
Based on all information presented, create a care plan for this patient’s bipolar disorder. Your plan should include (a) a statement of the drug-related needs and/or problems, (b) the goals of therapy, (c) a patient-specific therapeutic plan, and (d) a plan for follow-up to assess therapeutic response and adverse effects.
Comorbid Psychiatric and Medical Conditions
Psychiatric
Lifetime prevalence rates of psychiatric comorbidity with bipolar disorder are 42% to 50%.16 Comorbidities, especially substance abuse, make establishing a definitive diagnosis more difficult and complicate treatment. Comorbidities also place the patient at risk for a poorer outcome, high rates of suicidality, and onset of depression.2 Psychiatric comorbidities include:
• Personality disorders
• Alcohol and substance abuse or dependence
• Anxiety disorders
• Panic disorder
• Obsessive-compulsive disorder
• Social phobia
• Eating disorders
• Attention deficit hyperactivity disorder
Medical comorbidities include:
• Migraine
• Multiple sclerosis
• Cushing’s syndrome
• Brain tumor
• Head trauma
TREATMENT
Desired Outcomes
Desired outcomes for the treatment of bipolar disorder are to:
• reduce the symptoms of mania.
• reduce the symptoms of bipolar depression.
• prevent the recurrence of manic and depressive episodes.
• avoid or minimize adverse treatment effects.
• promote treatment adherence.
• maintain or improve quality of life and improve functioning.
General Approach to Treatment
Treatment guidelines for manic and depressive episodes of bipolar disorder are included in Table 39–2.
Although not all patients achieve asymptomatic remission, this is a goal of treatment. The mainstay of drug therapy has been mood stabilizing drugs, but studies increasingly support the use of antipsychotic drugs as monotherapy or adjunctively with mood stabilizing drugs, discussed below. A person entering treatment for a first mood episode in bipolar disorder must have a complete assessment and careful diagnosis to rule out nonpsychiatric causes. A variety of conditions can cause similar symptoms (Table 39–3). Since early and accurate diagnosis is essential to maximizing response to treatment, pharmacologic and nonpharmacologic therapy should begin as soon as possible. Treatment is often lifelong. Comorbid conditions should also be addressed aggressively.
Suicidality Risk
Patients should be assessed for their potential for violence and harm to others. Friends or family can be asked to remove from home, guns, caustic chemicals, medications, and objects which the person might use to harm self or others. Risk factors for suicide include severity of depression, feelings of hopelessness, comorbid personality disorder, and a history of a previous suicide attempt.18
Nonpharmacologic Therapy
Interpersonal, family, or group therapy with a licensed psychiatric nurse practitioner/clinical nurse specialist, psychologist, social worker, or counselor assists individuals with bipolar disorder to establish and maintain a daily routine and sleep schedule and to improve interpersonal relationships.19,20 These therapies may help treat and protect against manic episodes.
Cognitive behavioral therapy (CBT) is a type of psychotherapy that combines cognitive and behavioral theories. It stresses the importance of recognizing patterns of cognition (thought) and how thoughts influence subsequent feelings and behaviors. Other people, situations, and events external to the individual are not seen as the sources of thoughts and behaviors. With CBT, patients are taught self-management skills to change their negative thoughts even if external circumstances do not change.
Electroconvulsive therapy (ECT) is the application of prescribed electrical impulses to the brain for the treatment of severe depression, mixed states, psychotic depression, and treatment refractory mania. It also may be used in pregnant women who cannot take carbamazepine, lithium, or divalproex (DVP).
Psychoeducation for patients, their families, and groups regarding chronicity of bipolar disorders, self-management through sleep hygiene, nutrition, exercise, stress reduction, and abstinence from alcohol or drugs is critical to the success of supporting the individual in managing bipolar disorder. The development of a crisis intervention plan is essential.
The following websites provide additional information:
• National Association of Cognitive Behavioral Therapists—http://www.nacbt.org/
Table 39–2 Guidelines for the Acute Treatment of Mood Episodes in Patients With Bipolar I Disorder
Table 39–3 Secondary Causes of Mania
|
General Medical Conditions |
|
Medications |
|
Illicit Substances |
From Ref. 17.
• National Association for the Mentally Ill—http://www.nami.org/
• National Institutes for Mental Health, Bipolar Disorder—http://www.nimh.nih.gov/healthinformation/bipolarmenu.cfm
Pharmacologic Therapy
Pharmacotherapy is the cornerstone of acute and maintenance treatment of bipolar disorder. Mood stabilizing drugs are first-line treatments and include lithium, DVP, carbamazepine, and lamotrigine. Atypical antipsychotics other than clozapine and paliperidone are also approved for treatment of acute mania. Lithium, lamotrigine, aripiprazole, olanzapine, and quetiapine are approved for maintenance therapy. Quetiapine’s maintenance therapy indication is adjunctive with lithium or DVP. Drugs used with less research support and without FDA approval include topiramate and oxcarbazepine. Benzodiazepines are used adjunctively for mania.
Mood stabilizing drugs are the primary treatment for bipolar depression. Among antipsychotic drugs, quetiapine as monotherapy and olanzapine in combination with fluoxetine are approved for bipolar depression. Antidepressants can be used, but usually along with a mood stabilizing agent to prevent a mood switch to mania and after the patient has failed to respond adequately to optimal mood stabilizing therapy21 Combinations of two mood stabilizing drugs or a mood stabilizing drug and either an antipsychotic or antidepressant drug are common, especially in acute mood episodes.
Mood stabilizer drugs are considered the primary pharmacotherapy for relapse prevention, and they are often combined with antipsychotic drugs. Aripiprazole, olanzapine, and quetiapine are approved for maintenance therapy.
Table 39–4 includes a summary of current drug therapy for bipolar disorder. An algorithm for treatment of bipolar mania is shown in Table 39–2.
Mood Stabilizing Drugs
The ideal mood stabilizing drug has four desired effects: treatment of acute mania, treatment of acute bipolar depression, prevention of manic relapse, and prevention of bipolar depression relapse. All currently approved mood stabilizing drugs have demonstrated efficacy over placebo for one or more of these effects, but there are differences among them with regard to specific patient populations. Choice of treatment is dictated by individual patient characteristics and history. Few studies have compared mood stabilizing drugs to each other in systematic clinical trials. Effect sizes across placebo-controlled trials of individual agents are generally similar. Lithium is often considered the first-choice drug for the classic presentation of bipolar disorder. Treatment of childhood bipolar disorder is less well researched. Lithium is FDA approved in children and adolescents as young as age 12. Among antipsychotic drugs, aripiprazole and risperidone are FDA approved in children and adolescents as young as age 10. Treatment of bipolar disorder during pregnancy and during breast-feeding is a challenge because of the risks of drug exposure in utero and transmission of drugs via breast milk.
Lithium
Lithium was the first approved mood stabilizing drug. It remains a first-line agent and sets the standard for efficacy against which other drugs are usually measured. It has antimanic efficacy, prevents bipolar disorder relapse, and more modest efficacy for bipolar depression.22 It remains the only drug classified as a mood stabilizer that is supported by multiple controlled trials in mania, depression, and relapse prevention. In most studies, lithium’s efficacy is equivalent to that of the anticonvulsant mood stabilizers and the atypical antipsychotic drugs.23 It is most effective for patients with few previous episodes, symptom-free interepisode remission, and a family history of bipolar disorder with good response to lithium. Patients with rapid cycling bipolar disorder are less responsive to lithium, however, than to other mood stabilizing drugs such as DVP.24 Additionally, its efficacy for bipolar depression is less robust than for mania.25 It may also be less effective in patients with mixed mood episodes (symptoms of mania and depression occurring simultaneously) and in mania secondary to nonpsychiatric illness.
Table 39–4 Product Formulation, Dose, and Clinical Use of Agents Used in the Treatment of Bipolar Disorder
Evidence shows lithium’s effect on suicidal behavior is superior to that of other mood stabilizing drugs.26 Lithium reduces the risk of deliberate self-harm or suicide by about 70%.
Mechanism of Action. Lithium’s pharmacologic mechanism of action is not well understood and involves multiple effects. Possibilities include altered ion transport, effects on neurotransmitter signaling, blocking adenyl cyclase systems, effects on inositol, neuroprotection or increased BDNF, and inhibition of second messenger systems.27
Dosing and Monitoring. Lithium is usually initiated at a dosage of 600 to 900 mg/day. Although it is most commonly given in a divided dosage, once-daily dosing is acceptable, especially with sustained-release formulations, and once-daily dosing can improve patient adherence and reduce some side effects. Lithium has a narrow therapeutic index, meaning the toxic dosage is not much greater than the therapeutic dosage. Lithium requires regular serum concentration monitoring as a guide to dosage titration and to minimize adverse effects. At least weekly monitoring is recommended until the patient is stabilized, then the frequency can be decreased. Well-maintained patients who tolerate lithium without difficulty can be monitored by serum concentration as infrequently as twice yearly. Dosage is titrated to achieve a serum lithium concentration of 0.6 to 1.4 mEq/L (mmol/L). Higher serum concentrations are usually required to treat an acute episode than to prevent relapse. Serum lithium maintained above 0.8 mEq/L (mmol/L) may be more effective at preventing relapse, however, than lower serum concentrations. The suggested therapeutic serum concentration range is based on a 12-hour postdose sample collection, usually a morning trough in patients taking more than one dose per day. At least 2 weeks at a suggested therapeutic serum concentration is required for an adequate trial of lithium. Table 39–5shows pharmacokinetic parameters and desired serum concentrations of mood stabilizing drugs used for bipolar disorder. It is common for lithium to be combined with other mood stabilizing drugs or antipsychotic drugs, if necessary, in order to achieve more complete remission of symptoms.
Adverse Effects. The most common adverse effects are GI upset, tremor, and polyuria,28 which are dose related. Nausea, dyspepsia, and diarrhea can be minimized by coadminist-ration with food, use of sustained-release formulations, and giving smaller doses more frequently to reduce the amount of drug in the GI tract at a given time. Tremor is present in up to 50% of patients. In addition to the approaches above, low-dose β-blocker therapy such as propranolol 20 to 60 mg/day often reduces the tremor.
Lithium impairs the kidney’s ability to concentrate urine due to its inhibitory effect on vasopressin. This causes an increase in urine volume and urinary frequency and a consequent increase in thirst. Polyuria and polydipsia occur in up to 70% of patients. A severe form of polyuria, when urine volume exceeds 3 L/day, is known as nephrogenic lithium-induced diabetes insipidus. It can be treated with hydrochlorothiazide or amiloride. If the former is used, the lithium dosage should be reduced by 33% to 50% to account for the drug-drug interaction that could increase serum lithium concentrations and cause toxicity. Long-term lithium therapy can cause structural kidney changes such as glomerular sclerosis or tubular atrophy. Once-daily dosing of lithium is less likely to cause renal adverse effects than divided-daily dosing.
Lithium is concentrated in the thyroid gland and can impair thyroid hormone synthesis. Although goiter is uncommon, as many as 30% of patients develop at least transiently elevated thyroid stimulating hormone (TSH) values. Lithium-induced hypothyroidism is not usually an indication to discontinue the drug. Patients can be supplemented with levothyroxine if continuation of lithium is desired.28
Other common adverse effects include poor concentration, acneiform rash, alopecia, worsening of psoriasis, weight gain, metallic taste, and glucose dysfunction. Lithium causes ECG. Less commonly, it can cause or worsen arrhythmias. Cardiologic evaluation is recommended for patients with pre-existing cardiac disease who are candidates for lithium therapy. A benign leukocytosis is also common.28
Lithium and other mood stabilizing drugs require baseline and routine laboratory monitoring to help determine medical appropriateness for initiation of therapy and monitoring of potential adverse effects. Guidelines for such monitoring are outlined in Table 39–6.
Acute lithium toxicity, which can occur at serum concentrations over 2 mEq/L (mmol/L), can be severe and life-threatening, necessitating emergency medical treatment. Symptoms include worsening of GI distress to include severe vomiting and diarrhea; deterioration in motor coordination including a coarse tremor, ataxia, and dysarthria; and impaired cognition. In its most severe form, seizures, cardiac arrhythmias, coma, and kidney damage have been reported. Treatment includes discontinuation of lithium, IV fluids to correct fluid and electrolyte imbalance, and osmotic diuresis or hemodialysis. In case of overdose, gastric lavage is indicated. Clinical symptoms can continue well after the serum concentration is lowered, as clearance from the CNS is slower than from the serum. Factors predisposing to lithium toxicity include fluid and sodium loss due to hot weather or exercise or drug interactions that increase serum lithium.28
Drug Interactions. Drug interactions involving lithium are common. Because lithium is not metabolized or protein bound, however, it is not associated with metabolic drug interactions that occur with other mood stabilizing drugs. Common and significant drug interactions involve thiazide diuretics, nonsteroidal anti-inflammatory drugs, and angiotensin-converting enzyme (ACE) inhibitor drugs. If a diuretic must be used with lithium and a thiazide is not required, loop diuretics such as furosemide are less likely to increase lithium retention. The ACE inhibitors can abruptly increase serum lithium with the potential of acute and fatal toxicity, even after months of no change in the serum lithium concentration. This combination is strongly discouraged.29
Table 39–5 Pharmacokinetics and Therapeutic Serum Concentrations of Lithium and Anticonvulsants Used in the Treatment of Bipolar Disorder
DVP Sodium and Valproic Acid
DVP sodium is comprised of sodium valproate and VPA. The delayed-release and extended-release formulations are converted in the small intestine into VPA, which is the systemically absorbed form. It was developed as an anticonvulsant, but also has efficacy for mood stabilization and migraine headaches. It is FDA approved for the treatment of the manic phase of bipolar disorder. It is generally equal in efficacy to lithium and some other drugs for bipolar mania. It has particular utility in bipolar disorder patients with rapid cycling, mixed mood features, and substance abuse comorbidity. Although not FDA approved for relapse prevention, studies support this use, and it is widely prescribed for maintenance therapy. DVP can be used as monotherapy or in combination with lithium or an antipsychotic drug.30
Mechanism of Action. The mechanism of action of DVP is not well understood. It is known to affect ion transport and enhances the activity of gamma-aminobutyric acid (GABA). Like lithium, it also has possible neuroprotective effects through enhancement of BDNF.31
Table 39–6 Guidelines for Baseline and Routine Laboratory Tests and Monitoring for Agents Used in the Treatment of Bipolar Disorder
Dosing and Monitoring. DVP is usually initiated at 500 to 1,000 mg/day, but studies indicate a therapeutic serum VPA concentration can be reached more quickly through a loading dose approach of 20 to 30 mg/kg/day. Using this approach, patients may respond with a significant reduction in symptoms within the first few days of treatment. The dosage is then titrated according to response, tolerability, and serum concentration. The most often referenced desired VPA serum concentration is 50 to 125 mcg/mL (347-866 μmoles/L), but it is not unusual for patients to require more than 100 mcg/mL (693 μmoles/L) for optimal efficacy. Some patients require high milligram dosages in order to reach a desired serum concentration. The suggested serum concentration range is based on morning sampling, which is a trough value for patients taking divided daily dosing. Serum concentration monitoring is recommended at least every 2 weeks until stabilized, then less frequently, sometimes as infrequently as twice yearly. The extended-release formulation can be taken once daily (see Table 39–4). If administered at night, a morning blood sampling is not an actual trough. The drug could be given in the morning so that blood sampling the following day would be a trough value and more easily interpreted. The systemic bioavailability of extended-release DVP is about 15% less than that of the delayed-release formulation. Patients who have difficulty swallowing large tablets can use the sprinkle formulation. The immediate-release formulation, either capsules or syrup, is generally given three or four times per day.30
Adverse Effects. The most common adverse effects of DVP are GI (loss of appetite, nausea, dyspepsia, diarrhea), tremor, and drowsiness. GI distress can be reduced by coadministration with food. The delayed-release and extended-release formulations are less likely to cause gastric distress than the immediate-release VPA. This is an advantage for DVP, along with fewer daily doses, which can improve patient adherence to treatment. Dosage reduction can reduce all of the common DVP side effects. As with lithium, a low-dose β-blocker may alleviate the tremor. Weight gain is also common, occurring in up to 50% of patients on maintenance therapy.30
Other adverse effects that are less common include alopecia or a change in hair color or texture. Hair loss can be minimized by supplementation with a vitamin containing selenium and zinc. Polycystic ovarian syndrome associated with increased androgen production has been reported. Thrombocytopenia is not uncommon, and the platelet count should be monitored periodically. It is a dose-related adverse effect and usually asymptomatic, but the drug is usually stopped if the platelet count decreases to less than 100 × 103/mm3 (100 × 109/L). More rare are hepatic toxicity and pancreatitis, which are not always dose related. Severe GI symptoms of hepatic or pancreatic toxicity include vomiting, pain, and loss of appetite. When these occur the patient should be evaluated for possible hepatitis or pancreatitis. DVP has a wide therapeutic index. Acute toxicity for high dosages or overdosage is not life-threatening.30
Drug Interactions. Drug interactions involving DVP are common. It is a weak inhibitor of some of the drug metabolizing liver enzymes and can affect the metabolism of other drugs. These include other anticonvulsants and tricyclic antidepressants. The interaction between DVP and lamotrigine is particularly important. The risk of a dangerous rash due to lamotrigine is increased when given concurrently with DVP. When lamotrigine is added to DVP, the initial lamotrigine dosage should be half the typical starting dosage, and lamotrigine should be titrated more slowly than usual. When DVP is added to lamotrigine, the lamotrigine dosage should be reduced by 50%. Conversely, the metabolism of DVP can be increased by enzyme-inducing drugs such as carbamazepine and phenytoin, while DVP may simultaneously slow metabolism of the other agents.29
Carbamazepine
Although long utilized as a mood stabilizing drug, only the extended-release formulation of carbamazepine has received FDA approval for treatment of bipolar disorder. Like DVP, it also has efficacy for mood stabilization, but is considered possibly less desirable as a first-line agent because of safety and drug interactions. It is sometimes reserved for patients who fail to respond to lithium or for patients with rapid cycling or mixed bipolar disorder. Carbamazepine can be used as monotherapy or in combination with lithium or an antipsychotic drug.32,33
Mechanism of Action. The mechanism of action of carbamazepine is not well understood. It blocks ion channels and inhibits sustained repetitive neuronal excitation, but whether this explains its efficacy as a mood stabilizing drug is not known.32
Dosing and Monitoring. Carbamazepine is usually initiated at 400 to 600 mg/day. The sustained-release formulation can be given in two divided doses. In addition to a formulation that is completely sustained-release, an additional extended-release formulation contains a matrix of 25% immediate-release, 40% extended-release, and 35% enteric-release beads.33 The suggested therapeutic serum concentration is 4 to 12 mcg/mL (17-51 μmol/L). As with DVP, some patients require high milligram dosages to achieve a desired serum concentration and therapeutic effect. The dosage can be increased by 200 to 400 mg/day as often as every 2 to 4 days to achieve the desired effect. Serum concentration monitoring is suggested at least every 2 weeks until stabilized, then less frequently.32
Adverse Effects. The most common adverse effects are drowsiness, dizziness, ataxia, lethargy, and confusion. At mildly toxic serum concentrations, it also causes diplopia and dysarthria. These effects can be minimized through dosage adjustments, use of sustained-release formulations, and giving more of the drug late in the day. GI upset is also common. Carbamazepine has an antidiuretic effect similar to the syndrome of inappropriate antidiuretic hormone secretion and can cause hyponatremia. Mild elevations in liver enzymes can occur, but hepatitis is less common. Mild, dose-related leukopenia is not unusual and not usually an indication for stopping the drug. More serious blood count abnormalities such as aplastic anemia and agranulocytosis are rare, but life-threatening.33 Suggested baseline and routine laboratory monitoring is reviewed in Table 39–6.
Drug Interactions. Carbamazepine induces the hepatic metabolism of many drugs, including other anticonvulsants, antipsychotics, some antidepressants, oral contraceptives, and antiretroviral agents. Carbamazepine is also an autoinducer, i.e., it induces its own metabolism. The dosage may require an increase after 1 month or so of therapy because of this effect. Conversely, the metabolism of carbamazepine can be slowed by enzyme inhibiting drugs such as some antidepressants, macrolide antibiotics including erythromycin and clarithromycin, azole antifungal drugs including ketoconazole and itraconazole, and grapefruit juice. Carbamazepine should not be given concurrently with clozapine because of the additive risk of agranulocytosis.29
Lamotrigine
Lamotrigine is effective for the maintenance treatment of bipolar disorder. It is more effective for depression relapse prevention than for mania relapse. Its primary limitation as an acute treatment is the time required for titration to an effective dosage. In addition to maintenance monotherapy, it is sometimes used in combination with lithium or DVP, although combination with DVP increases the risk of rash, and lamotrigine dosage adjustment is required.34
Mechanism of Action. The mechanism of action of lamotrigine appears to involve blockage of ion channels and effects on glutamate transmission, although the precise mechanism in bipolar disorder is not clear.34
Dosing and Monitoring. Lamotrigine is usually initiated at 25 mg daily for the first 1 to 2 weeks, then increasing in a dose-doubling fashion every 1 to 2 weeks to a target dosage of 200 to 400 mg/day. If lamotrigine is added to DVP, the starting dosage is 25 mg every other day with a slower titration to reduce the risk of rash. If DVP is added to lamotrigine, the lamotrigine dosage should be reduced by 50% for the same reason. If lamotrigine therapy is interrupted for more than a few days, it should be restarted at the initial dosage. Serum concentration monitoring is not routinely recommended for patients with bipolar disorder.34
Adverse Effects. The lamotrigine adverse effect of greatest significance is a maculopapular rash, occurring in up to 10% of patients.34 Although usually benign and temporary, some rashes can progress to life-threatening Stevens-Johnson syndrome. The risk of rash is greater with a rapid dosage titration and when given concurrently with DVP or other metabolic enzyme inhibitors. The risk is minimal when the dosage titration schedule is slow. Other side effects include dizziness, drowsiness, headache, blurred vision, and nausea. In contrast to other mood stabilizing drugs such as lithium and DVP, lamotrigine does not significantly influence body weight.
Drug Interactions. Drug interactions involving lamotrigine are usually due to induction or inhibition of its metabolism by other drugs. It does not affect drug metabolizing hepatic enzymes on its own, but other drugs that affect these pathways can have a significant effect on lamotrigine’s clearance. In particular, DVP slows the rate of elimination of lamotrigine by about half, necessitating dosage reduction. Conversely, carbamazepine increases the rate of lamotrigine metabolism. Upward adjustment in the lamotrigine dosage may be needed as a result.29
Oxcarbazepine
Oxcarbazepine is an analogue of carbamazepine, developed as an anticonvulsant. An advantage over carbamazepine is that routine monitoring of hematology profiles and serum concentrations are not indicated as the drug is less likely to cause hematologic abnormalities.35 Additionally, drug interactions are less significant, although it is at least a mild inducer of certain metabolic pathways, and vigilance for drug interactions is needed, especially with oral contraceptives. Oxcarbazepine appears in the most recent treatment algorithms for bipolar disorder,36 but clinical trial data are limited. A systematic review concluded that there are insufficient data from well-designed clinical trials to provide guidance on its use.37
Adverse Effects. Adverse effects due to oxcarbazepine include drowsiness, dizziness, GI upset, and hyponatremia, the latter two of which may be more likely than with carbamazepine.35
Others
High potency benzodiazepine agents such as clonazepam and lorazepam have been used as adjunctive therapy, especially during acute mania episodes, to reduce anxiety and improve sleep.38 Topiramate is commonly used for its putative mood stabilizing effects, but unpublished, well-designed, randomized, controlled trials sponsored by the manufacturer showed no difference between topiramate and placebo for treatment of bipolar disorder. Uncontrolled, open-label data suggest possible use as an adjunctive agent.39 Gabapentin has shown no efficacy over placebo and is not recommended for patients with bipolar disorder. One of the few randomized, placebo-controlled trials of gabapentin in bipolar disorder actually showed a statistical inferiority compared to placebo.40 As complementary or alternative medicines gain wider usage, omega-3 fatty acids have been used in mood disorders. Insufficient well-designed studies exist to support a recommendation of routine use or to establish a place in therapy relative to usual therapies.
Antipsychotic Drugs
Conventional antipsychotic drugs such as chlorpromazine and haloperidol have long been used in the treatment of acute mania. Atypical antipsychotic drugs including aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone have been approved for the treatment of bipolar mania or mixed mood episodes as monotherapy or in combination with mood stabilizing drugs.23 Aripiprazole, olanzapine, and quetiapine are also approved for maintenance therapy for prevention of manic relapse. The combination of olanzapine and fluoxetine is approved for treatment of acute bipolar depression. Quetiapine is approved as monotherapy for acute bipolar depression and as adjunctive therapy with lithium or DVP for prevention of bipolar depression relapse. Approval of antipsychotic drugs in bipolar disorder patients applies without regard to the presence of psychotic symptoms. In comparative studies, atypical antipsychotic drugs are equivalent in efficacy to lithium and DVP for treatment of acute mania. Treatment guidelines include antipsychotic drugs as first-line therapy.36 Of interest is evidence that the combination of mood stabilizing drugs and antipsychotic drugs is more likely to achieve remission of acute manic episodes than monotherapy with either.23 The quetiapine data in relapse prevention of both manic and bipolar depression episodes likewise favored combination therapy over mood stabilizing drug monotherapy.41
The mechanisms of action, usual dosages, pharmacoki-netics, adverse effects, and drug interactions involving antipsychotic drugs are discussed in detail in the chapter on schizophrenia. Dosages in bipolar disorder are similar to those used in schizophrenia. Higher dosages are often required to treat an acute episode than to prevent relapse. The recommended dosage of aripiprazole for bipolar disorder is 20 to 30 mg/day, somewhat higher than the average dosage used in schizophrenia.42 The recommended dosage for quetiapine in treatment of acute bipolar depression is 300 mg/day, less than the 600 mg/day recommended in acute mania.43
Atypical antipsychotic drugs are less likely than conventional antipsychotics to cause neurologic side effects, especially movement abnormalities. As a group, however, they are more likely to cause metabolic side effects, such as weight gain, glucose dysregulation, and dyslipidemia.44 Among the atypical antipsychotic drugs approved for treatment of bipolar disorder, olanzapine is more likely to cause metabolic side effects. Quetiapine and risperidone cause less metabolic effects than olanzapine. Aripiprazole and ziprasidone are least associated with effects on weight, glucose, and lipids. Metabolic adverse effects data regarding paliperidone in acute and limited long-term studies show mild weight gain and little effect on glucose and lipids.45 More experience is needed to fully understand paliperidone’s profile. Paliperidone is not FDA approved for bipolar disorder at present. The chapter on schizophrenia discusses adverse effects of antipsychotic drugs in more detail.
Antidepressants
Treatment of depressive episodes in bipolar disorder patients presents a particular challenge because of the risk of a drug-induced mood switch to mania, although there is not complete agreement about such risk. The FDA requires the product label of all antidepressant drugs to contain language about the potential risk of inducing a mood switch to mania. Randomized, controlled data show no advantage for adjunctive antidepressant use compared to mood stabilizer therapy alone.46 Treatment guidelines suggest lithium or lamotrigine as first-line therapy.36,47 However, the guidelines do not reflect the more recent data on olanzapine and quetiapine, discussed above. When usual treatment fails, efficacy data support use of antidepressants.21
Guidelines agree that when antidepressants must be used, they should be combined with a mood stabilizing drug to reduce the risk of mood switch to hypomania or mania.36,47 The question of which antidepressant drugs are less likely to cause a mood switch is not resolved, but tricyclic antidepressants are thought to carry a greater risk of treatment-emergent mania. A randomized comparison of venlafaxine, sertraline, and bupropion as adjunctive therapy to a mood stabilizer showed venlafaxine with the highest risk of a mood switch to mania or hypomania and bupropion with the least.48
Special Populations
Assessment and management by appropriate psychiatric specialists is important for special populations such as pediatrics, geriatrics, pregnancy, and others.
Pediatrics
Evidence regarding treatment of bipolar disorder in children and adolescents is more limited than in adults. Children and adolescents appear to be particularly sensitive to medication side effects. With these caveats, an increasing body of evidence supports the use of mood stabilizing drugs and atypical antipsychotic drugs in children and adolescents with bipolar disorder. Lithium is FDA approved for treatment of bipolar disorder in children and adolescents as young as age 12. Aripiprazole and risperidone are FDA approved in children and adolescents as young as age 10. The guidelines additionally support DVP, carbamazepine, olanzapine, quetiapine, and risperidone.49
Initial dosages of drug therapy in the pediatric population are lower than in adults. Metabolic elimination rates of many drugs are increased in children, however, so they may actually require higher dosages on a weight-adjusted basis. Dosages are titrated carefully according to response and tolerability. For lithium, DVP, and carbamazepine, serum concentration monitoring is recommended as a guide to dosage adjustment and minimizing adverse effects.
Children and adolescent patients are often more sensitive to drug side effects than adults. In particular, they are likely to experience significant weight gain due to atypical antipsychotic drugs.50 Cognitive toxicity, manifested as confusion, memory or concentration impairment, or impaired learning, is often difficult to detect and is a special consideration in the pediatric population so that intellectual and educational development is not hindered by drug therapy.
Comorbid conditions must be addressed in order to maximize desired outcomes. For comorbid bipolar disorder and attention deficit hyperactivity disorder when stimulant therapy is indicated, treatment of mania is recommended before starting the stimulant in order to avoid exacerbation of mood symptoms by the stimulant.
Geriatrics
Treatment of elderly patients with bipolar disorder requires special care because of increased risks associated with concurrent medical conditions and drug-drug interactions. General medical conditions including endocrine, metabolic, or infectious diseases can mimic mood disorders. Patients should be evaluated for such medical illnesses that may cause or worsen mood symptoms. As physiologic systems change with aging, elimination of drugs is often slowed. Examples are slowed renal elimination of lithium and slowed hepatic metabolism of carbamazepine and VPA. As a result, dosages of drugs required for therapeutic effect are generally lower in geriatric patients. Also, changes in membrane permeability with aging increase risk of CNS side effects. Increased frequency of patient monitoring is often required, including serum drug concentration monitoring.
Vigilance for drug-drug interactions is required because of the greater number of medications prescribed to elderly patients and enhanced sensitivity to adverse effects. Pharmacokinetic interactions include metabolic enzyme induction or inhibition and protein binding displacement interactions, for example, DVP and warfarin. Pharmacodynamic interactions include additive sedation and cognitive toxicity, which increase risk of falls and other impairments.
Pregnancy and Postpartum
Treatment of bipolar disorder during pregnancy is fraught with controversy and conflicting recommendations. The key issue is the relative risk of teratogenicity with drug use during pregnancy versus risk of bipolar relapse without treatment with consequent potential harm to both the pregnant patient and the fetus. Therapeutic judgments depend on the history of the patient and whether the pregnancy is planned or unplanned. Treatment is best managed when the pregnancy is planned. Clinicians should discuss the issue with every patient with bipolar disorder who is of childbearing potential. A pregnancy test should be obtained prior to initiating drug therapy. For a patient with severe bipolar disorder, a history of multiple mood episodes, rapid cycling, or suicide attempts, discontinuing treatment, even for a planned pregnancy, is unwise. For a patient with a remote history of a single mood episode with subsequent long stability and who is contemplating pregnancy, the answer is less clear. Patients should be provided clear and reliable information about risks versus benefits of stopping or continuing therapy in order to make an informed decision. Patients who decide to discontinue drug therapy prior to pregnancy should taper medications slowly in order to reduce risk of relapse.51
Lithium administration during the first trimester is associated with Ebstein’s anomaly in the infant, a downward displacement of the tricuspid valve into the right ventricle. Although more likely to occur in children of patients who took lithium during pregnancy, the absolute risk is considered small, around 0.1%. Pharmacokinetic handling of lithium changes as pregnancy progresses. Renal lithium clearance increases, which requires a dosage increase to maintain a therapeutic serum concentration. It may be advisable to decrease or discontinue lithium at term or the onset of labor to avoid toxicity postpartum when there is a large reduction in fluid volume.52
Lithium can cause hypotonicity and cyanosis in the neonate, usually termed the “floppy baby” syndrome. Most data indicate normal neurobehavioral development once these symptoms resolve. Lithium is readily transferred via breast milk. Breast-feeding is not advised for patients who are taking lithium.28
VPA and carbamazepine are human teratogens. Neural tube defects such as spina bifida occur in up to 9% of infants exposed during the first trimester. The risk of neural tube defects is related to exposure during the third and fourth weeks following conception. As such, women with unplanned pregnancies may not know they are pregnant until after the risk of exposure has occurred. Carbamazepine can cause fetal vitamin K deficiency. Vitamin K is important for facial growth and for clotting factors. Risk of facial abnormalities is increased with carbamazepine and VPA, and neonatal bleeding is increased in infants of mothers who are treated with carbamazepine during pregnancy.51,52
Less data are available on other anticonvulsant mood stabilizing drugs. Lamotrigine may be associated with an increased risk of oral clefts in association with first trimester exposure.51
Conventional antipsychotic drugs have been available for many years, and more data are available on their use in pregnancy compared to atypical antipsychotic drugs, but treatment guidelines for bipolar disorder do not otherwise support conventional antipsychotics as an initial choice in treatment.
Patient Encounter, Part 4: Outcome Evaluation
Following initial assessment, including evaluation of potential suicidality, support systems, and need for inpatient versus outpatient treatment, MW was hospitalized briefly, then followed in the community on medication along with psychotherapy. She has abstained from illicit substances and has returned to her job. She has responded well to treatment with sustained-release lithium carbonate 900 mg once daily at bedtime with a snack. Steady-state 12-hour serum lithium concentrations have stabilized at 0.9 mEq/L (mmol/L). She now returns to clinic for routine follow-up. She has tolerated the lithium except for a mild tremor and a gain of 3.2 kg (7 lb). She is willing to accept these side effects for now, but asks about how long she must take medication since she is now feeling well.
How would you assess therapeutic and adverse effects of treatment for this patient?
How would you educate the patient regarding the need for continued maintenance treatment?
Use of antidepressant drugs during pregnancy is discussed in the chapter on depression.
OUTCOME EVALUATION
Assessment of Therapeutic Effects
Effective interviewing skills and a therapeutic relationship with the patient are essential to assessing response to treatment. Understand the particular symptom profile and needs of individual patients. These become the primary therapeutic monitoring parameters. In addition to the clinical interview, some clinicians utilize symptom rating scales such as the Young Mania Rating Scale (YMRS) for mania and the Hamilton Depression Rating Scale (Ham-D, discussed in the chapter on depression). Check serum concentrations of mood stabilizing drugs as a guide to dosage adjustment for optimal efficacy. The frequency of follow-up visits depends on response, tolerability, adherence, and other factors.
Patient Care and Monitoring
1. Assess the patient’s symptoms and review the past history. Review the family history, including the history of response to treatment by family members.
2. Obtain an initial medical evaluation to rule out other causes of mood episodes.
3. Obtain a thorough medication-use history, including present and past drugs, prescription and nonprescription drugs, the patient’s self-assessment of response and side effect problems, alcohol, tobacco, caffeine, illicit substances, herbal products, dietary supplements, allergies, and adherence.
4. Assess potential drug-disease, drug-drug, and drug-food interactions.
5. Evaluate physiologic parameters that may influence pharmacokinetics.
6. Develop a plan for monitoring therapeutic outcomes, focusing on the individual symptom profile, and level of function of each patient. Include a plan for dosage adjustments or alternate therapy if the patient fails to respond adequately. Include serum drug concentration monitoring as appropriate.
7. Develop a monitoring plan for drug side effects. Include measures to prevent side effects as well as management if they occur. Include appropriate laboratory measures.
8. Determine the role of nonpharmacologic therapy and how it is to be integrated with drug therapy.
9. Educate the patient on the nature of bipolar disorder, its treatment, what to expect with regard to response and side effects, and stress the need for adherence to treatment, even when feeling well.
10. Encourage a healthy lifestyle, including eliminating or stopping substance abuse, smoking cessation, and encouraging proper nutrition and exercise.
Assessment of Adverse Effects
Adverse effects cause more nonadherence to prescribed therapy than any other factor. Monitor patients regularly for adverse effects and health status, especially since mood stabilizing drugs and antipsychotic drugs commonly cause metabolic side effects such as weight gain. Repeat laboratory tests for renal and thyroid function for patients taking lithium and hematology and liver function for patients taking carbamazepine or DVP. Annual measurement of serum lipase may be advisable for patients taking DVP. More specific discussion of metabolic side effect monitoring of patients taking atypical antipsychotic drugs is discussed in the chapter on schizophrenia.
Patient Education
Patient education improves adherence to treatment, which reduces risk of relapse. This is especially important because responsiveness to treatment declines as the number of mood episodes increases. Discuss the nature and chronic course of bipolar disorder and the risks of repeated relapses. Help patients understand that treatment of bipolar disorder is not a cure, but many patients can enjoy symptom-free or nearly symptom-free function. Make clear that long-term recovery is dependent on adherence to both pharmacologic and nonpharmacologic treatment. Explain the purpose of medication, common side effects to expect, and how to respond to them. Provide the patient and family with written information about medication indications, benefits, risks, and side effects. Discuss less frequent but more dangerous side effects of drugs, and give written instructions on seeking medical attention immediately should they occur.
Abbreviations Introduced in This Chapter
Self-assessment questions and answers are available at http://www.mhpharmacotherapy.com/pp.html.
REFERENCES
1. American Psychiatric Association. DSM-IV-TR: Diagnostic and Statistical Manual of Mental Disorders, Text Revision, 4th ed. Washington, DC: American Psychiatric Association, 2000.
2. Krishnan KR. Psychiatric and medical comorbidities of bipolar disorder. Psychosom Med 2005;67:1–8.
3. Thase ME. Mood disorders: Neurobiology. In: Sadock BJ, Sadock VA, eds. Kaplan and Sadock’s Comprehensive Textbook of Psychiatry, 8th ed. Philadelphia: Lippincott Williams & Wilkins, 2005:1594–1603.
4. Shih RA, Belmonte PL, Zandi PP. A review of the evidence from family, twin and adoption studies for a genetic contribution to adult psychiatric disorders. Int Rev Psychiatry 2004;16:260–283.
5. Hajek T, Carrey N, Alda M. Neuroanatomical abnormalities as risk factors for bipolar disorder. Bipolar Disord 2005;7:393–403.
6. Mahmood T, Silverstone T. Serotonin and bipolar disorder. J Affect Disord 2001;66:1–11.
7. Kim H, McGrath BM, Silverstone PH. A review of the possible relevance of inositol and the phosphatidylinositol second messenger system (PI-cycle) to psychiatric disorders—Focus on magnetic resonance spectroscopy (MRS) studies. Hum Psychopharmacol 2005;20:309–326.
8. Post RM. Role of BDNF in bipolar and unipolar disorder: Clinical and theoretical implications. J Psychiatr Res 2007;41:979–990.
9. Hirschfeld RM. Bipolar spectrum disorder: Improving its recognition and diagnosis. J Clin Psychiatry 2001;62(Suppl 14):5–9.
10. Perugi G, Micheli C, Akiskal HS, et al. Polarity of the first episode, clinical characteristics, and course of manic depressive illness: A systematic retrospective investigation of 320 bipolar I patients. Compr Psychiatry 2000;41:13–18.
11. Judd LL, Akiskal HS, Schettler PJ, et al. The long-term natural history of the weekly symptomatic status of bipolar I disorder. Arch Gen Psychiatry 2002;59:530–537.
12. Judd LL, Akiskal HS, Schettler PJ, et al. A prospective investigation of the natural history of the long-term weekly symptomatic status of bipolar II disorder. Arch Gen Psychiatry 2003;60:261–269.
13. Hirschfeld RM, Holzer C, Calabrese JR, et al. Validity of the mood disorder questionnaire: A general population study. Am J Psychiatry 2003;160:178–180.
14. Berk M, Dodd S. Bipolar II disorder: A review. Bipolar Disord 2005;7:11–21.
15. Slama F, Bellivier F, Henry C, et al. Bipolar patients with suicidal 65:1035–1039.
16. McElroy SL, Altshuler LL, Suppes T, et al. Axis I psychiatric comorbidity and its relationship to historical illness variables in 288 patients with bipolar disorder. Am J Psychiatry 2001;158:420–426.
17. Akiskal HS. Mood disorders: Clinical features. In: Sadock BJ, Sadock VA, eds. Kaplan and Sadock’s Comprehensive Textbook of Psychiatry, 8th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2005:1611–1651.
18. Valtonen H, Suominen K, Matere O, et al. Suicidal ideation and attempts in bipolar I and II disorders. J Clin Psychiatry 2005;66:1456–1462.
19. Otto MW, Reilly-Harrington N, Sachs GS. Psychoeducational and cognitive-behavioral strategies in the management of bipolar disorder. J Affect Disord 2003;73:171–181.
20. Miklowitz DJ. Adjunctive psychotherapy for bipolar disorder: State of the evidence. Am J Psychiatry 2008;165:1408–1419.
21. Salvi V, Fagiolini A, Swartz HA, et al. The use of antidepressants in bipolar disorder. J Clin Psychiatry 2008;69:1307–1318.
22. Geddes JR, Burgess S, Hawton K, et al. Long-term lithium therapy for bipolar disorder: Systematic review and meta-analysis of randomized controlled trials. Am J Psychiatry 2004;161:217–222.
23. Scherk H, Pajonk FG, Leucht S. Second-generation antipsychotic agents in the treatment of acute mania. A systematic review and meta-analysis of randomized controlled trials. Arch Gen Psychiatry 2007;64:442–455.
24. Schneck CD. Treatment of rapid-cycling bipolar disorder. J Clin Psychiatry 2006;67(Suppl 11):22–27.
25. Bowden CL, Calabrese JR, Sachs G, et al. A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with bipolar I disorder. Arch Gen Psychiatry 2003;60:392–400.
26. Cipriani A, Pretty H, Hawton K, Geddes JR. Lithium in the prevention of suicidal behavior and all-cause mortality in patients with mood disorders: A systematic review of randomized trials. Am J Psychiatry 2005;162:1805–1819.
27. Marmol F. Lithium: Bipolar disorder and neurodegenerative diseases. Possible cellular mechanisms of the therapeutic effects of lithium. Prog Neuropsychopharmacol Biol Psychiatry 2008;32:1761–1771.
28. Lithium package insert. Roxane Laboratories. Columbus, OH, 2007.
29. Sandson NB, Armstrong SC, Cozza KL. An overview of psychotropic drug-drug interactions. Psychosomatics 2005;46:464–494.
30. Divalproex package insert. Abbott Laboratories. North Chicago, IL, 2008.
31. Walz JC, Frey BN, Andreazza AC, et al. Effects of lithium and valproate on serum and hippocampal neurotrophin-3 levels in an animal model of mania. J Psychiatr Res 2008;42:416–421.
32. Harrison TS, Keating GM. Extended-release carbamazepine capsules in bipolar I disorder. CNS Drugs 2005;19:709–716.
33. Carbamazepine extended-release capsules package insert. Validus Pharmaceuticals. Parsippany, NJ, 2007.
34. Lamotrigine package insert. GlaxoSmithKline. Research Triangle Park, NC, 2007.
35. Oxcarbazepine package insert. Novartis Pharmaceuticals. East Hanover, NJ, 2007.
36. Suppes T, Dennehy DB, Hirschfeld RMA, et al. The Texas implementation of medication algorithms: Update to the algorithms for treatment of bipolar I disorder. J Clin Psychiatry 2005;66:870–886.
37. Vasudev A, Macritchie K, Watson S, et al. Oxcarbazepine in the maintenance treatment of bipolar disorder. Cochrane Database Syst Rev 2008, issue 1:CD005171.
38. Nardi AE, Perna G. Clonazepam in the treatment of psychiatric disorders: An update. Int Clin Psychopharmacol 2006;21:131–142.
39. Goodnick PJ. Anticonvulsants in the treatment of bipolar mania. Expert Opin Pharmacother 2006;7:401–410.
40. Pande AC, Crockatt JG, Janney CA, et al. Gabapentin in bipolar disorder: A placebo-controlled trial of adjunctive therapy. Bipolar Disord 2000;2:249–255.
41. Vieta E, Suppes T, Eggens I, et al. Efficacy and safety of quetiapine in combination with lithium or divalproex for maintenance of patients with bipolar I disorder (international trial 126). J Affect Disord 2008;109:251–263.
42. Keck PE, Marcus R, Tourkodimitris S, et al. A placebo-controlled, double-blind study of the efficacy and safety of aripiprazole in patients with acute bipolar mania. Am J Psychiatry 2003;160:1651–1658.
43. Thase ME, Macfadden W, Weisler RH, et al. Efficacy of quetiapine monotherapy in bipolar I and II depression. J Clin Psychopharmacol 2006;26:600–609.
44. American Diabetes Association, American Psychiatric Association, American Association of Clinical Endocrinologists, North American Association for the Study of Obesity. Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care 2004;27:596–601.
45. Kramer M, Simpson G, Maciulis V, et al. Paliperidone extended-release tablets for prevention of symptom recurrence in patients with schizophrenia. A randomized, double-blind, placebo-controlled study. J Clin Psychopharmacol 2007;27:6–14.
46. Sachs GS, Nierenberg AA, Calabrese JR, et al. Effectiveness of adjunctive antidepressant treatment for bipolar depression. N Engl J Med 2007;356:1711–1722.
47. International Consensus Group on Bipolar I Depression Treatment Guidelines. J Clin Psychiatry 2004;65:569–579.
48. Leverich GS, Altshuler LL, Frye MA, et al. Risk of switch in mood polarity to hypomania or mania in patients with bipolar depression during acute and continuation trials of venlafaxine, sertraline, and bupropion as adjuncts to mood stabilizers. Am J Psychiatry 2006;163:232–239.
49. Kowatch RA, Fristad M, Birmaher B, et al. Treatment guidelines for children and adolescents with bipolar disorder. J Am Acad Child Adolesc Psychiatry 2005;44:213–235.
50. McIntyre RS, Jerrell JM. Metabolic and cardiovascular adverse events associated with antipsychotic treatment in children and adolescents. Arch Pediatr Adolesc Med 2008;162:929–935.
51. Cohen LS. Treatment of bipolar disorder during pregnancy. J Clin Psychiatry 2007;68(Suppl 9):4–9.
52. Yonkers KA, Wisner KL, Stowe Z, et al. Management of bipolar disorder during pregnancy and the postpartum period. Am J Psychiatry 2004;161:608–620.