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16. Opler LA, Klahr DM, Ramirez PM: Pharmacologic treatment of delusions. Psychiatr Clin North Am 18:379-391, 1995. 17. Serreti A, Lattuada E, Cusin C, Smeraldi E: Factor analysis of delusional disorder syrnptomatology. Compr Psychiatry 40(2): 143-147, 1999. 18. Stoudemire A, Riether A: Evaluation and treatment of paranoid syndromes in the elderly. Gen Hosp Psychiatry 9:267-274, 1987. 19. Webb W Paranoid conditions seen in psychiatric medicine. Psychiatr Med 8:37-48, 1990.

12. BIPOLAR DISORDERS

Marshall R. Thomas, M.D
1. What is bipolar disorder? How is it different from manic-depressiveillness?
Bipolar disorder encompasses a heterogeneous group of disorders characterized by cyclical disturbances in mood, cognition, and behavior. The diagnosis requires a history of mania for at least 1 week or hypomania for at least 4 days. Bipolar I disorder refers to patients who have had at least one episode of mania. Bipolar I1 disorder refers to patients with a history of hypomania and major depressive episodes. Cyclothymia refers to patients with chronic (at least 2-year duration) mood swings that fluctuate between hypomania and minor but not major depression.

MD Md M mD M = Maaic Egisode D = Major Depressive Episodc

md

m = H y p d c Episode d = Minor Depnssivc Episodc

Modified from Goodwin F, Jamison K: Manic-Depressive Illness. New York, Oxford University Press, 1990.

In 1921, the German psychiatrist Emil Kraepelin introduced the term manic-depressive insanity, which included patients with recurrent unipolar depression as well as bipolar disorder and distinguished both groups from schizophrenia, which he termed dementia praecox. Kraepelin emphasized

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the similarities in course and outcome between patients with highly recurrent mood disorders, regardless of polarity. In 1962, Leonard introduced the term bipolar and emphasized differences between unipolar and bipolar patients. Many researchers argue that modern adherence to Leonards bipolarhnipolar dichotomy, although clarifying certain issues, has caused clinicians to overlook the similarities between bipolar and many unipolar patients, who share a common pattern of recurrence, remission, and exacerbation. The modern concept of bipolar spectrum disorder encompasses patients with bipolar I and I1 disorders, cyclothymia, hyperthymia (chronic hypomania), and pseudounipolar depression. Pseudounipolar depressives are patients with a highly recurrent unipolar illness, a positive family history for bipolar disorder, and a positive therapeutic response to antibipolar treatments.

2. Describe the epidemiology of bipolar disorder. The lifetime risk for bipolar I disorder is 0.6-0.9% in industrialized nations, with no apparent
gender differences; unipolar depression, however, is twice as common in women as it is in men. Differing criteria for what constitutes hypomania have made it difficult to determine the prevalence of bipolar I1 and cyclothymic disorders. Bipolar I1 disorder is probably at least as common as bipolar I, and the lifetime prevalence of cyclothymia is estimated at 0.4-1.0%. Over the last 50 years, all mood disorders have increased in prevalence, with an earlier age of onset in each successive generation-a phenomenon referred to as the cohort effect. Family studies find that if one parent has a major affective disorder the risk to the offspring is 25-30%, whereas if both parents have an affective disorder the risk to the offspring may be as high as 5 6 7 5 % . Suicide is common in untreated bipolar disorder; 25-50% of patients attempt suicide at least once. Seasonal variations exist; depression is more common in the spring (March through May) and autumn (September through November), whereas mania is more common in the summer. The peak incidence of suicide occurs in May, with a second peak in October.

3. How is mania recognized?

Manic states range in severity from milder hypomania to psychotic or delirious manic states. The symptomatology evolves as the episode becomes more severe. The mood in mania may be elated or euphoric, but as severity increases the mood is more likely to become irritable, labile, and dysphoric. Thoughts may race; as mania progresses, thinking becomes disorganized, expansive, and grandiose. Behavior increases from early physical hyperactivity, pressured speech, and decreased need for sleep to later manifestations of hypersexuality, increased impulsivity, and risk taking.

Manic Episode: Diagnostic Criteria

Distinct period of elevated, expansive, or irritable mood: At least 1 week Or hospitalized Three of the following: four if mood only irritable: Inflated self esteem or grandiosity Distractibility Decreased need for sleep Increased activity Pressured speech Excessive involvement in pleasurable activities Flight of ideas or thoughts racing with high risk of painful consequences Marked impairment, psychosis, or hospitalization Not due to direct effect of substance or medical condition From American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington, DC, American Psychiatric Association, 1994, with permission.

Hypomanic Episode: Diagnostic Criteria

Distinct period of elevated, expansive, or irritable mood (at least 4 days) Three additional symptoms: four if mood only irritable Unequivocal change in functioning Change observable by others

Table continued on following page

Bipolar Disorders
Hypomanic Episode: Diagnostic Criteria (Continued) Episode not severe enough to cause: Marked impairment Hospitalization Psychosis Not due to direct effects of a substance or general medical condition
~ ~~

67

From American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington, DC, American Psychiatric Association, 1994, with permission.

4. What is a mixed state? A mixed state is diagnosed when the patient simultaneously meets criteria for mania and major depression. Mixed states are common, occurring in approximately 40% of manic patients. Mixed states are sometimes difficult to distinguish from or are misdiagnosed as agitated depressions and borderline conditions. Mixed states are more common in patients with substance abuse and neurologic disorders (e.g., head injury) and are associated with increased suicidality, chronicity, and poorer response to lithium.

5. What is the clinical significance of bipolar I1 disorder? Bipolar I1 (BP 11) disorder is diagnosed in patients with episodes of hypomania interspersed
with episodes of major depression. Clinically, patients usually present during periods of depression. Often the diagnosis is not clear, because both hypomania and depression may be associated with irritability, and the psychomotor symptoms of hypomania may be subtle. BP I1 disorder is more common in women. BP I1 tends to run in families (breeds true), and patients who present as BP I1 tend to stay in the same category; they have subsequent episodes of hypomania but not mania. Bipolar I1 disorder should not be viewed as a minor form of BP I, because psychosocial morbidity, substance abuse, and suicide attempts are at least as common in BP 11. What constitutes the best treatment course for patients with BP needs further study. Patients with BP I1 show a predominance of depression, but antidepressant treatments may induce rapid cycling and mixed states, as they do in BP I disorder. Patients with BP I1 also may be biologically heterogeneous. For example, severe environmental stressors such as prolonged abuse or neglect may cause forms of mood disregulation that phenotypically resemble BP I1 (referred to as bipolar ZZphenocopy)in patients without family histories of affective disorders.

6. How are bipolar and unipolar depression differentiated? About 10-20% of hospital first admissions for depression later develop a bipolar disorder. Careful scrutiny of the patients history for episodes of mania or hypomania may help to make the diagnosis in some cases. The clinical course of bipolar depression is characterized by premorbid cyclothymic temperament; recurrences; and early-age, rapid, and postpartum onsets. Symptomatically bipolar depressives are more likely to demonstrate psychosis, hypersomnia, anergia (low energy), and severe shut-down depressions that are immobilizing. Bipolar depressives also are more likely to have family histories of bipolar disorder and familial loading for affective disorders in general. In the absence of a premorbid history of mania, hypomania, or cyclothymia,no single associated finding is pathognomonic for bipolar disorder, but clusters of such factors make the diagnosis more likely.
7. Describe the course of illness issues in bipolar disorder. In the past there has been a tendency to underestimate the rate of recurrence and to overestimate the age of onset of bipolar disorder. Many bipolar adolescents are misdiagnosed as conduct-disordered or schizophrenic, because they may demonstrate labile mood, abnormal thinking, and disturbed behavior several years before their first recognizable major affective episode. For bipolar patients, the mean age of first impairment due to psychiatric symptoms is 18.7 years; the mean age of first treatment is 22 years; and the mean age of first hospitalization is 25.8 years. The lag between age offirst impairment and age ofjirst treatment is cause for concern in light of data suggesting that early intervention and treatment may prevent the development of a more malignant course of illness.

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The rate of cycling increases with each successive episode. The average free interval between the first and second episode is 5 years, but by the fourth episode cycles are occurring at least yearly. Although duration of episodes demonstrates interindividual variability, the average untreated manic episode lasts 4 months and the average depressive episode 6-9 months. Manic episodes often begin abruptly over hours to days. Bipolar depressions usually take weeks to develop, but they still have a more rapid onset than unipolar depression. Approximately 20% of bipolar patients demonstrate rapid cycling. Rapid cycling is more common in women, patients with BP 11, and patients who have received antidepressant treatments. Rapid cyclers may have a poorer response to lithium and a higher rate of hypothyroidism. In clinical cohorts, another 20% of bipolar patients have a chronic course with no free interval between episodes. A history of chronicity, substance abuse, and mixed states is associated with poorer outcome.

8. Describe the relationship between stress and onset of affective episodes in bipolar disorder.
At times it is difficult to sort out whether stress has led to an episode, or the prodromal symptoms of an episode have led to the stress. Investigations suggest that stressors are statistically more likely to be associated with the onset of episodes early in the course of illness. This finding, along with the finding of increasing cycling, have suggested that the illness may kindle itself and become increasingly endogenous over time. In kindling, a model borrowed from neurology, a subthreshold stimulus applied at a regular interval over time becomes capable of inducing seizure activity. Interpersonal and work difficulties are common precipitants associated with mood destabilization. Sleep reduction may be a final common pathway that leads to mania in a variety of situations, including stress-induced sleep disruption, parturition, and travel. There also is a high rate of bipolarity in patients whose moods demonstrate seasonal variation.

9. List medical conditions that may cause, mimic, or exacerbate bipolar disorder.
Organic factors can cause or exacerbate both mania and depression. The DSM-IV provides a separate diagnostic category for organically derived mood disorders: mood disorder due to . . . [indicate the general medical condition]. Historically, the term secondary mania has been used to designate manic states that arise from neurologic, endocrinologic, metabolic, infectious, or other medical conditions. Many organic factors may contribute to depression or mania individually, but few can engender a true bipolar syndrome with cycling between two states.
Organic Causes of Bipolar Mood Syndromes

Drugs Neurologic factors Metabolic factors Infection

Isoniazid, steroids, disulfram Multiple sclerosis, closed head injury, CNS tumors, epilepsy, Huntingtons disease, cerebrovascular accident Thyroid disorders, postoperative states, adrenal disorders, vitamin B 12 deficiency, electrolyte abnormalities AIDS dementia, neurosyphilis, influenza

Modified from Goodwin F, Jamison K: Manic-Depressive Illness. New York, Oxford University Press, 1990. Patients with an organic affective disorder are less likely to have a positive family history and may respond to treatment of the underlying condition. Other organic affective syndromes, such as those associated with brain trauma and multiple sclerosis, are not reversible but benefit from antibipolar treatments. Patients with a genetic predisposition to bipolarity may have a lower threshold for developing organic affective syndrome secondary to organic stressors.

10. What psychiatric conditions are commonly comorbid with bipolar disorder? Bipolar disorder is the axis I disorder most likely to be associated with comorbid substance abuse or dependence; 60% of bipolar patients demonstrate abuse or dependence in one form or another. A study by the National Institutes of Mental Health (NIMH) found that 46% of bipolar patients

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abused or were dependent on alcohol, and 41% abused or were dependent on marijuana, cocaine, opiates, barbiturates, or hallucinogens. All forms of substance abuse are more common in manic or mixed phases of the illness. Comorbid substance abuse is associated with significantly poorer outcomes and increased rates of suicide. Anxiety symptoms, axis I1 disorders, and certain psychotic conditions are found more commonly in patients with bipolar disorder. During mixed manic states and depressive episodes, bipolar patients may experience extreme anxiety that may remit with control of the affective disorder. Some bipolar patients may appear character-disordered (borderline or narcissistic), because their mood disorder is inadequately treated, whereas others demonstrate a comorbid axis I1 diagnosis in the absence of mood disregulation. Up to 50% of bipolar patients have psychotic symptoms such as delusions or hallucinations at some point in the course of their illness. The presence of psychotic symptoms only during periods of prominent mood disturbance distinguishes psychotic affective disorders from schizophrenia and schizoaffective disorder, in which psychotic symptoms exist outside of periods of mood disturbance.

11. What are the advantages and disadvantages of using lithium in the treatment of bipolar disorder? Advantages: Lithium has been in clinical use for over 40 years. It appears to be highly effective for mild manic symptoms and classic euphoric mania. Although lithium is less effective in treating bipolar depression, approximately 50% of bipolar patients with mild-to-moderate depression respond to treatment if given enough time. Lithium appears more effective in treating with mania-depression-interval (MDI) as opposed to depression-mania-interval (DMI) sequences. One distinct advantage of lithium for some patients is the fact that its standard preparations are significantly less expensive than other antimanic drugs. Disadvantages: Despite lithiums remarkable efficacy in euphoric mania, 30-50% of bipolar patients either are unable to tolerate or fail to respond to lithium. Even for patients who benefit the rate of response is slow: 10-14 days for mania and 4-8 weeks for depression. Gastrointestinal distress, cognitive dullness, polyuria, and tremor represent common acute effects. Weight gain is a common cause of discontinuation over the long term; 25% of patients gain 10 pounds or more. Approximately 10% of patients develop hypothyroidism. Elderly patients with compromised renal function require careful dosage adjustment. Patients with mixed states, severe mania, psychosis, substance abuse, and a history of neurologic insults are less likely to respond to lithium monotherapy.
12. What are the advantages and disadvantages of using anticonvulsants in the treatment of bipolar disorder? Although lithium is considered by many clinicians to be the first-line drug in the treatment of mania and bipolar mood cycling, many patients either are unable to tolerate or fail to respond to lithium. As a result, in the last 15-20 years, there has been increasing interest in the use of anticonvulsants, particularly valproic acid and carbamazepine, to treat bipolar mood disorders. Controlled trials have demonstrated the efficacy of both drugs in acute mania, and studies of valproic acid have suggested a more rapid onset of antimanic action compared with lithium. Valproic acid, like lithium, is FDA-approved for the treatment of acute mania. More recently, investigators and clinicians have looked at the use of lamohigine, gabapentin, and topiramate for patients with bipolar disorder. The disadvantages of these agents are mainly related to side effects. Valproic acid usually is well tolerated, although weight gain is an issue of concern for some patients. Rapid loading at 500 mg 3 timeslday can be accomplished in hospital settings for many acutely agitated patients. Carbamazepine is more difficult to dose and requires a more gradual upward titration. Carbamazepine also autoinduces its own metabolism and heteroinduces the metabolism of other drugs. As a result, careful drug level monitoring is required, and other drugs, such as antipsychotics and birth control pills, may be rendered less effective unless dosage adjustments are made. Lamotrigine is associated with a potentially life threatening rash, especially in pediatric patients. Gabapentin is relatively well tolerated, but is of questionable efficacy. A common side effect of topiramate is weight loss, which is an advantage for some patients.

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13. How does stage of illness affect treatment strategy in bipolar disorder? The treatment strategy in bipolar disorder depends on the current stage of the illness, dimensional assessment of the illness, and knowledge of past treatment. The treatment of acute mania (described in Chapter 49) includes the use of antimanic drugs and, depending on the severity of illness, adjunctive agents such as sedative-hypnotics, benzodiazepines, and antipsychotic agents. The treatment for acute depression (discussed in more detail in the controversies section below) is complicated in bipolar patients by the need to minimize the use of antidepressant agents. Preventive treatment with antibipolar agents usually is indicated, because bipolar disorder almost always is recurrent. The high rate of suicide attempts in all phases of illness dictates an ongoing assessment of safety issues throughout the course of treatment. Recent studies suggest that many patients may do better long-term with antibipolar combination treatments (e.g., lithium plus valproic acid) instead of more traditional antimanic monotherapy strategies (e.g., lithium or valproic acid used alone).

CONTROVERSIES
14. What is the treatment for bipolar depression? Issue. All antidepressants appear capable of inducing mania, mixed states, and mood cycling, thus worsening the long-term course of the illness. Discussion. Patients with mild-to-moderate bipolar depression may respond to antimanic agents such as lithium alone, although there is often a significant lag time of up to 8 weeks before a full antidepressant response. Tricyclic antidepressants (TCAs) should be avoided, because they may be more likely than other antidepressants to induce cycling and also appear to be marginally effective in the treatment of bipolar depression. Bupropion also can induce mania, at least in some patients. Recent data suggest that selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine, sertraline, and paroxetine, may be less likely to induce mania and hypomania than TCAs and monoamine oxidase inhibitors (MAOIs). MAOIs appear to be particularly effective in patients with anergic depressions or atypical symptoms (mood reactivity, hypersomnia, hyperphagia, leaden fatigue, and rejection sensitivity), many of whom may be bipolar. Currently, most clinicians attempt to treat mild-to-moderate bipolar depression without an antidepressant. Some clinicians prefer augmentation with a second antimanic agent before adding an antidepressant. If an antidepressant is required, a short-acting SSRI (sertraline or paroxetine) or bupropion is the first choice. If these are ineffective, an MA01 or electroconvulsive therapy may be used. Patients with rapid cycling depressions or mixed states of mania and concurrent depression require cessation of antidepressant agents and treatment with anticonvulsant combination strategies. 15. What is the role of antipsychotic agents in the treatment of bipolar disorder? Issue. Traditional antipsychotic agents (neuroleptics) frequently have been prescribed to patients with bipolar disorder. Many patients begin these agents when hospitalized for acute mania, but then continue on antipsychotics post hospital discharge after the acute symptoms have resolved. Clinicians should avoid unnecessarily exposing patients to these agents since the older class of antipsychotics is associated with risks of drug-induced extra pyramidal symptoms, neuroleptic-induced dysphoria, and potentially irreversible tardive dyskinesia. Discussion. 60% of patients with bipolar disorder experience psychotic symptoms at some time during the course of their illness. The high historical use of antipsychotic agents in bipolar patients may relate to the fact that clinicians and patients have found that antipsychotic agents are helpful in obtaining and maintaining a clinical response. The side effects of the older antipsychotic agents, however, meant that this therapeutic advantage was purchased at a potentially high cost to the patients. In recent years, a new generation of antipsychotics has been developed that is much less likely to cause drug-induced parkinsonism and tardive dyskinesia. The newer atypical antipsychotic agents, which include clozapine, risperidone, olanzapine, and quetiapine (with additional agents in the pipeline) combine 5 HT2 post synaptic antagonism with D, receptor blockade. In addition to fewer neurologic side effects, these newer agents have positive effects on mood, anxiety, impulsivity, and aggression.

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Clozapine, olanzapine, and, to a lesser extent, risperidone have all been studied in patients with bipolar mood disorders. Clozapine appears to have a powerful anti-manic and mood stabilizing effect and is useful in treatment resistant bipolar disorder. Olanzapine and risperidone may have stronger anti-depressant effects, but appear to induce mania in some patients. Nevertheless, controlled trials of olanzapine have shown its efficacy in treatment of acute mania and have resulted in FDA approval for use in acute mania.
BIBLIOGRAPHY
1. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington, DC, American Psychiatric Association, 1994. 2. Baldessarini RJ, et al: Pharmacological treatment of bipolar disorder throughout the life cycle. In Shulman KI, Tohen M (eds): Mood Disorders Across the Life Span. New York, Wiley-Liss, 1996, pp 299-338. 3. Calabrese JR, et al: Spectrum of activity of lamotrigine in treatment-refractory bipolar disorder. Am J Psychiatry 156(7):1019-1 023,1999. 4. Freeman MP, Stoll AL: Mood stabilizer combinations: A review of safety and efficacy. Am J Psychiatry 155( I): 12-21, 1998. 5. Ghaemi S, et al: Use of atypical antipsychotic agents in bipolar and schizoaffective disorders: Review of the empirical literature. J Clin Psychopharmacol 19(4):354-361, 1999. 6. Goodwin F, Jamison K: Manic-Depressive Illness. New York, Oxford University Press, 1990. 7. McElroy S, et al: Clinical and research implications for the diagnosis of dysphoric and mixed mania or hypomania. Am J Psychiatry 149:1633, 1992. 8. Nathan PE, Gorrnan JM (eds): A Guide to Treatments that Work. New York, Oxford University Press, 1998. 9. Post RM, et al: A history of the use of anticonvulsants as mood stabilizers in the last two decades of the 20th century. Neuropsychobiology 38(3): 152-166, 1998. 10. Schou M: The effect of prophylactic lithium treatment on mortality and suicidal behavior: A review for clinicians. J Affective Disorders 50(2-3):253-259, 1998. 11. Tohen M, et al: Olanzapine versus placebo in the treatment of acute mania. Am J Psychiatry 156(5):702-709, 1999.

13. DEPRESSIVE DISORDERS

Lawson R. Wukin, M.D

1. What are the seven secrets of depression? Depression is (1) common, ( 2 )often missed, ( 3 ) not hard to diagnose if you look for it, (4) often severe, ( 5 ) often recurrent, (6) costly, and (7) highly treatable. These facts are secrets in the sense that they are not well understood by the American public or by many physicians. Depression is among the five most common disorders seen in a primary care physicians office. Unrecognized and untreated depression has been acknowledged as a major public health problem in the United States for the past 20 years. As many as half of the cases of depressive disorders go unrecognized by the patient or the doctor, and among those recognized most will remain untreated. The reasons for such neglect include stigma, misunderstandings about the seriousness and treatability of depression, and preferential attention by patient and doctor to somatic complaints. The disability caused by depressive disorders rivals that of coronary artery disease and is greater than the disability resulting from chronic lung disease or arthritis, according to the Medical Outcomes Study.I5 The cost of depressive disorders in terms of treatment, work missed, and loss of function approximates $43 billion annually in the U.S. Depression is associated with 80% of suicides. Yet it is highly treatable, with 80% of patients responding to antidepressant therapy, psychotherapy, or both, when treated by qualified professionals. The cost of diagnosis and treatment is small, relative to other common severe medical disorders, whereas the cost of not treating a depressive disorder is great.