Bipolar disorder, possibly more than any of

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1 BIPOLAR DISORDER: A SYNDROME IN EVOLUTION Jeffrey A. Lieberman, MD, * and Charles B. Nemeroff, MD, PhD ABSTRACT Diagnosing and treating bipolar disorder offers an array of challenges to the clinician. It is a multidimensional syndrome that can have numerous clinical presentations with a variety of symptom domains in the same individual. It can be difficult to diagnose and evidence shows that it can often be misdiagnosed. With that challenge, it is important to review the various aspects of bipolar disorder and the approaches to treatment, old and new. A review of the latest scientific data can guide us to make informed clinical decisions to make a difference in the quality of care for our bipolar patients. (Adv Stud Med. 2004;4(10D):S881-S891) Bipolar disorder, possibly more than any of the other syndromes in psychiatry, is in the process of evolution and re-evaluation. Although the disorder was previously thought to afflict approximately 1% of the population, more recent epidemiologic studies indicate that it is much more prevalent; some studies *Thad and Alice Eure Distinguished Professor of Psychiatry, Pharmacology, and Radiology, Vice Chairman for Research and Scientific Affairs, Department of Psychiatry, Director, Mental Health and Neurosciences Clinical Research Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina. Reunette W. Harris Professor and Chairman, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia. Address correspondence to: Jeffrey A. Lieberman, MD, Department of Psychiatry, University of North Carolina, 7025 Neuroscience Hospital, CB 7160, Chapel Hill, NC jlieberman@unc.edu. suggest that 5% or more of the population may suffer from the disorder. This marked increase in prevalence estimates is primarily because of the inclusion of individuals who have milder but still clinically relevant and often disabling forms of the disorder. Furthermore, there is increasing recognition and emphasis on the treatment of the depressed phase of the disorder. The depressed phase of the illness is manifested more frequently, carries high morbidity and mortality, and is often difficult to treat effectively. In addition to the evolution in conceptualization and diagnosis of the disorder, treatment options are expanding rapidly. Until recently, lithium and valproate were the only agents the Food and Drug Administration (FDA) approved for the treatment of the disorder. With increasing recognition of the clinical importance of the disorder, research into the clinical management of the many expressions of the bipolar syndrome has increased dramatically. This, in turn, has resulted in a greatly improved understanding of the neurobiology of the disorder and an increased number of new agents available for effective intervention. As these treatments evolve, we are increasingly able to target treatments specific to an individual and illness phase, thus maximizing treatment effectiveness while minimizing the side-effect burden. PREVALENCE OF THE DISORDER Until recently, it was generally thought that approximately 1% of the population suffered from bipolar disorder. However, these estimates were based primarily on patients with bipolar I syndrome. It is becoming increasingly clear that a larger percentage of the population suffer from the varying forms of the disorder. 1 The increase in rates found in many of the more recent studies can be attributed to the increased diagnosis of bipolar type II patients and the inclusion Advanced Studies in Medicine S881

2 of softer clinical manifestations of the disorder. 2,3 Although 4 days is the minimum requirement for the diagnosis of a hypomanic episode in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), patients frequently experience episodes lasting 1 to 3 days. 4 Antidepressant-induced mania, sometimes referred to as bipolar III, may also indicate the presence of an underlying bipolar disorder. Several studies have found a high rate of bipolarity in patients presenting with depression. Akiskal et al noted that 30% to 55% of a cohort of patients with major depression suffered from some form of bipolar disorder if softer and subthreshold forms of the illness were included. 2 In a prospective study of 108 consecutive patients with anxiety and depressive symptoms in a family practice setting, 5 the rate of bipolar spectrum disorders including types I, II, III, and cyclothymia was 25.9%. The bipolar diagnosis was frequently not recognized at the time of initial treatment. In an Italian study of depressed outpatients in a private practice setting, the rate of bipolar I was found to be 4% and the rate of bipolar II was noted to be 45%. 6 A French multicenter study conducted by Hantouche et al was designed to test the feasibility of validating the diagnosis of soft bipolar spectrum by practicing clinicians. 7 Of the 537 patients with major depressive disorder, the rate of bipolar type II disorder was found to be 22% at initial evaluation. After training and more systematic evaluation, the rate was found to nearly double to 40%. Therefore, increasing clinician awareness and sensitivity to the signs of the disorder resulted in much higher diagnostic rates. In a study by Angst and Presig, after the onset of illness, bipolar patients spent approximately 19% of their lives in mood episodes, and the naturalistic follow-up study by Goldberg et al found that only 41% of bipolar patients had a good overall outcome over 4.5 years. 8,9 PSYCHOSOCIAL ISSUES Patients with bipolar disorder are at much higher risk for interpersonal and psychosocial difficulties. Many patients with bipolar disorder experience a broad variety of psychosocial difficulties. Calabrese et al assessed the functional status of 3059 individuals in the community with bipolar I or II disorder. 10 Approximately 50% of the bipolar sample reported experiencing serious problems at work compared to 25% of the controls. Approximately 25% of the bipolar cohort had been arrested, jailed, or convicted of a crime more serious than driving while intoxicated compared to only 5% of controls. Individuals with bipolar disorder also experienced difficulties in social and family interactions. Women tended to have more problems with social and family life, whereas men had more difficulty with legal issues. Altshuler et al found that the Global Assessment of Functioning scale correlated negatively with the Hamilton Rating Scale for Depression (HAM-D), even though none of the patients had HAM-D scores high enough to diagnose a clinical depression. 11 Therefore, even subsyndromal depressive symptoms resulted in increased overall functional impairment. GENETIC FACTORS Although bipolar disorder is one of the most heritable of the psychiatric disorders, identifying the specific genes involved in the disorder remains difficult. Bipolar disorder appears to be oligogenic (ie, multiple susceptibility genes each contribute a small effect to the expression of the syndrome). 12,13 The genes responsible for the disorder are probably common in the general population and it is only when specific combinations of these genetic elements are present that the syndrome is manifested. Therefore, separation of the genetic combinations from normal controls may be difficult as the genetic contributions overlap. Furthermore, differing genetic patterns may result in similar phenotypic expressions of the disorder, making generalization of results difficult. Pharmacogenetics, or the determination of genetic markers in patients responding to a particular medication, is a promising approach to developing individually targeted psychopharmacologic interventions. 14 For example, it has been observed clinically that lithium responders have distinct clinical characteristics. By analyzing genetic markers in lithium responders, specific genetic loci have been identified. 15 In this manner a distinct clinical, biologic, and genetic profile of the responders may be identified. DSM-IV DIAGNOSTIC CRITERIA The criteria for a manic episode as outlined in the DSM-IV 16 require the presence of a period of elevated, expansive, or irritable mood lasting at least 1 week. S882 Vol. 4 (10D) November/December 2004

3 The duration may be briefer if a hospitalization is required. Three or more associated symptoms must be present (4 or more if the mood is only irritable), including inflated self-esteem or grandiosity, decreased need for sleep, increased verbalization or pressure of speech, insomnia or hypersomnia, psychomotor agitation or retardation, flight of ideas, distractibility, increased goal-directed activity, and excessive involvement in pleasurable activities with a high potential for painful consequences. At least 1 manic episode must be present for a diagnosis of bipolar I disorder. A diagnosis of bipolar II disorder requires the presence of at least 1 or more episodes of major depression and at least 1 hypomanic episode. A hypomanic episode consists of a distinct period of elevated, expansive, or irritable mood lasting at least 4 days. At least 3 associated symptoms must be present (4 if the mood is irritable). The associated symptoms are similar to those listed for manic episode, although only 7 associated symptoms are listed instead of the 9 listed for manic criteria. Cyclothymic disorder is characterized by at least 2 years of brief periods of mild depression and hypomania, lasting a few days to a few weeks. One year is required for children or adolescents. There must be no period of euthymia lasting more than 2 months. During the first 2 years of the disorder, the individual must not have experienced a manic, mixed, or major depressive episode. DELAYS TO DIAGNOSIS Despite the greater attention recently given to the disorder, problems with delay in diagnosis and misdiagnosis are still very common. Hirschfeld et al surveyed 600 members of the National Depressive and Manic Depressive Association (now the Depression and Bipolar Support Alliance [DBSA]) with bipolar disorder for their experience with the mental health system. 17 More than 33% of the group sought help within 1 year after symptom onset. However, 69% indicated that they were misdiagnosed, most frequently with major depressive disorder. Those patients who were initially misdiagnosed saw an average of 4 physicians before the correct diagnosis was made. The correct diagnosis was not made for more than 10 years in more than 33% of the sample. The rate of accurate diagnosis was little better than that noted in a 1994 survey in the same group. 18 In that study, 73% of patients noted that they had been misdiagnosed initially. Even when a previous manic or hypomanic episode occurred, there was still a high rate of misdiagnosis. 19 INCREASING DIAGNOSTIC ACCURACY The varied presentation and expression of the bipolar syndromes make for diagnostic confusion, misinterpretation of symptoms, and delay of treatment. There are several aspects of symptom expression that make for problems in accurate diagnosis, including the intermittent expression of symptoms, frequent absence of classic manic symptoms, late presentation of mania, and difficulties in obtaining accurate history among others (Table 1). Alternatively, there are several aspects of the presentation of the bipolar patient that should raise the clinician s suspicions to the presence of the syndrome, even in the absence of the clear or full expression of the disorder (Table 2). For example, anger or irritability, even in the absence of significant depressive symptoms, may indicate the presence of bipolar disorder. Benazzi noted that patients with depression expressing angry affect were more comparable to bipolar patients as compared to those patients without anger. 20 The age of onset of depression was lower in patients with anger. Other indicators of the presence of a bipolar syndrome include positive family histories of mania, antidepressant-induced manic symptoms, increased mood lability, more motor retardation, a greater frequency of depressive episodes, a more severe course of illness, and a more Table 1. Causes of Delays in Diagnosis of Bipolar Disorder Intermittent expression of symptoms Frequent absence of classic manic symptoms Presence of subsyndromal symptoms Difficulty obtaining history owing to poor insight or lack of recall of previous episodes Presentation of mania late in the course of illness Overlap with other syndromes (eg, borderline personality disorder, impulse disorders, ADHD) Variable psychotic phenomena, including mood incongruent phenomena Substance abuse may mimic or obscure symptoms ADHD = attention-deficit hyperactivity disorder. Advanced Studies in Medicine S883

4 Table 2. Diagnostic Clues to the Bipolar Disorder Syndrome Presence of angry affect or irritability, even in the absence of other affective symptoms Poor response to antidepressants Promiscuity or impulsive tendencies Aggressive behaviors, especially if impulsive Presence of a personality disorder, especially borderline or narcissistic History of childhood ADHD, especially with poor response to stimulants Childhood behavioral problems Family history of bipolar disorder Childhood onset of depression Acute onset and offset of depression ADHD = attention-deficit hyperactivity disorder. acute onset and offset of affective symptoms. 21,22 Temperamental character traits or periods of high energy, even if brief, may also be clues to the diagnosis. 19 Bipolar patients frequently also manifest impulse problems, promiscuity, and aggressive behavior. Because many of the traits in bipolar patients may be adaptive or positive, they may not be viewed as clinically significant. For example, a successful hard-driving executive who has boundless energy and requires little sleep may be seen as well suited to his/her position rather than an individual requiring clinical attention. Alternatively, an outgoing and engaging individual is often viewed as very well adapted socially and may be envied for his/her social skills and capacities. However, on careful history taking, there is often evidence of other symptoms typical of mania or depression. COMORBIDITY Comorbidity is common in bipolar disorder. In a study of 288 outpatients with bipolar I or II disorder, 65% met criteria for a lifetime history of another disorder. 23 Anxiety disorders were reported in 42%, whereas the rate of comorbid eating disorders was 5%. A history of substance abuse was found in 42% of the sample. The rate of comorbidity was similar among patients with bipolar I and II. Comorbid anxiety has been associated with early onset, more rapid cycling, increase in course severity, poor response to treatment, and poor outcome Psychiatric comorbidity has been noted to be higher in patients with bipolar II compared to patients with bipolar I in some studies, 23 but not in others. 27 A high rate of substance abuse has been consistently noted in patients with bipolar disorder and is higher than the rate observed in most other axis I disorders. In a study by Chengappa et al, 57.8% of patients with bipolar I were found to abuse drugs and alcohol. 28 In patients with bipolar II, the rate was found to be 39%. In a retrospective study of 267 outpatients with bipolar disorder, the lifetime rate of alcoholism was noted to be higher in men (49%) than women (29%). 29 Compared to the general population, the increased risk rate was much higher in women (odds ratio = 7.35) compared to the increase in men (odds ratio = 2.77). The presence of comorbid substance abuse significantly worsens the prognosis. Worsened outcome among substance abusers may be related to increased problems with compliance, increased denial, problems differentiating symptoms in the presence of substance abuse, and other factors. The rate of comorbid personality disorders also tends to be high in bipolar disorder. In a study of remitted bipolar patients, 28.8% were found to have comorbid personality disorders, primarily of the cluster B and cluster C subtypes. 30 Many of the symptoms of borderline personality disorder overlap with those symptoms found in bipolar patients, and a significant proportion of patients with borderline personality actually may be suffering from bipolar syndrome. In one study, 44% of patients diagnosed with borderline personality disorder were thought to have bipolar disorder. 31 If patients with antidepressant-induced switching to mania were included, the rate increased to 69%. MANIA Acute mania is the most dramatic phase of the bipolar syndrome and requires rapid and effective treatment to avoid multiple untoward consequences. Bipolar disorder accounts for 1 in 7 psychiatric emergencies. 32 In cases of extreme agitation or threatening behavior, intramuscular (IM) injections of medications may be required. Until recently, the most commonly used combination of agents was IM haloperidol and lorazepam. Although this combination was effec- S884 Vol. 4 (10D) November/December 2004

5 tive in controlling acute symptoms, significant side effects such as acute extrapyramidal symptoms, including dystonia, and excess sedation often occurred. IM atypical antipsychotic formulations are now available. Ziprasidone is available in an IM formulation and has been noted to be effective within 15 to 30 minutes with minimal motor side effects or sedation. 33 Olanzapine has also been found to be effective in IM formulation and has been shown to be equivalent to haloperidol in effectiveness. 34 MIXED EPISODES Increased attention is appropriately being given to mixed manic episodes. Mixed episodes were first described by Kraepelin and are characterized by the presence of depressive and manic symptoms during the index episode. 35 They may represent a more virulent form of the illness and have been associated with increased suicidal ideation, refractoriness to treatment, and a poor response to lithium. 36 In a survey of 184 adult inpatients, 58% of patients with mixed mania were suicidal compared to only 1.3% of patients with pure mania. 37 Suicide attempts before the index episode were also increased in those patients with mixed episodes (37% vs 8%). The probability of achieving remission declined by 49% for each prior suicide attempt. DEPRESSION Although the manic episodes associated with bipolar disorder tend to be the more dramatic element of the disorder, it is the depressed phase that predominates in most patients and is often the most difficult to treat. In a 13- year prospective study of 146 bipolar I patients, it was found that patients reported depressed mood 32% of the time, manic/hypomanic symptoms 9% of the time, and mixed symptoms 6% of the time. 38 In a 15-year followup study, it was found that depressive episodes of illness in patients with bipolar I lasted significantly longer than manic episodes. 39 Morbidity was higher during the entire follow-up period in patients who initially presented with a depressed episode. PSYCHOTIC FEATURES Although psychosis is commonly observed in the bipolar syndrome, it has received much less systematic study than the affective elements of the disorder. In a study of 179 patients hospitalized with a manic episode, individuals with psychotic features had greater overall impairment as measured on the Global Assessment Scale. 40 However, the severity of mania scores did not differ between the psychotic and nonpsychotic cohorts. Treatments that successfully treated mania also decreased psychosis severity scores. Coryell et al found that psychotic features were associated with a greater amount of time ill during the 5- year follow-up period. 41 However, the time to initial recovery and time to first relapse was not different between the psychotic and nonpsychotic cohorts. Response to acute lithium treatment was also similar between the 2 groups. Keck et al did not note any difference between psychotic and nonpsychotic bipolar I cohorts and did not find any distinguishing demographic, psychosocial, or vocational variables. 42 A family history of bipolar disorder was significantly more common in patients with nonpsychotic forms of the disorder. The presence of psychosis, whether it was mood congruent, surprisingly did not result in a worse overall outcome in this study. In a study of 50 patients with bipolar disorder followed for 8 months after their first hospitalization for a manic episode, mood-incongruent psychotic features were found to result in more weeks with psychosis compared to patients with mood-congruent psychosis. 43 The mood-incongruent group had poorer overall functioning during follow-up. SUICIDE RISK Suicide rates are high in bipolar disorder and early onset of the disorder is associated with increased suicide rates. 44 It has been estimated that at least 25% to 50% of all patients with bipolar disorder attempt suicide at least once. 45 Suicide rates among patients with bipolar disorder average 0.4% per year, which is more than 20 times higher than in the general population. 46 In a Swedish study of hospitalized patients with bipolar disorder, the standardized mortality ratios for suicide was 15.0 for males and 22.4 for females. 47 This compared to rates in unipolar depression of 20.9 and 27.0, respectively. Treatment with lithium has been shown to decrease suicide rates dramatically. In a study of pooled data from 34 studies of patients, the risk for all suicidal acts per 100 person-years was 3.10 without lithium. 48 This rate dropped dramatically to during treatment compared to the baseline rate for the Advanced Studies in Medicine S885

6 general population. In one study, the risk of suicide was higher during treatment with divalproex compared to lithium. 49 The risk of death was 2.7 times higher with divalproex. Some of the risk factors for suicide among patients with bipolar disorder are acute depression, especially when there is hopelessness, turmoil, global insomnia, anhedonia, and anxiety or panic; mixed episodes and cycling within an episode; substance abuse; aggression/impulsivity; history of suicide attempts (personal or familial); and early onset of the disorder. MEASURING OUTCOMES There are several rating scales that are used for the assessment of symptom severity in patients with bipolar disorder. The Young Mania Rating Scale (YMRS) 50 is one of the most widely used in research for the manic phase of the illness. The YMRS consists of 11 clinician-rated questions. Rated items include elevated mood, motor activity, sexual interest, sleep, irritability, speech rate and amount, languagethought disorder, thought content, disruptive-aggressive behavior, appearance, and insight. Alternately, the Mania Rating Scale 51 has been used in recent studies This is based on an 11-item scale derived from the Schedule for Affective Disorders and Schizophrenia, Change Version; total score measures severity of manic symptoms. There are several rating scales for the measurement of depression symptom severity. The HAM-D 55 in a 21- and 17-item format are the most commonly used. This is a clinician-rated scale to assess the presence and magnitude of depressed mood, guilty feelings, suicidality, sleep difficulties, anxiety, and weight loss among others. The Montgomery-Asberg Depression Rating Scale 56 is also widely used and assesses for treatment changes in the severity of a variety of symptoms, including depressed mood, sleep, appetite, energy, concentration, and suicidality. The Positive and Negative Syndrome Scale 57,58 is one of the most widely used scales for dimensions associated with schizophrenia and other psychotic disorders. There are 30 clinician-rated questions that assess the extent of positive symptoms, such as delusions, hallucinations, and thought disorganization; negative symptoms include items such as blunted affect, emotional withdrawal, poor rapport, and social withdrawal, in addition to general psychopathology. SCREENING FOR BIPOLAR DISORDER To improve the diagnosis of bipolar disorder, Hirschfeld et al developed the Mood Disorder Questionnaire (MDQ). 59 This screening instrument includes 13 yes/no questions concerning manic or hypomanic symptoms. The respondent is also queried as to the presence of multiple simultaneous symptoms and the psychosocial problems that they may have caused. The screen is considered positive if multiple symptoms are present at the same time and they are of at least moderate severity. The MDQ has been translated in several languages and is available online through the DBSA Web site at In a nationwide survey of adults using the MDQ, the lifetime prevalence of bipolar disorder I and II was found to be 3% (4% after nonresponse bias included). 17 The highest prevalence rate was in the 18- to 24-year age group at 9%. The high rate in this age group is considered to be partially an artifact; however, it highlights the tendency for early onset of the disorder. Thirty-three percent of the sample reported experiencing difficulties before age 15 years, and 27% reported the onset of difficulties between ages 15 years and 19 years. 17 Only 20% of patients with positive screens indicted that they had previously received a diagnosis of bipolar disorder by a physician and 33% had been diagnosed with unipolar disorder. Life charting has also been shown to be an effective means of detecting and tracking periods of mood instability and response to treatment. 60,61 Life charting can help clinicians monitor the episodic course of the illness and the treatment response to often complicated medication regimens. It may aid patients and families to identify early signs of decompensation and to gain insight into the course of the disorder. Manuals and forms for clinicians and patients are available at Charting.htm. PSYCHOPHARMACOLOGIC ADVANCES After the introduction of lithium in the early 1950s, there were few advances in the treatment of bipolar disorder for several decades. Although lithium was clearly efficacious, the medication appeared to work well primarily in a particular subgroup of patients. A good response to lithium has been associ- S886 Vol. 4 (10D) November/December 2004

7 ated with an episodic course interspersed by euthymic periods, 4 or less cycles per year, and a family history of bipolar disorder. Alternatively, a poor lithium response may be predicted by early onset, rapid cycling (more than 4 episodes per year), a chronic course, mixed episodes, and a history of substance abuse The anticonvulsant carbamazepine was subsequently also found to be effective in mood stabilization 65 and appeared to be efficacious in a different subpopulation of patients compared to lithium. 66 Valproate was also found to be effective in stabilizing mood and offered a differential treatment response compared to lithium. 64 In a study by Bowden et al, divalproex and lithium were found to be significantly more effective compared to placebo in reducing the symptoms of acute mania. 67 The efficacy of divalproex was determined to be independent of prior responsiveness to lithium. There are several new antiepileptic agents that are increasingly being used in the treatment of acute mania. Lamotrigine is effective for the prevention of manic and depressive episodes. 68,69 Lamotrigine is particularly effective in the treatment of bipolar depression, but was not effective in the treatment of acute mania in 3 studies. However, the titration schedule must be kept slow to minimize the risk of potentially serious Stevens-Johnson syndrome, especially if used concurrently with valproate. 70 Oxcarbazepine possesses a chemical structure similar to carbamazepine, 71 but its efficacy in bipolar disorder has not been established. The side effects are less serious than those side effects observed with carbamazepine. 72 Topiramate also may be a useful adjunctive agent, but double-blind, placebo-controlled studies failed to demonstrate efficacy in acute mania. 73,74 Topiramate, in contrast to many of the other mood-stabilizing and antipsychotic drugs, has the advantage of inducing weight loss in some individuals. It has been used as an adjunctive agent to offset the weight-enhancing effects of medications, such as olanzapine. 75 ATYPICAL ANTIPSYCHOTICS IN BIPOLAR DISORDER The atypical antipsychotic agents are playing an increasing role in the acute and long-term treatment of bipolar disorder. In contrast to the typical antipsychotics that bind to dopamine D 2 receptors at greater than 90%, the atypical agents all possess a greater affinity for the 5-HT 2A receptor than the dopamine D 2 receptor and occupy the dopamine D 2 receptor at 70% or less. Each of the atypical agents also possesses a unique pharmacologic profile that is associated with varying clinical actions and side-effect profiles. These distinctions allow the clinician to tailor treatment to the specific individual. Olanzapine was the first of the atypical antipsychotics approved for the treatment of bipolar disorder. It has been shown to be effective in several studies, alone and in combination with other mood stabilizers. 76,77 Clozapine, the first of the atypical agents available, also has been shown to be effective. Similar to its role in schizophrenia, 78 clozapine has been shown to be effective in treatment-resistant bipolar disorder. 79 However, its side-effect burden, including the risk of agranulocytosis, 80 precludes the use of this agent as first-line therapy. Of all of the atypical agents, olanzapine and clozapine are the most likely to induce weight gain, hyperlipidemia, and disturbances in glucose metabolism. 81 Therefore, caution should be used in administration of these agents in patients already at risk for such problems. 82 Obesity in the general population is reaching epidemic proportions and has continued to increase over the past several decades. 83 Patients with bipolar disorder 42 or schizophrenia are already at higher risk for health problems and chronic medical illnesses compared to the general population. Medicationinduced obesity and the associated metabolic syndrome increase this risk even further. In addition to the health risks, obesity may result in higher noncompliance rates. 84 In a study by Zajecka et al, olanzapine monotherapy was compared to treatment with divalproex in hospitalized acutely manic patients. 85 No differences were noted in efficacy between the 2 agents. However, patients treated with olanzapine experienced more weight gain and somnolence. The weight gain after 3 weeks on olanzapine was 4.0 kg compared to 2.5 kg on divalproex. There was one death in a patient treated with olanzapine who developed diabetic ketoacidosis. Fontaine et al estimated that the lives saved from suicide prevention with clozapine were nearly offset by the estimated rate of life-years lost through obesity. 86 Quetiapine has been shown to be effective as an adjunctive therapy to lithium and divalproex, 87 enhancing the clinical effect of both of these agents. In a study of pooled data from several double-blind placebo-controlled studies, quetiapine monotherapy Advanced Studies in Medicine S887

8 was shown to be more effective compared to placebo in patients with bipolar I. 88 The average dose of quetiapine was 600 mg/day in this study. Recent studies have shown quetiapine to be effective as monotherapy 89,90 and adjunctive treatment with mood stabilizers 91,92 in bipolar mania. Calabrese et al reported that quetiapine was shown to be an effective and well-tolerated treatment for bipolar depression and was not associated with treatment-emergent mania. 93 Although there is some weight gain with quetiapine, it is much more modest compared to clozapine or olanzapine. 94 Ziprasidone has also recently been approved by the FDA for the treatment of acute mania and mixed episodes. In a 3-week double-blind study, ziprasidone 40 to 80 mg twice daily was more effective in acute mania and mixed episodes (with or without psychosis) compared to placebo on a variety of measures. 52 Separation from placebo was noted on the Mania Rating Scale by the second day of the study and was sustained throughout the length of the study. Patients on ziprasidone did not experience weight gain or clinically significant electrocardiogram changes. Affective symptoms were also improved in a cohort of patients with schizoaffective disorder. 95 In a 52-week, openlabel extension of the 3-week study, ziprasidone demonstrated long-term symptom and global improvement in patients with bipolar disorder while displaying a weight- and lipid-neutral profile. 96 Similar to the other atypical agents, ziprasidone acts as an antagonist of serotonin 2A (5-HT 2A ) and D 2 receptors, with greater affinity for 5-HT 2A. Effect on the 5-HT 2c, 5-HT 1D, and 5-HT 1A receptors has been suggested to explain the capacity of ziprasidone to ameliorate negative symptoms and improve cognition. 97,98 Ziprasidone also inhibits the reuptake of serotonin and norepinephrine, which may underlie antidepressant properties of the agent. 99 With regard to side effects, ziprasidone treatment is associated with very low rates of weight gain compared to all the other atypical agents other than aripiprazole. Allison et al reported that in at least 81 trials, the greatest weight gain was noted with clozapine (4.45 kg) and olanzapine (4.15 kg). 100 Weight gain on risperidone was intermediate at 4.15 kg and there was negligible weight gain on ziprasidone at 0.04 kg. The data on quetiapine were insufficient and aripiprazole was not included in the analysis. Risperidone was compared to placebo in a 3-week double-blind placebo-controlled study in acute bipolar mania. 101 A flexible dose of 1 to 6 mg/day was used, with the average dose being 4.1 mg/day. Risperidone was significantly better compared to placebo as early as day 3 and continued throughout the study. Risperidone may result in extrapyramidal symptoms, usually at higher doses. 102 Prolactin increases, menstrual irregularities, and sexual dysfunction may also be observed with this atypical agent. In a study comparing risperidone (1 6 mg/day) to quetiapine ( mg/day), the rate of sexual dysfunction was 50% in the risperidone cohort compared to 16% in the quetiapine cohort. 103 Prolactin levels were increased in patients treated with risperidone (mean = 57.7 mg/ml) compared to levels in patients receiving quetiapine (13.8 ng/ml). Only 11.7% of patients spontaneously volunteered that sexual dysfunction was present before administration of the questionnaire in the study. Because patients may not make a connection between the onset of the sexual problems and the medications, it is important that these problems be actively elicited by the clinician. Aripiprazole, the last atypical agent to be introduced, also has been demonstrated to be an effective treatment of acute mania. In a 3-week double-blind study of 262 patients with bipolar disorder manifesting manic or mixed symptoms, 15 to 30 mg per day of aripiprazole was found to be superior to placebo. 104 The response rate on medication was 42% compared to 21% for patients receiving placebo. Aripiprazole has recently received FDA approval for treatment of acute mania. CONCLUSIONS Bipolar disorder is one of the most clinically complex syndromes in psychiatry. It is a multidimensional syndrome characterized by mood, behavioral, cognitive, and perceptual symptoms and has a propensity for recurrence in more than 90% of patients. 105,106 The burden of this disorder causes tremendous individual suffering and societal costs when left untreated or inadequately treated. The many varying forms of presentations between individuals and within the same patient make accurate diagnosis difficult. The treatment algorithms are also complex because the many different phases of the disorder need to be treated effectively. Despite the many complexities, our understanding of the disorder has been rapidly evolving, as have the range of psychopharmacologic interventions. For many years, S888 Vol. 4 (10D) November/December 2004

9 lithium was the only effective treatment available. We now have many new anticonvulsants and atypical agents to help manage this disorder. Targeted use of these agents allows for rapid and long-term mood stabilization in most patients while minimizing potential side effects. REFERENCES 1. Hirschfeld RM. Bipolar spectrum disorder: improving its recognition and diagnosis. J Clin Psychiatry. 2001; 62(suppl 14): Akiskal HS, Bourgeois ML, Angst J, et al. Re-evaluating the prevalence of and diagnostic composition within the broad clinical spectrum of bipolar disorders. J Affect Disord. 2000;59(suppl 1):S5-S Angst J. The emerging epidemiology of hypomania and bipolar II disorder. J Affect Disord. 1998;50: Perugi G, Akiskal HS. The soft bipolar spectrum redefined: focus on the cyclothymic, anxious-sensitive, impulse-dyscontrol, and binge-eating connection in bipolar II and related conditions. Psychiatr Clin North Am. 2002;25: Manning JS, Haykal RF, Connor PD, Akiskal HS. On the nature of depressive and anxious states in a family practice setting: the high prevalence of bipolar II and related disorders in a cohort followed longitudinally. Compr Psychiatry. 1997;38: Benazzi F. Prevalence of bipolar II disorder in outpatient depression: a 203-case study in private practice. J Affect Disord. 1997;43: Hantouche EG, Akiskal HS, Lancrenon S, et al. Systematic clinical methodology for validating bipolar-ii disorder: data in mid-stream from a French national multi-site study (EPI- DEP). J Affect Disord. 1998;50: Angst J, Presig M. Course of a clinical cohort of unipolar, bipolar and schizoaffective patients. Results of a prospective study from 1959 to Schweiz Arch Neurol Psychiatr. 1995;146: Goldberg J, Harrow M, Grossman L. Course and outcome in bipolar affective disorder: a longitudinal follow-up study. Am J Psychiatry. 1995;152: Calabrese JR, Hirschfeld RM, Reed M, et al. Impact of bipolar disorder on a U.S. community sample. J Clin Psychiatry. 2003;64: Altshuler LL, Gitlin MJ, Mintz J, et al. Subsyndromal depression is associated with functional impairment in patients with bipolar disorder. J Clin Psychiatry. 2002;63: Craddock N, Jones I. Molecular genetics of bipolar disorder. Br J Psychiatry. 2001;41:S128-S Mathews CA, Reus VI. Genetic linkage in bipolar disorder. CNS Spectr. 2003;8: Mamdani F, Groisman IJ, Alda M, Turecki G. Pharmacogenetics and bipolar disorder. Pharmacogenomics J. 2004;4: Turecki G, Grof P, Grof E, et al. Mapping susceptibility genes for bipolar disorder: a pharmacogenetic approach based on excellent response to lithium. Mol Psychiatry. 2001;6: American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Washington, DC: American Psychiatric Press; Hirschfeld RA, Lewis L, Vornik LA. Perceptions and impact of bipolar disorder: how far have we really come? Results of the National Depressive and Manic-Depressive Association 2000 survey of individuals with bipolar disorder. J Clin Psychiatry. 2003;64: Lish JD, Dime-Meenan S, Whybrow PC, et al. The National Depressive and Manic-Depressive Association (DMDA) survey of bipolar members. J Affect Disord. 1994;31: Hirschfeld RA, Williams JB, Spitzer RL, et al. Development and validation of a screening instrument for bipolar spectrum disorder: the Mood Disorder Questionnaire. Am J Psychiatry. 2000;157: Benazzi F. Major depressive disorder with anger: a bipolar spectrum disorder? Psychother Psychosom. 2003;72: Bowden CL. Strategies to reduce misdiagnosis of bipolar depression. Psychiatr Serv. 2001;52: Ghaemi SN, Ko JY, Goodwin FK. Cade s disease and beyond: misdiagnosis, antidepressant use, and a proposed definition for bipolar spectrum disorder. Can J Psychiatry. 2002;47: 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: Feske U, Frank E, Mallinger AG, et al. Anxiety as a correlate of response to the acute treatment of bipolar I disorder. Am J Psychiatry. 2000;157: Henry C, Van den Bulke D, Bellivier F, et al. Anxiety disorders in 318 bipolar patients: prevalence and impact on illness severity and response to mood stabilizer. J Clin Psychiatry. 2003;64: Young LT, Cooke RG, Robb JC, et al. Anxious and non-anxious bipolar disorder. J Affect Disord. 1993;29: Rihmer Z, Szadoczky E, Furedi J, et al. Anxiety disorders comorbidity in bipolar I, bipolar II and unipolar major depression: results from a population-based study in Hungary. J Affect Disord. 2001;67: Chengappa KN, Levine J, Gershon S, Kupfer DJ. Lifetime prevalence of substance or alcohol abuse and dependence among subjects with bipolar I and II disorders in a voluntary registry. Bipolar Disord. 2000;2: Frye MA, Altshuler LL, McElroy SL, et al. Gender differences in prevalence, risk, and clinical correlates of alcoholism comorbidity in bipolar disorder. Am J Psychiatry. 2003;160: George EL, Miklowitz DJ, Richards JA, et al. The comorbidity of bipolar disorder and axis II personality disorders: prevalence and clinical correlates. Bipolar Disord. 2003;5: Deltito J, Martin L, Riefkohl J, et al. Do patients with borderline personality disorder belong to the bipolar spectrum? J Affect Disord. 2001;67: Allen MH, Currier GW. Use of restraints and pharmacotherapy in academic psychiatric emergency services. Gen Hosp Psychiatry. 2003;161: Daniel DG, Potkin SG, Reeves KR, et al. Intramuscular (IM) ziprasidone 20 mg is effective in reducing acute agitation associated with psychosis: a double-blind, randomized trial. Psychopharmacology (Berl). 2001;155: Advanced Studies in Medicine S889

10 34. Breier A, Meehan K, Birkett M, et al. A double-blind, placebocontrolled dose-response comparison of intramuscular olanzapine and haloperidol in the treatment of acute agitation in schizophrenia. Arch Gen Psychiatry. 2002;59: Akiskal HS. The prevalent clinical spectrum of bipolar disorders: beyond DSM-IV. J Clin Psychopharmacol. 1996; 16(suppl 1):4S-14S. 36. Bowden CL. Dosing strategies and time course of response to antimanic drugs. J Clin Psychiatry. 1996;57(suppl 13): Goldberg JF, Garno JL, Portera L, et al. Qualitative differences in manic symptoms during mixed versus pure mania. Compr Psychiatry. 2000;41: 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: Turvey CL, Coryell WH, Arndt S, et al. Polarity sequence, depression, and chronicity in bipolar I disorder. J Nerv Ment Dis. 1999;187: Swann AC, Daniel DG, Kochan LD, et al. Psychosis in mania: specificity of its role in severity and treatment response. J Clin Psychiatry. 2004;65: Coryell W, Leon AC, Turvey C, et al. The significance of psychotic features in manic episodes: a report from the NIMH collaborative study. J Affect Disord. 2001;67: Keck PE Jr, McElroy SL, Havens JR, et al. Psychosis in bipolar disorder: phenomenology and impact on morbidity and course of illness. Compr Psychiatry. 2003;44: Strakowski SM, Williams JR, Sax KW, et al. Is impaired outcome following a first manic episode due to mood-incongruent psychosis? J Affect Disord. 2000;61: Perlis RH, Miyahara S, Marangell LB, et al. Long-term implications of early onset in bipolar disorder: data from the first 1000 participants in the systematic treatment enhancement program for bipolar disorder (STEP-BD). Biol Psychiatry. 2004;55: Jamison KR. Suicide and bipolar disorder. J Clin Psychiatry. 2000;61(suppl 9): Tondo L, Isacsson G, Baldessarini R. Suicidal behavior in bipolar disorder: risk and prevention. CNS Drugs. 2003;17: Osby U, Brandt L, Correia N, et al. Excess mortality in bipolar and unipolar disorder in Sweden. Arch Gen Psychiatry. 2001;58: Baldessarini RJ, Tondo L, Hennen J. Lithium treatment and suicide risk in major affective disorders: update and new findings. J Clin Psychiatry. 2003;64(suppl 5): Goodwin FK, Fireman B, Simon GE, et al. Suicide risk in bipolar disorder during treatment with lithium and divalproex. JAMA. 2003;290: Young RC, Biggs JT, Ziegler VE, Meyer DA. A rating scale for mania: reliability, validity and sensitivity. Br J Psychiatry. 1978;133: Endicott J, Spitzer RL. A diagnostic interview: the schedule for affective disorders and schizophrenia. Arch Gen Psychiatry. 1978;35: Keck PE Jr, Versiani M, Potkin S, et al. Ziprasidone in the treatment of acute bipolar mania: a three-week, placebocontrolled, double-blind, randomized trial. Am J Psychiatry. 2003;160: Segal S, Riesenberg RA, Ice K, et al. Ziprasidone in mania: double-blind, placebo-controlled trial. Paper presented at: the American Psychiatric Association Institute on Psychiatric Services; October 2003; Boston, Mass. 54. Potkin SG, Keck PE, Giller E, et al. Ziprasidone in bipolar mania: efficacy across patient subgroups [abstract]. Paper presented at: the 2004 Annual Meeting of the American Psychiatric Association; 2004; New York, NY. 55. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960;23: Montgomery SM. Depressive symptoms in acute schizophrenia. Prog Neuropsychopharmacol. 1979;3: Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull. 1987;13: Kay SR, Opler LA, Lindenmayer JP. Reliability and validity of the positive and negative syndrome scale for schizophrenics. Psychiatry Res. 1988;23: Hirschfeld RM, Calabrese JR, Weissman MM, et al. Screening for bipolar disorder in the community. J Clin Psychiatry. 2003;64: Denicoff KD, Leverich GS, Nolen WA, et al. Validation of the prospective NIMH-Life-Chart Method (NIMH-LCM-p) for longitudinal assessment of bipolar illness. Psychol Med. 2000;30: Denicoff KD, Smith-Jackson EE, Disney ER, et al. Preliminary evidence of the reliability and validity of the prospective life-chart methodology (LCM-p). J Psychiatr Res. 1997; 31: Grof P, Alda M, Grof E, et al. The challenge of predicting response to stabilising lithium treatment: the importance of patient selection. Br J Psychiatry Suppl. 1993;21: Passmore MJ, Garnham J, Duffy A, et al. Phenotypic spectra of bipolar disorder in responders to lithium versus lamotrigine. Bipolar Disord. 2003;5: Swann AC, Bowden CL, Calabrese JR, et al. Differential effect of number of previous episodes of affective disorder on response to lithium or divalproex in acute mania. Am J Psychiatry. 1999;156: Post RM, Denicoff KD, Frye MA, et al. A history of the use of anticonvulsants as mood stabilizers in the last two decades of the 20th century. Neuropsychobiology. 1998;38: Greil W, Kleindienst N. Concepts in the treatment of bipolar disorder. Acta Psychiatr Scand. 2003;418: Bowden CL, Brugger AM, Swann AC, et al. Efficacy of divalproex vs lithium and placebo in the treatment of mania. The Depakote Mania Study Group [published correction appears in JAMA. 1994;271:1830]. JAMA. 1994;271: Hahn CG, Gyulai L, Baldassano CF, Lenox RH. The current understanding of lamotrigine as a mood stabilizer. J Clin Psychiatry. 2004;65: Herman E. Lamotrigine: a depression mood stabiliser. Eur Neuropsychopharmacol. 2004;14(suppl 2):S89-S Guberman AH, Besag FM, Brodie MJ, et al. Lamotrigineassociated rash: risk/benefit considerations in adults and children. Epilepsia. 1999;40: May TW, Korn-Merker E, Rambeck B. Clinical pharmacokinetics of oxcarbazepine. Clin Pharmacokinet. 2003; 42: Ghaemi SN, Berv DA, Klugman J, et al. Oxcarbazepine treatment of bipolar disorder. J Clin Psychiatry. 2003; 64: Vieta E, Sanchez-Moreno J, Goikolea JM, et al. Adjunctive topiramate in bipolar II disorder. World J Biol Psychiatry. 2003;4: S890 Vol. 4 (10D) November/December 2004

11 74. Wang PW, Ketter TA, Becker OV, Nowakowska C. New anticonvulsant medication uses in bipolar disorder. CNS Spectr. 2003;8: , Vieta E, Sanchez-Moreno J, Goikolea JM, et al. Effects on weight and outcome of long-term olanzapine-topiramate combination treatment in bipolar disorder. J Clin Psychopharmacol. 2004;24: Bhana N, Perry CM. Olanzapine: a review of its use in the treatment of bipolar I disorder. CNS Drugs. 2001;15: Tohen M, Goldberg JF, Gonzalez-Pinto Arrillaga AM, et al. A 12-week, double-blind comparison of olanzapine vs haloperidol in the treatment of acute mania. Arch Gen Psychiatry. 2003;60: Lieberman JA. Maximizing clozapine therapy: managing side effects. J Clin Psychiatry. 1998;59(suppl 3): Suppes T, Ozcan ME, Carmody T. Response to clozapine of rapid cycling versus non-cycling patients with a history of mania. Bipolar Disord. 2004;6: Alvir JM, Lieberman JA. Agranulocytosis: incidence and risk factors. J Clin Psychiatry. 1994;55(suppl B): Meyer JM. A retrospective comparison of weight, lipid, and glucose changes between risperidone- and olanzapine-treated inpatients: metabolic outcomes after 1 year. J Clin Psychiatry. 2002;63: Nasrallah HA. Factors in antipsychotic drug selection: tolerability considerations. CNS Spectr. 2003;8(suppl 2): Mokdad AH, Bowman BA, Ford ES, et al. The continuing epidemics of obesity and diabetes in the United States. JAMA. 2001;286: Weiden PJ, Mackell JA, McDonnell DD. Obesity as a risk factor for antipsychotic noncompliance. Schizophr Res. 2004;66: Zajecka JM, Weisler R, Sachs G, et al. A comparison of the efficacy, safety, and tolerability of divalproex sodium and olanzapine in the treatment of bipolar disorder. J Clin Psychiatry. 2002;63: Fontaine KR, Heo M, Harrigan EP, et al. Estimating the consequences of anti-psychotic induced weight gain on health and mortality rate. Psychiatry Res. 2001;101: Sachs G, Chengappa KN, Suppes T, et al. Quetiapine with lithium or divalproex for the treatment of bipolar mania: a randomized, double-blind, placebo-controlled study. Bipolar Disord. 2004;6: Jones M, Huizar K. Quetiapine monotherapy for mania associated with bipolar disorder. Paper presented at: the 5th International Conference on Bipolar Disorder; June 12-14, 2003; Pittsburgh, Pa. 89. Goldberg JF. Effective dose of quetiapine in the treatment of bipolar mania [abstract]. Paper presented at: the 2004 Annual Meeting of the American Psychiatric Association; 2004; New York, NY. 90. Fleck DE, Dunayevich E, Knepple ED, et al. Efficacy and safety of quetiapine compared with divalproex sodium for treatment of acute mania [abstract]. Paper presented at: the 2004 Annual Meeting of the American Psychiatric Association; 2004; New York, NY. 91. Sachs GS. Combination treatment for acute mania. Paper presented at: the 2004 Annual Meeting of the American Psychiatric Association; 2004; New York, NY. 92. Sussman N, Mullen J, Sweitzer DE. Mania remission rates and euthymia with quetiapine combination therapy [abstract]. Paper presented at: the 2004 Annual Meeting of the American Psychiatric Association; 2004; New York, NY. 93. Calabrese JR, MacFadden W, McCoy R, et al. Doubleblind, placebo-controlled study of quetiapine in bipolar depression [abstract]. Paper presented at: the 2004 Annual Meeting of the American Psychiatric Association; 2004; New York, NY. 94. Melkersson K, Dahl ML. Adverse metabolic effects associated with atypical antipsychotics: literature review and clinical implications. Drugs. 2004;64: Keck PE, Reeves KR, Harrigan EP, et al. Ziprasidone in the short-term treatment of patients with schizoaffective disorder: results from two double-blind, placebo-controlled, multicenter studies. J Clin Psychopharmacol. 2001;21: Keck PE, Potkin SG, Warrington L, et al. Efficacy and safety of ziprasidone in bipolar disorder: short- and long-term data [abstract]. Paper presented at: the 2004 Annual Meeting of the American Psychiatric Association; 2004; New York, NY. 97. Harvey PD. Ziprasidone and cognition: the evolving story. J Clin Psychiatry. 2003;64(suppl 19): Stahl SM, Shayegan DK. The psychopharmacology of ziprasidone: receptor-binding properties and real-world psychiatric practice. J Clin Psychiatry. 2003;64(suppl 19): Schmidt AW, Lebel LA, Howard HR Jr, Zorn SH. Ziprasidone: a novel antipsychotic agent with a unique human receptor binding profile. Eur J Pharmacol. 2001;425: Allison DB, Mentore JL, Heo M, et al. Antipsychoticinduced weight gain: a comprehensive research synthesis. Am J Psychiatry. 1999;156: Hirschfeld RM, Keck PE Jr, Kramer M, et al. Rapid antimanic effect of risperidone monotherapy: a 3-week multicenter, double-blind, placebo-controlled trial. Am J Psychiatry. 2004;161: Brown WJ, Dobson AJ, Mishra G. What is a healthy weight for middle aged women? Int J Obes Relat Metab Disord. 1998;22: Knegtering R, Castelein S, Bous H, et al. A randomized open-label study of the impact of quetiapine versus risperidone on sexual functioning. J Clin Psychopharmacol. 2004;24: 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: Hopkins HS, Gelenberg AJ. Treatment of bipolar disorder: how far have we come? Psychopharmacol Bull. 1994;30: Shulman KI, Tohen M, Kutcher SP. Mood Disorders Across the Life Span. New York, NY: John Wiley & Sons, Inc; Advanced Studies in Medicine S891