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R E V I E W

A R T I C L E

Bipolar Disorder: Improving Diagnosis and Optimizing Integrated Care
J. L. Culver, B. A. Arnow, and T. A. Ketter
Stanford University, Department of Psychiatry and Behavioral Sciences
Bipolar disorder is a chronic, severe condition commonly causing substantial mortality and psychosocial morbidity. Challenges in recognition can delay the institution of appropriate management, whereas misdiagnosis may initiate pharmacologic interventions that adversely affect the condition’s course. Pharmacotherapy remains the foundation of treatment. In addition to efficacy, tolerability is an important consideration in medication choice, particularly for long-term maintenance because of its impact on adherence. Mood stabilizers are the classic treatments for bipolar disorder. Newer agents such as atypical antipsychotics may offer efficacy and/or tolerability advantages compared with other medications. The role of antidepressants in bipolar disorder remains controversial. Growing evidence indicates that adjunctive psychosocial interventions improve long-term functioning; consequently, psychologists are becoming increasingly involved in the longterm care of patients with bipolar disorder. This review seeks to update psychologists and related healthcare professionals on recent advances and the current limitations in the diagnosis and treatment of bipolar disorder. © 2006 Wiley Periodicals, Inc. J Clin Psychol 63: 73–92, 2007. Keywords: bipolar disorder; diagnosis; care; treatment; psychotherapy

Introduction Bipolar disorder is a chronic, severe condition that imposes substantial mortality and psychosocial morbidity on all aspects of a patient’s life (American Psychiatric Association [APA], 2002). The debilitating effects of bipolar disorder can adversely affect employment, education, finances, and relationships to the detriment of the patient and the family (APA, 2002; Jamison, 2000). A consequence of this high burden of morbidity is an increase in the likelihood of attempted and completed suicide, which may be higher for patients with bipolar disorder than with other mental illnesses.
We thank Bill Wolvey, BSc (PAREXEL MMS), who provided medical writing support on behalf of AstraZeneca. Correspondence concerning this article should be addressed to: Jenifer L. Culver, Research Associate, Clinical Psychologist, Stanford University Bipolar Disorders Clinic, 401 Quarry Road, Stanford, CA 94305; e-mail: jculver@stanford.edu

JOURNAL OF CLINICAL PSYCHOLOGY, Vol. 63(1), 73–92 (2007) © 2007 Wiley Periodicals, Inc. Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jclp.20333

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The considerable health burden of bipolar disorder translates into substantial societal costs. By one estimate, the cost of bipolar disorder in 1991 was $45 billion in the United States alone (Woods, 2000). By other analyses, the lifetime cost of patients with onset of bipolar disorder in 1998 was $24 billion (Begley et al., 2001). On a global scale, bipolar disorder has been ranked the fifth leading cause of disability among individuals aged 15– 44 years and the ninth leading cause of years of life lost due to death or disability (World Health Organization, 2001). Despite the burden imposed by bipolar disorder on individuals and on society, this disorder continues to be poorly recognized, even among healthcare professionals (Ghaemi, Boiman, & Goodwin, 2000; Hirschfeld, Lewis, & Vornik, 2003; Lish, Dime-Meenan, Whybrow, Price, & Hirschfeld, 1994). Inadequacies in the identification and management of bipolar disorder, although documented over a decade ago (Lish et al., 1994), remain important problems (Hirschfeld, Lewis et al., 2003). The underdiagnosis or misdiagnosis of bipolar disorder, and consequent inappropriate management, represent significant clinical problems that can have devastating effects on patients (Dunner, 2003; Grunze et al., 2002; Hirschfeld, Lewis et al., 2003). For example, prepubertal children misdiagnosed with attention-deficit/hyperactivity disorder (ADHD) may receive stimulants, and adults misdiagnosed with (unipolar) major depressive disorder may receive antidepressants, both of which can exacerbate the course of bipolar disorder. In this article, we examine how the diagnosis and management of bipolar disorder may be enhanced to reduce the considerable burden of this disease on patients and their caregivers. Particular attention is devoted to providing current evidence-based information to aid psychologists and other practitioners of psychosocial interventions— psychotherapists, psychiatrists, and social workers—who are increasingly called upon to provide services that may substantially benefit the long-term outcome of patients with this severe, lifelong condition. Bipolar Disorder Features Bipolar disorder usually follows a recurrent and chronic course, with episodes of mania or hypomania and depression interspersed with periods of less-severe mood disturbance as well as times with normal mood (euthymia). The periodicity and the severity of the mood episodes are, however, highly individualized (APA, 2002). A manic episode is defined in the Diagnostic and Statistical Manual of Mental Disorders, 4 th Edition, Text Revision (DSM-IV-TR; APA, 2000) as a period of abnormally and persistently elevated, expansive, or irritable mood, lasting at least one week (or briefer if the patient is hospitalized). Associated symptoms include inflated self-esteem, decreased need for sleep, overtalkativeness, distractibility, racing thoughts, and impulsivity manifested by excessive involvement in pleasurable activities with a high potential for painful consequences (e.g., sexual indiscretions, unrestrained shopping sprees). Although mania often begins with pleasurable feelings of bright mood, heightened energy, and increased goal-directed activity, progression to problematic euphoria, severe irritability, and even psychosis can rapidly follow. By definition, mania is severe, and entails psychosis, hospitalization, or serious impairment of social or occupational function. Hypomania is a less severe form of mood elevation that does not involve marked impairment in occupational functioning, social activities, or relationships and is not accompanied by hospitalization or psychotic features. For some patients, function may be enhanced during hypomania; as a result, they may not appreciate that such periods are abnormal.
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A major depressive episode is characterized by at least 2 weeks of pervasively depressed mood or loss of interest or pleasure, accompanied by symptoms such as weight loss or gain, appetite disturbance, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue, inability to concentrate, indecisiveness, and recurrent thoughts of death or suicidal ideation. In severe cases, patients may experience hallucinations or delusions. About 40% of patients with bipolar disorder experience mixed episodes, where symptoms of both mania and depression occur at the same time (Evans, 2000). Bipolar disorder may have its onset with a manic, hypomanic, mixed, or depressive episode. It appears that men are more likely than women to present initially with a manic episode (Kahn, Ross, Printz, & Sachs, 2000; Lish et al., 1994), and women and younger patients are more likely to present initially with a depressive episode (Bowden, 2001). Patients commonly experience several depressive episodes before their first manic episode (APA, 2002). Indeed, depressive symptoms appear more pervasive than mood elevation symptoms in patients with bipolar disorder. Prospective longitudinal studies in bipolar I disorder show that depressive symptoms are present for over 30% of the time, whereas manic symptoms are present for about 10% of the time (Judd et al., 2002; Post et al., 2003). The predominance of depressive symptoms is even greater in bipolar II disorder (Judd et al., 2003). Depression also appears to predominate in patients’ evaluations of the impact of bipolar disorder on their quality of life (Vojta, Kinosian, Glick, Altshuler, & Bauer, 2001). On average, patients experience four episodes during the first 10 years of the disorder (Kahn et al., 2000), so that several years may elapse between the first few affective episodes. However, in the absence of treatment, the cycle length typically shortens (Kahn et al., 2000; Kleinman et al., 2003; Namjoshi & Buesching, 2001). With time, episodes tend to become spontaneous rather than reactive, more frequent, more severe, and ultimately resistant to treatment. Rapid cycling, defined as the occurrence of at least four affective episodes in a year, affects approximately 10% to 20% of patients with bipolar disorder at some stage during their lifetime (Coryell et al., 2003). Rapid cycling is more common in women than men, more common in bipolar II disorder, and more frequently associated with reduced responsiveness to medication (Kupka, Luckenbaugh, Post, Leverich, & Nolen, 2003).

Definitions and Prevalence The DSM-IV-TR (APA, 2000) categorizes primary bipolar disorder into four main types: bipolar I, bipolar II, cyclothymia, and bipolar disorder not otherwise specified (NOS). In addition, patients may experience symptoms of bipolar disorder secondary to medical disorders or use of prescription medications (including antidepressants and stimulants), illicit drugs, or alcohol. A diagnosis of bipolar I disorder requires a history of at least one manic or mixed episode, though the vast majority of patients with bipolar I disorder experience depression more pervasively. Perhaps half of such patients will have experienced one or more depressive episodes before the first manic episode, increasing the risk of misdiagnosis with (unipolar) major depressive disorder. Patients with bipolar II disorder have a history of recurrent major depressive episodes and hypomanic episodes. Cyclothymic disorder is diagnosed in patients who have never met criteria for manic, mixed, or major depressive episodes but have experienced periods of depressive and hypomanic symptoms for at least 2 years with no symptom-free period lasting longer than 2 months. A diagnosis of
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bipolar disorder NOS is assigned to patients with evidence of mood disruptions (e.g., hypomanias but not syndromal major depressive episodes) who fail to meet the criteria for the above-mentioned specific bipolar disorders. A dimensional construct, as opposed to the above categorical approach, has been suggested as an alternative to the DSM-IV-TR classification system (Akiskal, 1996; Akiskal & Pinto, 1999; Dunner, 2003). This classification, referred to as bipolar spectrum disorder, allows inclusion of patients with softer symptoms and would encompass those with antidepressant-induced hypomanic symptoms (Akiskal et al., 2000). The broader concept of bipolar spectrum disorder may more meaningfully capture the diversity of presentations of bipolar symptoms in the clinical setting (Akiskal, 1996). Adopting this classification may also result in more patients receiving appropriate treatment for bipolar disorder (Hirschfeld, Calabrese et al., 2003). Estimates of the lifetime prevalence of bipolar disorder reflect the method of classification and diagnostic approach adopted. Large studies suggest a prevalence ranging from 1.3% to 3.7% of the general population (Hirschfeld, Calabrese et al., 2003; Regeer et al., 2004; Regier et al., 1984, 1990). Including the more widely defined bipolar spectrum disorder, the prevalence may be as high as 7% (Akiskal et al., 2000; Dunner, 2003; Kessler et al., 2005; Kleinman et al., 2003). A recent screening study identified bipolar disorder in 9.8% of patients seeking primary medical care (Das et al., 2005).

Diagnosing Bipolar Disorder Unfortunately, delayed diagnosis is common in patients with bipolar disorder. Often several years elapse between the onset of symptoms and accurate diagnosis (Lish et al., 1994; Suppes et al., 2001). Failure to seek help, in part because of the perceived stigma of having a mental illness, contributes to this phenomenon. An estimated 35% of the patients who have bipolar disorder fail to seek treatment after the initial episode for up to 10 years (Evans, 2000). The inability of medical and mental health providers to recognize and correctly diagnose bipolar disorder adds further to the delay in instituting appropriate care. An individual with bipolar disorder may see three or four physicians over the course of a decade before the correct diagnosis is established (Hirschfeld, Lewis et al., 2003; Kahn et al., 2000; Lish et al., 1994). An incorrect diagnosis is made in a third of patients with bipolar disorder who present during their first episode, and almost half of all patients hospitalized with an initial major depressive episode (particularly if this occurs in a child, adolescent, or young adult) may, in fact, ultimately prove to have bipolar disorder (Evans, 2000; Goldberg, Harrow, & Whiteside, 2001). Establishing the correct diagnosis is complicated by the similarity and overlap of symptoms between bipolar disorder and other psychiatric disorders, including ADHD and unipolar depression in children, and unipolar depression and substance abuse in adolescents (APA, 2000; Bowden, 2001; Dunner, 2003; Hirschfeld, Lewis et al., 2003). Because patients often present initially with depressive symptoms, a misdiagnosis of unipolar depression is common, although this misdiagnosis can also occur in patients presenting with a mixed episode, which may be misdiagnosed as agitated depression (Bowden, 2001; Ghaemi et al., 2000). Compared with unipolar depression, bipolar depression is associated with more mood lability and psychomotor retardation (Caligiuri & Ellwanger, 2000; Mitchell et al., 2001), as well as appetite increase (or lack of appetite loss) and weight gain (or lack of weight loss) (Hartman, 1968; Kupfer et al., 1972; Papadimitriou, Dikeos, Daskalopoulou, & Soldatos, 2002; Rao et al., 2002). Depression during bipolar II disorder is associated with an earlier age of onset than for unipolar
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depression, more recurrences, more atypical (hyperphagic, hypersomnic, anergic) and mixed features, a higher frequency of suicidal thoughts and hypersomnia during the index episode, and a more frequent family history of bipolar II disorder and major depression (Benazzi, 2000, 2003; Hantouche et al., 1998). Recognition of hypomania presents another diagnostic challenge. Patients present with hypomania less frequently, in part because hypomanic characteristics may be perceived as normal by patients, family members, or physicians (Bowden, 2001; Dunner, 2003; Hirschfeld, 2001). One study has suggested that increased goal-directed activity may be a frequent hypomanic symptom, which, in a semi-structured interview, can assist diagnosis (Benazzi, 2003). Systematic screening for hypomania in patients with DSMIV-TR-defined major depressive episodes has increased the rate of diagnosis of bipolar II disorder from 22% to 40% (Hantouche et al., 1998). Also, as many patients may fail to recognize hypomanic episodes, collateral history from significant others can substantially increase diagnostic sensitivity (Gershon & Guroff, 1984). An additional diagnostic complication is that the DSM-IV-TR definition of hypomania—that is, a distinct change in behavior lasting at least 4 days—excludes many patients with briefer episodes of mood elevation who might fulfill a more inclusive definition (Bowden, 2001; Dunner, 2003). Furthermore, patients with severe episodes of mania or depression in bipolar disorder accompanied by prominent psychotic symptoms may be incorrectly diagnosed as having schizophrenia (APA, 2000; Bowden, 2001; Dunner, 2003; Hirschfeld, Lewis et al., 2003). Making a correct diagnosis of bipolar disorder is hindered further by the high prevalence of comorbid psychiatric conditions. Indeed, comorbidity is so common that it is considered the rule rather than the exception in bipolar disorder (Sachs, 2003). Substance abuse, alcoholism, and anxiety disorders are particularly frequent comorbidities (Brady & Sonne, 1995; Evans, 2000) and may be patients’ chief complaints, distracting clinicians from obtaining a history of prior or concurrent symptoms of bipolar disorder. Consequences of Misdiagnosis A delayed or incorrect diagnosis can have significant consequences for the patient with bipolar disorder. Among these, the most serious is the increased risk of suicide. Up to 50% of patients with bipolar disorder attempt suicide at least once and up to 20% die by suicide, with the risk highest in the early phases of the illness (Jamison, 2000; Kahn et al., 2000; Woods, 2000). Maintenance therapy with lithium appears associated with a sevenfold reduction in suicide rates in patients with bipolar disorder (Tondo & Baldessarini, 2000). Delayed or incorrect diagnosis denies patients the benefits of therapy in reducing suicide risk (Baldessarini, Tondo, & Hennen, 2003). Delay in diagnosis and implementation of appropriate treatment additionally leaves patients at risk for poor symptom control, functional impairment, as well as relationship and employment problems, increasing the personal and societal burden of illness (Dunner, 2003; Kahn et al., 2000). In addition, delays may impair the response to subsequent appropriate treatment, worsening the prognosis (Kahn et al., 2000; Post & Weiss, 2004). Finally, an incorrect diagnosis may lead to interventions that exacerbate the illness course. For example, treatment with an antidepressant alone (without concomitant mood stabilizer or antimanic agent) based on a diagnosis of unipolar depression may induce a switch in mood to manic or mixed episode, or trigger rapid cycling (Altshuler et al., 1995; Dunner, 2003; Ghaemi et al., 2000; Sachs, Koslow, & Ghaemi, 2000). There is also evidence that inappropriate medical interventions to treat depressive states in patients with bipolar disorder may decrease subsequent responses to mood stabilizers (Bowden, 2001; Winsberg, DeGolia, Strong, & Ketter, 2001).
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Improving the Diagnosis Several measures may be adopted to improve the recognition and diagnosis of bipolar disorder. Given that a majority of patients with bipolar disorder who seek treatment do so when depressed rather than when manic or hypomanic (APA, 2002; Hirschfeld, 2001), it is recommended that the possibility of a bipolar diagnosis be excluded in all patients who present with depressive symptoms, even if mild. This is of particular importance in the diagnosis of bipolar II disorder, where depression is commonly the presenting symptom and hypomania may be rarely described by the patient. The patient’s personal history should be assessed for evidence of behaviors that indicate a history of manic, hypomanic, or mixed episodes, and the family history should be reviewed to determine the presence of mood (particularly bipolar) disorder in relatives. Clinicians should also probe carefully about mood dysfunction and lability (APA, 2002; Bowden, 2001; Hirschfeld, Calabrese et al., 2003). When possible, inclusion of the patient’s family and close support group in the evaluation is likely to be helpful, as patients themselves often fail to report such information, whether by choice, through a lack of understanding of its significance, or because this behavior is perceived as normal. Discussion with a close family member may also reveal aspects of the patient’s behavior that are less likely to be displayed in an office or hospital environment, such as impulsivity (Bowden, 2001). A diagnosis of bipolar disorder should be considered routinely in patients referred for psychological assessment of substance abuse or anxiety disorders, or following attempted suicide or criminal offenses. Increased awareness of symptoms or behaviors indicative of bipolar disorder in a patient previously diagnosed with another mental illness, such as unipolar depression or schizophrenia, could also reduce the number of patients who continue to receive inappropriate treatment (Bowden, 2001). Clinicians should explore the possibility that comorbid conditions, such as eating disorders, substance abuse, or anxiety disorders—common in patients with bipolar disorder—may be obscuring the diagnosis. A four-item screening checklist, devised by Hirschfeld (personal communication), may help health professionals establish whether a risk of bipolar disorder exists. Patients with presumptive unipolar depression, anxiety disorder, substance use disorder, schizophrenia, or ADHD may be briefly assessed with this checklist to exclude bipolar disorder. The checklist comprises the following questions: 1. Has there ever been a period of time when you were not your usual self and . . . • you felt so good or so hyper that other people thought you were not your normal self or you were so hyper that you got into trouble? • you got much less sleep than usual and found that you didn’t really miss it? • thoughts raced through your head or you couldn’t slow your mind down? • you had much more energy than usual? 2. How much of a problem did any of these cause you—like being unable to work; having family, money, or legal troubles; getting into arguments or fights? (no problem; minor problem; moderate problem; serious problem) Answering yes to two or more items in question 1 and moderate or serious to question 2 warrants further screening with a tool such as the Mood Disorders Questionnaire (MDQ; Hirschfeld et al., 2000). The MDQ has been validated in an outpatient setting, where it was shown to take less than 5 minutes to complete and where a positive MDQ assessment identified 7 out of 10 patients with bipolar disorder. Moreover, a negative
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MDQ assessment successfully excluded 9 out of 10 patients without bipolar disorder (Hirschfeld et al., 2000). The utilization of tools such as these by clinical psychologists and related health professionals would help exclude a diagnosis of bipolar disorder in all patients who present with depression. Approaches to Management Objectives in the management of bipolar disorder include effective treatment of acute episodes of mania and depression, ongoing prevention of relapses, and attainment of healthy functioning through symptom control (Figure 1). During episodes of bipolar depression, in particular, reducing the risk of suicide is a key objective. Once the acute symptoms of mania or depression have been resolved, long-term management is required to prevent recurrence, which remains a lifelong risk in patients with bipolar disorder (APA, 2002). As most pharmacotherapies have limited utility in the acute treatment or prevention of depression in bipolar disorder, psychotherapies can be important adjuncts. Increasing evidence supports a combination of pharmacotherapy and psychotherapy for achieving optimal long-term outcome (Vieta et al., 2005). Choosing the most appropriate management plan for an individual patient, potentially with pharmacotherapeutic and psychotherapeutic components, remains a major clinical challenge. When choosing the appropriate pharmacotherapy, consideration should be given to its efficacy and tolerability profile, such that it fulfills patient expectations and encourages adherence to treatment. Rates of medication nonadherence in bipolar disorder are high. One study of patients with affective disorders (80% with bipolar disorder) observed that approximately one third took less than 30% of their medication as prescribed (Scott & Pope, 2002). Nonadherence is related, at least in part, to medication-adverse effects—to which patients with bipolar disorder appear to show an increased susceptibility (Berk & Berk, 2003; Chue & Kovacs, 2003; Sachs, 2003). Therefore, good tolerability and safety of treatment in the long term are key considerations during the maintenance phase. Other reasons for nonadherence in patients with bipolar disorder include a lack of understanding of the illness and negative beliefs about medication (Morselli et al., 2003; Peralta & Cuesta, 1998). The utilization of psychosocial intervention, by addressing these

Figure 1. Therapeutic objectives in the management of bipolar disorder. The presentation of bipolar disorder as a chronic relapsing disease means that management is divisible into acute and maintenance phases. In acute phases, the objective of treatment is remission of manic or depressive symptoms with return of full psychological functioning. In the maintenance phase, therapy aims to maintain functioning and prevent relapse. Journal of Clinical Psychology DOI 10.1002/jclp

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issues, has been shown to enhance long-term medication adherence and outcome in patients with bipolar disorder (Colom et al., 2003) and is an example of how successful long-term management may benefit from an integrated approach, combining pharmacologic treatment and psychosocial intervention. Pharmacologic Treatment Pharmacotherapy remains the foundation for the acute and long-term management of manic, mixed, and depressive episodes of bipolar disorder. Figure 2 illustrates an approach representative of standards of care for the pharmacologic treatment of manic or mixed episodes, based on guidelines from the APA (2002). The APA recommendations for the pharmacotherapy of bipolar depression are outlined in Figure 3. However, not all guidelines support the APA’s approach to bipolar depression; for example, the World Federation of Societies of Biological Psychiatry differs in recommending a combination of antidepressant and conventional mood stabilizer as a first-line approach for all depressed patients, not only those with severe depression (Grunze et al., 2002). Advances in the pharmacotherapy of bipolar disorders are sufficiently rapid such that guidelines published only 4 years ago are already in need of additional revision (Ketter, 2005). Medications used in acute treatment may be expected to show efficacy within days to a few weeks. Once acute mood stabilization is achieved, the major focus of long-term maintenance treatment is to prevent relapse, reduce new-onset comorbidities, lower suicide risk, limit adverse effects, and optimize function. Patients who remain well on longterm treatment should be encouraged to continue their regimen to prevent relapse, which is frequent if therapy ceases—a 50% relapse rate has been reported within 5 months of abruptly stopping lithium (Suppes et al., 1995). If patients cease treatment, they are also at elevated risk of suicide (Tondo et al., 2000). Often combination therapies are needed, with about three quarters of patients taking more than one medication (Kupfer et al., 2002). Even with administration of medications according to guidelines, outcomes remain inadequate for a large proportion of patients with bipolar disorder. Approximately two

Figure 2. Recommendations for pharmacologic treatment of manic/mixed episodes in patients with bipolar disorder (American Psychiatric Association, 2002). Journal of Clinical Psychology DOI 10.1002/jclp

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Figure 3. Recommendations for pharmacologic treatment of depressed episodes in patients with bipolar disorder (APA, 2002). Guidelines issued by the World Federation of Societies of Biological Psychiatry (Grunze et al., 2002) recommend a combination of an antidepressant and a mood stabilizer as a first-line approach for all depressed patients, not only for those with severe depression.

thirds of patients with bipolar disorder report persistence of substantial depressive or manic symptoms over one year of follow up, and only about 10% are illness-free (Post et al., 2003). Up to 60% of patients fail to regain full occupational and social functioning (MacQueen, Young, & Joffe, 2001). In view of these limitations of pharmacotherapies, adjunctive psychotherapies are commonly necessary. Mood stabilizers. The mood stabilizers (lithium, valproate, carbamazepine, and lamotrigine) are crucial agents in the management of bipolar disorder (Ketter, 2005). Lithium, valproate, and carbamazepine are indicated for the treatment of acute mania; lithium and lamotrigine are indicated for maintenance treatment. Lithium, valproate, and carbamazepine appear to “stabilize mood from above,” in that they are more effective for the mood-elevation aspects of the disorder (Ketter & Calabrese, 2002). In contrast, lamotrigine appears to “stabilize mood from below,” being more effective for the depressive aspects of bipolar disorder. Unfortunately, efficacy or tolerability with these agents is commonly inadequate, necessitating frequent usage of other medication options (described below) as well as combination therapies. Atypical antipsychotics. Atypical antipsychotics have emerged as important treatment options for patients with bipolar disorder (Ketter, 2005). The current APA (2000) guideline supports the use of antipsychotic agents as monotherapy for less severe manic and mixed episodes, in combination with either lithium or valproate for severe manic and mixed episodes, and as maintenance therapy in patients with persistent psychosis. Atypical antipsychotics are preferred over typical antipsychotics by the APA because of their more benign side-effect profile. In addition, a role for atypical antipsychotics in psychotic bipolar depression is advocated (APA, 2002; Dunner, 2005). Ongoing research into the efficacy of the atypical antipsychotics continues to extend their potential applications in bipolar disorder. Atypical antipsychotics have shown efficacy in short-term trials in bipolar mania, both as monotherapy (for aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone) and in combination with other agents (for olanzapine, quetiapine, and risperidone; Bowden et al., 2005; Hirschfeld et al., 2004; Keck, Marcus et al., 2003; Keck, Versiani
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et al., 2003; McIntyre, Brecher, Paulsson, Huizar, & Mullen, 2005; Sachs, Grossman, Ghaemi, Okamoto, & Bowden, 2002; Tohen et al., 2002; Tohen et al., 2000; Tohen et al., 1999; Yatham, Paulsson, Mullen, & Vagero, 2004; Yatham et al., 2003). Trials of olanzapine (particularly when combined with fluoxetine) and quetiapine have also demonstrated significant improvements in patients with bipolar depression (Calabrese et al., 2005; Tohen et al., 2003). Olanzapine and quetiapine additionally demonstrate efficacy as monotherapy or add-on therapy in the difficult-to-treat rapid-cycling group (Gonzalez-Pinto et al., 2004; Sanger et al., 2003; Vieta et al., 2002). A study of maintenance therapy over 47 weeks showed superiority of olanzapine over divalproex for reduction in manic symptoms (Tohen et al., 2003). Olanzapine and aripiprazole have been approved for maintenance treatment in bipolar disorder (Keck et al., 2006; Tohen et al., 2006). The literature suggests that the atypical antipsychotics share approximately equivalent efficacy in bipolar disorder but possess different and distinctive side-effect profiles (Keck, Marcus et al., 2003; Keck, Versiani et al., 2003; Ketter, 2005; Sachs et al., 2002; Tohen et al., 2000). Olanzapine and clozapine are associated with the greatest risk of weight gain, diabetes, and dyslipidemia (American Diabetes Association, American Psychiatric Association, American Association of Clinical Endocrinologists, & North American Association for the Study of Obesity, 2004). Risperidone is associated with prolactin elevation and extrapyramidal symptoms, and ziprasidone and aripiprazole with akathisia (Bowles & Levin, 2003; Kleinberg, Davis, de Coster, Van Baelen, & Brecher, 1999; Mandoki, 1995; Sachs et al., 2002; Sharif, 2003). Quetiapine has been associated with sedation—also an effect of other atypical antipsychotics—and dry mouth (Sachs et al., 2004). Clinical impressions suggest a rank order for risk of sedation (highest first) of clozapine, olanzapine, quetiapine, and risperidone (Zarate, 2000). Zarate also suggested that anticholinergic side effects, such as constipation, urinary retention, bowel obstruction, and dry mouth, are less likely to be a problem with quetiapine and risperidone compared with aripiprazole and clozapine (Zarate, 2000). Because, as mentioned above, good tolerability is likely to be associated with greater adherence to treatment, consideration of likely side effects forms an important element in the choice of atypical antipsychotics. Antidepressants. Although antidepressants are foundational agents for the management of unipolar depression, their role in the management of bipolar disorder remains controversial, because these agents are implicated in causing switches into mania, hypomania, or cycle acceleration (APA, 2002). Thus, the use of antidepressants in the absence of antimanic agents in patients with bipolar disorder is avoided. Recently, the labeling of all antidepressants has been amended to warn of the risk of mood worsening (suicidal ideation) with these agents. Thus, in patients with bipolar disorder, efforts are commonly made to limit exposure to antidepressants, either by attempting to discontinue them relatively soon (compared to unipolar depression) after control of acute depressive symptoms, or by using other agents such as mood stabilizers and atypical antipsychotics to address the depressive symptoms. However, a minority (perhaps 15%) of patients with bipolar disorder who respond to and tolerate adding antidepressants to antimanic agents may do better with longer-term administration (Altshuler et al., 2003). Psychosocial interventions. Even when patients adhere to their pharmacotherapy, relapse rates may be high. In a yearlong naturalistic study by Post et al. (2003), patients were depressed for 33% and were manic for 11% of the year while receiving an average
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of four different psychotropic drugs. Approximately one in four of the patients was ill for more than three quarters of the time. There is growing evidence that the benefits of pharmacotherapy can be enhanced if combined with psychosocial interventions, particularly when psychosocial interventions are continued regularly during the course of long-term management (Vieta et al., 2005). Controlled trials indicate that integrated administration of pharmacological and psychoeducational interventions can help improve long-term outcomes in bipolar disorders. The psychoeducational component of such interventions may offer particular benefits because many medications commonly used to treat mania and depression are associated with dose-related side effects. Educating patients and their families about what to expect from treatment, the possible adverse effects, and what action to take, if any, should these effects develop, may help patients obtain maximal benefit from therapy (Newman, Leahy, Beck, Reilly-Harrington, & Gyulai, 2002). The impact of life events and stressors on the onset and relapse of bipolar disorder (Johnson & Miller, 1997; Johnson & Roberts, 1995; Malkoff-Schwartz et al., 2000) suggests a potential role for psychosocial intervention in its management (Jones, 2004; Kahn et al., 2000). The research base supporting the benefits of psychosocial interventions in bipolar disorder is not as comprehensive as in unipolar depression (Pampallona, Bollini, Tibaldi, Kupelnick, & Munizza, 2004; Thase et al., 1997) or schizophrenia (Pilling et al., 2002); however, there are emerging data from large, randomized, controlled trials (APA, 2002; Gonzalez-Pinto et al., 2004; Grunze et al., 2002; Jones, 2004; Otto, ReillyHarrington, & Sachs, 2003). Psychosocial interventions are common (Lembke et al., 2004) and are clearly important components of integrated care for patients with bipolar disorder. They are particularly likely to be of benefit in the maintenance phase of treatment (compared to during acute mania) when they may impact on subsyndromal symptoms and help to prevent relapse (Jones, 2004). The primary goals of psychosocial interventions in patients with bipolar disorder are symptom reduction, prevention of episodes, and optimization of function. Psychosocial treatments approach these goals via several routes, each emphasized to varying levels by the different evidence-based treatments. These include psychoeducation about bipolar disorder and its treatment, enhancing adherence to medications, improving social and occupational functioning, increasing recognition of prodromal symptoms to facilitate early intervention, and addressing behavioral and environmental factors (e.g., irregular sleep/wake cycles, psychosocial stressors, expressed emotion) that may lead to relapse. Effective management of bipolar disorder requires self-management, and psychosocial interventions can provide patients with the necessary skills, knowledge, and tools to better achieve this. Psychoeducational approaches. Psychoeducational approaches are aimed at providing patients with information about bipolar disorder and its treatment. Goals of psychoeducation include increasing patients’ understanding and acceptance of their disorder to decrease stigma and enhance treatment compliance. Some psychoeducational interventions emphasize prodromal symptom recognition and the development of coping skills to prevent relapse. The patient plays a key role in psychoeducational interventions and is encouraged to be actively engaged. Results from controlled trials have demonstrated that the addition of psychoeducation to medical management can delay relapse and reduce the number of relapses among patients with bipolar disorder (Colom et al., 2003; Perry, Tarrier, Morriss, McCarthy, & Limb, 1999) and can increase patients’ knowledge about their pharmacotherapy, resulting in more positive attitudes toward it (Peet & Harvey, 1991). Research by Colom and
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colleagues (2003), for example, provided evidence that adjunctive group psychoeducation reduced the number of relapsed patients and the number of recurrences per patient, and increased time to depressive, manic, hypomanic, and mixed recurrences in comparison with a control group given supportive group therapy (Figure 4). Cognitive–behavioral therapy. Cognitive–behavioral therapy (CBT) has a history of demonstrated efficacy in the treatment of unipolar depression, and results from recent studies indicate that it may also be an efficacious treatment for bipolar disorder. Cognitive– behavioral therapy for bipolar disorder focuses on changing dysfunctional cognitions and maladaptive behaviors that contribute to mood dysregulation and increase vulnerability to mood episodes. Cognitive–behavioral therapy, as adapted for bipolar disorder, consists of the traditional components of this therapy as employed for patients with unipolar depression, with the addition of psychoeducation about bipolar disorder and adaptation of cognitive behavioral skills to increase awareness of mood, improve ability to recognize prodromes, and teach intervention to prevent escalation into a syndromal mood episode. Early controlled studies comparing adjunctive CBT with medication alone indicated that adjunctive CBT yielded fewer relapses, hospitalizations, and subsyndromal mood fluctuations (Lam & Gale, 2000; Scott, Garland, & Moorhead, 2001). In addition, treatment with CBT resulted in improved adherence to medication regimens and psychosocial functioning (Lam & Gale, 2000; Scott et al., 2001). Recently, Lam and colleagues (2003) found that adjunctive cognitive therapy (CT) resulted in fewer relapses and fewer episodes of depression and mania, even after controlling for previous episodes. Furthermore, patients receiving adjunctive CT had less than half the number of hospitalizations (15% vs. 33%) and spent only approximately one third of the time hospitalized for bipolar

Figure 4. Efficacy of group psychoeducation as an adjunct to pharmacotherapy in prevention of recurrence of mania, depression, or mixed episodes. Patients in receipt of standard pharmacologic therapy were randomly assigned to receive either 21 weekly unstructured group meetings (control) or 21 weekly group psychoeducation sessions. Curves show patients remaining free of relapse during the 21 weeks of treatment and follow-up period, log rank1 9.3, p .03. From “A Randomized Trial on the Efficacy of Group Psychoeducation in the Prophylaxis of Recurrences in Bipolar Patients Whose Disease Is in Remission,” by F. Colom, E. Vieta, A. Martinez-Aran, M. Reinares, J. M. Goikolea, A. Benabarre, A., et al., 2003, Archives of General Psychiatry, 60, 402– 407. Copyright 2003. Reprinted with permission. Journal of Clinical Psychology DOI 10.1002/jclp

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episodes compared with those receiving medication alone. In addition, patients receiving adjunctive CT over 12 months showed better coping with emergent manic symptoms, increased self-reported medication compliance, and better social functioning compared with those who received medication alone. Family-focused therapy. Family treatments have received attention based on research indicating that high levels of expressed emotion (characterized by family overinvolvement and criticism) among family members are associated with increased risk of relapse and poor outcomes in bipolar disorder patients (Miklowitz, Goldstein, Nuechterlein, Snyder, & Doane, 1986). The family-focused therapy (FFT) approach of Miklowitz and colleagues (Goldstein & Miklowitz, 1994) includes an assessment of the family and focuses on psychoeducation, communication skills training, and problem solving. Randomized controlled trials have supported the use of FFT in bipolar disorder. A recent study found that patients receiving adjunctive FFT were less likely to relapse and survived an average of 20 weeks longer before relapsing compared with treatment by two sessions of crisis management (Miklowitz et al., 2003). A similar study by Rea and colleagues (Rea et al., 2003) found no benefit of FFT in reducing the risk of relapse; however, patients receiving FFT had fewer relapses than those receiving individually focused treatment. Other benefits of FFT included greater reductions in affective symptom scores (Miklowitz et al., 2003), better medication adherence (Miklowitz et al., 2003), and lower risk of rehospitalization over a 2-year period (Rea et al., 2003). The results of these studies provide evidence that FFT may be a useful adjunct to pharmacotherapy for decreasing the risk of relapse and hospitalization frequently associated with bipolar disorder. Interpersonal and social rhythm therapy. Interpersonal and social rhythm therapy (IPSRT) for bipolar disorder was adapted from interpersonal therapy by Frank and colleagues (1997) at the University of Pittsburgh. IPSRT integrates psychoeducation, social rhythm therapy, and interpersonal psychotherapy components in a treatment specifically designed for the management of patients with bipolar disorder. IPSRT combines the basic principles of interpersonal psychotherapy with behavioral techniques to address the link between mood and life events affecting social rhythms. Goals of IPSRT include helping patients stabilize their daily routines, reduce interpersonal problems, and adhere to medication regimens (Frank, Swartz, & Kupfer, 2000). Early studies have not found evidence that IPSRT is superior to control treatments in improving symptomatology or risk for relapse, although IPSRT has been found to result in greater stability of patients’ social rhythms compared with a control treatment (Frank et al., 1997; Frank et al., 2005). In addition, evidence suggests that changing therapy modality (e.g., from IPSRT to a control therapy or vice versa) resulted in poorer outcomes compared with not changing therapy modality. These findings support the notion that instability (in this case of treatment regimens) can contribute to increased vulnerability to relapse in patients with bipolar disorder. A program of pharmacotherapy (primarily with lithium) and adjunctive psychotherapy comprised of IPSRT or intensive clinical management over 2 years significantly reduced suicide attempts among patients with bipolar I disorder (Rucci et al., 2002). Psychotherapy may therefore extend the protection against suicide offered by lithium or other appropriate therapy. It is becoming increasingly clear that evidence-based adjunctive psychotherapy is an important part of good clinical practice in the management of bipolar disorder, as highlighted by recommendations for the inclusion of psychosocial interventions within bipolar
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disorder treatment practice guidelines (APA, 2002). The evidence reviewed here confirms that adjunctive psychosocial treatment is important in this population. Selection of the optimal psychosocial treatment is limited by the lack of head-to-head comparisons among these interventions. It is likely that treatment choice will be influenced by patient choice and the availability of therapists trained in the delivery of specific interventions. In the absence of available therapists trained in the more structured psychotherapies (CBT, FFT, and IPSRT), psychoeducation will play an important role in the effective treatment of patients with bipolar disorder. It targets aspects central to many of the treatments discussed here (enhancing illness awareness, improving medication adherence, teaching prodromal symptom detection and relapse prevention, regulating sleep/wake cycles, and strengthening the patient’s support system). Conclusions Current delays between onset of symptoms and correct diagnosis leave patients with bipolar disorder with an impaired quality of life and at increased risk of self-harm. Inappropriate treatment because of misdiagnosis may exacerbate the disorder and make it increasingly resistant to treatment in the longer term. An increased recognition of bipolar disorder among psychiatrists, psychologists, and other healthcare professionals combined with an awareness of new management approaches may reduce the burden of the condition on patients, their families, and society. In pharmacologic management, in addition to mood stabilizers, treatment options include atypical antipsychotics, which increasingly appear to offer benefits not only during acute mania but also during acute bipolar depression and in maintenance therapy. Psychiatrists, psychologists, and other practitioners of psychosocial interventions can benefit by reviewing recent research demonstrating the importance of evidence-based adjunctive psychotherapy in the effective integrated management of bipolar disorder. References
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Journal of Clinical Psychology

DOI 10.1002/jclp