Improving Diagnosis

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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 substan-

tial mortality and psychosocial morbidity. Challenges in recognition candelay the institution of appropriate management, whereas misdiagnosis

may initiate pharmacologic interventions that adversely affect the conditions

course. Pharmacotherapy remains the foundation of treatment. In addition

to ef ficacy, tolerability is an important consideration in medication choice,

particularly for long-term maintenance because of its impact on adher-

ence. Mood stabilizers are the classic treatments for bipolar disorder. Newer

agents such as atypical antipsychotics may of fer ef ficacy and/or tolerabil-

ity advantages compared with other medications. The role of antidepres-

sants in bipolar disorder remains controversial. Growing evidence indicates

that adjunctive psychosocial interventions improve long-term functioning;

consequently, psychologists are becoming increasingly involved in the long-term 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: 7392, 2007.

Keywords: bipolar disorder; diagnosis; care; treatment; psychotherapy

Introduction

Bipolar disorder is a chronic, severe condition that imposes substantial mortality andpsychosocial morbidity on all aspects of a patients life (American Psychiatric Associa-

tion [APA], 2002). The debilitating effects of bipolar disorder can adversely affect employ-

ment, 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:[email protected]


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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 aged1544 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 manage-

ment of bipolar disorder, although documented over a decade ago (Lish et al., 1994),

remain important problems (Hirschfeld, Lewis et al., 2003). The underdiagnosis or mis-

diagnosis of bipolar disorder, and consequent inappropriate management, represent sig-

nificant 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 stimu-

lants, 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 informa-

tion to aid psychologists and other practitioners of psychosocial interventions

psychotherapists, psychiatrists, and social workerswho 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 impul-

sivity 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 psy-

chosis, hospitalization, or serious impairment of social or occupational function. Hypo-mania is a less severe form of mood elevation that does not involve marked impairment

74 Journal of Clinical Psychology, January 2007


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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 ordelusions.

About 40% of patients with bipolar disorder experience mixed episodes, where symp-

toms 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 epi-

sode (APA, 2002). Indeed, depressive symptoms appear more pervasive than mood ele-

vation symptoms in patients with bipolar disorder. Prospective longitudinal studies inbipolar 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 evalua-

tions 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 dis-

order (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 ulti-

mately 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 depres-

sion 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 historyof recurrent major depressive episodes and hypomanic episodes. Cyclothymic disorder is

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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 dis-

order, 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 classi-

fication 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; Regeeret al., 2004; Regier et al., 1984, 1990). Including the more widely defined bipolar spec-

trum 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 sev-

eral 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 depres-

sion 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



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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 presentwith hypomania less frequently, in part because hypomanic characteristics may be per-

ceived 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 DSM-

IV-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 substan-

tially increase diagnostic sensitivity (Gershon & Guroff, 1984). An additional diagnostic

complication is that the DSM-IV-TR definition of hypomaniathat is, a distinct changein behavior lasting at least 4 daysexcludes 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 consid-

ered 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 seven-

fold 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 ( Dun-

ner, 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



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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 patients 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 rela-

tives. Clinicians should also probe carefully about mood dysfunction and lability (APA,

2002; Bowden, 2001; Hirschfeld, Calabrese et al., 2003). When possible, inclusion of the

patients 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 patients behavior

that are less likely to be displayed in an office or hospital environment, such as impul-

sivity (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 inap-

propriate treatment (Bowden, 2001). Clinicians should explore the possibility that comor-bid conditions, such as eating disorders, substance abuse, or anxiety disorderscommon

in patients with bipolar disordermay 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, schizo-

phrenia, 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 didnt really miss it?

thoughts raced through your head or you couldnt slow your mind down?

you had much more energy than usual?

2. How much of a problem did any of these cause youlike 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 ques-tion 2 warrants further screening with a tool such as the Mood Disorders Questionnaire



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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 theacute 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 phar-

macotherapeutic 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 encour-

ages 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 effectsto

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

Fi 1 Th ti bj ti i th t f bi l di d Th t ti f bi l di d



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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 treat-

ment 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 guide-

lines support the APAs approach to bipolar depression; for example, the World Federa-

tion of Societies of Biological Psychiatry differs in recommending a combination of

antidepressant and conventional mood stabilizer as a first-line approach for all depressedpatients, not only those with severe depression (Grunze et al., 2002). Advances in the

pharmacotherapy of bipolar disorders are sufficiently rapid such that guidelines pub-

lished 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 sui-

cide risk, limit adverse effects, and optimize function. Patients who remain well on long-

term treatment should be encouraged to continue their regimen to prevent relapse, which

is frequent if therapy ceasesa 50% relapse rate has been reported within 5 months of

abruptly stopping lithium (Suppes et al., 1995). If patients cease treatment, they are alsoat 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



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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 lam-

otrigine) are crucial agents in the management of bipolar disorder (Ketter, 2005). Lith-

ium, valproate, and carbamazepine are indicated for the treatment of acute mania; lithium

and lamotrigine are indicated for maintenance treatment. Lithium, valproate, and carba-

mazepine 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, lamot-

rigine 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 treat-

ment 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. Atyp-

ical 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 psy-

chotic bipolar depression is advocated (APA, 2002; Dunner, 2005). Ongoing research

into the efficacy of the atypical antipsychotics continues to extend their potential appli-

cations in bipolar disorder.Atypical antipsychotics have shown efficacy in short-term trials in bipolar mania,

Figure 3. Recommendations for pharmacologic treatment of depressed episodes in patients with bipolar dis-

order (APA, 2002). Guidelines issued by the World Federation of Societies of Biological Psychiatry (Grunzeet al., 2002) recommend a combination of an antidepressant and a mood stabilizer as a first-line approach for alldepressed patients, not only for those with severe depression.



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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 olan-

zapine (particularly when combined with fluoxetine) and quetiapine have also demon-

strated 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 equiva-

lent 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 Psy-

chiatric Association, American Association of Clinical Endocrinologists, & North Amer-

ican 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

sedationalso an effect of other atypical antipsychoticsand 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 obstruc-

tion, 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, consider-

ation of likely side effects forms an important element in the choice of atypical

antipsychotics.

Antidepressants. Although antidepressants are foundational agents for the manage-

ment of unipolar depression, their role in the management of bipolar disorder remains

controversial, because these agents are implicated in causing switches into mania, hypo-mania, 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 rel-

atively soon (compared to unipolar depression) after control of acute depressive symp-

toms, 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).



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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 psycho-

educational 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) sug-gests 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, Reilly-

Harrington, & 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 treat-

ment (compared to during acute mania) when they may impact on subsyndromal symp-

toms 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 provid-

ing patients with information about bipolar disorder and its treatment. Goals of psycho-

education include increasing patients understanding and acceptance of their disorder to

decrease stigma and enhance treatment compliance. Some psychoeducational interven-

tions 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 psychoeduca-tion to medical management can delay relapse and reduce the number of relapses among



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colleagues (2003), for example, provided evidence that adjunctive group psychoeduca-

tion reduced the number of relapsed patients and the number of recurrences per patient,

and increased time to depressive, manic, hypomanic, and mixed recurrences in compar-

ison with a control group given supportive group therapy ( Figure 4).

Cognitivebehavioral therapy. Cognitivebehavioral 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. Cognitivebehavioral 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 recog-

nize prodromes, and teach intervention to prevent escalation into a syndromal moodepisode.

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, treat-

ment 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 epi-

sodes of depression and mania, even after controlling for previous episodes. Further-

more, 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 randomlyassigned to receive either 21 weekly unstructured group meetings (control) or 21 weekly group psychoeduca-tion sessions. Curves show patients remaining free of relapse during the 21 weeks of treatment and follow-up

i d l k 9 3 03 F A R d i d T i l th Effi f G P h d ti i th



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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 overinvolve-

ment and criticism) among family members are associated with increased risk of relapse

and poor outcomes in bipolar disorder patients (Miklowitz, Goldstein, Nuechterlein, Sny-

der, & 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. Ran-

domized 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 sur-

vived an average of 20 weeks longer before relapsing compared with treatment by twosessions 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 symp-

tom 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 col-

leagues (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 med-

ication 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 resultin 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 out-

comes compared with not changing therapy modality. These findings support the notion

that instability (in this case of treatment regimens) can contribute to increased vulnera-

bility to relapse in patients with bipolar disorder.

A program of pharmacotherapy (primarily with lithium) and adjunctive psychother-

apy 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 orother appropriate therapy.

It is becoming increasingly clear that evidence based adjunctive psychotherapy is an



14/21

disorder treatment practice guidelines (APA, 2002). The evidence reviewed here con-

firms 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 treat-

ments discussed here (enhancing illness awareness, improving medication adherence,

teaching prodromal symptom detection and relapse prevention, regulating sleep/wake

cycles, and strengthening the patients 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. Inap-

propriate 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 com-

bined 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 dur-

ing 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-basedadjunctive psychotherapy in the effective integrated management of bipolar disorder.

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