Vol. 22, No. 04 / November 2010

Differential Diagnosis of Bipolar Disorder

• Diagnostic Criteria • Differentiating Between Unipolar and Bipolar Depression • Differential Diagnosis Beyond Unipolar Depression • Differentiating Between Bipolar I and Bipolar II and BD-NOS Disorders • Gender and Bipolar Disorder • Age-Related Features of Bipolar Disorder • Diagnosis of a Bipolar Prodrome and the Case for Early Intervention • Screening Tools • Conclusions

Associate Professor of Psychiatry and Pharmacology, University of Toronto, Head, Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, Ontario, Canada 

Bipolar disorder (BD) is a common psychiatric condition with a lifetime prevalence of 1.0% for bipolar I disorder (BD I), 1.1% for bipolar II disorder (BD II), and 2.4% for subthreshold BD.¹ In the primary care setting, results of several studies indicate that 20% to 30% of individuals who have clinically significant depressive symptoms and are receiving antidepressant treatment actually have a bipolar spectrum condition.^2-5 Recent studies reported increased rates of BD diagnoses in adult and pediatric outpatient populations during the past decade.^6,7

Several factors contribute to the rising rate of BD diagnosis across multiple healthcare settings, including broader conceptualization of the diagnostic criteria (eg, BD II/bipolar spectrum), high rate of misdiagnosis, “overdiagnosis” (notably in pediatric populations), increased attention by the lay public and media, and in some cases, reimbursement incentives for a diagnosis of BD.^7,8 It has been speculated that the observed increase in rate (cohort effect) could be due to an anticipation effect (actual increase in rate or onset at a younger age, due to presence of unstable nucleotides).⁹ This phenomenon has been documented in other neurologic disorders such as Huntington’s chorea.¹⁰ A report on national trends (1994–95; 2002–03) in the diagnosis and treatment for BD has also shown an increase in youth visits (from 25 to 1003 per 100,000) and adult visits (from 905 to 1679 per 100,000).⁶ These data could be potentially misinterpreted, due to revisits by the same patient with increased symptoms. Further studies are needed for standardized data collection and accurate diagnosis of BD.

There are several reports in which individuals received a diagnosis of BD when a more appropriate diagnosis may have been major depressive disorder (MDD), personality disorder, and externalizing behavioral disorders (in pediatric populations).⁸ Although ”overdiagnosis” of BD may add to the rising rate, a more critical issue is the delay in diagnosis and its negative effect on outcomes. It has been amply documented that the delay in BD diagnosis and, consequently, its treatment is the rule rather than the exception. For example, several organizations, notably the Depression Bipolar Support Alliance (DBSA), have reported that, on average, approximately 10 years often will elapse from the onset of symptoms to the correct establishment of the diagnosis.¹¹ Moreover, investigators from the Stanley Foundation Network and the National Depressive and Manic Depressive Association reported that the interval between the onset of BD symptoms and the initiation of pharmacotherapy is approximately 10 years.^12,13 Similarly, a recent study (N=115) found that one-third of first episode patients who fulfilled Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV) criteria for BD I did not receive treatment during the 8-year study duration.¹⁴ This diagnostic delay unnecessarily contributes to increased relapse risk, chronicity, and suicidality in the bipolar population. Taken together, the epidemiologic and clinical data underscore the need to improve detection and diagnosis of patients with BD.

Diagnostic Criteria

In the United States, the most widely used source for diagnosing BD is the DSM-IV.¹⁵ Diagnostic criteria for major depressive, manic, hypomanic, and mixed episodes are described in Tables 1–4.¹⁵ The essential feature of BD I is the presence of one or more manic or mixed episodes (at a minimum of 1 week or any time if psychosis is present or hospitalization is required) with or without a history of depressive episodes.¹⁵ BD II is characterized by the presence of at least one hypomanic episode (at a minimum of 4 days) with recurrent episodes of depression.¹⁵

A diagnosis of cyclothymic disorder is made when a patient has repeated mood swings that are not severe enough to be diagnosed as mania or depressive episodes, but rather fulfill diagnostic criteria for hypomania and dysthymia (ie, subthreshold depression lasting for at least 2 years without a euthymic episode of at least 2 months).¹⁵ Another variation is bipolar disorder not otherwise specified (BD-NOS) (Table 5),¹⁵ when patients have manic and depressive symptoms that do not meet BD criteria.^15,16 Patients with BD-NOS may experience impairing symptoms for long durations. For example, one study (N=263) showed that in children and adolescents with BD-NOS (n=92), the time to recovery was longer than in those with BD I and BD II (P≤0.05).¹⁷

Differentiating Between Unipolar and Bipolar Depression

Depressive symptoms and episodes dominate the course of BD and frequently predate periods of mania or hypomania in most patients.^18-21 These episodes are typically the reason individuals will seek healthcare services for BD.²² Establishing whether a depressive episode is presenting in the context of MDD or BD is arguably the most challenging element of differential diagnosis. No specific sign or symptom of depression is unique to MDD or BD. There are, however, features that may help clinicians differentiate depressive episodes associated with BD from those associated with MDD (Table 6).^{5,15,21,23-31} For example, ruling out a history of hypomania initially can provide some direction for diagnosis. To minimize misdiagnosis of BD, perhaps all patients who show signs of depression should be evaluated for a history of previous hypomania (periods of increased energy and decreased need for sleep).

Individuals with BD are more likely to have an earlier age of onset (typically before 25 years of age).^5,23 An initial presentation of a major depressive episode at age 20 years has a higher likelihood of being associated with BD than one that begins after age 30 years. The longitudinal course of illness can occasionally be a helpful differentiating factor. Individuals with BD exhibit a greater tendency to cyclicity, since they have a higher rate of recurrence and shorter symptom-free intervals compared with individuals with MDD.²³

Individuals with BD may have a more abrupt onset of depressive symptoms, whereas symptoms in MDD have a more insidious onset.^21,32 Although both BD and MDD are subject to seasonal variability, individuals with BD appear more likely to report seasonal variation and mood destabilization with sleep deprivation and/or transmeridian travel.^21,23,26 Mood disorders frequently occur during reproductive life events in women. Females with BD frequently report index depression, mixed state, or mania at the time of menses and postpartum.²⁷ Increasingly, reports are documenting premenstrual worsening of bipolar symptoms that is often erroneously diagnosed as premenstrual dysphoric disorder. It is also not uncommon to see mood destabilization during the menopausal transition.^28,33

Although there are no features of a depressive episode that are pathognomonic for bipolar depression (or unipolar depression), phenomenologic studies have documented symptomatic patterns that differentially affect the bipolar population. For example, patients with BD are more likely to report and/or present with reversed vegetative features commonly associated with atypical depression (eg, increased appetite, hypersomnia).^23,26,29

Clinicians should be cognizant of other clinical presentations such as atypical depression and psychotic features also observed in patients with MDD.²⁹ The numerous clinical features rarely peculiar to MDD or BD underscore the importance of a thorough and longitudinal examination.³⁴ Careful patient monitoring may reveal, for example, subsyndromal hypomania, an integral component of depressive episodes in patients with BD, especially BD II. Hypomanic symptoms include irritability and increased distractibility, psychomotor agitation, crowding of thoughts, and talkativeness or pressured speech. Such features are often labeled as agitation or “agitated depression,” which were historically conceptualized as part of mixed states.³⁵ One feature that distinguishes agitated depression from dysphoria is decreased energy and increased need for sleep.^36,37

While agitated depression is present in MDD, some clinical experience suggests it is more common in patients with BD. In contrast, a prospective epidemiologic study with a 20-year follow-up period (Zurich study), found that agitated depression was as common in MDD as in BD II.³⁰ Combined agitated and retarded depressive states were, however, found to be more commonly bipolar than unipolar depression.³⁰

Currently, antidepressants are not approved for the treatment of BD, since there is inconsistent evidence to support their efficacy and safety. Several reports suggest that adding an antidepressant to a mood stabilizer does not increase the treatment efficacy. For example, in a study involving patients with depression, 23.5% (42/179) patients who received a mood stabilizer plus an antidepressant had a durable recovery, compared with 27.3% (51/187) patients who received a mood stabilizer and placebo (P=0.40).³⁸ In bipolar patients with depression and manic symptoms, antidepressants did not accelerate time to recovery compared with mood stabilizers alone, and increased severity of manic symptoms in some patients.³⁹ The large European Mania in Bipolar Longitudinal Evaluation of Medication (EMBLEM) study (N=2416) found that patients in maintenance phase who were taking antidepressants had significantly higher Clinical Global Impressions-Bipolar Disorder (CGI-BP) scale depression scores (P<0.001) and a significantly higher rate of depression relapse (P<0.001) at 12 weeks and 24 months. This indicated that they were more likely to have a higher risk of depression relapse during follow-up.⁴⁰

Some evidence suggests that antidepressants may be beneficial and safe for a subpopulation of bipolar patients. For example, analysis of complex medication regimens of 4035 subjects before entering Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) found that polypharmacy was most often associated with antidepressants or atypical antipsychotics. These data indicated that there was a potential need for including antidepressants in treatment for patients with complex and recurrent/nonresponsive depressive episodes.⁴¹ Most experts agree that for BD I, antidepressants should only be used in combination with mood stabilizers; however, there is no consensus about whether or not antidepressants should be prescribed as monotherapy in BD II.⁴²

Differential Diagnosis Beyond Unipolar Depression

Differential diagnosis of BD extends beyond MDD and addresses such potential confounds as underlying medical comorbidity, anxiety disorders, persistent externalizing behavioral conditions (eg, attention deficit hyperactivity disorder [ADHD]), personality disorders, and substance abuse disorders. In general, if an adult patient reports neither attentional or externalizing behavioral problems as a child, then ADHD (with a usual onset in childhood or adolescence) is unlikely to play a causative role.¹⁵ ADHD is a common differential diagnosis for pediatric presentations consistent with the symptomatology of BD.⁴³ Adult ADHD phenotype is also commonly seen in individuals with BD or MDD. A large (N=1000, STEP-BD) systematic evaluation of adult patients with BD showed that ADHD was frequent and associated with a more severe course of BD.⁴⁴

A more recent study (N=300) reported that the ADHD phenotype was commonly seen in bipolar (and MDD) patients and was associated with greater illness burden and complexity.⁴⁵ Personality disorders are defined as an enduring or lifelong pattern of chaotic, stormy, unstable relationships and work history.¹⁵ For example, an estimated 40% of patients with BD have a concurrent personality disorder.⁴⁶ In the differential diagnosis of psychiatric disorders, the importance of first ruling out comorbid medical conditions, iatrogenic side effects, medication-induced mood episodes (eg, anabolic steroids), and alcohol or substance abuse applies universally. Thyroid disturbances are common medical conditions that present with mood instability, depression, or anxiety, and are frequently misinterpreted as psychiatric disorders. Substance abuse disorders are particularly challenging, since their associated signs and symptoms overlap considerably and mimic those of BD. More precisely, the clinical presentation of patients with substance abuse disorders may mask an as yet undiagnosed and coexisting BD. In such cases, a careful patient history should be taken with particular attention given to phenomenology as well as to the temporal relationship between the substance abuse and the presenting psychopathologic condition.

As substance use disorders often begin after the onset of BD, early identification of the illness provides an opportunity to initiate preventive measures.¹² A recent analysis of published literature indicates that medical comorbidities are prevalent in patients with BD.⁵ Three or more comorbid medical conditions were present in 40% of patients. Moreover, patients may have different sensitivities to stress-related medical comorbidities such as neurologic, circulatory, and metabolic disorders, resulting in a higher prevalence of epilepsy, multiple sclerosis, migraine, and circulatory disorders. While these health matters are common, they are most often underrecognized and suboptimally treated.⁵

Differentiating Between Bipolar I and Bipolar II and BD-NOS Disorders

Differentiating between BD I, BD II, and BD-NOS presents formidable challenges, particularly when evaluating an outpatient who has had mood instability and recurrent episodes of depression. The specific diagnosis has important implications for treatment and prognosis, and relatively clear-cut distinctions can be made upon presentation. For example, while bipolar mania is usually accompanied by severe impairment, BD II hypomania is associated with relatively minor impairment and behavioral changes without psychotic features. As discussed previously, duration of illness may be longer in patients with BD-NOS compared with BD I and BD II.¹⁷ Hypomania, overall, is a milder presentation of shorter duration, with less severe symptomatology and less functional impairment. Hypomanias are, by definition, at least 4 days in duration, whereas manias last at least a week, although this duration requirement does not need to be met if the patient is psychotic or requires hospitalization.¹⁵ While hospital admission strongly implies a severe disorder, the current reimbursement and insurance landscape suggests that patients who do not have an admission record should also be carefully considered. There is a decidedly gray area for patients with moderate to severe impairment (ie, those presenting with problems at work or home who are still able to manage the activities of daily living and who do not have an obvious history of psychosis or hospitalization). Here, the evidence base supporting diagnostic and therapeutic decision making is limited, emphasizing the importance of good clinical judgment and collaborative discussion with clinicians, caregivers, family, and friends who know the patient well. A zone of delimitation has not been identified wherein BD I and BD II can be meaningfully disambiguated in many clinical circumstances.

Depressive symptoms predominate in patients with both BD I and BD II. A seminal study by Judd and coworkers found that patients with BD I spent approximately 300% more time with depressive symptoms than with manic symptoms.¹⁸ In BD II, the proportion of weeks patients spent with symptoms of depression was almost 40-fold greater compared with hypomanic symptoms.¹⁹ More recently, Altshuler and coworkers showed that the possibility of having depressive symptoms was significantly higher for women than for men.⁴⁷ The depressive symptoms of BD I may account for more workforce disability than observed in MDD. For example, results of a large study (N=20,747, based on Canadian Community Health Survey) showed that compared with MDD, individuals with BD had a significantly lower annual income (P<0.05), higher odds of reporting mental health disability days in the past 2 weeks (odds ratio [OR]=1.6; 95% confidence interval [CI]=1.0–2.6), and lower odds of “good job security” (OR=0.6, 95% CI=0.5–0.9).⁴⁸

Patients with BD II, unlike those with BD I, frequently report 5 or more depressive episodes.⁴⁹ Differences have also been observed in the psychosocial disability and working capacity. For example, a study that compared these domains in patients with BD I, BD II, or MDD via semistructured interviews across 15 years found that the inability to carry out work role functions was 30% in patients with BD I, compared with 20% and 21% in BD II and MDD, respectively.⁵⁰ Taken together, these data show that the symptomatology of depression constitutes a significantly greater part of the clinical picture in BD II than in BD I.

Establishing an unambiguous distinction between the two requires a detailed patient history, with a clear focus on the clinical presentation and its evolving symptomatology.

Gender and Bipolar Disorder

Bipolar I disorder affects men and women equally.^1,15 However, BD II is more common in women than men.^1,15 Gender-related differences have been noted in several studies. Compared with men, women with BD tend to have a greater disposition toward depression.^15,47 Although men are likely to experience higher substance abuse than women in general, women with BD have a higher rate of alcohol abuse (7-fold) than women in the general population.⁵¹ Women may be more prone to rapid cycling and mixed states, which may present diagnostic challenges.⁵² Further, women are particularly susceptible to illness onset and/or destabilization during reproductive events, including menarche, pregnancy, postpartum, and menstrual transition.⁵³ Also, patterns of comorbidity may differ between women and men; women have higher rates of lifetime comorbid eating disorder and drug and alcohol use. Besides, the relative risk of substance abuse is higher in women than in men.⁵⁴

Migrane headaches and metabolic syndrome are other common comorbidities observed in patients with BD. Migraine is more common among patients with BD than in the general population and appears to be more common among women in both populations.^28,31,55 Several factors that appear to contribute to the higher observed rates of metabolic syndrome in patients with BD include common physiologic etiologies (eg, abnormalities in cortisol regulation), unfavorable lifestyle and behavioral patterns (eg, cigarette smoking, physical inactivity, poor diet), and the metabolic effects of medications used to treat this illness, particularly atypical antipsychotics.⁵⁶ Further, some evidence suggests that metabolic syndrome, a constellation of interrelated abnormalities comprising hypertension, insulin resistance, elevated body mass index, central adiposity, and dyslipidemia, may be more common in the bipolar population than in the general population.⁵⁷ A comprehensive analysis of literature on metabolic syndrome and BD, mania, and manic-depression supports this observation and indicates that the increase in metabolic syndrome is due to the clustering of risk factors, negative health behaviors, and treatment-related weight gain.⁵⁸

As discussed in a subsequent chapter, the co-occurrence of the metabolic syndrome in patients with BD is associated with a more complex presentation, an overall more serious illness with respect to course and outcome, and a less favorable response to treatment.⁵⁸ For example, bipolar patients with metabolic syndrome also have an elevated risk of depressive symptoms/ episodes and suicidality. Comorbid metabolic syndrome may thus be a marker of greater disease burden. There is also the possibility that BD with comorbid metabolic syndrome may represent a phenotype that increases the risk of suicidality through direct and indirect factors.⁵⁸

Age-Related Features of Bipolar Disorder

Numerous studies suggest that the onset of BD typically occurs between the ages of 15 and 25 years.^1,20,21,59 Pediatric BD may first appear much like an adult-onset presentation, with recurrent episodes of mania and depression. Compared with adults, pediatric-onset bipolar disorders tend to be more mixed, frequently presenting with both mania and depression.^43,60 Rapid cycling is also more common in pediatric presentations. In contrast with the more stable, episodic course that often occurs in adults with BD, pediatric patients are more likely to report and/or manifest a chronic, nonremitting, rapid-cycling confluence of manic and depressive symptomatology.

An estimated 10% of bipolar patients present with late-onset BD, with the first episode of mania occurring after the age of 60 or 65 years.⁶¹ The symptomatology of late-onset mania overlaps with younger-age–onset BD. Yet, there are some features that are more commonly seen in late-onset conditions. For example, there often is a behavioral component that dominates the clinical picture in older-onset BD, the disorder is more often mixed, and psychotic features are more prominent.¹⁵ Of interest, a retrospective study of 67 patients with late-onset BD reported that, on average, the first manic episode occurred 10 years after the first depressive episode.⁶² Almost one-half of the patients followed in one study had at least 3 depressive episodes before their first manic attack.⁶² Like the bipolar patient population in general, late-onset patients tend to have hypertension, dyslipidemia, and/ or other cardiometabolic abnormalities and the risk factors demand tight clinical management.^63,64

Brain imaging studies also show a high rate of cerebrovascular disease in the late-onset patient population.^65,66 Vascular-related changes in white matter may be causally related at least in part to late-onset BD. Notably, cerebrovascular disease mechanisms are thought to damage frontolimbic circuits involved in the pathophysiology of mania.^65,66

Diagnosis of a Bipolar Prodrome and the Case for Early Intervention

Timely diagnosis and individualized care are critical to treatment success. The earlier the illness is diagnosed and treated, the more likely it is that patients will achieve symptomatic remission and functional recovery.^67-69 Longitudinal evaluation of patients provides the opportunity to clarify the diagnosis. For example, one study (N=413) that followed bipolar spectrum disorders in children and adolescents for 4 years found that 40% of the participants had syndromal or subsyndromal symptoms during 75% of the follow-up, and 38% patients with BD-NOS converted to BD I or BD II.¹⁶ Prognostic data prove persuasive for early and aggressive therapeutic interventions. For example, patients who experience frequent bipolar episodes are more likely to develop irreversible functional impairment.^67-69 These and related data support ongoing efforts to investigate a putative prodromal state for BD.^70,71 Descriptive studies have yielded important yet incomplete data. Adolescents and young adults with a family history of BD presenting with mood instability should arguably be conceptualized as at risk. A family history of BD has implications for a potential prodrome and may provide contextual insights for differential diagnosis.

Although there are no biologic markers for BD, patients may have volumetric brain changes early in the course of their illness. A meta-analysis of magnetic resonance imaging (MRI) studies concluded that patients with first-episode bipolar disorders have significant reductions in total intracranial and white matter volumes compared with controls.⁷² Patients with BD are more likely to report histories of assaultive trauma than the general population.⁷³ In this patient population, childhood abuse (sexual or physical) has been linked with changes in brain volume; however, MRI findings from various studies are somewhat inconsistent. In contrast with consistently seen small hippocampal volume in patients with MDD, brain morphometric data in bipolar disease are mixed, and show smaller, similar, or larger hippocampal volumes in women compared with controls.^74-77 It is likely that clinical factors like childhood abuse influence such morphometric variability.⁷⁷

Clinical research into states antecedent to bipolar presentation has targeted patient populations with externalizing behavioral disorders like ADHD and dysthymic, cyclothymic, or hyperthymic personalities.^20,78 To date, these data are far from conclusive, and important clinical and scientific questions remain unresolved. Presently, the DSM-IV provides critical guidance for the diagnosis of BD, although close attention to features as soft signs can certainly shape assessment and diagnosis (Table 6).

Screening Tools

The overarching aim of screening tools is to detect a phenotype consistent with BD. Validated screening tools balance sensitivity (the ability to unambiguously identify bipolar patients) with specificity, while appropriately addressing other key psychometric variables. Ideally, screening tools improve the signal-to-noise ratio during differential diagnosis, reducing false-positives and simultaneously reducing false-negatives or failure to recognize BD in a given patient. Nevertheless, the final assessment tool is the psychiatrist’s own judgment. Obtaining a longitudinal history, longitudinal self-rating by the patient, and monitoring by the psychiatrist may be helpful in accurate and timely diagnosis.

Screening instruments available for BD are described in Table 7^79-83; the most commonly used is the Mood Disorder Questionnaire (MDQ).⁷⁹ This is a self-report, paper-and-pencil, single-page questionnaire that consists of 13 yes-or-no items derived largely from the DSM-IV criteria. The questionnaire includes a yes-or-no item examining whether the reported symptoms occurred at the same time and an additional item assessing the level of functional impairment.⁷⁹

A positive screen for BD on the MDQ includes answering “yes” for at least 7 of the yes-or-no symptom items; “yes” for co-occurrence of symptoms; and scoring “moderate” or “serious” for impairment.⁸⁴ In one study assessing the clinical utility and reliability of the MDQ, Hirschfeld and colleagues screened 649 primary care patients receiving antidepressant treatment and reported that 138 (21.3%) were positive for BD.³ Overall, 86 of the 138 patients who screened positive on the MDQ and 94 of the 511 MDQ-negative patients completed the Structured Clinical Interview (SCID) for DSM confirming or rejecting a diagnosis of BD.³ While these psychometric data are beyond the scope of this review, the MDQ correctly identified 45 of 59 patients with SCID-diagnosed BD and 80 of 121 patients without BD, supporting its use as an initial screening instrument.³ In other studies, the MDQ has shown false-positives when screening for BD and borderline personality disorder and limited sensitivity as a screening tool for psychiatric outpatients.^85,86 Taken together, the available evidence indicates that a screening tool like the MDQ may be a helpful adjunct but it does not supplant a thorough clinical evaluation with input from third parties who can provide meaningful observational information pertinent to the patient. The MDQ is a screening tool and does not “diagnose” BD, nor does it “rule out” BD. While in academic centers, more structured clinical interviews such as the Mini International Neuropsychiatric Interview (MINI) and the SCID may be used frequently, these instruments are not always practical in the clinical setting due to time constraints.

In the absence of an ideal scale for measuring symptoms, many clinicians use the Montgomery-Asberg Depression Rating Scale (MADRS), the Hamilton Rating Scale for Depression (HAM-D), the Inventory of Depressive Symptomology (IDS), and the Patient Health Questionnaire (PHQ-9), along with a mania scale, such as the Young Mania Rating Scale (YMRS), which can help to differentiate between BD I and BD II.^87-91 Although the screening tools described above are useful in the diagnoses, careful assessment of the patient’s psychological history is important in making the diagnosis. Further information is available in Chapter 3.

Conclusions

Bipolar disorder is a common psychiatric condition that often goes unrecognized or misdiagnosed for several years before patients receive appropriate treatment. The most common differential diagnosis of BD is MDD. Clinicians are encouraged to consider screening tools but are reminded that their positive and negative predictive values are suboptimal and do not replace a thorough clinical assessment. In addition, patient features (eg, young age, family history) and a precipitous onset of depression can provide clinical clues suggestive of a diagnosis of BD. Differential diagnosis of BD requires a careful patient history informed by results of assessment tools (eg, HAM-D, MADRS, YMRS), a detailed patient interview, and input from family and other individuals close with the patient.

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