The Bipolar Spectrum in Psychiatric and General Medical Practice

Hagop S. Akiskal, MD

Dr. Akiskal is director of the International Mood Center in the Department of Psychiatry at the University of California, and chief of the Mood Disorders Program in the Veterans Administration Healthcare System, both in San Diego.

Disclosure: Dr. Akiskal is a consultant for and is on the speaker’s bureaus of Abbott, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, and Sanofi-Synthelabo.

Please direct all correspondence to: Hagop S. Akiskal, MD, University of California, San Diego, International Mood Center, Department of Psychiatry, 3350 La Jolla Village Dr, La Jolla, CA 92161-0603; Tel: 619-552-8585; Fax: 619-534-8598; E-mail: [email protected].

Abstract

This introductory article examines the emerging scientific and clinical literature on bipolar types beyond those in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). These include new “softer” expressions of bipolarity, such as type II with briefer hypomanias, type II½, type III, and type IV. Patients within the soft spectrum beyond the DSM-IV prototypes are highly prevalent in private psychiatric, community mental health, and general medical practice. Thus, identifying bipolar disorder as a spectrum has clinically meaningful implications for comorbid conditions, the nature of a putative shared underlying pathophysiology, clinical management, and public health.

Introduction

Until recently, it was believed that bipolar disorder occurred in 1% of the general population. This figure pertains to what is known as bipolar I disorder (manic-depressive illness). However, the current bipolar schema in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV),¹ also includes bipolar II, cyclothymia, and bipolar not otherwise specified. Thus, it should not come as a surprise that, in a wave of new epidemiologic studies, the prevalence of the entire spectrum has been revised up to at least 5% of the general population.² Although the DSM-IV does not use the construct of “bipolar spectrum,” its bipolar subtypes implicitly adhere to such a broad schema.

The work reviewed in this article examines the emerging scientific and clinical literature on bipolar types beyond DSM-IV bipolar I and II. These include new “softer” expressions of bipolarity, such as type II with briefer hypomanias, type II½ (depression superimposed on cyclothymia), type III (depression plus antidepressant-associated hypomania), and type IV (depression superimposed on a hyperthymic temperament).^2,3

Patients within the soft spectrum beyond the DSM-IV prototypes are highly prevalent in psychiatric and primary care community and private practice settings. However, they often present clinically with a volatile mix of depression and biographical instability (ie, so-called erratic personality disorders), along with addictive, phobic-anxious, panic, and bulimic comorbidities. History of hypomania is more often than not overshadowed by the lifelong nature of these complex manifestations. It is important for psychiatrists, other mental health professionals, and general medical practitioners to be vigilant concerning the bipolar spectrum in patients presenting with the foregoing conditions. They should therefore conduct a diligent search for hypomania.

There is credible evidence that, depending on the study and the setting, somewhere between 30% and 70% of all depressions observed in clinical settings belong to this complex spectrum.² The atheoretical position of the DSM-IV diagnostic system may serve as a blueprint for a research document, but regrettably it does not do justice to the clinical complexity of bipolarity as seen by the practitioner, nor does the DSM-IV provide any guidance on how to make sense of the conditions that accompany bipolar illness. Reformulating bipolar disorder as a spectrum has clinically meaningful implications for comorbidity, the nature of a putative shared underlying pathophysiology, clinical management, and public health.

Defining the Bipolar Spectrum

There is an emerging international consensus² that bipolar disorder extends beyond the boundaries of an illness historically defined by an alternation of mania and depression. Indeed, between the extremes of full-blown manic-depressive illness (ie, bipolar I, where the patient has at least one acute manic episode) and strictly-defined unipolar depression (without personal or family history of mania or hypomania), there exists a prevalent spectrum of soft bipolar conditions with various admixtures of depression, hypomania, and temperamental instability.³

Those with spontaneous hypomania are now formally considered bipolar II in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Text Revision (DSM-IV-TR).⁴ Moreover, in many clinically depressed patients, elements of hypomanic activation can occur during an episode of major depressive disorder (MDD), resulting in “depressive mixed states” (which are not officially recognized in the DSM-IV). These patients pose diagnostic and therapeutic challenges for clinicians.^3,5,6 Depressions with antidepressant-associated hypomania also appear, on the basis of extensive recent work,^2,7 to be related to bipolar II (although some refer to them as bipolar III, also not an official rubric in the DSM-IV). Premorbid and interepisodic cyclothymic (a variant of bipolar II⁸) or hyperthymic traits (ie, bipolar type IV, consisting of overcheerful, overenergetic, and overconfident people who succumb to depression in their 40s and 50s⁹) represent prominent characteristics of other soft expressions of this spectrum. Patients across the soft spectrum may present with depression, anxiety, or mood swings. These mood swings are recurrent, biphasic, and abrupt, and are frequently induced by antidepressants (or stimulant and alcohol abuse) and/or by seasonal changes.³ Falling in and out of love and other excitements that could lead to sleep deprivation represent common contributory factors to the instability of these patients.^3,9 Table 1 presents this proposed bipolar spectrum schema.

Although the DSM-IV-TR only includes bipolar types I and II, the aforementioned schema provides characterization for the remainder of the spectrum types, which in the DSM-IV are dubbed under the nondescript rubric of “bipolar not otherwise specified.” The proper specification of the entire spectrum is important for clinical practice. It makes little sense for a diagnostic manual developed for clinicians to categorize patients as having an unspecified disorder. Most physicians diagnose and manage conditions on the border of prototypical disorders. This is where the DSM-IV fails them. For a more in-depth description of this schema, the reader is referred to work by Akiskal and Pinto.⁹

Bipolar Disorder in Clinical and Community Settings

There has been a major recent research thrust in the study of bipolar disorder in its psychotic and ambulatory variants. It is now well accepted that mania can manifest in extreme psychotic forms,¹⁰ including “schizobipolar” phenotypes.¹¹ Careful research has also delineated mixed or dysphoric forms of mania that also frequently reach psychotic proportions.^12-17 Patients with such intense activation typically require psychiatric hospitalization. Current data indicate that at least two depressive symptoms exclusive of insomnia and agitation are sufficient for defining dysphoric mania. More provocatively, such mixed manic forms have been shown to arise from the baseline of a dysthymic (depressive) temperament, whereas pure mania is more typically superimposed on a hyperthymic temperament.

Current official systems of classification (such as the DSM-IV) are couched within the unipolar-bipolar distinction, yet a newer conceptual framework, in development since 1977,^3,9,18-21 has accumulated data in favor of the existence of a prevalent group of intermediary, predominantly ambulatory, conditions. Recent studies in psychiatric settings,^3,22-24 in general medical practice,²⁵ and in the community^26-29 have revealed a large spectrum of patients with soft or subtle signs of bipolarity. Bipolar II, the best known of these conditions, was first delineated by Dunner and colleagues.³⁰ Typically these patients present with MDD, but upon expert interviewing³¹ reveal a history of activated behavior, mood lability, explosive behavior, or marked irritability.³² The soft bipolar spectrum, which is more prevalent than full-blown manic-depressive illness, constitutes a “clinical bridge” between unipolar and psychotic bipolar disorders,³ indicating the need for a partial return to Kraepelin’s³³ broad concept of manic-depressive illness.

Based on the finding that depressive forms exceed definite bipolar cases in manic-depressive pedigrees by 4–5-fold,¹¹ Akiskal and Mallya³ estimated in 1987 that the rates for the bipolar spectrum should be 4% to 5%. Epidemiologic studies have actually shown that these softer expressions of bipolarity have a prevalence range of 3.7% to 8.3%,^26-29 as opposed to the conventionally reported rate of 1% for manic-depressive illness.³⁴ Most interestingly, in private psychiatric, community mental health,^2,3 and general medical²⁵ settings, somewhere between 30% and 70% of patients presenting with MDD belong to the bipolar spectrum.

Focus on the Soft Spectrum

There are several intermediary conditions between bipolar I and strictly-defined unipolar MDD. The common feature of these intermediate bipolar conditions is the occurrence of manic activation at a subthreshold level.^3,9 Bipolar II, the most prototypical of the soft bipolar spectrum, appears to be the most prevalent clinical expression of bipolar disorders.³⁵ Spontaneous hypomania is needed for the diagnosis of bipolar II. Because bipolar II patients present clinically with depression and almost never with hypomania, the diagnosis of bipolar II requires skillful interviewing about history of such episodes. Current clinical guidelines² indicate that the duration of hypomanic episodes is less important when numerous such episodes have occurred in the past. Hypomania is a distinct episode of mild elevation of mood, positive thinking, and increased activity level occurring over at least a few days. It is distinguished from ordinary happiness by the tendency of episodes to recur (happiness usually does not, unfortunately) and by the fact that it can be mobilized by antidepressants.³ Despite DSM-IV conventions to the contrary, the preponderance of evidence based on family history for bipolar disorder and clinical course^2,7 indicates that hypomania during antidepressant treatment of an episode of MDD merits a bipolar designation (ie, bipolar III).

Individual hypomanic episodes may also be associated with positive emotions and creative thinking.³⁶ However, the judgment of patients may be impaired. Repeated episodes of hypomania in association with mood swings may cumulatively contribute to the unstable course of bipolar II disorder, as well.² Moreover, the experience of hypomania itself is often that of a “nervous high,” with marked irritable and hostile admixtures. According to the DSM-IV, hypomania typically presents without the marked impairment characteristic of manic episodes. Judging from the above symptoms of hypomania, however, the DSM-IV characterization of bipolar II as a milder condition is misleading. Table 2 provides a summary of findings on hypomanic episodes taken from clinical experience.^3,9,18

Another characteristic of some, but not all, bipolar II patients is their labile cyclothymic temperamentality⁸ prior to and between MDD episodes.²⁴ These patients, who can be considered “cyclothymic depressives,” exhibit a great deal more instability than bipolar II patients who present without cyclothymia; in fact, they are often mistaken for patients with borderline personality disorder. Prospective follow-up leading to MDD and/or hypomania rather than mania,¹⁸ and familial bipolar history, are the strongest evidence for the inclusion of these patients within the bipolar spectrum.⁸ One might consider them bipolar II variants or bipolar II½.⁹ The validated self-rated criteria for cyclothymia³⁷ are summarized in Table 3. Patients with MDD endorsing at least six of these criteria are likely to belong to this bipolar variant.

In yet another soft bipolar subgroup, hypomanic and cyclothymic episodes as such are absent; instead, the individual has a persistent upbeat disposition, is overoptimistic, and functions at a high level of energy and confidence premorbidly and between depressive episodes. Unlike hypomania, which is an episode distinct from the patient’s habitual self, the hyperthymic traits of bipolar IV patients represent their habitual baseline.³⁸ These traits have been found to define a subtype of MDD with bipolar family history indistinguishable from other disorders in the spectrum.^9,22 The criteria for the hyperthymic temperament³ are summarized in Table 4. It is usually best to elicit these traits by clinical interview or from significant others; a patient with MDD meeting at least four of these criteria can be clinically assigned to bipolar type IV.

Evidence for the importance of temperamental attributes in defining bipolar spectrum subtypes has come from the National Institute of Mental Health Collaborative Study of Depression (CDS) database. As demonstrated in a 12-year prospective examination of bipolar switching in the CDS,³⁹ trait attributes consisting of “mood-lability” and “energetic-activity” permit a more precise characterization of the bipolar spectrum than the hypomanic periods emphasized in the DSM-IV and the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10).⁴⁰ To properly diagnose soft bipolar conditions, the clinician must therefore carefully assess lifelong cyclothymic (mood-labile) or hyperthymic (active-energetic) traits. MDD episodes often complicate the life course in these individuals, and during these episodes, their conditions would therefore warrant the additional diagnosis of bipolar spectrum disorders.

In official diagnostic systems, bipolarity is characterized by the presence of alternating manic (or hypomanic) and depressive phases. However, a more fundamental characteristic of bipolarity is the reversal of the basic temperament into its opposite episode.⁴¹ Research^22,24 has actually shown that the MDD expression in bipolar II disorder commonly arises from cyclothymic temperament. On the other hand, bipolar I disorder, characterized by a predominance of manic attacks, is more likely to arise from a dysthymic or hyperthymic temperament and, in bipolar I, a hyperthymic baseline is typically limited to patients with a predominantly manic course. Thus, the biphasic disturbance in bipolar illness often consists of the development of episodes that can be considered opposite in polarity to that of the antecedent temperament.⁴¹

As a result, the depressive episodes of many patients with soft bipolarity arising from cyclothymic and/or hyperthymic baseline are often mixed in nature (ie, isolated hypomanic symptoms, such as psychomotor acceleration, flight of ideas, and intense sexual arousal, intrude into MDD).^3,5,42 Clinicians, when confronted with activated (labile, aroused, hostile, or agitated) MDD patients in psychiatric or general medical settings, must first rule out a bipolar spectrum condition. The same is true for a proportion of major depressions with intense anxious-phobic arousal.⁴³

Comorbidity Within the Bipolar Spectrum

Mixed bipolar depressive states are ignored in both the DSM-IV and the ICD-10. This failure to recognize the bipolar nature of the volatile mix of temperament, depression, and anxious-phobic features often gives rise to such misleading characterologic diagnoses as borderline, histrionic, psychopathic,^18,44 or atypical depressions.⁴⁵

In the offspring of bipolar patients, affective storms can be misconstrued as attention-deficit/hyperactivity disorder (ADHD) and/or conduct disorder.^46-48 ADHD and bipolar are distinct disorders, yet they often coexist. Thus, if family history is bipolar, considering these patients as a special ADHD-bipolar subtype is justified. Although such overlap is most common in manic or mixed manic children, it is at times observed in adults across the bipolar spectrum.

Substance and alcohol abuse are particularly prevalent among soft bipolar conditions.^18,49,50 They often represent an attempt to enhance the hyper periods (with stimulants), rather than an attempt to self-medicate during depressed periods.³² Often comorbid appetitive behaviors, such as bulimia,⁵¹ can also be considered to have relevance to the bipolar spectrum. McElroy and colleagues⁵¹ contend that other impulse-control disorders, such as kleptomania and gambling, might have affinities to the bipolar spectrum as well. This is not to say that addictive, bulimic, and impulse-control disorders are secondary to bipolarity. Their common coexistence with bipolar disorder raises the possibility of shared underlying neurobiologic mechanisms. This is analogous to the common coexistence of obesity, diabetes, and hypertension, which are all diseases in their own right that are linked by the metabolic syndrome.

Bipolar spectrum patients with prominent temperamental dysregulation also appear vulnerable to the cycling effect of antidepressants.^18,52,53 The excesses of bipolar II patients and the associated circadian disruptions appear relevant to the irregular cycling so often encountered in ambulatory bipolar patients today. A soft bipolar diagnosis is crucial, precisely because these patients need protection from antidepressant monotherapy (eg, with mood-stabilizing anticonvulsants or atypical antidepressants).

Interestingly, current data also suggest an intriguing association between soft bipolar conditions, especially cyclothymic conditions, and artistic creativity. Individuals with hyperthymic temperament are also over-represented among prominent individuals in leadership positions.⁵⁴ In the same vein, professional achievement is over-represented among healthy relatives of bipolar patients.^55,56 Thus, high achievement in various professional domains, or family history for such achievement, in the patient presenting with clinical depression can be used as a clinical pointer in favor of soft bipolarity.

On a more clinical note, pointers toward bipolarity include certain course, episode, phenomenological, and familial characteristics listed in Table 5.^3,9,19

Discussion

Since bipolar spectrum was first proposed,^18,19 the literature has been enriched by conceptual extensions, modifications, and/or research in favor of the spectrum of bipolarity.^57-68 The material reviewed in this article refers to the phenomenology, course, and familial aspects of the spectrum. It is likely that genetic heterogeneity exists, underlying the bipolar spectrum.^69-71 This does not rule out the possibility that biological commonalities may be shared by the spectrum.

Although the concept of bipolar spectrum has been criticized on methodologic grounds,⁷² the evidence reviewed herein has documented that the spectrum and its comorbidities are prevalent conditions in both psychiatric and general medical settings. In the differential diagnosis of depressive, anxious-phobic, and panic states, the clinician must consider bipolar II and its variants. Comorbidity is high with addictive, bulimic, and borderline conditions. Migraine⁷³ can also coexist with soft bipolar disorders, as can other psychophysiological disorders⁶¹ beyond the scope of this review. This means that bipolarity can present clinically with the foregoing nonaffective features. Given emerging data on the link between bipolarity and suicidality,⁷⁴ the recognition and proper management of the bipolar spectrum and its comorbidities is relevant to suicide prevention.^75,76

The emerging literature on the bipolar spectrum is beginning to impact psychiatric practice worldwide,⁷⁷ as well as pathophysiologic understanding of putative common temperamental and molecular genetic mechanisms underlying the spectrum and its comorbidities.⁷⁸ The bipolar spectrum is also relevant to family and general medical practice,^79-82 which represents the de facto field for prevalent affective disorders, ADHD, and substance and alcohol use disorders.

Conclusion

It has not been the purpose of this overview on the bipolar spectrum concept and its adjoining conditions to demolish the edifice of the diagnostic prototypes embodied in the DSM-IV. The clinician should use these prototypic descriptions as a guide to identify the most likely diagnosis that best fits a patient presenting with an elusive and complex array of affective manifestations subthreshold to the classical bipolar type. In adults, these manifestations are typically comorbid with anxious, migrainous, addictive, bulimic, and erratic personality disturbances. The DSM-IV provides no guidance as to why these disorders often coexist with bipolar illness, nor does it provide any rationale for prioritizing one diagnosis over another. To focus on the presenting condition exhorted by the DSM-IV, while sensible, is not necessarily always the best diagnostic solution. Because of its therapeutic and prognostic implications, it is important not to miss a bipolar spectrum diagnosis in the patients described in this review. Early age of onset, episodic or cyclic course, marked seasonality, mixity, and bipolar family history can serve as markers for a bipolar diathesis in such patients.

It is meaningful to consider that this illness, while operationally distinct from its commonly co-occurring disorders, may nonetheless share underlying neurobiologic mechanisms with them. This style of thinking is an incentive to contemporary molecular oligogenic studies in the field of bipolar and related disorders.⁷⁸ This model postulates various combinations of shared genes among the adjoining disorders of bipolarity and the bipolar spectrum itself.

Taking these factors into account, the concept of the bipolar spectrum can serve to bridge practice, clinical research, and more basic research in psychiatry.⁸³ In fact, spectrum concepts of mental illness may represent a promising alternative to the DSM-IV.⁸⁴ PP

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