Lowering the Diagnostic Threshold for Bipolar Disorder: The Wrong Stuff?

Lowering the Diagnostic Threshold for Bipolar Disorder: The Wrong Stuff?

Joseph F. Goldberg, MD

In this issue of The Journal of Clinical Psychiatry, Mark Zimmerman, MD, provides a thoughtful and provocative overview of controversies regarding subthreshold manic or hypomanic symptoms as the possible harbinger of an eventual diagnosis of bipolar disorder in patients with no prior manic or hypomanic episodes.1 The concerns he raises are timely in light of proposed changes for DSM-5 that would blur the unipolar-bipolar distinction through the "mixed features specifier" for major depression (http://www.dsm5.org/proposedrevision/Pages/BipolarandRelatedDisorders.aspx). Echoing cautionary sentiments expressed by earlier writers, Zimmerman argues against what Baldessarini2(p5) called "the premature and potentially misleading widening and dilution of the bipolar disorder concept," noting that (1) longitudinal studies reveal that only a minority of individuals with subthreshold mania/hypomania progress to bipolar I or II diagnoses; (2) in the absence of external diagnostic validators (such as established biomarkers), clinical signs and symptoms are merely a rough proxy for defining true cases; and (3) individual symptoms are nonpathognomonic, meaning that when subthreshold symptoms are taken out of context, or outside the full constellation of features that define a manic or hypomanic syndrome, they could represent a variety of conditions other than bipolar disorder. Consequently, he concludes, more harm than good would likely come from reflexively equating subthreshold manic or hypomanic symptoms with bipolar disorder, capturing more false-positive than true-positive cases and missing other nonbipolar diagnoses that have different treatments and outcomes.

• Manic or hypomanic syndromes are defined by coherent constellations of interrelated signs and symptoms that involve changes in mood, energy, cognition, speech, behavior, and sleep.
• Individual or subthreshold manic or hypomanic symptoms are not pathognomonic and should encourage a broad, rigorous differential diagnosis.

Zimmerman’s concerns are well taken. For decades, debate over the overdiagnosis versus underdiagnosis of bipolar disorder has been driven more by popular perception, promotional "disease state" awareness advertising by industry, and consumer advocacy campaigns rather than by strides in diagnostic precision. Survey data of outpatient practices reveal nearly a doubling of bipolar disorder diagnoses in adults and an astounding 40-fold increase among youth from the mid-1990s through the mid-2000s,3 suggesting forces at play other than vast scientific advances in disease classification. A key problem in lowering the diagnostic threshold for bipolar disorder has been psychiatrists’ historically inconsistent approach to differentiating bipolar disorder from other forms of psychopathology. In the 1970s, American psychiatrists tended to diagnose schizophrenia more often than bipolar disorder as compared to British psychiatrists,4 a trend that reversed sharply after publication of DSM-III5; in later decades, confusion and debate arose over discriminating bipolar disorder from unipolar depression,6 borderline personality disorder,7,8 substance-induced mood disorders,9 and attention-deficit/hyperactivity disorder.10 The lay public perceives the "misdiagnosis" of bipolar disorder as an egregious deviation from the standard of care rather than a reflection of imprecise technology and lack of sustained consensus within the field about what does and does not constitute bipolar disorder versus other disorders.

Psychiatric diagnoses such as bipolar disorder remain defined purely by their phenomenology, akin to migraine, Meniere’s disease, tinnitus, trigeminal neuralgia, irritable bowel syndrome, and fibromyalgia. But it is hard to discriminate among possible conditions that fall within a differential diagnosis if the component elements of a defined syndrome are deconstructed and evaluated without considering the broader clinical context in which they arise. A young adult woman with high interpersonal sensitivity who becomes upset after quarreling with an intimate relation does not consequently "rapidly cycle" all night. The businessman who rises to the occasion of increased work demands with gusto cannot volitionally summon up hypomania at will, nor does a manic episode typically end in convenient synchrony with the completion of an arduous work or social obligation. All of medicine hinges on relative context and differential diagnostic rigor, using exclusionary criteria to filter out false-positive cases, as when one evaluates such nonpathognomonic symptoms as chest pain, shortness of breath, or edema. As noted by Ghaemi,11 Hippocratic medicine favors treatments aimed at coherent disease entities rather than random symptom medleys. Zimmerman warns that, if we de-emphasize syndromal criteria, more confusion than clarity will result, and neither science nor patient care will likely advance.

Perhaps the most compelling point raised by Zimmerman involves caution over presumptions that treatments for bipolar disorder (notably, mood stabilizers) would be expected to yield greater benefits than other treatments (notably, antidepressants) in patients who have never had a full manic or hypomanic episode. No clinical trials have ever examined whether mood-stabilizing medicines have value (or if antidepressants are deleterious) in that setting, making it hard to proffer evidence-based treatment recommendations. In fact, a post hoc analysis using the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) database found that subthreshold mania features during major depression did not predict poorer outcome with antidepressants.12 The proposition that improved emotional well-being from a mood stabilizer de facto implies a bipolar diagnosis perpetuates the unsubstantiated notion that drug response confers information about etiology. That slippery-slope argument could equally be used to suggest that successful diuresis with furosemide implies a cardiogenic explanation for peripheral edema, that selective serotonin reuptake inhibitor response in panic disorder points to an underlying major depression, or, for that matter, that divalproex-responsive mania suggests underlying migraine or epilepsy.

What does the field need in order to replace opinion with evidence? A first step would be to empirically validate an operational definition of subthreshold bipolar disorder (ie, vetting and testing criteria such as those proposed by Ghaemi et al,13 based on identified exclusion as well as inclusion criteria), symptom context (eg, symptoms are not better accounted for by another mental disorder), and longitudinal course. Key symptoms may hold particular value over others for discriminating bipolar from nonbipolar mood disorders, as has recently been suggested in the case of psychomotor activation.14 Endophenotype studies (eg, cognitive function), particularly in unaffected first-degree relatives, may ultimately further help to discriminate true cases from phenocopies. Intervention studies should follow rather than precede diagnostic clarification, and treatment recommendations for a proposed entity cannot emerge in the absence of meaningful empirical trials.

References

1. Zimmerman M. Would broadening the diagnostic criteria for bipolar disorder do more harm than good? implications from longitudinal studies of subthreshold conditions. J Clin Psychiatry. 2012;73(4):437-443.

2. Baldessarini RJ. A plea for integrity of the bipolar disorder concept. Bipolar Disord. 2000;2(1):3-7. PubMed doi:10.1034/j.1399-5618.2000.020102.x

3. Moreno C, Laje G, Blanco C, et al. National trends in the outpatient diagnosis and treatment of bipolar disorder in youth. Arch Gen Psychiatry. 2007;64(9):1032-1039. PubMed doi:10.1001/archpsyc.64.9.1032

4. Kendell RE, Cooper JE, Gourlay AJ, et al. Diagnostic criteria of American and British psychiatrists. Arch Gen Psychiatry. 1971;25(2):123-130. PubMed doi:10.1001/archpsyc.1971.01750140027006

5. Stoll AL, Tohen M, Baldessarini RJ, et al. Shifts in diagnostic frequencies of schizophrenia and major affective disorders at six North American psychiatric hospitals, 1972-1988. Am J Psychiatry. 1993;150(11):1668-1673. PubMed

6. Ghaemi SN, Sachs GS, Chiou AM, et al. Is bipolar disorder still underdiagnosed? are antidepressants overutilized? J Affect Disord. 1999;52(1-3):135-144. PubMed doi:10.1016/S0165-0327(98)00076-7

7. Deltito J, Martin L, Riefkohl J, et al. Do patients with borderline personality disorder belong to the bipolar spectrum? J Affect Disord. 2001;67(1-3):221-228. PubMed doi:10.1016/S0165-0327(01)00436-0

8. MacKinnon DF, Pies R. Affective instability as rapid cycling: theoretical and clinical implications for borderline personality and bipolar spectrum disorders. Bipolar Disord. 2006;8(1):1-14. PubMed doi:10.1111/j.1399-5618.2006.00283.x

9. Goldberg JF, Garno JL, Callahan AM, et al. Overdiagnosis of bipolar disorder among substance use disorder inpatients with mood instability. J Clin Psychiatry. 2008;69(11):1751-1757. PubMed doi:10.4088/JCP.v69n1110

10. Atmaca M, Ozler S, Topuz M, et al. Attention deficit hyperactivity disorder erroneously diagnosed and treated as bipolar disorder. J Atten Disord. 2009;13(2):197-198. PubMed doi:10.1177/1087054709332407

11. Ghaemi SN. Toward a Hippocratic psychopharmacology. Can J Psychiatry. 2008;53(3):189-196.PubMed

12. Perlis RH, Uher R, Ostacher M, et al. Association between bipolar spectrum features and treatment outcomes in outpatients with major depressive disorder. Arch Gen Psychiatry. 2011;68(4):351-360. PubMed doi:10.1001/archgenpsychiatry.2010.179

13. Ghaemi SN, Ko JY, Goodwin FK. "Cade’s disease" and beyond: misdiagnosis, antidepressant use, and a proposed definition for bipolar spectrum disorder. Can J Psychiatry. 2002;47(2):125-134.PubMed

14. Cassano GB, Rucci P, Benvenuti A, et al. The role of psychomotor activation in discriminating unipolar from bipolar disorders: a classification-tree analysis. J Clin Psychiatry. 2012;73(1):22-28. PubMed doi:10.4088/JCP.11m06946

Submitted: March 5, 2012; accepted March 5, 2012.

Corresponding author: Joseph F. Goldberg, MD, 128 East Ave, Norwalk, CT 06851 ([email protected]).

Drug name: divalproex (Depakote and others).

Author affiliations: Department of Psychiatry, Mount Sinai School of Medicine, New York, New York; and Affective Disorders Research Program, Silver Hill Hospital, New Canaan, Connecticut.

Potential conflicts of interest: Dr Goldberg has served as a consultant to Dey and Grunenthal; has received honoraria from Eli Lilly; and has been a member of speakers/advisory boards for AstraZeneca, Eli Lilly, Merck, Sunovion, and Dey.

Funding/support: None reported.

J Clin Psychiatry 2012;73(4):443-444 (doi:10.4088/JCP.12com07760)

© Copyright 2012 Physicians Postgraduate Press, Inc.