“Cade’s Disease” and Beyond: Misdiagnosis, Antidepressant Use, and a Proposed Definition for Bipolar Spectrum Disorder

S Nassir Ghaemi, MD1, James Y Ko, AB2, Frederick K Goodwin, MD3

The diagnosis and treatment of bipolar disorder (BD) has been inconsistent and frequently misunderstood in recent years. To identify the causes of this problem and suggest possible solutions, we undertook a critical review of studies concerning the nosology of BD and the effects of antidepressant agents.

Both the underdiagnosis of BD and its frequent misdiagnosis as unipolar major depressive disorder (MDD) appear to be problems in patients with BD. Underdiagnosis results from clinicians’ inadequate understanding of manic symptoms, from patients’ impaired insight into mania, and especially from failure to involve family members or third parties in the diagnostic process.

Some, but by no means all, of the underdiagnosis problem may also result from lack of agreement about the breadth of the bipolar spectrum, beyond classic type I manic-depressive illness (what Ketter has termed “Cade’s Disease”). To alleviate confusion about the less classic varieties of bipolar illness, we propose a heuristic definition, “bipolar spectrum disorder.” This diagnosis would give greater weight to family history and antidepressant-induced manic symptoms and would apply to non-type I or II bipolar illness, in which depressive symptom, course, and treatment response characteristics are more typical of bipolar than unipolar illness.

The role of antidepressants is also controversial. Our review of the evidence leads us to conclude that there should be less emphasis on using antidepressants to treat persons with this illness.

(Can J Psychiatry 2002;47:125–134)

Key Words: bipolar disorder, manic-depressive illness, antidepressants, diagnosis, treatment, nosology, mood stabilizers

Résumé : La « maladie de Cade » et au-delà : erreur de diagnostic, utilisation des antidépresseurs et proposition d’une définition du trouble du spectre bipolaire

Misdiagnosis and consequent mistreatment of bipolar disorder (BD) are potentially life-threatening issues for patients, yet in contemporary practice there exist several potential inadequacies in the diagnosis of BD. A synergy of cultural and clinical factors results in its common misdiagnosis. Baldessarini has noted that the culture of modern medical practice appears to be guided by a “pharmacocentric view of the world” (1). This is to say that the rate of diagnosis of an illness, as well as scientific interest in a particular disease, is often increased following the introduction of new medications for it (2). Thus, the sheer number of antidepressants available may influence the diagnosis of unipolar major depression, often to the detriment of BD diagnosis. This may be exacerbated by the fact that virtually all patients with BD experience long periods of depression (3), which usually causes more subjective distress than does mania. As such, patients are more likely to seek help for depression than for mania. Given a growing awareness of the need to diagnose and treat depression, increases in depression research, and a rise in public interest, the underdiagnosis of BD is an understandable result. Further, limitations of the DSM-IV nosology may impede the diagnosis of BD, because the DSM-IV has rather broad criteria for MDD and narrow criteria for BD. Pharmacocentric logic may have helped to perpetuate the underdiagnosis problem, but it could also steer the mental health community in a new direction, with the emergence of a new generation of mood-stabilizing agents derived from novel anticonvulsants and atypical neuroleptic agents.

Underdiagnosis and Misdiagnosis of Classic Type I BD (“Cade’s Disease”)

Empirical Evidence

Even standard mania, bipolar I disorder, is prone to underdiagnosis, as reviewed below. Ketter has suggested using the term “Cade’s disease” in honour of John Cade, the discoverer of lithium, to refer to classic, lithium-responsive, type I manic-depressive illness (Terence Ketter, 2002, personal communication). The Epidemiologic Catchment Area (ECA) study, upon which much of the conventional wisdom regarding the prevalence of BD is based, reported that mania and hypomania occur in 1.2% of the general population over a lifetime (4). This prevalence is about one-fourth that of major depression and somewhat higher than the prevalence of schizophrenia.

The 4 to 1 ratio of unipolar to bipolar disorder has been doubted by researchers specializing in BD. In a comprehensive review of the epidemiological literature, Goodwin and Jamison (3) estimated a 2 to 1 ratio of unipolar to bipolar disorder; in an epidemiologic study among the Amish, the observed ratio was 1 to 1 (5).

Follow-up studies on the diagnostic validity of the ECA study cast further doubt upon its findings. Anthony and associates found quite poor interrater agreement (kappa values) for Axis I psychiatric diagnoses in 1 of 5 cities in the ECA study (the Baltimore site). They used a gold standard of clinical reappraisal based on DSM-III criteria to reassess diagnoses made by the lay researchers using the Diagnostic Interview Schedule (DIS; a research diagnostic interview designed for use in the ECA [4,6]). In the ECA study, no kappa value exceeded 0.35, although conventionally acceptable kappas for epidemiological studies are generally above 0.70. Further, the kappa for mania was an abysmal 0.05. As such, in only 5% of cases in this sample were the data used in the ECA study confirmed by clinicians experienced in diagnosing mania. Helzer and colleagues reported similar findings at the St Louis ECA site (7). These problems with the ECA data were further highlighted by Dohrenwend (8). Robins, the developer of the DIS, also expressed concern about those findings (9). It is quite possible that the ECA data have contributed to the neglect of research on BD.

The Iowa 500 project (10) reported that consulting hospital charts resulted in increased diagnosis of mania in relatives of psychiatric probands. Surprisingly, even the most rigorous research-based clinical interview (mean duration, 102 minutes) underestimated the incidence of mania in relatives by almost one-third (morbidity risk 1.9 [SD 1.07] excluding hospital charts, compared with 5.3 [SD 1.73] including hospital charts). It is clear that many patients forget or deny past hospitalization for mania in the course of clinical interviews. In the absence of external sources of information (as was the case in the ECA study), the diagnosis of BD is probably underestimated. The frequency of BD misdiagnosis has been assessed in a few recent empirical studies. In 1 survey, 48% of the members of the National Depressive and Manic Depressive Association (NDMDA) reported that they had seen 3 or more mental health professionals before receiving a diagnosis of BD (11); 57% of the members received another major psychiatric diagnosis during that time most commonly unipolar major depressive disorder (MDD) (44%), followed by schizophrenia (34%). On average, it took 8 years of clinical treatment before the diagnosis of BD was correctly made. However, the results should be interpreted with some caution, because it is possible that people with poor treatment experiences are more likely to gravitate toward the NDMDA. Also, because the data are based on a self-report survey rather than a clinical interview, they may not be generalizable.