Subtypes of Mania Determined by Grade of Membership Analysis Frederick Cassidy, M.D., Carl F. Pieper, M.P.H., D.P.H., and Bernard J. Carroll, M.B., Ph.D. Classical descriptions of mania subtypes extend back to hostility and paranoia, and the complete absence of euphoria Kraepelin; however, in marked contrast to the study of or humor. The second mixed mania Pure Type displayed a depression subtypes, validation of mania subtypes by true, incongruous mixture of affects: periods of classical multivariate statistical methods has seldom been attempted. manic symptoms with euphoria, elation, humor, We applied Grade of Membership (GOM) analysis to the grandiosity, psychosis, and psychomotor activation, rated clinical features of 327 inpatients with DSM-III-R switching frequently to moderately depressed mood with mania diagnoses. GOM is a type of latent structure pressured anxiety and irritability. This multivariate multivariate analysis, which differs from others of this type analysis validated classical clinical descriptions of the major in making no a priori distributional assumptions about subtypes of mania. Two distinct forms of mixed manic groupings. We obtained 5 GOM Pure Types with good face episodes were identified. DSM-III-R criteria did not reliably validity. The major Kraepelinian forms of “hypomania,” identify either of these two natural groups of mixed bipolar “acute mania,” “delusional mania,” and “depressive or patients. As occurs in depression, this clinical heterogeneity anxious mania” were validated. The major new finding is of of mania may influence response to drug treatments. two mixed mania presentations, each with marked lability of [Neuropsychopharmacology 25:373–383, 2001] mood. The first of these displayed a dominant mood of severe © 2001 American College of Neuropsychopharmacology. depression with labile periods of pressured, irritable Published by Elsevier Science Inc. KEY WORDS: Mania; Subtypes; Mixed states; Kraepelin; hilarious mania (Robertson 1890). Weygandt suggested Diagnosis; Grade of membership classification dividing manic–depressive episodes into manic, de- pressed, and mixed states (Weygandt 1901). Kraepelin A century ago, following the acceptance of manic–depres- also divided manic–depressive disorder into manic, de- sive illness as a nosologic construct, the subtyping of pressed, and mixed states (Kraepelin 1921). He went on manic episodes was first addressed. Robertson proposed to develop an elaborate nosology of three manic sub- two varieties of acute mania: furious or raging mania and types (hypomania, acute mania, and delirious mania) and no fewer than six mixed subtypes (depressive or anxious mania, excited depression, mania with poverty From the Duke-Umstead Bipolar Disorders Program (FC), of thought, manic stupor, depression with flight of Department of Psychiatry and Behavioral Sciences, Duke Univer- sity, Durham, North Carolina; Center for the Study of Aging and ideas, and inhibited mania). Most of these mixed or Human Development (CFP), Department of Community and Fam- transitional manic–depressive states were predicated ily Medicine, Duke University Medical Center, Durham, North on varying admixtures of three basic elements: mood, Carolina; Pacific Behavioral Research Foundation (BJC), Carmel, California, USA psychic activity, and motor activity (Sims 1988; Good- Address correspondence to: Dr. F. Cassidy, Duke-Umstead Bipo- win and Jamison 1990). lar Disorders Program, Box 3414 DUMC, Durham, NC 27710. Tel.: The study of manic subtypes then remained essen- 919-575-7801; Fax: 919-575-4069; E-mail: [email protected] Received August 8, 2000; revised November 17, 2000; accepted tially dormant until 1969, when Winokur, Clayton, and January 8, 2001. Reich (Winokur et al. 1969) reported on the high fre- NEUROPSYCHOPHARMACOLOGY 2001–VOL. 25, NO. 3 © 2001 American College of Neuropsychopharmacology Published by Elsevier Science Inc. 0893-133X/01/$–see front matter 655 Avenue of the Americas, New York, NY 10010 PII S0893-133X(01)00223-8 374 F. Cassidy et al. NEUROPSYCHOPHARMACOLOGY 2001–VOL. 25, NO. 3 quency of depressive symptoms in mania. They set an external variables thought to be related, but not causative arbitrary standard of diagnostic criteria for mixed bipo- of the internal structures (e.g., demographic characteris- lar episodes (corresponding to Kraepelin’s anxious or tics). Thus, individual variables may be more or less re- depressive mania) by requiring the full depressive as lated to a pure type, and individual patients may demon- well as the full manic syndrome. Without clear valida- strate partial membership in more than one group. The tion, that standard was adopted by the American Psy- statistically defined symptom profiles are termed Pure chiatric Association in DSM-III, DSM-III-R, and DSM-IV. Types. As recently discussed by Nurnberg et al. (1999), We and others have called attention to problems with the two Pure Types may represent different disease processes DSM criteria for mixed bipolar episode in recent publica- or the same disease process that is expressed differently tions (McElroy et al. 1992; Cassidy et al. 1997). The other because of different patient attributes or different stages manic and mixed bipolar subtypes proposed by Kraepe- in the progression of a disease. By maximum likelihood lin were never addressed in the DSM classifications. estimates, complementary coefficients of loading by sub- In marked contrast to the intensive study and classi- jects on the Pure Types are derived. The subject’s degree fication of depressive episodes (Kendell 1976), the sub- or grade of membership in a Pure Type is denoted by a typing of manic episodes by multivariate statistical coefficient of association, gik, which defines the degree to methods has been generally neglected. A few years af- which the ith person belongs to the kth Pure Type. This co- ter publication of the now classic volume of Winokur, efficient may range from 0 to 1.0. A subject may be a Clayton, and Reich (1969), some investigators proposed member of one Pure Type exclusively but more com- a statistical typology of euphoric-grandiose (EG) and monly will have partial membership in more than one paranoid-destructive (PD) mania (Beigel and Murphy Pure Type. Each internal variable used to determine the 1971; Murphy and Beigel 1974). By factor analysis, de- GOM Pure Types has a calculated coefficient, kjl that de- pressive symptoms were associated with the PD symp- scribes each of the k Pure Types in terms of the probabil- toms. This view ignored the work of Winokur, Clayton, ity that it will have the lth response to the jth variable. and Reich (1969),, but it became quite influential and These coefficients also lie between 0 and 1.0. After the found its way into many textbooks. As we have previ- symptom profiles representing the GOM Pure Types are ously discussed (Cassidy et al. 1998a), the clinical sam- defined, subjects are then allocated to GOM groups ac- ples used in those studies were inadequate. cording to their predominant gik loadings, as described in Our own factor analysis of symptoms rated in 237 Methods. To recapitulate, a GOM Pure Type is a symptom manic patients by the Scale for Manic States (SMS, Cassidy profile; whereas, a GOM group is a subset of the cohort of et al. 1998a, 1998b), did not confirm the EG and PD factors subjects. of Beigel, Murphy, and Double (Beigel and Murphy 1971; Murphy and Beigel 1974; Double 1990). Rather, we found five distinct, orthogonal factors that represent key clinical METHODS domains of mania; namely, (1) depression and dysphoric mood; (2) psychomotor acceleration; (3) psychosis; (4) he- We studied 327 adult inpatients at John Umstead Hospi- donic activation; and (5) irritable aggression. The first fac- tal (JUH), a state psychiatric hospital serving 16 counties tor comprised the symptoms depressed mood, guilt in north-central North Carolina. All met DSM-III-R crite- feelings, anxiety, lability, and suicidal tendency. This ria and carried clinical diagnoses of bipolar disorder, dysphoria factor was quite distinct from the factor com- manic or mixed. In most cases, the manic episode led to prising irritable aggression. The distribution of scores on involuntary commitment to inpatient status. Clinical fea- the dysphoria factor was bimodal, which suggested that a tures were evaluated with the Scale for Manic States distinct group of mixed manic episodes could be identi- (SMS, Cassidy et al. 1998b). This scale comprises 15 clas- fied. Dilsaver et al. (1999) confirmed our key findings that sic features of mania and five features relevant to mixed paranoia and aggression comprise a factor distinct from bipolar states. Each sign or symptom is rated from 0 to 5 depressed mood in manic patients and that the distribu- in severity, with descriptive anchor statements provided tion of scores on the depression factor is bimodal. for scores of 1,3, and 5. Ratings were completed based on As we earlier proposed (Cassidy et al. 1998b) we now patient interview, chart review, and observation on the approach the issue of mania subtypes with a powerful ward. Further details of the rating procedure and on the multivariate statistical technique, Grade of Membership validity and reliability of the SMS are presented else- (GOM) analysis. A general description of GOM and its where (Cassidy et al. 1998a, 1998b). associated principles is available (Swartz et al. 1986). Briefly, GOM is a type of latent structure analysis, but dif- Study Cohort ferent from others of this type in making no a priori dis- tributional assumptions about groupings. Rather than as- The 327 patients included 156 males and 171 females. sume discrete latent classes, GOM assumes “fuzzy sets” There were 284 (86.9%) meeting DSM-III-R criteria for bi- for which the degrees of membership can be specified polar disorder, manic episode, and 43 (13.1%) diagnosed both for internal variables (signs and symptoms) and for bipolar disorder, mixed episode. The mean age was 42.2, NEUROPSYCHOPHARMACOLOGY 2001–VOL. 25, NO. 3 Mania Determined by Grade of Membership Analysis 375 SD 14.0 years, with a range from 18 to 82.