Psychiatric Annals

CLINICAL SUBTYPING OF SCHIZOPHRENIA 

Heterogeneity, Subtypes, and Longitudinal Course in Schizophrenia

Wayne S Fenton, MD

Abstract

A 28-year-old man has learned to adapt to nearly continuous auditory hallucinations by reminding himself that they are "really" his own thoughts. His condition has improved significantly with medication, allowing him to graduate with honors from a local university and secure admission to a prestigious business school.

A 52-year-old woman has resided in a board and care home for more than 15 years. Every day she sits on the porch smoking cigarettes and drinking coffee. When spoken to, she responds only after a long pause with a twoor three-word answer. She offers no complaints. She bathes twice a week only when prompted and supervised.

A middle-aged man arrives by bus at the gate of the White House in Washington, DC. He is obviously distraught, demanding to speak with the President to warn him of the imminent threat to national security from "space beings" who have been using electrical energy to read his brain wave patterns.

Although these three individuals are very different from one another, they are considered to be suffering from the same psychiatric disorder. Individuals with schizophrenia differ markedly from one another not only in symptoms and disabilities, but also in predisposing risk factors, age and type of illness onset, course and progression of illness, response to treatment, and associated biologic abnormalities. One approach to reconciling the clinical heterogeneity of schizophrenia has involved efforts to define subtypes.

Are schizophrenia subtypes valid? Despite nearly a century of research, we do not yet know whether schizophrenia is a single disease entity or a diverse group of etiologically distinct conditions.1 Andreasen2 posits a unitary "misconnection syndrome" as the final result of accumulated risk factors and the common origin of diverse clinical presentations of schizophrenia. Other investigators believe that pathophysiologic heterogeneity is more likely.3 In the absence of knowledge of etiology, the validity of schizophrenia subtypes must be measured by their utility in identifying patients sharing common risk factors or biologic vulnerability markers, and in predicting course, response to treatment, outcome, or associated familial psychopathology.4

This article provides a brief historical review of two influential approaches to subtyping: the classic schizophrenia subtypes (paranoid, hebephrenic, and undifferentiated) and the more recent deficit-non-deficit subtype distinction. Specifically, data from the Chestnut Lodge Schizophrenia Subtype Study evaluating the temporal stability and predictive validity of these subtypes are described.

BACKGROUND

Classic Subtypes

Throughout the 19th century, European physicians used a confusing array of nosologies to describe forms of insanity that occurred in young persons and often progressed to apathy, disorganization, and dementia.5 Sander6 described paranoid psychosis in the 1860s. In the 1870s, Hecker7 described hebephrenia as a disease of adolescence leading to silly behavior and deterioration. Kahlbaum8 described catatonia as a stupor without evidence of gross neurologic disease. In his 1896 textbook, Kraepelin9 used two clinical features - youthful onset and progressive deterioration - to subsume the syndromes of paranoia, hebephrenia, and catatonia under the term dementia praecox, coined 50 years earlier by Morel.10 Kraepelin's intent was to separate the self-limiting, periodic, and affective processes (manic-depressive illness) from the chronic and progressive ones (dementia praecox).

With further observation, Kraepelin recognized that the data did not always fit his theory. Paranoia often developed slowly in later life and only sometimes progressed to dementia. In the sixth edition of his textbook,11 these patients were referred to as having dementia praecox, paranoid type. In his description of "the group of schizophrenias," Bleuler12 included the subtype simple schizophrenia, a gradual deterioration unaccompanied by the acute episodes, delusions, and hallucinations seen with other subtypes. Kraepelin13 incorporated the subtype dementia simplex into the eighth edition of his textbook.

The four classic subtypes of…

A 28-year-old man has learned to adapt to nearly continuous auditory hallucinations by reminding himself that they are "really" his own thoughts. His condition has improved significantly with medication, allowing him to graduate with honors from a local university and secure admission to a prestigious business school.

A 52-year-old woman has resided in a board and care home for more than 15 years. Every day she sits on the porch smoking cigarettes and drinking coffee. When spoken to, she responds only after a long pause with a twoor three-word answer. She offers no complaints. She bathes twice a week only when prompted and supervised.

A middle-aged man arrives by bus at the gate of the White House in Washington, DC. He is obviously distraught, demanding to speak with the President to warn him of the imminent threat to national security from "space beings" who have been using electrical energy to read his brain wave patterns.

Although these three individuals are very different from one another, they are considered to be suffering from the same psychiatric disorder. Individuals with schizophrenia differ markedly from one another not only in symptoms and disabilities, but also in predisposing risk factors, age and type of illness onset, course and progression of illness, response to treatment, and associated biologic abnormalities. One approach to reconciling the clinical heterogeneity of schizophrenia has involved efforts to define subtypes.

Are schizophrenia subtypes valid? Despite nearly a century of research, we do not yet know whether schizophrenia is a single disease entity or a diverse group of etiologically distinct conditions.1 Andreasen2 posits a unitary "misconnection syndrome" as the final result of accumulated risk factors and the common origin of diverse clinical presentations of schizophrenia. Other investigators believe that pathophysiologic heterogeneity is more likely.3 In the absence of knowledge of etiology, the validity of schizophrenia subtypes must be measured by their utility in identifying patients sharing common risk factors or biologic vulnerability markers, and in predicting course, response to treatment, outcome, or associated familial psychopathology.4

This article provides a brief historical review of two influential approaches to subtyping: the classic schizophrenia subtypes (paranoid, hebephrenic, and undifferentiated) and the more recent deficit-non-deficit subtype distinction. Specifically, data from the Chestnut Lodge Schizophrenia Subtype Study evaluating the temporal stability and predictive validity of these subtypes are described.

BACKGROUND

Classic Subtypes

Throughout the 19th century, European physicians used a confusing array of nosologies to describe forms of insanity that occurred in young persons and often progressed to apathy, disorganization, and dementia.5 Sander6 described paranoid psychosis in the 1860s. In the 1870s, Hecker7 described hebephrenia as a disease of adolescence leading to silly behavior and deterioration. Kahlbaum8 described catatonia as a stupor without evidence of gross neurologic disease. In his 1896 textbook, Kraepelin9 used two clinical features - youthful onset and progressive deterioration - to subsume the syndromes of paranoia, hebephrenia, and catatonia under the term dementia praecox, coined 50 years earlier by Morel.10 Kraepelin's intent was to separate the self-limiting, periodic, and affective processes (manic-depressive illness) from the chronic and progressive ones (dementia praecox).

With further observation, Kraepelin recognized that the data did not always fit his theory. Paranoia often developed slowly in later life and only sometimes progressed to dementia. In the sixth edition of his textbook,11 these patients were referred to as having dementia praecox, paranoid type. In his description of "the group of schizophrenias," Bleuler12 included the subtype simple schizophrenia, a gradual deterioration unaccompanied by the acute episodes, delusions, and hallucinations seen with other subtypes. Kraepelin13 incorporated the subtype dementia simplex into the eighth edition of his textbook.

The four classic subtypes of schizophrenia (paranoid, hebephrenic, catatonic, and undifferentiated) have figured in nearly every public classification of schizophrenia of the 20th century.14'15

Deficit Subtype

The distinction between positive and negative schizophrenia is ubiquitous historically, and no single person can lay claim to its original formulation.16 In the 19th century, Iackson speculated that negative symptoms came from diseaseinduced loss of higher mental functioning, and positive symptoms from release phenomena secondary to this loss of higher control.17 Kraepelin described "two principa] disorders that characterize the malady (dementia praecox)" that map onto the positive-negative distinction: "a weakening of those emotional activities which permanently form the mainspring of volition and . . . the loss of the inner unity of activities of intellect, emotion, and volition."13 Bleuler may have had a similar dichotomy in mind in his distinction between fundamental and accessory symptoms.12,18 Strauss et al.19 explicitly hypothesized that positive and negative symptoms represented distinct pathophysiologies. Soon thereafter, Crow20 postulated two syndromes (type 1 and type 2 schizophrenia) characterized respectively by good premorbid functioning, acute onset, and positive symptoms responsive to treatment, and poor premorbid functiorring, gradual onset, negative symptoms resistant to treatment, and intellectual and behavioral deterioration.

Although positive and negative schizophrenia were initially regarded as existing at opposite ends of a continuum,21 subsequent studies indicated that many patients demonstrated both types of symptoms.22

Recognizing (1) the relative independence of positive, negative, and disorganized symptoms as separable symptom domains in schizophrenia and (2) the possibility that negative symptoms can be transient and /or secondary to exogenous factors such as depression, anxiety, demoralization, or overmedication, Carpenter et al.23 defined the deficit syndrome as a subtype of schizophrenia characterized by primary enduring negative symptoms. As indicated in Table 1, the deficit syndrome subtype is diagnosed when secondary causes of negative symptoms have been ruled out and negative symptoms have endured for more than 1 year. Defined in this way, the deficit concept attempts to operationalize the "weakening of those emotional activities which permanently form the mainspring of volition" described by Kraepelin.13

SUBTYPES, COURSE, AND OUTCOME IN SCHIZOPHRENIA

To explore the validity of schizophrenia subtypes in denning groups of patients with distinctive courses of illness and outcome trajectories, detailed medical records from a unique cohort of patients treated at Chestnut Lodge Hospital between 1955 and 1975 were used. These patients were retrospectively diagnosed according to modern diagnostic and schizophrenia subtype criteria. Index admission subtype diagnoses were obtained for 187 patients in the follow-up study with a research diagnosis of schizophrenia. In addition, sufficiently detailed records from previous hospitalizations were available in the charts of 125 (67%) of the patients to allow subtype assignment at the time of an earlier (usually the first) hospitalization. This admission occurred an average of 4.5 years before index admission. Follow-up data describing the longitudinal course of disease and outcome were obtained by means of interviews with patients, their families, or both an average of 23 years after index admission.

Table

TABLE 1Diagnostic Criteria for the Deficit Syndrome of Schizophrenia

TABLE 1

Diagnostic Criteria for the Deficit Syndrome of Schizophrenia

The combining of independently collected first admission (mean year 1954), index admission (mean year 1958), and follow-up (mean year 1981) data allowed construction of the natural history of scHzophrenia and its subtypes during a period of several decades. As described previously, clinical variables were selected as significant elements of the natural history of schizophrenia and grouped into eight natural history domains: genetic predisposition, developmental predisposition, premorbid functioning, features of illness onset, early course of illness, subtype stability, long-term functional outcome, and suicide risk.24'25 Patients with different schizophrenia subtype diagnoses could then be compared across variables in each natural history domain. The utilities of both the classic subtypes and the deficit-non-deficit distinction in defining groups of patients with similar natural histories of illness were evaluated.

Classic Subtypes

Similar to the DSM-III-R,26 the research diagnoses employed for classic schizophrenia subtypes were hierarchical in this study. Hebephrenia (disorganized subtype) was defined by disorganized thought, bizarre behavior, and flat or inappropriate affect. Paranoid schizophrenia was characterized by delusions or hallucinations and the absence of symptoms sufficient to meet entena for hebephrenia. Patients with undifferentiated schizophrenia failed to meet criteria for either specific subtype. Thus, patients with hebephrenia could meet criteria for paranoid schizophrenia, but the converse was not true. With these definitions, significant differences in the longitudinal profiles of the classic schizophrenia subtypes were discernable. Overall, 78 (42%) of the patients were diagnosed as having paranoid schizophrenia, 26 (14%) as having hebephrenia, and 83 (44%) as having undifferentiated schizophrenia.

Paranoid schizophrenia had an older age of onset and often developed rapidly in patients with good functioning premorbidly. The early course of illness was most often intermittent during the first 5 years. Exacerbations and remissions appeared responsive to stresses and life events, and the likelihood of an eventual fair to good outcome was nearly 50% despite a relatively high (10%) risk of suicide. Hebephrenia, in contrast, often developed early and insidiously. It was associated with poor functioning premorbidly and a higher frequency of a family history of mental illness. The early course of illness was often continuous and remissions, when present, were rarely complete. The illness appeared unreactive to life events and in nearly 90% of the cases resulted in permanent disability across all outcome domains. The clinical course of undifferentiated schizophrenia was one of early and insidious onset of illness and poor functioning premorbidly; in most of the cases, the illness appeared to be a gradual extension of marginal, odd, or eccentric premorbid personality functioning. The illness was often continuous with limited remissions, but outcome was variable. Complete recovery was tesa common than in paranoid schizophrenia, and deterioration and permanent disability were less common than in hebephrenia. Symptomatology was often "quiet" rather than flagrant, with a stable degree of disability maintained.

Deficit-Non-Deficit Subtype

The subtype diagnosis of deficit syndrome requires the enduring présence of two or more negative symptoms (restricted affect, anhedonia, poverty of speech, diminished sense of purpose, and a^minished social drive). These symptoms must be judged as primary (ie, not fully accounted for by depression, anxiety, the effect of neuroleptic medication, or environmental deprivation).

Patients from the Chestnut Lodge cohort were retrospectively rediagnosed as having deficit (N = 46) and non-deficit (N = 141) forms of schizophrenia, and these subtypes were compared across parameters of natural history of illness. The data revealed that prior to illness onset, deficit patients were less likely to be married; however, few other differences emerged. Illness onset was often insidious for deficit patients, and once established, illness was nearly always continuous with few remissions and little reactivity to life events. Negative symptoms were often present at illness onset among deficit patients and increased in severity during the first 5 years of illness. Once established, the deficit syndrome was highly stable, and nearly always associated with poor outcome and permanent disability. The data supported the validity of the deficit concept as a subtype of schizophrenia with a relatively distinct natural history, and perhaps as the subtype most associated with progressive functional impairment.27 Furthermore, even without exposure to neuroleptic medications, one-third of the patients with the deficit syndrome were observed to have tardive dyskinesia-like movement disorder.28

Subtype Overlap and Progression

An analysis of the classic and deficit subtypes demonstrated partial, but not complete, overlap. Among deficit patients, few (9%) were paranoid, many (39%) were hebephrenic, and most (52%) were undifferentiated. Conversely, most (70%) of the hebephrenic patients, but few (5%) of the paranoid patients, met criteria for the deficit syndrome.

The availability of subtype diagnoses at both first and index admissions separated by approximately 5 years allowed an assessment of subtype progression during the early course of schizophrenia. The classic subtypes were moderately stable between first admission and index admission, but approximately one-third of the patients changed subtype during this time. When changes occurred, they were in the direction of an increasing proportion of patients being diagnosed as having hebephrenia or undifferentiated subtypes. The deficit syndrome was relatively rare at first admission (10%), but not uncommon (25%) at index admission. Once established, the deficit syndrome was rather stable: most (10 of 12; 83%) of the patients with deficit syndrome at first admission retained this subtype. Thus, when change occurred, it was usually in the direction of nondeficit to deficit. Taken together, the data suggest that for some patients with schizophrenia, subtypes evolve over time in the direction of less to more severe.29

Table 2 summarizes the association of classic schizophrenia subtypes and the deficit syndrome with illness onset, middle course, and outcome.30 Although subtypes reduce illness heterogeneity, they do not eliminate it, particularly for the relatively large number of patients characterized as undifferentiated or non-deficit.

CONCLUSION

Prediction of long-term outcome is one element of validity in the definition of meaningful subtypes of schizophrenia. Retained throughout the 20th century, classic subtypes of schizophrenia are categoric, based on patients' predominant clinical symptoms. These subtypes show moderate temporal stability and are more useful as predictors of outcome after several years than they are early in the illness. Because an individual patient's subtype is likely to differ at different phases of illness, it is not surprising that studies in other domains suggest inconsistent validity for the classic subtypes in relation to familial aggregation,31 neuropsychological functioning,32 cerebral metabolism,33 and other external validators.34

Table

TABLE 2Course and Subtypes of Schizophrenia in the Chestnut Lodge Follow-up Cohort

TABLE 2

Course and Subtypes of Schizophrenia in the Chestnut Lodge Follow-up Cohort

The concept of the deficit syndrome is based on a view of the psychopathology of schizophrenia consisting of at least three semi-independent symptom domains: psychosis (delusions and hallucinations), disorganized symptoms (thought disorder and bizarre behavior), and deficit symptoms.35 Individual patients may show symptoms from one, two, or all three domains. Different neural circuits may be involved in the pathophysiology of these symptom domains.36'37 The deficit syndrome as a categoric subtype is diagnosed based on the presence of primary enduring negative symptoms, irrespective of the presence or absence of other symptom domains.

The deficit syndrome shows considerable stability. Approximately 10% of patients demonstrate the deficit syndrome at illness onset, and another 15% develop the syndrome during the first several years of illness.27 Once established, the deficit syndrome rarely remits and is associated with a high probability of long-term functional disability.27 Beyond subtype stability and predictive validity within schizophrenia, the deficit syndrome has been associated with functional and structural imaging variables,38,39 neurophysiologic and neurocognitive measures,40-42 oculomotor dysfunction,43-44 and environmental risk factors.45,46

If the symptomatic heterogeneity of schizophrenia is a reflection of independent underlying pathophysiologies, schizophrenia subtypes validated by biologic and illness course variables will be useful in assembling homogeneous patient samples for testing etiologic hypotheses.37 Under these circumstances, comparisons of patients with and without the domain of psychopathology under study will be more informative than broad comparisons of patients with schizophrenia and normal control subjects.

Consistent with the association of the deficit syndrome with more pervasive neurophysiologic deficits, some evidence indicates a poorer response to psychosocial treatment for patients with this illness.47 In terms of a pharmacologic response, however, superior reduction of positive symptoms has been found with clozapine for both deficit and non-deficit patients.48,49 Thus, considerations beyond subtype per se are required to predict treatment response. As discussed in this issue of Psychiatric Annals, subtyping schizophrenia based on associated clinical features may be of particular value in selecting optimal pharmacologic interventions.

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49. Rosenheck R, Dunn L, Peszke M, et al. Impact of clozapine on negative symptoms and on the deficit syndrome in refractory schizophrenia: Department of Veterans Affairs Cooperative Study Group on Clozapine in Refractory Schizophrenia. Am J Psychiatry. 1999;156:88-93.

TABLE 1

Diagnostic Criteria for the Deficit Syndrome of Schizophrenia

TABLE 2

Course and Subtypes of Schizophrenia in the Chestnut Lodge Follow-up Cohort

10.3928/0048-5713-20001001-07

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