 |
|
Relationship Between Positive and Negative Symptoms of Schizophrenia and Schizotypal Symptoms in Nonpsychotic Relatives
Ayman Fanous, MD;
Charles Gardner, PhD;
Dermot Walsh, MB,FRCPI;
Kenneth S. Kendler, MD
Arch Gen Psychiatry. 2001;58:669-673.
ABSTRACT
| |
Background Continuous rather than categorical measures of psychopathology may provide greater statistical power to detect susceptibility loci for schizophrenia. However, it has not been established that the dimensions of schizophrenic symptomatology and personality traits in nonpsychotic individuals share etiological factors. We therefore sought to clarify the relationship between positive and negative symptoms of schizophrenic probands and dimensions of schizotypy in their first-degree relatives.
Methods In the Roscommon Family Study, we examined the ability of positive and negative symptoms in probands to predict 7 factors of schizotypy in nonpsychotic relatives using regression analysis. These consisted of positive, negative, and avoidant symptoms; odd speech; suspicious behavior; social dysfunction; and symptoms of borderline personality disorder. We examined 3 proband groups: schizophrenia (n = 127); schizophrenia, simple schizophrenia, and schizoaffective disorder (n = 178); and all nonaffective psychoses (n = 216), and their nonpsychotic relatives (n = 309, 477, and 584, respectively).
Results Positive symptoms in all nonaffective psychoses probands predicted positive schizotypy ( = 0.1972, P = .0004), social dysfunction ( = 0.0719, P = .0489), and borderline personality disorder symptoms ( = 0.1327, P = .0084) in relatives, while negative symptoms predicted negative schizotypy ( = 0.2069, P = .0002), odd speech ( = 0.2592, P = .0001), suspicious behavior ( = 0.2749, P = .0001), and social dysfunction ( = .2398, P = .0002). Proband negative symptoms and borderline personality disorder symptoms in relatives in the schizophrenia, simple schizophrenia, and schizoaffective disorder group were inversely related ( = -0.1185, P = .05).
Conclusions Positive and negative symptoms in schizophrenia predict corresponding schizotypal symptoms in relatives. This provides evidence that these schizophrenic symptom factors (1) are etiologically distinct from each other and (2) occur on an etiological continuum with their personality-based counterparts.
INTRODUCTION
PSYCHIATRISTS from a variety of theoretical perspectives, including Kraepelin1 and Bleuler,2 have noted that family members of patients with schizophrenia often have odd personality features, including social isolation, poor interpersonal relationships, unusual thought content, and odd speech.3-9 These traits were combined into our current concept of schizotypy by Spitzer et al in DSM-III.10 Despite the familial relationship between schizophrenia and schizotypy and substantial evidence for a genetic basis to schizophrenia,11 the extent to which the dimensions of schizophrenia and schizotypy share familial etiological factors is unknown.
Establishing that normal and disease states represent end points of a single continuum of liability has important implications for understanding the genetic architecture of not only schizophrenia, but other complex disorders as well, such as hypertension and diabetes, where affection is defined quantitatively, not qualitatively. Establishing such a continuum of liability in schizophrenia will inform the methodology of molecular genetic studies, where it has been difficult to define an optimal phenotype.11 Quantitative trait loci analysis may be statistically more powerful than traditional linkage methods in detecting susceptibility genes for complex disorders,12 but its use assumes the genetic continuity of normal and disease states.
Schizophrenic psychopathology is multidimensional and heterogeneous.13-14 Factor analytic studies often result in positive, negative, and disorganization factors.15-20 Like schizophrenia, schizotypy is multidimensional and heterogeneous, and is composed of factors that resemble those of schizophrenia.21-23 Some are composed of attenuated forms of classical positive and negative symptoms. Positive schizotypy comprises ideas of reference, illusions, and magical thinking, while negative schizotypy includes poor rapport, aloofness, and guardedness.21
We know of only one study that has addressed the existence of a single continuum of liability for schizophrenic and schizotypal symptoms, showing that negative symptoms in schizophrenic probands were correlated, at the trend level (P<.10), with negative symptoms in their relatives.24 The correlation was greater than a similar one observed for positive symptoms. This study, however, included ill relatives in the analysis.
To further investigate this question, we examined the relationship between classic positive and negative symptoms of schizophrenic probands and dimensions of schizotypy in their first-degree relatives in the Roscommon Family Study. We hypothesized that positive and negative schizophrenic symptoms in probands would predict, respectively, positive and negative schizotypal symptoms. We also predicted relationships between proband negative symptoms and avoidant schizotypy and social dysfunction, as asociality is a prominent negative symptom,14 and since negative symptoms are robustly related to social dysfunction.25-26
SUBJECTS AND METHODS
SUBJECTS
The Roscommon Family Study is an epidemiologically based family study of major mental illness in the west of Ireland. Two groups of index probands were examined: (1) schizophrenic—all cases with a diagnosis of schizophrenia from the population-based Roscommon County Case Register27 (n = 303), and (2) affective—a randomly chosen subsample of the cases from the Case Register with a diagnosis of major affective disorder. Because of budgetary restrictions, 75% of these cases were included (n = 99). Of the schizophrenic probands, 18 had been ascertained through 2 private hospitals cooperating with the registry. We were unable to obtain access to these individuals, reducing the number of schizophrenic probands to 285. An average of 15 years after onset, we attempted to follow up all 384 index probands, of whom 37 were dead, 23 were untraceable, 50 refused interview, and 274 were personally interviewed by 1 of 2 Irish psychiatrists. Medical records were obtained for 359 probands. In cases of incomplete data, collateral histories, from either family members or community nurses, were obtained for an additional 52 index probands. In our judgment, sufficient clinical information was available to render a psychiatric diagnosis in 375 of these cases, of whom 126 individuals (123 from the original schizophrenic group and 3 from the original affective group) met DSM-III-R28 criteria for schizophrenia. These diagnostic reviews were performed by one of us (K.S.K.) or Alan Gruenberg, MD, using a blind best-estimate procedure with demonstrated high interrater reliability.29 Of these 126 subjects, 99 were personally interviewed, and 102 had 1 or more relatives with a personal interview or hospital record.
We attempted to personally interview, blind to proband status, all first-degree relatives, aged 16 years and older and residing in the island of Ireland or central and eastern England, of the index probands and a group of unscreened population controls matched for age and sex. We also attempted to obtain and abstract psychiatric hospital records for all hospitalized relatives. As several individuals and families were ascertained more than once, we used the general proband method, in which all individuals are counted once for each time they are independently ascertained.30
Personal interviews were completed in 86% of living traceable relatives (n = 1753), including 342 relatives of probands meeting DSM-III-R criteria for schizophrenia. Their mean ± SD age was 46 ± 16 years and 49% were male. For an additional 12 relatives of the DSM-III-R schizophrenic probands, only hospital records were available. Herein, we present results on the relatives of probands with a personal interview and/or a hospital record.
DIAGNOSES
The personal interview with probands and relatives was based on the Structured Clinical Interview for DSM-III-R31 diagnoses for Axis I disorders and the Structured Interview for Schizotypy32 for schizophrenia-related Axis II disorders. Blind, best-estimate diagnoses using all available information were also made for all relatives with personal interviews and/or hospital records using DSM-III-R criteria by 2 psychiatrists (K.S.K. or Alan M. Gruenberg, MD). In addition to coding diagnoses, these 2 psychiatrists completed the Major Symptoms of Schizophrenia Scale (MSSS).33 This is an instrument designed for use in a best-estimate procedure that codes key symptom and course features as assessed over the entire course of illness. It was designed to allow the experienced clinician to integrate the relative prominence of clinical features over the entire course of illness. The MSSS contains 9 key symptomatic dimensions: delusions (any), schneiderian delusions, hallucinations, positive thought disorder (such as loosening of associations), catatonic symptoms (including stupor and excitement), depressive symptoms, and manic symptoms. In addition, the MSSS rates chronicity of course and global outcome. All symptom variables were coded on 5-point scales. Details are available on request, but the following general guidelines were adopted for the symptomatic variables: 1, clearly not present; 2, possibly present but subthreshold; 3, clearly present but moderate; 4, clearly present and prominent; and 5, clearly present and severe. The reliability of the MSSS was tested on 47 cases with psychotic illness rated blindly by both psychiatrists. Intraclass correlations for these 11 variables ranged from 0.60 for catatonic symptoms to 0.91 for manic symptoms, with a mean ± SD for all 11 variables of 0.77 ± 0.11.
In this study, we performed analyses using 3 definitions of proband caseness: (1) probands with a DSM-III-R diagnosis of schizophrenia (n = 127); (2) probands with diagnoses of schizophrenia, simple schizophrenia, and schizoaffective disorder (n = 178); (3) probands with any of the above diagnoses as well as delusional disorder, schizophreniform disorder, brief reactive psychosis, and psychosis, not otherwise specified (n = 216). We examined all first-degree relatives of these 3 proband groups, excluding those with diagnoses of schizophrenia, schizoaffective disorder, delusional disorder, schizophreniform disorder, brief reactive psychosis, and psychosis, not otherwise specified (n = 309, 477, and 584, respectively).
STATISTICAL ANALYSIS
A factor analysis was performed by the method of principal components with varimax rotation using the SAS procedure FACTOR34 on the 9 symptoms of the MSSS, selecting factors with an eigenvalue of 1.0 or greater. As outlined previously,35 this yielded the 3 factors: (1) negative—with high loadings on negative thought disorder, affective deterioration, positive thought disorder, and catatonia; (2) positive—with high loadings on schneiderian delusions, any delusions, and hallucinations; and (3) affective—with high loadings on manic and depressive symptoms. As detailed elsewhere,21 a similar factor analysis was performed on all 25 items of the Structured Interview for Schizotypy. This yielded 7 factors: positive, negative, and avoidant symptoms, social dsyfunction, suspicious behavior, and symptoms of borderline personality disorder (BPD).
Missing items were imputed by assigning them the mean score of the items in their respective factor. Subjects missing 50% or more of necessary data were excluded from analysis. All scale scores were transformed into standardized scores with mean of 0 and SD of 1. Regression analyses were performed with positive and negative scores of probands as independent variables and all 7 schizotypy factor–derived scores of relatives as dependent variables. Age and sex of relatives and relationship to proband were entered as covariates. A weighted least squares approach was used, weighting for the number of members per family. Analyses were implemented using the GLM procedure in SAS.34 The results of the above analyses are presented without Bonferroni corrections. We present results using 2-tailed P values.
RESULTS
The standardized regression slopes and P values of all analyses are presented in Table 1. More inclusive definitions of caseness were generally associated with more statistically significant results. Proband negative symptoms predicted more schizotypy factors in relatives. These included the negative factor, odd speech, suspicious behavior, and social dysfunction. Negative symptoms also had an inverse relationship with symptoms of borderline personality disorder (BPD) in the analysis of schizophrenia, simple schizophrenia, and schizoaffective disorder probands. Positive symptoms in probands predicted positive schizotypy, BPD symptoms, and social dysfunction in relatives.
|
|
|
|
Relationship Between Positive and Negative Symptoms of Schizophrenia and Dimensions of Schizotypy in Nonpsychotic Relatives*
|
|
|
COMMENT
In this study, we examined the hypothesis that positive and negative symptoms of schizophrenia share familial etiological factors with corresponding dimensions of schizotypy by relating symptom scores in psychotic probands with scores on 7 schizotypy factors in their nonpsychotic relatives. Our purpose was to elucidate the etiological lines of demarcation in the schizophrenia spectrum and to further characterize the pathway between familial etiological factors and the expression of clinical phenotype in schizophrenia. Although a previous study of this sample showed that the deficit syndrome was associated with social isolation in relatives,36 this is the first study to show that schizophrenia and schizotypy share familial etiological factors for both their positive and negative dimensions.
The results generally confirmed our hypotheses. Overall, negative symptoms had statistically significant relationships with more schizotypy factors than did positive symptoms. This coheres with the general notion that negative symptoms have greater familial, and possibly genetic, bases than do positive symptoms. Evidence suggesting this is their association with greater family history,37 worse premorbid functioning,38-40 and greater longitudinal stability.41-43 Furthermore, the phenomenological resemblance between positive schizotypal symptoms such as magical thinking and illusions on one hand, and positive schizophrenic symptoms on the other, appears to be less than that between negative symptoms of schizotypy21 and schizophrenia.14
The observed relationships between negative symptoms and negative schizotypy and social dsyfunction have face validity, but those with suspicious behavior, odd speech, and BPD symptoms were unexpected. Suspicious behavior might be explained by possible phenomenological overlap with the negative symptoms asociality and poor rapport.14 Furthermore, one of the items loading on our negative schizotypy factor was guardedness21, which intuitively resembles suspiciousness. Features of BPD, however, such as affective instability, inappropriate anger, and impulsivity, seem opposite to classic negative symptoms,14 which may explain the inverse relationship between them.
We were unable to confirm our hypothesis that negative symptoms would predict avoidant schizotypy in relatives. This was indeed surprising, as asociality is an important negative symptom.14 Our avoidant schizotypy factor, however, while including social isolation, also loaded on the anxiety-related traits hypersensitivity, anxiety, and social anxiety, making an etiological relationship with negative symptoms less intuitively appealing. Furthermore, proband clinical features did not predict anxiety disorders in relatives in a prior study of this sample.35
We did not expect to find an etiological relationship between negative symptoms and odd speech. However, in several factor analyses,44-45 including the one performed on this sample,35 the negative factor loaded on odd speech or disorganization. Furthermore, parents of nonparanoid schizophrenic individuals manifest greater levels of formal thought disorder than do parents of paranoid schizophrenic individuals,46 and this subtype should be associated with lower levels of negative symptoms than are other subtypes, based on its operational definition in DSM-III-R.28
Positive symptoms were significantly related to positive schizotypy, social dysfunction, and BPD symptoms. Social dysfunction had significant relationships with both positive and negative symptoms, which may indicate that it is etiologically related to severity of illness rather than specific symptom dimensions. The relationship with BPD symptoms may be related to the propensity for some patients with BPD to exhibit stress-induced paranoia or other mild psychoticlike symptoms, as operationalized in the DSM-III-R criteria.28
The effect sizes (regression slopes) of the analyses did not change substantially when the definition of proband affection was broadened to include nonschizophrenic psychotic disorders, while significance levels increased substantially. This supports the spectrum concept of schizophrenia—that several disorders share with schizophrenia the same underlying liability.47-50 This was consistent with a previous study of this sample in which the spectrum concept was formally tested by fitting a multiple threshold model to the data.50
Our results indicate that from a familial perspective, the positive and negative dimensions of schizophrenia "breed true" as their attenuated personality-based variants in nonpsychotic individuals. This suggests that the influence of familial etiological factors determining the expression of these symptom dimensions reaches across the boundary of psychotic illness to phenomena currently classified under the rubric of personality. The specificity of the relationships between the positive schizophrenic and schizotypy factors, as well as between the negative schizophrenic and schizotypy factors, further validates the etiological distinctness of some schizophrenic symptom domains, as suggested by sibling resemblance for clinical features.51-57
These results provide validation for quantitative phenotype definition in genetic linkage and association studies. As genes are likely to comprise substantial components of the familial etiological factors shared by the dimensions of schizophrenia and schizotypy, the same genes would presumably be involved in both phenotypes. This strategy may increase the power of such studies by including more "units" of genetic liability to schizophrenia in analysis.12, 58
These results should be interpreted in the context of 4 methodological limitations. First, neither the Structured Interview for Schizotypy nor the MSSS examined all possibly relevant signs and symptoms of schizotypy and schizophrenia, respectively. Furthermore, the 2 scales differ in their comprehensiveness, with the Structured Interview for Schizotypy containing many more items than the MSSS. Both the assessment instrument used and the number of items included in factor analysis may have a significant impact on the composition and number of factors extracted. Perhaps the use of other instruments would have led to different relationships between the factors of schizophrenia and schizotypy. Our use of only 2 factors may be an oversimplification of the multifaceted variability of schizophrenic psychopathology, but there is no consensus in the field about the number of dimensions that best represents the full clinical picture of schizophrenia.19 We opted to use positive and negative symptoms because of their historical prominence and their conception in the minds of many clinicians as core illness dimensions.
Second, the use of different covariates may have resulted in different relationships between the factors of schizophrenia and schizotypy. We used age, sex, and relationship to proband. It may be argued that we should have also controlled for social class of the relatives, as this predicted several schizotypy factors.21 However, when this covariate was used in a prior study, it had no impact on the prediction of proband diagnoses of psychotic disorders by schizotypy factors.21
Third, it is not possible to determine whether the results obtained herein are due to genetic as opposed to environmental factors. In addition, an argument made by Kendler et al51 with respect to sibling resemblance for psychotic syndromes may apply here. This would hold that the correlations between relatives as reported here might be due not only to susceptibility genes for schizophrenia but also to genes determining temperament and intellect. Future studies should attempt to partial out these effects.
Fourth, while we tested a hypothesis about primary negative symptoms, or those due to the disease itself, it was not possible to differentiate between these and secondary negative symptoms in probands. Secondary negative symptoms may result from depression, medication-induced parkinsonism, and chronicity.59-61 To differentiate between these and primary negative symptoms, it would have been necessary to perform negative symptom ratings before and after treatment,60 which would be impractical in a genetic-epidemiological sample such as ours. This possible confound may have decreased the effect sizes obtained in the regression analyses, although a recent study showed that while negative symptoms were associated with greater family history, the deficit syndrome was not.62
AUTHOR INFORMATION
Accepted for publication February 5, 2001.
This project was largely supported by grants MH41953 and MH54150 from the National Institute of Mental Health, Rockville, Md. Additional support came from the Scottish Rite Benevolent Foundation's Schizophrenia Research Program, Northern Masonic Jurisdiction, United States.
Corresponding author and reprints: Ayman Fanous, MD, Box 980126, Richmond, VA 23298-0126 (e-mail: ahfanous{at}hsc.vcu.edu).
From the Departments of Psychiatry (Drs Fanous, Gardner, and Kendler) and Human Genetics (Dr Kendler), Medical College of Virgina of Virginia Commonwealth University, Virginia Institute for Psychiatric and Behavioral Genetics (Drs Fanous, Gardner, and Kendler); and St Loman's Hospital, Dublin, Ireland (Dr Walsh).
REFERENCES
| |
1. Kraepelin E, trans, Barclay RM, trans. Dementia Praecox and Paraphrenia. 8th ed. Huntington, NY: Krieger Publishing; 1971.
2. Bleuler E. Dementia Praecox, or The Group of Schizophrenias. New York, NY: International Universities Press; 1950.
3. Kendler KS. Diagnostic approaches to schizotypal personality disorder: a historical perspective. Schizophr Bull. 1985;11:538-553.
4. Kendler KS, McGuire M, Gruenberg AM, O'Hare A, Spellman M, Walsh D. The Roscommon Family Study, III: schizophrenia-related personality disorders in relatives. Arch Gen Psychiatry. 1993;50:781-788.
ABSTRACT
5. Maier W, Lichtermann D, Minges J, Heun R. Personality disorders among the relatives of schizophrenia patients. Schizophr Bull. 1994;20:481-493.
6. Baron M, Gruen R, Rainer JD, Kane J, Asnis L, Lord S. A family study of schizophrenic and normal control probands: implications for the spectrum concept of schizophrenia. Am J Psychiatry. 1985;142:447-455.
FREE FULL TEXT
7. Silverman JM, Siever LJ, Horvath TB, Coccaro EF, Klar H, Davidson M, Pinkham L, Apter SH, Mohs RC, Davis KL. Schizophrenia-related and affective personality disorder traits in relatives of probands with schizophrenia and personality disorders. Am J Psychiatry. 1993;150:435-442.
FREE FULL TEXT
8. Katsanis J, Iacono WG, Beiser M. Anhedonia and perceptual aberration in first-episode psychotic patients and their relatives. J Abnorm Psychol. 1990;99:202-206.
PUBMED
9. Clementz BA, Grove WM, Katsanis J, Iacono WG. Psychometric detection of schizotypy: perceptual aberration and physical anhedonia in relatives of schizophrenics. J Abnorm Psychol. 1991;100:607-612.
FULL TEXT
|
ISI
| PUBMED
10. Spitzer RL, Endicott J, Gibbon M. Crossing the border into borderline personality and borderline schizophrenia: the development of criteria. Arch Gen Psychiatry. 1979;36:17-24.
ABSTRACT
11. Kendler KS. Schizophrenia: genetics. In: Sadock BJ, Sadock VA, eds. Comprehensive Textbook of Psychiatry. Baltimore, Md: Williams & Wilkins; 1999:942-968.
12. Risch N. Linkage strategies for genetically complex traits, II: the power of affected relative pairs. Am J Hum Genet. 1990;46:229-241.
ISI
| PUBMED
13. Cancro RC, Lehmann HE. Schizophrenia: clinical features. In: Sadock BJ, Sadock VA, eds. Comprehensive Textbook of Psychiatry. Baltimore, Md: Williams & Wilkins; 1999:1169-1199.
14. Andreasen NC. Negative symptoms in schizophrenia: definition and reliability. Arch Gen Psychiatry. 1982;39:784-788.
ABSTRACT
15. Strauss JS, Carpenter WT Jr, Bartko J. The diagnosis and understanding of schizophrenia, part III: speculations on the processes that underlie schizophrenic symptoms and signs. Schizophr Bull. 1974;11:61-69.
16. Liddle PF. The symptoms of chronic schizophrenia: a re-examination of the positive-negative dichotomy. Br J Psychiatry. 1987;151:145-151.
FREE FULL TEXT
17. Bilder RM, Mukherjee S, Rieder RO, Pandurangi AK. Symptomatic and neuropsychological components of defect states. Schizophr Bull. 1985;11:409-419.
18. Murphy BM, Burke JG, Bray JC, Walsh D, Kendler KS. An analysis of the clinical features of familial schizophrenia. Acta Psychiatr Scand. 1994;89:421-427.
PUBMED
19. Stuart GW, Pantelis C, Klimidis S, Minas IH. The three-syndrome model of schizophrenia: meta-analysis of an artefact. Schizophr Res. 1999;39:233-242.
PUBMED
20. Lenzenweger MF, Dworkin RH. The dimensions of schizophrenia phenomenology: not one or two, at least three, perhaps four. Br J Psychiatry. 1996;168:432-440.
FREE FULL TEXT
21. Kendler KS, McGuire M, Gruenberg AM, Walsh D. Schizotypal symptoms and signs in the Roscommon Family Study: their factor structure and familial relationship with psychotic and affective disorders. Arch Gen Psychiatry. 1995;52:296-303.
ABSTRACT
22. Bergman AJ, Harvey PD, Mitropoulou V, Aronson A, Marder D, Silverman J, Trestman R, Siever LJ. The factor structure of schizotypal symptoms in a clinical population. Schizophr Bull. 1996;22:501-509.
23. Gruzelier JH. The factorial structure of schizotypy, part I: affinities with syndromes of schizophrenia. Schizophr Bull. 1996;22:611-620.
24. Tsuang MT. Genotypes, phenotypes, and the brain: a search for connections in schizophrenia. Br J Psychiatry. 1993;163:299-307.
FREE FULL TEXT
25. Jackson HJ, Minas IH, Burgess PM, Joshua SD, Charisiou J, Campbell IM. Negative symptoms and social skills performance in schizophrenia. Schizophr Res. 1989;2:457-463.
FULL TEXT
|
ISI
| PUBMED
26. Bellack AS, Morrison RL, Wixted JT, Mueser KT. An analysis of social competence in schizophrenia. Br J Psychiatry. 1990;156:809-818.
FREE FULL TEXT
27. Walsh D, O'Hare A, Blake B, Halpenny JV, O'Brien PF. The treated prevalence of mental illness in the Republic of Ireland—the three county case register study. Psychol Med. 1980;10:465-470.
ISI
| PUBMED
28. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition. Washington, DC: American Psychiatric Association; 1987.
29. Kendler KS, McGuire M, Gruenberg AM, O'Hare A, Spellman M, Walsh D. The Roscommon Family Study, I: methods, diagnosis of probands, and risk of schizophrenia in relatives. Arch Gen Psychiatry. 1993;50:527-540.
ABSTRACT
30. Crow JF. Problems of ascertainment in the analysis of family data. In: Neel JV, Shaw NW, Schull WJ, eds. Genetics and the Epidemiology of Chronic Diseases. Washington DC: US Dept of Health, Education, and Welfare; 1965:23-44.
31. Spitzer RL, Williams JB, Gibbon M. Structured Clinical Interview for DSM-III-R. New York, NY: Biometrics Research Dept, New York State Psychiatric Institute; 1987.
32. Kendler KS, Lieberman JA, Walsh D. The Structured Interview for Schizotypy (SIS): a preliminary report. Schizophr Bull. 1989;15:559-571.
33. Kendler KS, McGuire M, Gruenberg AM, Walsh D. An epidemiologic, clinical, and family study of simple schizophrenia in County Roscommon, Ireland. Am J Psychiatry. 1994;151:27-34.
FREE FULL TEXT
34. SAS Institute. SAS/STAT User's Guide, Version 6. Vols 1 and 2. 4th ed. Cary, NC: SAS Institute; 1990.
35. Kendler KS, McGuire M, Gruenberg AM, Walsh D. Clinical heterogeneity in schizophrenia and the pattern of psychopathology in relatives: results from an epidemiologically based family study. Acta Psychiatr Scand. 1994;89:294-300.
PUBMED
36. Kirkpatrick B, Ross DE, Walsh D, Karkowski L, Kendler KS. Family characteristics of deficit and nondeficit schizophrenia in the Roscommon Family Study. Schizophr Res. 2000;45:57-64.
FULL TEXT
|
ISI
| PUBMED
37. Kay SR. Significance of the positive-negative distinction in schizophrenia. Schizophr Bull. 1990;16:635-652.
38. Gupta S, Rajaprabhakaran R, Arndt S, Flaum M, Andreasen NC. Premorbid adjustment as a predictor of phenomenological and neurobiological indices in schizophrenia. Schizophr Res. 1995;16:189-197.
FULL TEXT
|
ISI
| PUBMED
39. Andreasen NC, Flaum M, Swayze II VW, Tyrrell G, Arndt S. Positive and negative symptoms in schizophrenia: a critical reappraisal. Arch Gen Psychiatry. 1990;47:615-621.
ABSTRACT
40. Peralta V, Cuesta MJ, de Leon J. Premorbid personality and positive and negative symptoms in schizophrenia. Acta Psychiatr Scand. 1991;84:336-339.
PUBMED
41. Fenton WS, McGlashan TH. Natural history of schizophrenia subtypes, II: positive and negative symptoms and long-term course. Arch Gen Psychiatry. 1991;48:978-986.
ABSTRACT
42. Pfohl B, Winokur G. The micropsychopathology of hebephrenic/catatonic schizophrenia. J Nerv Ment Dis. 1983;171:296-300.
ISI
| PUBMED
43. Pfohl B, Winokur G. The evolution of symptoms in institutionalized hebephrenic/catatonic schizophrenics. Br J Psychiatry. 1982;141:567-572.
FREE FULL TEXT
44. Peralta V, Cuesta MJ, de Leon J. An empirical analysis of latent structures underlying schizophrenic symptoms: a four-syndrome model. Biol Psychiatry. 1994;36:726-736.
FULL TEXT
|
ISI
| PUBMED
45. Dollfus S, Everitt B. Symptom structure in schizophrenia: two-, three- or four-factor models? Psychopathology. 1998;31:120-130.
PUBMED
46. Rund BR, Blakar RM. Schizophrenic patients and their parents: a multimethod design and the findings from an illustrative empirical study of cognitive disorders and communication deviances. Acta Psychiatr Scand. 1986;74:396-408.
PUBMED
47. Gershon ES, DeLisi LE, Hamovit J, Nurnberger JI Jr, Maxwell ME, Schreiber J, Dauphinais D, Dingman II CW, Guroff JJ. A controlled family study of chronic psychoses: schizophrenia and schizoaffective disorder. Arch Gen Psychiatry. 1988;45:328-336.
ABSTRACT
48. Faraone SV, Tsuang MT. Familial links between schizophrenia and other disorders: application of the multifactorial polygenic model. Psychiatry. 1988;51:37-47.
PUBMED
49. Kendler KS, McGuire M, Gruenberg AM, Spellman M, O'Hare A, Walsh D. The Roscommon Family Study, II: the risk of nonschizophrenic nonaffective psychoses in relatives. Arch Gen Psychiatry. 1993;50:645-652.
ABSTRACT
50. Kendler KS, Neale MC, Walsh D. Evaluating the spectrum concept of schizophrenia in the Roscommon Family Study. Am J Psychiatry. 1995;152:749-754.
FREE FULL TEXT
51. Kendler KS, Karkowski-Shuman L, O'Neill FA, Straub RE, MacLean CJ, Walsh D. Resemblance of psychotic symptoms and syndromes in affected sibling pairs from the Irish Study of High-Density Schizophrenia Families: evidence for possible etiologic heterogeneity. Am J Psychiatry. 1997;154:191-198.
ABSTRACT
52. Ross DE, Kirkpatrick B, Karkowski LM, Straub RE, MacLean CJ, O'Neill FA, Compton AD, Murphy B, Walsh D, Kendler KS. Sibling correlation of deficit syndrome in the Irish study of high-density schizophrenia families. Am J Psychiatry. 2000;157:1071-1076.
FREE FULL TEXT
53. Loftus J, Delisi LE, Crow TJ. Factor structure and familiality of first-rank symptoms in sibling pairs with schizophrenia and schizoaffective disorder. Br J Psychiatry. 2000;177:15-19.
FREE FULL TEXT
54. Cardno AG, Jones LA, Murphy KC, Sanders RD, Asherson P, Owen MJ, McGuffin P. Sibling pairs with schizophrenia or schizoaffective disorder: associations of subtypes, symptoms and demographic variables. Psychol Med. 1998;28:815-823.
FULL TEXT
|
ISI
| PUBMED
55. Loftus J, DeLisi LE, Crow TJ. Familial associations of subsyndromes of psychosis in affected sibling pairs with schizophrenia and schizoaffective disorder. Psychiatry Res. 1998;80:101-111.
FULL TEXT
| PUBMED
56. DeLisi LE, Goldin LR, Maxwell ME, Kazuba DM, Gershon ES. Clinical features of illness in siblings with schizophrenia or schizoaffective disorder. Arch Gen Psychiatry. 1987;44:891-896.
ABSTRACT
57. Cardno AG, Jones LA, Murphy KC, Sanders RD, Asherson P, Owen MJ, McGuffin P. Dimensions of psychosis in affected sibling pairs. Schizophr Bull. 1999;25:841-850.
58. Brzustowicz LM, Honer WG, Chow EW, Hogan J, Hodgkinson K, Bassett AS. Use of a quantitative trait to map a locus associated with severity of positive symptoms in familial schizophrenia to chromsome 6p. Am J Hum Genet. 1997;61:1388-1396.
FULL TEXT
| PUBMED
59. Carpenter WT Jr, Heinrichs DW, Wagman AMI. Deficit and nondeficit forms of schizophrenia: the concept. Am J Psychiatry. 1988;145:578-583.
FREE FULL TEXT
60. Miller DD, Flaum M, Arndt S, Fleming F, Andreasen NC. Effect of antipsychotic withdrawal on negative symptoms in schizophrenia. Neuropsychopharmacology. 1994;11:11-20.
PUBMED
61. Kelley ME, van Kammen DP, Allen DN. Empirical validation of primary negative symptoms: independence from effects of medication and psychosis. Am J Psychiatry. 1999;156:406-411.
FREE FULL TEXT
62. Malaspina D, Goetz RR, Yale S, Berman A, Friedman JH, Tremeau F, Printz D, Amador X, Johnson J, Brown A, Gorman JM. Relation of familial schizophrenia to negative symptoms but not to the deficit syndrome. Am J Psychiatry. 2000;157:994-1003.
FREE FULL TEXT
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
Schizophrenia, Psychiatric Genetics, and Darwinian Psychiatry: An Evolutionary Framework
Pearlson and Folley
Schizophr Bull 2008;34:722-733.
ABSTRACT
| FULL TEXT
Genetic Heterogeneity, Modifier Genes, and Quantitative Phenotypes in Psychiatric Illness: Searching for a Framework
Fanous and Kendler
Focus 2006;4:423.
ABSTRACT
| FULL TEXT
Data Gathering: Biased in Psychosis?
Van Dael et al.
Schizophr Bull 2006;32:341-351.
ABSTRACT
| FULL TEXT
The Pathophysiology of Schizophrenia Disorders: Perspectives From the Spectrum
Siever and Davis
Am. J. Psychiatry 2004;161:398-413.
ABSTRACT
| FULL TEXT
Familial Aggregation of Delusional Proneness in Schizophrenia and Bipolar Pedigrees
Schurhoff et al.
Am. J. Psychiatry 2003;160:1313-1319.
ABSTRACT
| FULL TEXT
|
