63
Journal of Affective Disorders, 20 (1990) 63-69 Elsevier
JAD 00740
A family study of lithium-responsive psychosis Frederic
J. Sautter I, Barbara
E. McDermott
’ and David L. Garver
2
’ Department of Psychiarry and Neurology, Tulane University School of Medicine, New Orleans, LA 70118, CJ.S.A and 2 Department of Psychiatry, University of Alabama, Birmingham, AL 35294, U.S.A. (Received 28 April 1988) (Accepted 2 May 1990)
Psychiatric life histories of 487 first-degree family members of 24 lithium-responsive (mood-incongruent) psychotics, 54 lithium-nonresponsive (mood-incongruent) psychotics, and 18 lithium-responsive patients with bipolar (manic-depressive) disorder were contrasted. While the morbid risk of schizophrenicspectrum was 11.1% in relatives of lithium-nonresponsive probands, the morbid risk for such disorders was only 2.4% in relatives of lithium-responsive (mood-incongruent) psychotics (P < 0.05). This lithium-responsive illness appears to be fan&ally, and perhaps genetically, distinct from the bulk of the schizophrenias.
Key words:
Lithium response; Family studies; Schizoaffective
Introduction It has become recognized that there are probably a number of illnesses nested within the schizophrenic spectrum. Research from our laboratory has indicated that one of these illnesses is a lithium-responsive subtype that presents with psychotic (mood-incongruent) symptoms similar to schizophrenia but has an illness course that is episodic. This article reports results of a family study designed to clarify the familial relationship between this lithium-responsive illness and
Address for correspondence: Frederic Department of Psychiatry and Neurology, School of Medicine, 1415 Tulane Avenue, 70118, U.S.A. 0165-0327/90/$03.50
J. Sautter, Ph.D., Tulane University New Orleans, LA
0 1990 Elsevier Science Publishers
disorder; Good-prognosis
schizophrenia
lithium-nonresponsive mood-incongruent psychosis on the one hand, and the bipolar affective disorders on the other. There have been numerous attempts to reduce the heterogeneity of the psychotic disorders by differentiating these disorders into more homogeneous subtypes. Such subtypes have been created on the basis of symptoms (Crow, 1980; Andreasen, 1987) illness course (McCabe et al., 1971) and biological markers (Van Kammen and Antelman, 1984). Work in our laboratory has focused upon resolving the heterogeneity of the mood-incongruent psychoses through the evaluation of drug response patterns. Our data indicate that while most mood-incongruent psychotic patients respond favorably to neuroleptics, a subtype of mood-incongruent psychotic patients also respond
B.V. (Biomedical
Division)
64
favorably to treatment with lithium (Hirschowitz et al., 1980). Lithium response in such patients has been demonstrated within the context of doubleblind, placebo-controlled drug trials (Garver et al., 1984) and data from other laboratories also indicate that schizophrenic patients may show a therapeutic response to lithium (Prein et al., 1972; Alexander et al., 1979). Data indicate that lithium-responsive and nonresponsive mood-incongruent psychotics cannot be differentiated on the basis of their clinical presentation (Garver et al., 1988). Studies from our laboratory have been designed to define this lithium-responsive mood-incongruent subtype along biologic parameters and on the basis of illness course and family patterns of illness. Our data indicate that these lithium-responsive psychotics often show abnormalities of lithium flow across red cell membranes (Garver et al., 1984); they evidence disturbances in receptor sensitivity to agonists such as apomorphine (Hirschowitz et al., 1982); and the majority of these patients show an episodic illness course with essentially full recovery between episodes (Hirschowitz et al., 1980). These lithium-responsive mood-incongruent patients also evidence a (temporary) reduction of psychotic symptoms during and following administration of a cholesterase inhibitor (Edelstein et al., 1981). Preliminary family studies have shown that the morbid risk of schizophrenic-spectrum disorder is substantially higher in relatives of lithium-nonresponsive mood-incongruent psychotics than in relatives of mood-incongruent psychotics that respond favorably to lithium (Sautter and Garver, 1985). In this report, we extend earlier family studies and present a more precise evaluation of the familial relationship between lithium-nonresponsive mood-incongruent psychotics, lithium-responsive mood-incongruent psychotics and the lithium-responsive bipolar disorders.
Emergency Service (PES). Each of the 96 psychotic probands underwent a 2-week drug-free diagnostic period during which time clinical diagnostics were performed according to SADSDSM-III (Endicott and Spitzer, 1978; APA, 1980) methods. At the end of the drug-free period, each patient received a 2-week trial of lithium carbonate at plasma levels rapidly adjusted to 0.8-1.4 mEq/l. Psychotic symptoms were quantitated biweekly during the drug-free period and the lithium trial employing a modified serial New Haven Schizophrenic Index (NHSI) (Astrachan et al., 1972). Probands were categorized as ‘lithium-responders’ if they showed a 35% reduction of baseline NHSI symptoms during the 1Cday lithium treatment and could go on to sustained remission of symptoms (NHSI I 5, CGI I 2) while maintained on lithium alone. * Probands not meeting these dual criteria were categorized as ‘nonresponders’ (Garver et al., 1984). Similarly, if a patient that is initially ‘lithium-responsive’ is found at follow-up or on subsequent hospitalization to no longer be responsive to lithium, that patient is classified as a ‘nonresponder’. Among the 24 lithium-responsive schizophrenic-like probands were 13 DSM-III schizophreniform disorders, five schizophrenics, and six psychotic (mood-incongruent) affective disorders; among the 54 lithium nonresponders were 10 DSM-III schizophreniform disorder patients and 44 schizophrenics. All 18 lithium-responsive bipolar patients showed mood-congruent psychotic symptoms. The mean age of the lithium-responsive mood-incongruent patients was 27.5 years; the mean age of the lithium-nonresponsive mood-incongruent patients was 25.7 years; the mean age of the lithium-responsive bipolar patients was 36.9 years. All consenting first-degree relatives (parents, offspring and siblings) of the three groups of probands underwent detailed SADS-L (Spitzer and Endicott, 1975) interviews. DSM-III diagnoses
Method Consenting patients were admitted to the Psychobiology Treatment Unit of the University of Cincinnati Hospital. Patients who consented to the treatment protocol were recruited from the University of Cincinnati Hospital Psychiatric
* The patients’ global symptoms Global Impression Scale (CGI) severity of illness. The range of at all’), 2 (‘borderline mentally erately ill’), 5 (‘markedly ill’), 6 the most extremely ill patients’).
were assessed on a Clinical which reflects the patients’ the ratings is 1 (‘normal, not ill’), 3 (‘mildly ill’), 4 (‘mod(‘severely ill’), and 7 (‘among
65
were then assigned to each of these relatives by an interviewer who was blind to the proband’s diagnosis and treatment response. When it was not possible to interview a relative (because of death, migration or refusal to participate), the family history method (Endicott et al., 1978) was used to assign a diagnosis. The mean age of all of the diagnosed relatives of the lithium-responsive schizophrenic-like probands was 38.4 years; the mean age of the diagnosed relatives of the nonresponsive probands was 39.7 years; the mean age of the diagnosed relatives of the lithium-responsive bipolar probands was 45.9 years. The relatives of the three groups of probands were compared to determine differences in the lifetime expectancy (morbid risk) of four classes of disorders: (1) DSM-III major depressive disorder; (2) DSM-III bipolar disorder; (3) DSM-III schizophrenia and schizoaffective disorder; and (4) DSM-III schizophreniform disorder. Morbid risk was determined by the Weinberg shorter method (Slater and Cowie, 1971). This method adjusts the sample size (BZ) by using the formula N - n, - 1/2n, with N representing the total number of relatives studied, n, the number of relatives who have not reached the risk period, and n the number of relatives within the risk period. The risk periods were as follows: schizophrenia, 15-39 years of age (Tsuang et al., 1980); unipolar affective disorder, 15-70 years of age (Loranger et al., 1982); bipolar affective illness, 15-60 years of age (Loranger et al., 1982); schizophreniform disorder, 15-60 years. * Statistical comparisons were performed hierarchically as recommended by Coryell and Zimmerman (1988). First, x2 tests were conducted to determine if group values differed overall. Then, if the groups differed at the 0.05 level, they were compared by means of the difference in proportions as modified
* The risk period for onset of fist episode of schizophreniform disorder has not been defined previously. Though the majority of our carefully diagnosed probands have the first episode of schizophreniform illness in the 20s or 30s. we have diagnosed first episode schizophreniform disorder as late as the 50s. We have, therefore, estimated the period of risk for schizophreniform disorder to be similar to that of bipolar illness: 15-60 years of age.
for use with morbid risk statistics and Trzebiatowska, 1976).
(Breborowicz
Results Information from the SADS-L was used to make lifetime DSM-III axis I diagnoses for each first-degree family member. Such lifetime diagnoses (including ‘never mentally ill’) could be made in 84.8% (413 of 487) of the first-degree relatives of the 96 participating probands. Two hundred and eighty-nine of those 413 diagnoses (70.0%) were made on the basis of direct interviews and 124 (30.0%) were made on the basis of a modification of the family history method that yields DSM-III diagnoses for unavailable relatives. Information pertaining to the number of relatives receiving a lifetime diagnosis and the method used to make the diagnosis for each of the three groups of relatives is presented in Table 1. The distribution of schizophrenia and schizophreniform disorder in relatives of the three groups of probands is shown in Table 2. The three groups of relatives differed significantly in terms of their morbid risk for schizophrenia (P -e 0.05); they did not differ significantly in terms of their risk for schizophreniform disorder. The relatives of the lithium-responsive mood-incongruent psychotics showed a morbid risk for schizophrenia of 2.4%; relatives of lithium-responsive bipolar patients showed a morbid risk for schizophrenia of 5.8%; and the morbid risk for the same disorder in relatives of lithium-nonresponsive probands was 11.1%. Post-hoc analyses indicate that the morbid risk for schizophrenia in the relatives of the lithium-responsive mood-incongruent probands was significantly higher than was evidenced in the relatives of the lithium-responsive mood-incongruent psychotics (P < 0.05); the relatives of lithium-nonresponsive mood-incongruent patients showed half the morbid risk for schizophrenia of relatives of the lithium-responsive bipolar probands (2.4% versus 5.8%). This difference was not statistically significant. The three groups of probands showed a similar morbid risk for DSM-III schizophreniform disorder. The relatives of the lithium-responsive mood-incongruent psychotics evidenced a morbid risk for schizophreniform disorder of 1.6%; rela-
66
TABLE
1
NUMBER OF RELATIVES RECEIVING A LIFETIME DIAGNOSIS AND METHOD USED TO RATE THE DIAGNOSIS IN RELATIVES OF PROBANDS WITH LITHIUM-RESPONSIVE MOOD-INCONGRUENT PSYCHOSIS, LITHIUM-NONRESPONSIVE MOOD-INCONGRUENT PSYCHOSIS, AND LITHIUM-RESPONSIVE BIPOLAR DISORDER Proband
Number Number Number Direct Family
of probands of relatives of relatives diagnosed interview (5%) history method (W)
Li-resp Mood-incong psychosis
Li-resp. bipolar disorder
Li-nonresp. mood-incong.
Total
24 126 113 (89.7%) 79 (69.9%) 34 (30.1%)
18 107 90 (84.1%) 59 (65.6%) 31 (34.4%)
54 254 210 (82.7%) 151 (71.9%) 59 (28.1%)
96 487 413 (84.8%) 289 (70.0%) 124 (30.0%)
tives of bipolar probands also showed a morbid risk of 1.7%; relatives of lithium-nonresponsive probands showed a morbid risk of 2.5% for DSMIII schizophreniform disorder. The lifetime incidence of unipolar major depressive disorder and bipolar disorder (mania) in the relatives of the three groups of probands is presented in Table 3. Inspection of the table reveals that a large proportion of the relatives had not passed through the risk period. Thus, the BZ (age-adjusted sample size) dropped significantly.
TABLE
The morbid risk for unipolar major depressive disorder in the relatives of the lithium-responsive mood-incongruent probands was 16.6%; the morbid risk for such illness in relatives of bipolar (manic) probands was 13.9%; the morbid risk for unipolar depression in the first-degree relatives of the lithium-nonresponsive mood-incongruent psychotics was 10.1%. Because of the reduced sample size and the conservative nature of the nonparametric test of significance, the three groups did not differ significantly.
2
SCHIZOPHRENIA AND SCHIZOPHRENIFORM SIVE MOOD-INCONGRUENT PSYCHOTICS, MOOD-INCONGRUENT PSYCHOTICS Proband
N
Li-responsive mood-incongruent psychotics (n = 24) Li-nonresponsive mood-incongruent psychotics (n = 54) Li-responsive bipolar (manic-repressive) disorder (n=18)
DISORDER IN FIRST-DEGREE LITHIUM-RESPONSIVE MANICS,
RELATIVES OF LITHIUM-RESPONAND LITHIUM-NONRESPONSIVE
BZ a
Schizophreniform Schizophrenia
114
64.5 84.0
Schizophreniform Schizophrenia
1 2
1.6% 2.4% *
210
120.5 152.5
Schizophreniform Schizophrenia
3 17
2.5% 11.1% *
90
58.5 68.5
Schizophreniform Schizophrenia
1 4
1.7% 5.8%
a BZ represents size of sample adjusted for period of risk. * x2 = 6.43’, df = 2, P < 0.05; lithium-resp. mood-incoxig. psychotics P < 0.05.
disorder
< lithium-nonresp.
(8) (%) *
mood-incong.
Morbid
psychotics;
risk
z = 2.36. df = 2,
67 TABLE
3
AFFECTIVE ILLNESS (DSM-III UNIPOLAR AND BIPOLAR DISORDER) IN FIRST-DEGREE RELATIVES RESPONSIVE MOOD-INCONGRUENT PSYCHOTICS, LITHIUM-RESPONSIVE MOOD-CONGRUENT AND LITHIUM-NONRESPONSIVE MOOD-INCONGRUENT PSYCHOTICS Proband
N
Li-responsive mood-incongruent psychotics (n = 24) Li-nonresponsive mood-incongruent psychotics (n=54) Li-responsive bipolar (manic-depressive) disorder (n =18)
114
a BZ represents
size of sample
Unipolar disorder Bipolar disorder
(%) (a)
Morbid
60.0 64.5
Unipolar Bipolar
10 3
16.6% 4.7%
210
108.5 120.5
Unipolar Bipolar
12 4
10.1% 3.3%
90
50.5 58.5
Unipolar Bipolar
7 6
13.9% 10.3%
adjusted
BZ a
for period
OF LITHIUMPSYCHOTICS,
risk
of risk.
Comparisons of the three groups of relatives for differences in the morbid risk for bipolar disorder revealed a trend towards significance (x2 = 4.96, df = 2, P < 0.1). The morbid risk for bipolar disorder in the first-degree relatives of the lithium-responsive bipolar probands was 10.3%; the morbid risk for bipolar disorder in relatives of lithium-responsive (mood-incongruent) psychotics was 4.7%; and the morbid risk for mania in relatives of lithium-nonresponsive (mood-incongruent) psychotics was 3.3%. The relatives of the lithium-responsive (mood-incongruent) probands showed a much lower morbid risk for bipolar disorder than did relatives of the lithium-responsive (mood-incongruent) probands. Discussion A primary objective of a series of studies from our laboratory has been to determine if lithium-responsive mood-incongruent psychosis represents a subtype that may be differentiated from the bulk of the mood-incongruent psychoses along a number of illness parameters. In this paper, we examine the familial relationship between this lithium-responsive subtype and the lithium-nonresponsive mood-incongruent psychoses on one hand and the lithium-responsive bipolar disorders on the other. First-degree relatives of lithium-respon-
sive probands showed a significantly lower morbid risk for schizophrenia than did relatives of moodincongruent psychotic probands that did not respond to lithium (2.4% versus 11.1%; P < 0.05). These data support earlier findings from our laboratory (Sautter and Carver, 1985) that suggest that lithium-responsive mood-incongruent psychosis is distinct from the bulk of the schizophrenias along familial parameters. Because the mood-incongruent psychotics that we have studied show a favorable response to lithium, the comparison of the family patterns of illness of the lithium-responsive mood-incongruent psychotics with those of relatives of the bipolar patients is of interest. The lithium-responsive mood-incongruent psychotics show a lower morbid risk for both schizophrenia (2.4% compared to 5.8%) and bipolar disorder (4.7% compared to 10.3%) than do the lithium-responsive bipolar patients. The two groups do not evidence similar patterns of familial psychopathology. It is interesting to note, however, that the first-degree relatives of our lithium-responsive mood-incongruent psychotics evidenced a relatively high morbid risk for major depressive disorder (16.6%) thus it is possible that there is some familial overlap between this lithium-responsive psychosis and unipolar depression. The fact that lithium-responsive mood-incon-
68
gruent psychosis differs from deteriorating schizophrenia along familial parameters does not constitute sufficient evidence to indicate that this disorder represents a distinct psychotic subtype. That hypothesis can only be accepted if it is shown that these patients can be discriminated from other psychotics along a number of theoretically salient disease parameters. It is for that reason that the data presented herein must be viewed within the context of other studies published by our laboratory. These studies indicate that when mood-incongruent psychotic patients are differentiated on the basis of therapeutic response to lithium they may also be reliably differentiated on the basis of illness course (Hirschowitz et al., 1980) and with respect to biological markers such as the lithium ratio (Garver et al., 1984) and the apomorphine-growth hormone response (Hirschowitz et al., 1982). This lithium-responsive psychotic disorder also differs from the bulk of the psychoses by virtue of a (temporary) reduction of psychotic symptoms during and following administration of a cholesterase inhibitor (Edelstein et al., 1981). It is important to note that lithium-responsive and nonresponsive mood-incongruent psychotics cannot be differentiated on the basis of clinical symptoms (Garver et al., 1988). These data converge on the hypothesis that lithium-responsive mood-incongruent psychosis may represent a distinct psychotic subtype. Because lithium-responsive mood-incongruent psychotics typically show a remitting course of illness (Hirschowitz et al., 1980), the results of this study are directly related to the findings of a number of other family studies that have examined the familial relationship between goodprognosis schizophrenia, the affective disorders and the deteriorating schizophrenias. Several investigators have reported that patients who have been classified as having either good-prognosis schizophrenia (McCabe et al., 1981) or DSM-III schizophreniform disorder (Fogelson et al., 1982) show a paucity of schizophrenia but a high incidence of affective disorder in first-degree family members. Conversely, other investigators have reported that patients with schizophreniform disorder show familial overlap with schizophrenia and not with the affective disorders (Coryell and Tsuang, 1982; Kendler et al., 1986). Our mood-in-
congruent probands represent a heterogeneous diagnostic group who show both a favorable response to lithium and a remitting course of illness: first-degree relatives of these probands show a paucity of schizophrenia as well as a high morbid risk for major depressive disorder (18.2%). These data support the notion that patients who evidence schizophrenic-like symptoms but show a remitting course of illness have a disease that is genetically distinct from the deteriorating schizophrenias and is more closely related to the affective disorders. It is important to be conservative in interpreting the results of this study: the sample sizes of the relatives are small. With these small sample sizes, the possibility of type II errors must be considered. Despite these limitations, these data support the hypothesis that lithium-responsive (mood-incongruent) psychosis is far&ally distinct from the schizophrenias and the fact that the first-degree relatives of such patients show a high morbid risk for major depressive disorders suggests that there is familial overlap between this lithium-responsive psychosis and the affective disorders. References Abrams, R. and Taylor, M.A. (1983) The genetics of schizophrenia: a reassessment using modem criteria. Am. J. Psychiatry 140, 171-175. Alexander, P.E., van Kammen, D.P. and Bunney, W.E. (1979) Antipsychotic effects of lithium in schizophrenia. Am. J. Psychiatry 136, 282-287. American Psychiatric Association Committee on Nomenclature and Statistics (1980) Diagnostic and Statistical Manual of Mental Disorder, 3rd edn. American Psychiatric Association, Washington, D.C. Andreasen, N.C. (1987) The diagnosis of schizophrenia. Schiz. Bull. 13, 9-22. Astrachan, B.M., Harrow, M., Adler, D., Braver, L., Schwartz, A., Schwartz, C. and Tucker, G. (1972) A checklist for the diagnosis of schizophrenia. Br. J. Psychiatry 121, 529-539. Baron, M., Gruen, R., Asnis, L. and Kane, J. (1982) Schizoaffective disorders, schizophrenia, and affective disorders: morbidity risk and genetic transmission. Acta Psychiatr. Stand. 65, 253-262. Bleuler, M. (1978) The Schizophrenic Disorders: Long-term Patient and Family Studies. (S.M. Clemens, trans.) Yale University Press, New Haven, CT. Breborowicz, G. and Trzebiatowska-Trzeciak, 0. (1976) A method of testing differences in morbidity risk for affective psychoses. Acta Psychiatr. Stand. 54, 353-358.
69 Coryell, W. and Tsuang, M.T. (1982) DSM-III schizophreniform disorder: comparisons with schizophrenia and affective disorder. Arch. Gen. Psychiatry 39, 66-69. Crow, T.J. (1980) Molecular pathology of schizophrenia: more than one disease process? Br. Med. J. 280, 66-68. Edelstein, P., Schultz,. J.R., Hirschowitz, J., Kanter, D.R. and Garver, D.L. (1981) Physostigmine and lithium response in the schizophrenias. Am. J. Psychiatry 138, 1078-1081. Endicott, J., Andreasen, N. and Spitzer, R.L. (1978) Family History Research Diagnostic Criteria, 3rd edn. Biometrics Research Division, New York Psychiatric Institute, New York, NY. Fischer, M.F. (1969) A Danish twin study of schizophrenia. Br. J. Psychiatry 115, 981-990. Fogelson, D.L., Cohen, B.M. and Pope, H.G. Jr. (1982) A study of DSM-III schizophreniform disorder. Am. J. Psychiatry 139, 1281-1285. Garver, D.L., Hitzemann, R. and Hirschowitz, J. (1984) Lithium ratio in vitro, diagnosis, and lithium response in the psychoses. Arch. Gen. Psychiatry 41, 497-505. Garver, D.L., Kelly, K., Fried, K.A., Magnusson, M.M. and Hirschowitz, J. (1988) Drug response patterns as a basis of nosology for the mood-incongruent psychoses (the schizophrenias). Psychol. Med. 18, 873-885. Gottesman, 1.1. and Shields, J. (1972) Schizophrenia and Genetics: A Twin Study Vantage Point. Academic Press, New York, NY. Guze, S.B., Cloninger, C.R., Martin, R.L. and Clayton, P.J. (1983) A follow-up and family study of schizophrenia. Arch. Gen. Psychiatry 40, 1273-1276. Heston, L. (1966) Psychiatric disorders in foster home reared children of schizophrenic mothers. Br. J. Psychiatry 112, 819-825. Hirschowitz, J., Casper, R., Garver, D.L. and Chang, S. (1980) Lithium response in good prognosis schizophrenia. Am. J. Psychiatry 137, 916-920. Hirschowitz, J., Zemlan, F.P. and Garver, D.L. (1982) Growth hormone levels and lithium ratios as predictors of success of lithium therapy in schizophrenia. Am. J. Psychiatry 139, 646649. Kendler, K.S. and Gruenberg, A.M. (1984) An independent analysis of the Copenhagen sample of the Danish Adoption Study of schizophrenia. VI: The relationship between psychiatric disorders as defined by DSM-III in the relatives and adoptees. Arch. Gen. Psychiatry 41, 555-564.
Kendler, K.S., Gruenberg, A.M. and Tsuang, M.T. (1985) Psychiatric illness in first-degree relatives of schizophrenic and surgical control patients: a family study using DSM-III criteria. Arch. Gen. Psychiatry 42, 770-779. Kendler, K.S., Gruenberg, A.M. and Tsuang, M.T. (1986) A DSM-III family study of the nonschizophrenic psychotic disorders. Am. J. Psychiatry 143, 1098-1105. Kety, S.S., Rosenthal, D., Wender, P.H. and Schulsinger, F. (1968) The types and prevalence of mental illness in the biological and adoptive families of adopted schizophrenics. J. Psychiatr. Res. 6 (Suppl. l), 345-360. Loranger, A.W., Oldham, J.M. and Tulis, E.H. (1982) Familial transmission of DSM-III borderline personality disorder. Arch. Gen. Psychiatry 39, 795. McCabe, M.S., Fowler, R.C., Cadoret, R.J. and Winokur, G. (1971) Familial differences in schizophrenia with good and poor prognosis. Psychol. Med. 1, 326-332. Pope, H.G., Jones, J.M., Cohen, B.M. and Lipinski, J.F. (1982) Failure to find evidence of schizophrenia in first-degree relatives of schizophrenic probands. Am. J. Psychiatry 139, 826-828. Prein, R.F., Caffey, E.M. and KIett, C.J. (1972) A comparison of lithium carbonate and chlorpromazine in the treatment of excited schizoaffectives. Arch. Gen. Psychiatry 27, 182189. Sautter, F.J. and Garver, D.L. (1985) Familial differences in lithium responsive versus lithium nonresponsive psychoses. J. Psychiatr. Res. 19, l-8. Slater, E. and Cowie, V.A. (1971) The Genetics of Mental Disorders. Oxford University Press, London. Spitzer, E.L. and Endicott, J. (1975) Schedule of Affective Disorders and Schizophrenia - Life Time Version (SADSL). Biometrics Research, New York, NY. Tsuang, M.T., Winokur, G. and Crowe, R.R. (1980) Morbidity risks of schizophrenia and affective disorders among first degree relatives of patients with schizophrenia, mama, depression and surgical conditions. Br. J. Psychiatry 137, 492-504. Van Kammen, V.P. and Antelman, S. (1984) Mini-review: Impaired noradrenergic transmission in schizophrenia. Life Sci. 34. 1403-1413.
Journal of Affective Disorders, 20 (1990) 63-69 Elsevier
JAD 00740
A family study of lithium-responsive psychosis Frederic
J. Sautter I, Barbara
E. McDermott
’ and David L. Garver
2
’ Department of Psychiarry and Neurology, Tulane University School of Medicine, New Orleans, LA 70118, CJ.S.A and 2 Department of Psychiatry, University of Alabama, Birmingham, AL 35294, U.S.A. (Received 28 April 1988) (Accepted 2 May 1990)
Psychiatric life histories of 487 first-degree family members of 24 lithium-responsive (mood-incongruent) psychotics, 54 lithium-nonresponsive (mood-incongruent) psychotics, and 18 lithium-responsive patients with bipolar (manic-depressive) disorder were contrasted. While the morbid risk of schizophrenicspectrum was 11.1% in relatives of lithium-nonresponsive probands, the morbid risk for such disorders was only 2.4% in relatives of lithium-responsive (mood-incongruent) psychotics (P < 0.05). This lithium-responsive illness appears to be fan&ally, and perhaps genetically, distinct from the bulk of the schizophrenias.
Key words:
Lithium response; Family studies; Schizoaffective
Introduction It has become recognized that there are probably a number of illnesses nested within the schizophrenic spectrum. Research from our laboratory has indicated that one of these illnesses is a lithium-responsive subtype that presents with psychotic (mood-incongruent) symptoms similar to schizophrenia but has an illness course that is episodic. This article reports results of a family study designed to clarify the familial relationship between this lithium-responsive illness and
Address for correspondence: Frederic Department of Psychiatry and Neurology, School of Medicine, 1415 Tulane Avenue, 70118, U.S.A. 0165-0327/90/$03.50
J. Sautter, Ph.D., Tulane University New Orleans, LA
0 1990 Elsevier Science Publishers
disorder; Good-prognosis
schizophrenia
lithium-nonresponsive mood-incongruent psychosis on the one hand, and the bipolar affective disorders on the other. There have been numerous attempts to reduce the heterogeneity of the psychotic disorders by differentiating these disorders into more homogeneous subtypes. Such subtypes have been created on the basis of symptoms (Crow, 1980; Andreasen, 1987) illness course (McCabe et al., 1971) and biological markers (Van Kammen and Antelman, 1984). Work in our laboratory has focused upon resolving the heterogeneity of the mood-incongruent psychoses through the evaluation of drug response patterns. Our data indicate that while most mood-incongruent psychotic patients respond favorably to neuroleptics, a subtype of mood-incongruent psychotic patients also respond
B.V. (Biomedical
Division)
64
favorably to treatment with lithium (Hirschowitz et al., 1980). Lithium response in such patients has been demonstrated within the context of doubleblind, placebo-controlled drug trials (Garver et al., 1984) and data from other laboratories also indicate that schizophrenic patients may show a therapeutic response to lithium (Prein et al., 1972; Alexander et al., 1979). Data indicate that lithium-responsive and nonresponsive mood-incongruent psychotics cannot be differentiated on the basis of their clinical presentation (Garver et al., 1988). Studies from our laboratory have been designed to define this lithium-responsive mood-incongruent subtype along biologic parameters and on the basis of illness course and family patterns of illness. Our data indicate that these lithium-responsive psychotics often show abnormalities of lithium flow across red cell membranes (Garver et al., 1984); they evidence disturbances in receptor sensitivity to agonists such as apomorphine (Hirschowitz et al., 1982); and the majority of these patients show an episodic illness course with essentially full recovery between episodes (Hirschowitz et al., 1980). These lithium-responsive mood-incongruent patients also evidence a (temporary) reduction of psychotic symptoms during and following administration of a cholesterase inhibitor (Edelstein et al., 1981). Preliminary family studies have shown that the morbid risk of schizophrenic-spectrum disorder is substantially higher in relatives of lithium-nonresponsive mood-incongruent psychotics than in relatives of mood-incongruent psychotics that respond favorably to lithium (Sautter and Garver, 1985). In this report, we extend earlier family studies and present a more precise evaluation of the familial relationship between lithium-nonresponsive mood-incongruent psychotics, lithium-responsive mood-incongruent psychotics and the lithium-responsive bipolar disorders.
Emergency Service (PES). Each of the 96 psychotic probands underwent a 2-week drug-free diagnostic period during which time clinical diagnostics were performed according to SADSDSM-III (Endicott and Spitzer, 1978; APA, 1980) methods. At the end of the drug-free period, each patient received a 2-week trial of lithium carbonate at plasma levels rapidly adjusted to 0.8-1.4 mEq/l. Psychotic symptoms were quantitated biweekly during the drug-free period and the lithium trial employing a modified serial New Haven Schizophrenic Index (NHSI) (Astrachan et al., 1972). Probands were categorized as ‘lithium-responders’ if they showed a 35% reduction of baseline NHSI symptoms during the 1Cday lithium treatment and could go on to sustained remission of symptoms (NHSI I 5, CGI I 2) while maintained on lithium alone. * Probands not meeting these dual criteria were categorized as ‘nonresponders’ (Garver et al., 1984). Similarly, if a patient that is initially ‘lithium-responsive’ is found at follow-up or on subsequent hospitalization to no longer be responsive to lithium, that patient is classified as a ‘nonresponder’. Among the 24 lithium-responsive schizophrenic-like probands were 13 DSM-III schizophreniform disorders, five schizophrenics, and six psychotic (mood-incongruent) affective disorders; among the 54 lithium nonresponders were 10 DSM-III schizophreniform disorder patients and 44 schizophrenics. All 18 lithium-responsive bipolar patients showed mood-congruent psychotic symptoms. The mean age of the lithium-responsive mood-incongruent patients was 27.5 years; the mean age of the lithium-nonresponsive mood-incongruent patients was 25.7 years; the mean age of the lithium-responsive bipolar patients was 36.9 years. All consenting first-degree relatives (parents, offspring and siblings) of the three groups of probands underwent detailed SADS-L (Spitzer and Endicott, 1975) interviews. DSM-III diagnoses
Method Consenting patients were admitted to the Psychobiology Treatment Unit of the University of Cincinnati Hospital. Patients who consented to the treatment protocol were recruited from the University of Cincinnati Hospital Psychiatric
* The patients’ global symptoms Global Impression Scale (CGI) severity of illness. The range of at all’), 2 (‘borderline mentally erately ill’), 5 (‘markedly ill’), 6 the most extremely ill patients’).
were assessed on a Clinical which reflects the patients’ the ratings is 1 (‘normal, not ill’), 3 (‘mildly ill’), 4 (‘mod(‘severely ill’), and 7 (‘among
65
were then assigned to each of these relatives by an interviewer who was blind to the proband’s diagnosis and treatment response. When it was not possible to interview a relative (because of death, migration or refusal to participate), the family history method (Endicott et al., 1978) was used to assign a diagnosis. The mean age of all of the diagnosed relatives of the lithium-responsive schizophrenic-like probands was 38.4 years; the mean age of the diagnosed relatives of the nonresponsive probands was 39.7 years; the mean age of the diagnosed relatives of the lithium-responsive bipolar probands was 45.9 years. The relatives of the three groups of probands were compared to determine differences in the lifetime expectancy (morbid risk) of four classes of disorders: (1) DSM-III major depressive disorder; (2) DSM-III bipolar disorder; (3) DSM-III schizophrenia and schizoaffective disorder; and (4) DSM-III schizophreniform disorder. Morbid risk was determined by the Weinberg shorter method (Slater and Cowie, 1971). This method adjusts the sample size (BZ) by using the formula N - n, - 1/2n, with N representing the total number of relatives studied, n, the number of relatives who have not reached the risk period, and n the number of relatives within the risk period. The risk periods were as follows: schizophrenia, 15-39 years of age (Tsuang et al., 1980); unipolar affective disorder, 15-70 years of age (Loranger et al., 1982); bipolar affective illness, 15-60 years of age (Loranger et al., 1982); schizophreniform disorder, 15-60 years. * Statistical comparisons were performed hierarchically as recommended by Coryell and Zimmerman (1988). First, x2 tests were conducted to determine if group values differed overall. Then, if the groups differed at the 0.05 level, they were compared by means of the difference in proportions as modified
* The risk period for onset of fist episode of schizophreniform disorder has not been defined previously. Though the majority of our carefully diagnosed probands have the first episode of schizophreniform illness in the 20s or 30s. we have diagnosed first episode schizophreniform disorder as late as the 50s. We have, therefore, estimated the period of risk for schizophreniform disorder to be similar to that of bipolar illness: 15-60 years of age.
for use with morbid risk statistics and Trzebiatowska, 1976).
(Breborowicz
Results Information from the SADS-L was used to make lifetime DSM-III axis I diagnoses for each first-degree family member. Such lifetime diagnoses (including ‘never mentally ill’) could be made in 84.8% (413 of 487) of the first-degree relatives of the 96 participating probands. Two hundred and eighty-nine of those 413 diagnoses (70.0%) were made on the basis of direct interviews and 124 (30.0%) were made on the basis of a modification of the family history method that yields DSM-III diagnoses for unavailable relatives. Information pertaining to the number of relatives receiving a lifetime diagnosis and the method used to make the diagnosis for each of the three groups of relatives is presented in Table 1. The distribution of schizophrenia and schizophreniform disorder in relatives of the three groups of probands is shown in Table 2. The three groups of relatives differed significantly in terms of their morbid risk for schizophrenia (P -e 0.05); they did not differ significantly in terms of their risk for schizophreniform disorder. The relatives of the lithium-responsive mood-incongruent psychotics showed a morbid risk for schizophrenia of 2.4%; relatives of lithium-responsive bipolar patients showed a morbid risk for schizophrenia of 5.8%; and the morbid risk for the same disorder in relatives of lithium-nonresponsive probands was 11.1%. Post-hoc analyses indicate that the morbid risk for schizophrenia in the relatives of the lithium-responsive mood-incongruent probands was significantly higher than was evidenced in the relatives of the lithium-responsive mood-incongruent psychotics (P < 0.05); the relatives of lithium-nonresponsive mood-incongruent patients showed half the morbid risk for schizophrenia of relatives of the lithium-responsive bipolar probands (2.4% versus 5.8%). This difference was not statistically significant. The three groups of probands showed a similar morbid risk for DSM-III schizophreniform disorder. The relatives of the lithium-responsive mood-incongruent psychotics evidenced a morbid risk for schizophreniform disorder of 1.6%; rela-
66
TABLE
1
NUMBER OF RELATIVES RECEIVING A LIFETIME DIAGNOSIS AND METHOD USED TO RATE THE DIAGNOSIS IN RELATIVES OF PROBANDS WITH LITHIUM-RESPONSIVE MOOD-INCONGRUENT PSYCHOSIS, LITHIUM-NONRESPONSIVE MOOD-INCONGRUENT PSYCHOSIS, AND LITHIUM-RESPONSIVE BIPOLAR DISORDER Proband
Number Number Number Direct Family
of probands of relatives of relatives diagnosed interview (5%) history method (W)
Li-resp Mood-incong psychosis
Li-resp. bipolar disorder
Li-nonresp. mood-incong.
Total
24 126 113 (89.7%) 79 (69.9%) 34 (30.1%)
18 107 90 (84.1%) 59 (65.6%) 31 (34.4%)
54 254 210 (82.7%) 151 (71.9%) 59 (28.1%)
96 487 413 (84.8%) 289 (70.0%) 124 (30.0%)
tives of bipolar probands also showed a morbid risk of 1.7%; relatives of lithium-nonresponsive probands showed a morbid risk of 2.5% for DSMIII schizophreniform disorder. The lifetime incidence of unipolar major depressive disorder and bipolar disorder (mania) in the relatives of the three groups of probands is presented in Table 3. Inspection of the table reveals that a large proportion of the relatives had not passed through the risk period. Thus, the BZ (age-adjusted sample size) dropped significantly.
TABLE
The morbid risk for unipolar major depressive disorder in the relatives of the lithium-responsive mood-incongruent probands was 16.6%; the morbid risk for such illness in relatives of bipolar (manic) probands was 13.9%; the morbid risk for unipolar depression in the first-degree relatives of the lithium-nonresponsive mood-incongruent psychotics was 10.1%. Because of the reduced sample size and the conservative nature of the nonparametric test of significance, the three groups did not differ significantly.
2
SCHIZOPHRENIA AND SCHIZOPHRENIFORM SIVE MOOD-INCONGRUENT PSYCHOTICS, MOOD-INCONGRUENT PSYCHOTICS Proband
N
Li-responsive mood-incongruent psychotics (n = 24) Li-nonresponsive mood-incongruent psychotics (n = 54) Li-responsive bipolar (manic-repressive) disorder (n=18)
DISORDER IN FIRST-DEGREE LITHIUM-RESPONSIVE MANICS,
RELATIVES OF LITHIUM-RESPONAND LITHIUM-NONRESPONSIVE
BZ a
Schizophreniform Schizophrenia
114
64.5 84.0
Schizophreniform Schizophrenia
1 2
1.6% 2.4% *
210
120.5 152.5
Schizophreniform Schizophrenia
3 17
2.5% 11.1% *
90
58.5 68.5
Schizophreniform Schizophrenia
1 4
1.7% 5.8%
a BZ represents size of sample adjusted for period of risk. * x2 = 6.43’, df = 2, P < 0.05; lithium-resp. mood-incoxig. psychotics P < 0.05.
disorder
< lithium-nonresp.
(8) (%) *
mood-incong.
Morbid
psychotics;
risk
z = 2.36. df = 2,
67 TABLE
3
AFFECTIVE ILLNESS (DSM-III UNIPOLAR AND BIPOLAR DISORDER) IN FIRST-DEGREE RELATIVES RESPONSIVE MOOD-INCONGRUENT PSYCHOTICS, LITHIUM-RESPONSIVE MOOD-CONGRUENT AND LITHIUM-NONRESPONSIVE MOOD-INCONGRUENT PSYCHOTICS Proband
N
Li-responsive mood-incongruent psychotics (n = 24) Li-nonresponsive mood-incongruent psychotics (n=54) Li-responsive bipolar (manic-depressive) disorder (n =18)
114
a BZ represents
size of sample
Unipolar disorder Bipolar disorder
(%) (a)
Morbid
60.0 64.5
Unipolar Bipolar
10 3
16.6% 4.7%
210
108.5 120.5
Unipolar Bipolar
12 4
10.1% 3.3%
90
50.5 58.5
Unipolar Bipolar
7 6
13.9% 10.3%
adjusted
BZ a
for period
OF LITHIUMPSYCHOTICS,
risk
of risk.
Comparisons of the three groups of relatives for differences in the morbid risk for bipolar disorder revealed a trend towards significance (x2 = 4.96, df = 2, P < 0.1). The morbid risk for bipolar disorder in the first-degree relatives of the lithium-responsive bipolar probands was 10.3%; the morbid risk for bipolar disorder in relatives of lithium-responsive (mood-incongruent) psychotics was 4.7%; and the morbid risk for mania in relatives of lithium-nonresponsive (mood-incongruent) psychotics was 3.3%. The relatives of the lithium-responsive (mood-incongruent) probands showed a much lower morbid risk for bipolar disorder than did relatives of the lithium-responsive (mood-incongruent) probands. Discussion A primary objective of a series of studies from our laboratory has been to determine if lithium-responsive mood-incongruent psychosis represents a subtype that may be differentiated from the bulk of the mood-incongruent psychoses along a number of illness parameters. In this paper, we examine the familial relationship between this lithium-responsive subtype and the lithium-nonresponsive mood-incongruent psychoses on one hand and the lithium-responsive bipolar disorders on the other. First-degree relatives of lithium-respon-
sive probands showed a significantly lower morbid risk for schizophrenia than did relatives of moodincongruent psychotic probands that did not respond to lithium (2.4% versus 11.1%; P < 0.05). These data support earlier findings from our laboratory (Sautter and Carver, 1985) that suggest that lithium-responsive mood-incongruent psychosis is distinct from the bulk of the schizophrenias along familial parameters. Because the mood-incongruent psychotics that we have studied show a favorable response to lithium, the comparison of the family patterns of illness of the lithium-responsive mood-incongruent psychotics with those of relatives of the bipolar patients is of interest. The lithium-responsive mood-incongruent psychotics show a lower morbid risk for both schizophrenia (2.4% compared to 5.8%) and bipolar disorder (4.7% compared to 10.3%) than do the lithium-responsive bipolar patients. The two groups do not evidence similar patterns of familial psychopathology. It is interesting to note, however, that the first-degree relatives of our lithium-responsive mood-incongruent psychotics evidenced a relatively high morbid risk for major depressive disorder (16.6%) thus it is possible that there is some familial overlap between this lithium-responsive psychosis and unipolar depression. The fact that lithium-responsive mood-incon-
68
gruent psychosis differs from deteriorating schizophrenia along familial parameters does not constitute sufficient evidence to indicate that this disorder represents a distinct psychotic subtype. That hypothesis can only be accepted if it is shown that these patients can be discriminated from other psychotics along a number of theoretically salient disease parameters. It is for that reason that the data presented herein must be viewed within the context of other studies published by our laboratory. These studies indicate that when mood-incongruent psychotic patients are differentiated on the basis of therapeutic response to lithium they may also be reliably differentiated on the basis of illness course (Hirschowitz et al., 1980) and with respect to biological markers such as the lithium ratio (Garver et al., 1984) and the apomorphine-growth hormone response (Hirschowitz et al., 1982). This lithium-responsive psychotic disorder also differs from the bulk of the psychoses by virtue of a (temporary) reduction of psychotic symptoms during and following administration of a cholesterase inhibitor (Edelstein et al., 1981). It is important to note that lithium-responsive and nonresponsive mood-incongruent psychotics cannot be differentiated on the basis of clinical symptoms (Garver et al., 1988). These data converge on the hypothesis that lithium-responsive mood-incongruent psychosis may represent a distinct psychotic subtype. Because lithium-responsive mood-incongruent psychotics typically show a remitting course of illness (Hirschowitz et al., 1980), the results of this study are directly related to the findings of a number of other family studies that have examined the familial relationship between goodprognosis schizophrenia, the affective disorders and the deteriorating schizophrenias. Several investigators have reported that patients who have been classified as having either good-prognosis schizophrenia (McCabe et al., 1981) or DSM-III schizophreniform disorder (Fogelson et al., 1982) show a paucity of schizophrenia but a high incidence of affective disorder in first-degree family members. Conversely, other investigators have reported that patients with schizophreniform disorder show familial overlap with schizophrenia and not with the affective disorders (Coryell and Tsuang, 1982; Kendler et al., 1986). Our mood-in-
congruent probands represent a heterogeneous diagnostic group who show both a favorable response to lithium and a remitting course of illness: first-degree relatives of these probands show a paucity of schizophrenia as well as a high morbid risk for major depressive disorder (18.2%). These data support the notion that patients who evidence schizophrenic-like symptoms but show a remitting course of illness have a disease that is genetically distinct from the deteriorating schizophrenias and is more closely related to the affective disorders. It is important to be conservative in interpreting the results of this study: the sample sizes of the relatives are small. With these small sample sizes, the possibility of type II errors must be considered. Despite these limitations, these data support the hypothesis that lithium-responsive (mood-incongruent) psychosis is far&ally distinct from the schizophrenias and the fact that the first-degree relatives of such patients show a high morbid risk for major depressive disorders suggests that there is familial overlap between this lithium-responsive psychosis and the affective disorders. References Abrams, R. and Taylor, M.A. (1983) The genetics of schizophrenia: a reassessment using modem criteria. Am. J. Psychiatry 140, 171-175. Alexander, P.E., van Kammen, D.P. and Bunney, W.E. (1979) Antipsychotic effects of lithium in schizophrenia. Am. J. Psychiatry 136, 282-287. American Psychiatric Association Committee on Nomenclature and Statistics (1980) Diagnostic and Statistical Manual of Mental Disorder, 3rd edn. American Psychiatric Association, Washington, D.C. Andreasen, N.C. (1987) The diagnosis of schizophrenia. Schiz. Bull. 13, 9-22. Astrachan, B.M., Harrow, M., Adler, D., Braver, L., Schwartz, A., Schwartz, C. and Tucker, G. (1972) A checklist for the diagnosis of schizophrenia. Br. J. Psychiatry 121, 529-539. Baron, M., Gruen, R., Asnis, L. and Kane, J. (1982) Schizoaffective disorders, schizophrenia, and affective disorders: morbidity risk and genetic transmission. Acta Psychiatr. Stand. 65, 253-262. Bleuler, M. (1978) The Schizophrenic Disorders: Long-term Patient and Family Studies. (S.M. Clemens, trans.) Yale University Press, New Haven, CT. Breborowicz, G. and Trzebiatowska-Trzeciak, 0. (1976) A method of testing differences in morbidity risk for affective psychoses. Acta Psychiatr. Stand. 54, 353-358.
69 Coryell, W. and Tsuang, M.T. (1982) DSM-III schizophreniform disorder: comparisons with schizophrenia and affective disorder. Arch. Gen. Psychiatry 39, 66-69. Crow, T.J. (1980) Molecular pathology of schizophrenia: more than one disease process? Br. Med. J. 280, 66-68. Edelstein, P., Schultz,. J.R., Hirschowitz, J., Kanter, D.R. and Garver, D.L. (1981) Physostigmine and lithium response in the schizophrenias. Am. J. Psychiatry 138, 1078-1081. Endicott, J., Andreasen, N. and Spitzer, R.L. (1978) Family History Research Diagnostic Criteria, 3rd edn. Biometrics Research Division, New York Psychiatric Institute, New York, NY. Fischer, M.F. (1969) A Danish twin study of schizophrenia. Br. J. Psychiatry 115, 981-990. Fogelson, D.L., Cohen, B.M. and Pope, H.G. Jr. (1982) A study of DSM-III schizophreniform disorder. Am. J. Psychiatry 139, 1281-1285. Garver, D.L., Hitzemann, R. and Hirschowitz, J. (1984) Lithium ratio in vitro, diagnosis, and lithium response in the psychoses. Arch. Gen. Psychiatry 41, 497-505. Garver, D.L., Kelly, K., Fried, K.A., Magnusson, M.M. and Hirschowitz, J. (1988) Drug response patterns as a basis of nosology for the mood-incongruent psychoses (the schizophrenias). Psychol. Med. 18, 873-885. Gottesman, 1.1. and Shields, J. (1972) Schizophrenia and Genetics: A Twin Study Vantage Point. Academic Press, New York, NY. Guze, S.B., Cloninger, C.R., Martin, R.L. and Clayton, P.J. (1983) A follow-up and family study of schizophrenia. Arch. Gen. Psychiatry 40, 1273-1276. Heston, L. (1966) Psychiatric disorders in foster home reared children of schizophrenic mothers. Br. J. Psychiatry 112, 819-825. Hirschowitz, J., Casper, R., Garver, D.L. and Chang, S. (1980) Lithium response in good prognosis schizophrenia. Am. J. Psychiatry 137, 916-920. Hirschowitz, J., Zemlan, F.P. and Garver, D.L. (1982) Growth hormone levels and lithium ratios as predictors of success of lithium therapy in schizophrenia. Am. J. Psychiatry 139, 646649. Kendler, K.S. and Gruenberg, A.M. (1984) An independent analysis of the Copenhagen sample of the Danish Adoption Study of schizophrenia. VI: The relationship between psychiatric disorders as defined by DSM-III in the relatives and adoptees. Arch. Gen. Psychiatry 41, 555-564.
Kendler, K.S., Gruenberg, A.M. and Tsuang, M.T. (1985) Psychiatric illness in first-degree relatives of schizophrenic and surgical control patients: a family study using DSM-III criteria. Arch. Gen. Psychiatry 42, 770-779. Kendler, K.S., Gruenberg, A.M. and Tsuang, M.T. (1986) A DSM-III family study of the nonschizophrenic psychotic disorders. Am. J. Psychiatry 143, 1098-1105. Kety, S.S., Rosenthal, D., Wender, P.H. and Schulsinger, F. (1968) The types and prevalence of mental illness in the biological and adoptive families of adopted schizophrenics. J. Psychiatr. Res. 6 (Suppl. l), 345-360. Loranger, A.W., Oldham, J.M. and Tulis, E.H. (1982) Familial transmission of DSM-III borderline personality disorder. Arch. Gen. Psychiatry 39, 795. McCabe, M.S., Fowler, R.C., Cadoret, R.J. and Winokur, G. (1971) Familial differences in schizophrenia with good and poor prognosis. Psychol. Med. 1, 326-332. Pope, H.G., Jones, J.M., Cohen, B.M. and Lipinski, J.F. (1982) Failure to find evidence of schizophrenia in first-degree relatives of schizophrenic probands. Am. J. Psychiatry 139, 826-828. Prein, R.F., Caffey, E.M. and KIett, C.J. (1972) A comparison of lithium carbonate and chlorpromazine in the treatment of excited schizoaffectives. Arch. Gen. Psychiatry 27, 182189. Sautter, F.J. and Garver, D.L. (1985) Familial differences in lithium responsive versus lithium nonresponsive psychoses. J. Psychiatr. Res. 19, l-8. Slater, E. and Cowie, V.A. (1971) The Genetics of Mental Disorders. Oxford University Press, London. Spitzer, E.L. and Endicott, J. (1975) Schedule of Affective Disorders and Schizophrenia - Life Time Version (SADSL). Biometrics Research, New York, NY. Tsuang, M.T., Winokur, G. and Crowe, R.R. (1980) Morbidity risks of schizophrenia and affective disorders among first degree relatives of patients with schizophrenia, mama, depression and surgical conditions. Br. J. Psychiatry 137, 492-504. Van Kammen, V.P. and Antelman, S. (1984) Mini-review: Impaired noradrenergic transmission in schizophrenia. Life Sci. 34. 1403-1413.
