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Psychosis as a predictor of response to lithium maintenance treatment in bipolar affective disorder
237
Journal ofAffective Disorders, 1 (1979) 237-245 0 Elsevier/North-Holland Biomedical Press
PSYCHOSIS AS A PREDICTOR MAINTENANCE TREATMENT
NORMAN E. ROSENTHAL JOSEPH FLEISS 4, DAVID
OF RESPONSE TO LITHIUM IN BIPOLAR AFFECTIVE DISORDER
‘, LEORA N. ROSENTHAL L. DUNNER 5 and RONALD
*, FRANK R. FIEVE
STALLONE 6
3,
’ Chief Resident, New York State Psychiatric Institute; 2 Graduate Student, Columbia University; 3 Ayerst Laboratories, Inc.; 4 Professor and Head, Division of Biostatisfics, School of Public Health, Columbia Universify; 5 Associate Director, Lithium Clinic, New York State Psychiatric Institute, and Associate Professor of Clinical Psychiatry at Columbia University College of Physicians and Surgeons; ’ Professor of Clinical Psychiatry at Columbia University College of Physicians and Surgeons and Chief of Psychiatric Research for Lithium Clinic at New York State Psychiatric Institute, New York, NY 10032 (U.S.A.) (Received (Revised, (Accepted
23 May, 1979) received 23 July, 24 July, 1979)
1979)
SUMMARY Sixty-six bipolar I lithium clinic patients were studied for a history of psychotic symptoms at some time during the course of their illness. Agreement between different sources of information was calculated, and the patient population was divided into psychotic and non-psychotic subgroups. Probability of remaining well on lithium for the different subgroups was analyzed by the life table method. Psychosis during mania appeared to be associated with especially good early lithium prophylaxis.
INTRODUCTION
The value of lithium carbonate in preventing relapses in manic depressive patients has been established. Nevertheless, even on adequate lithium maintenance treatment, relapses do occur. The purpose of this study is to examine a group of bipolar I clinic patients for a history of psychotic symptoms, in particular delusions and hallucinations, during mania and depression, and to determine what predictive value, if any, these symptoms have on the length of time that patients remain well after lithium treatment is started.
All correspondence Clinical Psychobiology 48239, 9000 Rockville
should be addressed to: Norman E. Rosenthal, Branch, National Institute of Mental Health, Pike, Bethesda, MD 20205, U.S.A.
M.D., Staff Fellow, Building 10, Room
238 METHODS
The study took place in the Lithium Clinic of the New York State Psychiatric Institute, and all patients taking part in it provided informed consent. The clinic and research records of all bipolar I patients were studied. All active bipolar I patients seen at the clinic between 1 September, 1977 and 31 March, 1978 were given a structured interview inquiring into a history of psychotic symptoms in mania and depression. The details of this interview have been described by Rosenthal et al. (1979). All patients who met the following criteria were included in this study: (a) diagnosis of primary affective disorder based on the criteria of Feighner et al. (1972); (b) a history of at least one previous hospitalization specifically for a manic attack, cf. Dunner et al. (1970); (c) normal mood at some time during their clinic follow-up of at least 4 weeks; and (d) sufficiently detailed clinical and research records. The presence or absence of previous psychotic symptoms during mania and/or depression was ascertained from 3 sources: (a) the clinic record; (b) the Schedule for Affective Disorders and Schizophrenia (SADS), cf. Endicott and Spitzer (1978); and (c) the structured interview previously mentioned. One hundred and fifteen patients met the diagnostic inclusion criteria, but of these only 66 were considered to have adequate records, defined as information available from at least two of the above sources. In 42 cases information was available from all 3 sources. Psychotic symptoms were classified into grandiose, paranoid and bizarre delusions, and visual and auditory hallucinations. Thought disorder was not included as a psychotic symptom as it appeared to be highly unreliably reported. Delusions were only regarded as present when patients’ beliefs were patently false and refractory to reason. Paranoid trends were thus not counted as delusions. The category ‘bizarre’ was somewhat arbitrary. Thus, a woman who believed she was about to be cannibalized by a band of hostile teenagers was judged to have both a paranoid and a bizarre delusion, whereas patients who believed they were being pursued by government agencies were regarded as having paranoid but not bizarre delusions. Decisions about the presence and nature of psychotic symptoms were made in consensus by two of the authors (N.E.R. and L.N.R.), who were blind to the patients’ subsequent course on lithium. Concordance between the 3 separate sources (chart, SADS and interview) as to diagnosis of psychosis and type of delusions, was computed by the kappa statistic, as described by Cohen (1960) and extended by Fleiss (1971) for use when more than one source of information is available. The patients were treated with lithium carbonate either on an open or double blind basis. Lithium treatment was considered to begin whenever the patient first received it, whether at the clinic or elsewhere. Most patients received their initial lithium treatment at the clinic. Data were recorded about duration of lithium treatment. For patients discharged from the clinic, it was noted whether they left in a normal mood state or not. Time until
239
failure was recorded in those patients who did not remain well, failure being defined as the development of an affective relapse (manic, depressive or cyclic) of such severity that a modification in the treatment, e.g., increase in dosage of lithium, hospitalization or addition of antidepressants or neuroleptics, was required. Further data noted included age when patient was first treated for illness, age of presentation to the clinic, sex of patient, number of affective episodes in the two years preceding lithium treatment, and mean serum lithium level on each patient until the end of the period under consideration. Formal statistical follow-up began 4 weeks after the patient was judged to have recovered from the index episode. Data were analyzed up to 15 December, 1978. Psychotic and non-psychotic groups were compared with respect to clinical variables. Outcome data were analyzed by the life table method, as described by Fleiss et al. (1976). This technique provides probabilities of remaining well from the start of follow-up through each of any number of consecutive time intervals. The technique also allows for inclusion of those patients who were discharged while still well at different points in the follow-up. A summary chi-square with one degree of freedom, described by Mantel (1966), is available for comparing entire sequences of probabilities. The patients treated on open medication were analyzed together with those treated blind, as Dunner et al. (1976), working with a large subset of this population, showed no significant differences between these two groups. RESULTS
Clinical characteristics Of the 66 patients who met the inclusion
criteria for this study, 44 (67%) were diagnosed as having been psychotic at some stage in their illness, according to at least one source. Thirty of these patients were psychotic during mania only, 5 during depression only, and 9 during both mania and depression. The nature of psychotic symptoms experienced and their frequencies are shown in Table 1. The commonest psychotic symptoms were
TABLE
1
FREQUENCY
AND DISTRIBUTION
OF PSYCHOTIC
Patients
Grandiose delusions Paranoid delusions Bizarre delusions Auditory hallucinations Visual hallucinations
N
%
23 23 18 20 14
35 35 27 30 21
SYMPTOMS
240
paranoid and grandiose delusions, each present in 35% of the population. The least common psychotic symptom was visual hallucinations (21% of pdpulation). ’ In Table 2 certain clinical features of the psychotic and non-psychotic groups are compared. It is of note that the psychotic group has a younger age of presentation to the clinic (P < 0.02). There is no difference, however, in sex ratio, age at first treatment, episode frequency during the two years prior to lit,hium treatment, and mean serum lithium level during the course of treatment. Reliability Concordance in diagnosis of psychosis between different sources was calculated initially on all 66 patients. The kappa values were 0.34 for psychosis at any time, 0.34 for psychosis during mania, and 0.15 for psychosis during depression. These values are rather low, cf. Landis and Koch (1977). In order to maximize the chances of demonstrating a difference between psychotic and non-psychotic groups, should such a difference exist, the concordance was recalculated on the basis of those 42 cases on whom information from all 3 sources was available. This analysis yielded somewhat higher values: kappa values were 0.43 for psychosis at any time, 0.49 for psychosis during mania, and 0.24 for psychosis during depression. It is apparent that psychosis in mania was diagnosed far more reliably than psychosis during depression, and that reliability, while still no better than fair, was considerably higher when all 3 sources were used. Reliability values for the different types of delusions were calculated. All values were low, but surprisingly the diagnosis of bizarre delusions was most reliable (kappa = 0.22). Reliability values for the others were much lower: for paranoid delusions, kappa = 0.10, and for grandiose delusions, kappa = 0.02. TABLE
2
CLINICAL
FEATURES
Data presented
OF THE POPULATION
as mean k SD. Psychotic (N = 44)
Non-psychotic (N = 22)
23 21
11 11
P
sex Male Female Age at first treatment Age of presentation
to clinic
Episode (No.
in past 2 years)
frequency of episodes
Mean lithium a NS: P > 0.05
on Student’s
27.4
i
9.4
32.2
k 9.1
NS
40.8
f 12.7
48.5
i 6.3
<0.02
0.3
0.4
+ 0.3
NS
0.18
0.85 f 0.24
0.5
+
0.79 i
level f-test (2-tailed).
NSa
NS
241
Outcome The rate of relapse on lithium is biphasic (see Fig. 1) and the majority of patients (over 70%) who failed within the 192 week period studied, did so in the first 36 weeks. Thereafter failure occurs at a much slower rate. When we compared psychotic with non-psychotic patient groups, we found a consistent trend for the psychotic group to remain well longer throughout the course of lithium treatment. When all 66 patients were considered, this trend reached statistical significance (x2 = 3.92, P < 0.05) between weeks 28 and 36, the significance level dropping as more patients from both groups failed or were discharged from the clinic. When we considered the subgroup of 42 patients on whom all 3 sources of information (chart, SADS and interview) were available, the difference in outcome between psychotic and nonpsychotic groups reached statistical significance between weeks 16 and 20 (x’ = 4.46, P < 0.05) and again became less pronounced over time. Having noted this difference in time until relapse between psychotic and non-psychotic groups, we wondered whether it was attributable to psychosis during mania, depression or both. Figure 1 illustrates graphically the probability of remaining well for non-psychotic patients, for patients who have been psychotic at any time, and for those who have been psychotic during mania only. It can be seen that the pattern of response of the psychotic 1.0
0.8
0.6
1
0
40
80
120
160
200
240
WEEKS Fig. 1. The probability of remaining well over time is illustrated for patients who have been psychotic at some time in their illness, patients who have been psychotic during mania only, and patients who have never been psychotic. The rapid, early rate of failure is less marked for the psychotic groups.
242 TABLE
3
RELATIONSHIP Group
Psychotic -(N = 44) Non-psychotic (N = 22) Psychotic -(N = 31) Non-psychotic (N=ll)
BETWEEN
PSYCHOSIS
No. of sources
At least two
Three
a 0.05 < P < 0.10. b P < 0.05. Probabilities compared
by Mantel
AND Kappa
0.34
0.43
LITHIUM
MAINTENANCE
RESPONSE
Cumulative probability remaining well (weeks) 16
32
0.84 a
0.78
0.64
0.49
0.84 h
0.80
0.55
0.45
of
192 b
0.47 0.31
a
0.30 0.30
chi-square.
manic group closely resembles that of the group who had been psychotic at any time. This is partly because the psychotic manic group constitutes a large proportion of the latter group (84%). The psychotic manic group was found to do significantly better than the non-psychotic group between weeks 28 and 36 (x2 = 4.36, P < 0.05). When patients with information from all 3 sources are considered, the difference between psychotic manics and non-psychotics falls just short of statistical significance (x’ = 3.32, 0.05 < P < 0.10,between weeks 16 and 24) probably due to the attenuated numbers (only 27 patients in the psychotic manic group). Fleiss et al. (1976) suggest caution in interpretation of life table results when sample sizes are small. When the 14 patients who had been psychotic during depression are compared with the 22 patients who had never been psychotic, no significant difference between groups was noted. Once again the small numbers involved dictate caution in drawing conclusions. Since the age of presentation to the clinic was lower in the psychotic than the non-psychotic group, we compared the probability of remaining well for patient groups falling above and below the median value for this variable. No significant difference was noted. DISCUSSION
Dunner et al. (1976) examined the pattern of failure of lithium maintenance treatment in bipolar I population and pointed out the biphasic nature
243
of lithium maintenance failure. These authors state that it would be clinically helpful to predict which patients will fail early, since their data suggested that such patients are also more prone to a second affective episode earlier than patients whose initial failure is delayed. From our data it appears that those patients with a history of mania not characterized by delusions or hallucinations are more likely to fail early than those patients who have had psychotic symptoms during mania. Pope and Lipinski (1978) have reviewed the literature on studies where manic depressives with psychotic or ‘schizophrenic’ symptoms are compared to more classical manic depressives with regard to lithium response. They conclude that ‘no controlled study has convincingly demonstrated a difference between manic depressive illness and good prognosis ‘schizo-affectives’ in their response to lithium carbonate; the trend of existing data suggests that they may respond equally’. These authors are careful to exclude from this statement studies which define their schizo-affective group as having impaired functioning between episodes or poor pre-morbid features. The ‘atypical cases’ in a lithium prophylaxis study by Baastrup and Schou (1967) fall into this category. In some of these cases delusions were present constantly even when patients were neither manic nor depressed. These patients had a less satisfactory response to lithium than the more typical manic depressives. Angst et al. (1969), on the other hand, in a lithium prophylaxis study, found their schizo-affective group to have a lower relapse rate than a group of manic depressives, though this did not reach statistical significance. They used 10.8 months as the time interval at which they compared the relapse rates. It is interesting to note that had we used this cut-off time in our data analysis, our between group difference would also have fallen short of statistical significance. This illustrates the superiority of the life table method, which allows for comparison at any of a large number of time intervals, over the use of an arbitrary cut-off point. Smulevitch et al. (1974) found lithium prophylaxis to be equally effective patients as compared to classical manic depressive in ‘schizo-affective’ patients. Perris (1974) found that lithium carbonate prevented relapses in his population of cycloid psychoses to an extent comparable to results found in classical manic depressives mentioned elsewhere in the literature, cf. Pope and Lipinski (1978). The above-mentioned studies are the major reports in the literature on the effects of lithium carbonate in preventing relapse in psychotic manics as compared with non-psychotic manics. Our results were rather surprising in that they would not have been anticipated by previous reports except, perhaps, the study of Angst et al. (1969). The fact that no previous study has shown psychosis in mania and specific psychotic symptoms to be predictive of response to lithium maintenance therapy may be due to the following factors: (a) the inclusion of poor prognostic patients in the psychotic groups; (b) different ways of dichotomizing groups, e.g., Rosenthal et al. (1979)
244
have shown that when a group of patients meeting the Research Diagnostic Criteria for schizo-affective disorder is compared with a mixed group of psychotic and non-psychotic manic depressives, there is no difference in rate of relapse on lithium; and (c) the use of methods of data analysis less sensitive than the life table method. Given that the psychotic manics have a lower rate of early relapse than the non-psychotic group, there remain various possible explanations for this finding. It may be due to a difference in pattern of relapse between these two groups whether patients are on lithium or not. The fact that we found no significant difference in episode frequency during the previous two years would appear to argue against this but it could be argued that this is a crude measure of the pattern of episode occurrence as compared with the more refined way in which relapse rate was analyzed. Another possible explanation is a difference in medication compliance between the two groups. We have no evidence that this differed between groups and there is no significant difference in mean lithium levels. It is conceivable, however, that some subtle form of non-compliance may have occurred in the non-psychotic group to a greater extent than in the psychotic group, though we have no reason to suspect that this was the case. This leaves us with the final possibility that there is some biological difference between those bipolar patients who have psychotic mania and those who do not. It is interesting that there is a proportion of patients (33% in our sample) who, even when all sources of information are considered, appear never to have been psychotic. Carlson and Goodwin (1973), observing untreated bipolar I patients longitudinally, also found that a similar proportion (30%) did not reach the final stage of mania. Thus the difference in relapse rate on lithium may be due to biological differences between psychotic and non-psychotic manic depressive patients. If this is the case, it would appear to be of some clinical, and considerable theoretical interest. ACKNOWLEDGEMENTS
The authors wish to acknowledge Heh Lee, MPH, Manager of Data Processing Section, Clinical Information Center, Sloan Kettering Memorial Hospital, for his statistical assistance. Supported by Federal Grant MH-21586, New York State Psychiatric Institute and Columbia Millhauser Depression Center. REFERENCES Angst, J., Dittrich, A. and Grof, P. Course of endogenous affective psychoses and its modification by prophylactic administration of imipramine and lithium, Int. J. Pharmacopsychiat., 2 (1969) l-11. Baastrup, P.C. and Schou, M., Lithium as a prophylactic agent - Its effect against recurrent depressions and manic-depressive psychosis, Arch. Gen. Psychiat., 16 (1967) 162-172.
245 Carlson, G.A. and Goodwin, F.K., The stages of mania manic episode, Arch. Gen. Psychiat., 28 (1973) 221-228. Cohen, J., A coefficient of agreement for nominal scales,
A longitudinal Educ.
Psychol.
analysis
of the
Measurement,
20 (1960) 37-46. Dunner, D.L., Fleiss, J.L. and Fieve, R.R., Lithium carbonate prophylaxis failure, Brit. J. Psychiat., 129 (1976) 40-44. Dunner, D.L. Gershon, ES. and Goodwin, F.K., Heritable factors in affective illness, Sci. Proc. Amer. Psychiat. Ass., 123 (1970) 187-188. Endicott, J. and Spitzer, R.L. A diagnostic interview -The schedule for affective disorders and schizophrenia. Arch. Gen. Psychiat., 35 (1978) 837-844. Feighner, J.P., Robins, E., Guze, S.B., Woodruff, Jr., R.A., Winokur, G. and Munoz, R., Diagnostic criteria for use in psychiatric research, Arch. Gen. Psychiat., 26 (1972) 57-63. Fleiss, J.L., Measuring nominal scale agreement among many raters, Psychol. Bull., 76 (1971) 378-382. Fleiss, J.L. Dunner, D.L., Stallone, F. and Fieve, R.R., The life table -A method for analyzing longitudinal studies, Arch. Gen. Psychiat., 33 (1976) 107-112. Landis, J.R. and Koch, G.G., The measurement of observer agreement for categorical data, Biometrics, 33 (1977) 159-174. Mantel, N., Evaluation of survival data and two new rank order statistics arising in its consideration, Cancer Chemother. Rep., 50 (1966) 163-170. Perris, C., A study of cycloid psychoses, Acta. Psychiat. Stand., Suppl. 253 (1974). Pope, Jr., H.G. and Lipinski, Jr., J.F., Diagnosis in schizophrenia and manic-depressive illness, Arch. Gen. Psychiat., 35 (1978) 811-828. Rosenthal, N.E., Rosenthal, L.N., Stallone, F., Dunner, D.L. and Fieve, R.R., The validation of RDC schizo-affective disorder, 1979, Unpublished. Smulevitch, A.B., Zavidovskaya, G.I., Igonin, A.L. and Mikhailova, N.M., The effectiveness of lithium in affective and schizo-affective psychoses, Brit. J. Psychiat., 125 (1974) 65-72.
Journal ofAffective Disorders, 1 (1979) 237-245 0 Elsevier/North-Holland Biomedical Press
PSYCHOSIS AS A PREDICTOR MAINTENANCE TREATMENT
NORMAN E. ROSENTHAL JOSEPH FLEISS 4, DAVID
OF RESPONSE TO LITHIUM IN BIPOLAR AFFECTIVE DISORDER
‘, LEORA N. ROSENTHAL L. DUNNER 5 and RONALD
*, FRANK R. FIEVE
STALLONE 6
3,
’ Chief Resident, New York State Psychiatric Institute; 2 Graduate Student, Columbia University; 3 Ayerst Laboratories, Inc.; 4 Professor and Head, Division of Biostatisfics, School of Public Health, Columbia Universify; 5 Associate Director, Lithium Clinic, New York State Psychiatric Institute, and Associate Professor of Clinical Psychiatry at Columbia University College of Physicians and Surgeons; ’ Professor of Clinical Psychiatry at Columbia University College of Physicians and Surgeons and Chief of Psychiatric Research for Lithium Clinic at New York State Psychiatric Institute, New York, NY 10032 (U.S.A.) (Received (Revised, (Accepted
23 May, 1979) received 23 July, 24 July, 1979)
1979)
SUMMARY Sixty-six bipolar I lithium clinic patients were studied for a history of psychotic symptoms at some time during the course of their illness. Agreement between different sources of information was calculated, and the patient population was divided into psychotic and non-psychotic subgroups. Probability of remaining well on lithium for the different subgroups was analyzed by the life table method. Psychosis during mania appeared to be associated with especially good early lithium prophylaxis.
INTRODUCTION
The value of lithium carbonate in preventing relapses in manic depressive patients has been established. Nevertheless, even on adequate lithium maintenance treatment, relapses do occur. The purpose of this study is to examine a group of bipolar I clinic patients for a history of psychotic symptoms, in particular delusions and hallucinations, during mania and depression, and to determine what predictive value, if any, these symptoms have on the length of time that patients remain well after lithium treatment is started.
All correspondence Clinical Psychobiology 48239, 9000 Rockville
should be addressed to: Norman E. Rosenthal, Branch, National Institute of Mental Health, Pike, Bethesda, MD 20205, U.S.A.
M.D., Staff Fellow, Building 10, Room
238 METHODS
The study took place in the Lithium Clinic of the New York State Psychiatric Institute, and all patients taking part in it provided informed consent. The clinic and research records of all bipolar I patients were studied. All active bipolar I patients seen at the clinic between 1 September, 1977 and 31 March, 1978 were given a structured interview inquiring into a history of psychotic symptoms in mania and depression. The details of this interview have been described by Rosenthal et al. (1979). All patients who met the following criteria were included in this study: (a) diagnosis of primary affective disorder based on the criteria of Feighner et al. (1972); (b) a history of at least one previous hospitalization specifically for a manic attack, cf. Dunner et al. (1970); (c) normal mood at some time during their clinic follow-up of at least 4 weeks; and (d) sufficiently detailed clinical and research records. The presence or absence of previous psychotic symptoms during mania and/or depression was ascertained from 3 sources: (a) the clinic record; (b) the Schedule for Affective Disorders and Schizophrenia (SADS), cf. Endicott and Spitzer (1978); and (c) the structured interview previously mentioned. One hundred and fifteen patients met the diagnostic inclusion criteria, but of these only 66 were considered to have adequate records, defined as information available from at least two of the above sources. In 42 cases information was available from all 3 sources. Psychotic symptoms were classified into grandiose, paranoid and bizarre delusions, and visual and auditory hallucinations. Thought disorder was not included as a psychotic symptom as it appeared to be highly unreliably reported. Delusions were only regarded as present when patients’ beliefs were patently false and refractory to reason. Paranoid trends were thus not counted as delusions. The category ‘bizarre’ was somewhat arbitrary. Thus, a woman who believed she was about to be cannibalized by a band of hostile teenagers was judged to have both a paranoid and a bizarre delusion, whereas patients who believed they were being pursued by government agencies were regarded as having paranoid but not bizarre delusions. Decisions about the presence and nature of psychotic symptoms were made in consensus by two of the authors (N.E.R. and L.N.R.), who were blind to the patients’ subsequent course on lithium. Concordance between the 3 separate sources (chart, SADS and interview) as to diagnosis of psychosis and type of delusions, was computed by the kappa statistic, as described by Cohen (1960) and extended by Fleiss (1971) for use when more than one source of information is available. The patients were treated with lithium carbonate either on an open or double blind basis. Lithium treatment was considered to begin whenever the patient first received it, whether at the clinic or elsewhere. Most patients received their initial lithium treatment at the clinic. Data were recorded about duration of lithium treatment. For patients discharged from the clinic, it was noted whether they left in a normal mood state or not. Time until
239
failure was recorded in those patients who did not remain well, failure being defined as the development of an affective relapse (manic, depressive or cyclic) of such severity that a modification in the treatment, e.g., increase in dosage of lithium, hospitalization or addition of antidepressants or neuroleptics, was required. Further data noted included age when patient was first treated for illness, age of presentation to the clinic, sex of patient, number of affective episodes in the two years preceding lithium treatment, and mean serum lithium level on each patient until the end of the period under consideration. Formal statistical follow-up began 4 weeks after the patient was judged to have recovered from the index episode. Data were analyzed up to 15 December, 1978. Psychotic and non-psychotic groups were compared with respect to clinical variables. Outcome data were analyzed by the life table method, as described by Fleiss et al. (1976). This technique provides probabilities of remaining well from the start of follow-up through each of any number of consecutive time intervals. The technique also allows for inclusion of those patients who were discharged while still well at different points in the follow-up. A summary chi-square with one degree of freedom, described by Mantel (1966), is available for comparing entire sequences of probabilities. The patients treated on open medication were analyzed together with those treated blind, as Dunner et al. (1976), working with a large subset of this population, showed no significant differences between these two groups. RESULTS
Clinical characteristics Of the 66 patients who met the inclusion
criteria for this study, 44 (67%) were diagnosed as having been psychotic at some stage in their illness, according to at least one source. Thirty of these patients were psychotic during mania only, 5 during depression only, and 9 during both mania and depression. The nature of psychotic symptoms experienced and their frequencies are shown in Table 1. The commonest psychotic symptoms were
TABLE
1
FREQUENCY
AND DISTRIBUTION
OF PSYCHOTIC
Patients
Grandiose delusions Paranoid delusions Bizarre delusions Auditory hallucinations Visual hallucinations
N
%
23 23 18 20 14
35 35 27 30 21
SYMPTOMS
240
paranoid and grandiose delusions, each present in 35% of the population. The least common psychotic symptom was visual hallucinations (21% of pdpulation). ’ In Table 2 certain clinical features of the psychotic and non-psychotic groups are compared. It is of note that the psychotic group has a younger age of presentation to the clinic (P < 0.02). There is no difference, however, in sex ratio, age at first treatment, episode frequency during the two years prior to lit,hium treatment, and mean serum lithium level during the course of treatment. Reliability Concordance in diagnosis of psychosis between different sources was calculated initially on all 66 patients. The kappa values were 0.34 for psychosis at any time, 0.34 for psychosis during mania, and 0.15 for psychosis during depression. These values are rather low, cf. Landis and Koch (1977). In order to maximize the chances of demonstrating a difference between psychotic and non-psychotic groups, should such a difference exist, the concordance was recalculated on the basis of those 42 cases on whom information from all 3 sources was available. This analysis yielded somewhat higher values: kappa values were 0.43 for psychosis at any time, 0.49 for psychosis during mania, and 0.24 for psychosis during depression. It is apparent that psychosis in mania was diagnosed far more reliably than psychosis during depression, and that reliability, while still no better than fair, was considerably higher when all 3 sources were used. Reliability values for the different types of delusions were calculated. All values were low, but surprisingly the diagnosis of bizarre delusions was most reliable (kappa = 0.22). Reliability values for the others were much lower: for paranoid delusions, kappa = 0.10, and for grandiose delusions, kappa = 0.02. TABLE
2
CLINICAL
FEATURES
Data presented
OF THE POPULATION
as mean k SD. Psychotic (N = 44)
Non-psychotic (N = 22)
23 21
11 11
P
sex Male Female Age at first treatment Age of presentation
to clinic
Episode (No.
in past 2 years)
frequency of episodes
Mean lithium a NS: P > 0.05
on Student’s
27.4
i
9.4
32.2
k 9.1
NS
40.8
f 12.7
48.5
i 6.3
<0.02
0.3
0.4
+ 0.3
NS
0.18
0.85 f 0.24
0.5
+
0.79 i
level f-test (2-tailed).
NSa
NS
241
Outcome The rate of relapse on lithium is biphasic (see Fig. 1) and the majority of patients (over 70%) who failed within the 192 week period studied, did so in the first 36 weeks. Thereafter failure occurs at a much slower rate. When we compared psychotic with non-psychotic patient groups, we found a consistent trend for the psychotic group to remain well longer throughout the course of lithium treatment. When all 66 patients were considered, this trend reached statistical significance (x2 = 3.92, P < 0.05) between weeks 28 and 36, the significance level dropping as more patients from both groups failed or were discharged from the clinic. When we considered the subgroup of 42 patients on whom all 3 sources of information (chart, SADS and interview) were available, the difference in outcome between psychotic and nonpsychotic groups reached statistical significance between weeks 16 and 20 (x’ = 4.46, P < 0.05) and again became less pronounced over time. Having noted this difference in time until relapse between psychotic and non-psychotic groups, we wondered whether it was attributable to psychosis during mania, depression or both. Figure 1 illustrates graphically the probability of remaining well for non-psychotic patients, for patients who have been psychotic at any time, and for those who have been psychotic during mania only. It can be seen that the pattern of response of the psychotic 1.0
0.8
0.6
1
0
40
80
120
160
200
240
WEEKS Fig. 1. The probability of remaining well over time is illustrated for patients who have been psychotic at some time in their illness, patients who have been psychotic during mania only, and patients who have never been psychotic. The rapid, early rate of failure is less marked for the psychotic groups.
242 TABLE
3
RELATIONSHIP Group
Psychotic -(N = 44) Non-psychotic (N = 22) Psychotic -(N = 31) Non-psychotic (N=ll)
BETWEEN
PSYCHOSIS
No. of sources
At least two
Three
a 0.05 < P < 0.10. b P < 0.05. Probabilities compared
by Mantel
AND Kappa
0.34
0.43
LITHIUM
MAINTENANCE
RESPONSE
Cumulative probability remaining well (weeks) 16
32
0.84 a
0.78
0.64
0.49
0.84 h
0.80
0.55
0.45
of
192 b
0.47 0.31
a
0.30 0.30
chi-square.
manic group closely resembles that of the group who had been psychotic at any time. This is partly because the psychotic manic group constitutes a large proportion of the latter group (84%). The psychotic manic group was found to do significantly better than the non-psychotic group between weeks 28 and 36 (x2 = 4.36, P < 0.05). When patients with information from all 3 sources are considered, the difference between psychotic manics and non-psychotics falls just short of statistical significance (x’ = 3.32, 0.05 < P < 0.10,between weeks 16 and 24) probably due to the attenuated numbers (only 27 patients in the psychotic manic group). Fleiss et al. (1976) suggest caution in interpretation of life table results when sample sizes are small. When the 14 patients who had been psychotic during depression are compared with the 22 patients who had never been psychotic, no significant difference between groups was noted. Once again the small numbers involved dictate caution in drawing conclusions. Since the age of presentation to the clinic was lower in the psychotic than the non-psychotic group, we compared the probability of remaining well for patient groups falling above and below the median value for this variable. No significant difference was noted. DISCUSSION
Dunner et al. (1976) examined the pattern of failure of lithium maintenance treatment in bipolar I population and pointed out the biphasic nature
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of lithium maintenance failure. These authors state that it would be clinically helpful to predict which patients will fail early, since their data suggested that such patients are also more prone to a second affective episode earlier than patients whose initial failure is delayed. From our data it appears that those patients with a history of mania not characterized by delusions or hallucinations are more likely to fail early than those patients who have had psychotic symptoms during mania. Pope and Lipinski (1978) have reviewed the literature on studies where manic depressives with psychotic or ‘schizophrenic’ symptoms are compared to more classical manic depressives with regard to lithium response. They conclude that ‘no controlled study has convincingly demonstrated a difference between manic depressive illness and good prognosis ‘schizo-affectives’ in their response to lithium carbonate; the trend of existing data suggests that they may respond equally’. These authors are careful to exclude from this statement studies which define their schizo-affective group as having impaired functioning between episodes or poor pre-morbid features. The ‘atypical cases’ in a lithium prophylaxis study by Baastrup and Schou (1967) fall into this category. In some of these cases delusions were present constantly even when patients were neither manic nor depressed. These patients had a less satisfactory response to lithium than the more typical manic depressives. Angst et al. (1969), on the other hand, in a lithium prophylaxis study, found their schizo-affective group to have a lower relapse rate than a group of manic depressives, though this did not reach statistical significance. They used 10.8 months as the time interval at which they compared the relapse rates. It is interesting to note that had we used this cut-off time in our data analysis, our between group difference would also have fallen short of statistical significance. This illustrates the superiority of the life table method, which allows for comparison at any of a large number of time intervals, over the use of an arbitrary cut-off point. Smulevitch et al. (1974) found lithium prophylaxis to be equally effective patients as compared to classical manic depressive in ‘schizo-affective’ patients. Perris (1974) found that lithium carbonate prevented relapses in his population of cycloid psychoses to an extent comparable to results found in classical manic depressives mentioned elsewhere in the literature, cf. Pope and Lipinski (1978). The above-mentioned studies are the major reports in the literature on the effects of lithium carbonate in preventing relapse in psychotic manics as compared with non-psychotic manics. Our results were rather surprising in that they would not have been anticipated by previous reports except, perhaps, the study of Angst et al. (1969). The fact that no previous study has shown psychosis in mania and specific psychotic symptoms to be predictive of response to lithium maintenance therapy may be due to the following factors: (a) the inclusion of poor prognostic patients in the psychotic groups; (b) different ways of dichotomizing groups, e.g., Rosenthal et al. (1979)
244
have shown that when a group of patients meeting the Research Diagnostic Criteria for schizo-affective disorder is compared with a mixed group of psychotic and non-psychotic manic depressives, there is no difference in rate of relapse on lithium; and (c) the use of methods of data analysis less sensitive than the life table method. Given that the psychotic manics have a lower rate of early relapse than the non-psychotic group, there remain various possible explanations for this finding. It may be due to a difference in pattern of relapse between these two groups whether patients are on lithium or not. The fact that we found no significant difference in episode frequency during the previous two years would appear to argue against this but it could be argued that this is a crude measure of the pattern of episode occurrence as compared with the more refined way in which relapse rate was analyzed. Another possible explanation is a difference in medication compliance between the two groups. We have no evidence that this differed between groups and there is no significant difference in mean lithium levels. It is conceivable, however, that some subtle form of non-compliance may have occurred in the non-psychotic group to a greater extent than in the psychotic group, though we have no reason to suspect that this was the case. This leaves us with the final possibility that there is some biological difference between those bipolar patients who have psychotic mania and those who do not. It is interesting that there is a proportion of patients (33% in our sample) who, even when all sources of information are considered, appear never to have been psychotic. Carlson and Goodwin (1973), observing untreated bipolar I patients longitudinally, also found that a similar proportion (30%) did not reach the final stage of mania. Thus the difference in relapse rate on lithium may be due to biological differences between psychotic and non-psychotic manic depressive patients. If this is the case, it would appear to be of some clinical, and considerable theoretical interest. ACKNOWLEDGEMENTS
The authors wish to acknowledge Heh Lee, MPH, Manager of Data Processing Section, Clinical Information Center, Sloan Kettering Memorial Hospital, for his statistical assistance. Supported by Federal Grant MH-21586, New York State Psychiatric Institute and Columbia Millhauser Depression Center. REFERENCES Angst, J., Dittrich, A. and Grof, P. Course of endogenous affective psychoses and its modification by prophylactic administration of imipramine and lithium, Int. J. Pharmacopsychiat., 2 (1969) l-11. Baastrup, P.C. and Schou, M., Lithium as a prophylactic agent - Its effect against recurrent depressions and manic-depressive psychosis, Arch. Gen. Psychiat., 16 (1967) 162-172.
245 Carlson, G.A. and Goodwin, F.K., The stages of mania manic episode, Arch. Gen. Psychiat., 28 (1973) 221-228. Cohen, J., A coefficient of agreement for nominal scales,
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20 (1960) 37-46. Dunner, D.L., Fleiss, J.L. and Fieve, R.R., Lithium carbonate prophylaxis failure, Brit. J. Psychiat., 129 (1976) 40-44. Dunner, D.L. Gershon, ES. and Goodwin, F.K., Heritable factors in affective illness, Sci. Proc. Amer. Psychiat. Ass., 123 (1970) 187-188. Endicott, J. and Spitzer, R.L. A diagnostic interview -The schedule for affective disorders and schizophrenia. Arch. Gen. Psychiat., 35 (1978) 837-844. Feighner, J.P., Robins, E., Guze, S.B., Woodruff, Jr., R.A., Winokur, G. and Munoz, R., Diagnostic criteria for use in psychiatric research, Arch. Gen. Psychiat., 26 (1972) 57-63. Fleiss, J.L., Measuring nominal scale agreement among many raters, Psychol. Bull., 76 (1971) 378-382. Fleiss, J.L. Dunner, D.L., Stallone, F. and Fieve, R.R., The life table -A method for analyzing longitudinal studies, Arch. Gen. Psychiat., 33 (1976) 107-112. Landis, J.R. and Koch, G.G., The measurement of observer agreement for categorical data, Biometrics, 33 (1977) 159-174. Mantel, N., Evaluation of survival data and two new rank order statistics arising in its consideration, Cancer Chemother. Rep., 50 (1966) 163-170. Perris, C., A study of cycloid psychoses, Acta. Psychiat. Stand., Suppl. 253 (1974). Pope, Jr., H.G. and Lipinski, Jr., J.F., Diagnosis in schizophrenia and manic-depressive illness, Arch. Gen. Psychiat., 35 (1978) 811-828. Rosenthal, N.E., Rosenthal, L.N., Stallone, F., Dunner, D.L. and Fieve, R.R., The validation of RDC schizo-affective disorder, 1979, Unpublished. Smulevitch, A.B., Zavidovskaya, G.I., Igonin, A.L. and Mikhailova, N.M., The effectiveness of lithium in affective and schizo-affective psychoses, Brit. J. Psychiat., 125 (1974) 65-72.