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Time-related cognitive deficiency in four different types of depression
Psychiatry Research 103 Ž2001. 237᎐247
Time-related cognitive deficiency in four different types of depression Peter NeuU , Ursula Kiesslinger, Peter Schlattmann, Friedel M. Reischies Department of Psychiatry, Freie Uni¨ ersitat ¨ Berlin, Eschenallee 3, 14050 Berlin, Germany Received 28 June 2000; received in revised form 15 December 2000; accepted 21 January 2001
Abstract Mild cognitive impairment often occurs in depressive illness. But it is unknown whether the occurrence or severity of cognitive deficits has diagnostic specificity. It is of interest to investigate whether there are time-related differences in cognitive functions characteristic of different kinds of depressive diagnoses, and therefore whether such differences might help to distinguish between types of depressive disorder. Eighty inpatients with a DSM-IV depressive episode Žunipolar, bipolar, dysthymic and schizoaffective disorder, depressive type. were assessed with a series of neuropsychological tests at the beginning and at the end of their hospital stays. A group of 62 matched healthy controls were assessed with the same series of tests at comparable intervals. The diagnostic sub-groups could not be distinguished by cognitive parameters in the time-course. At the time of admission the inpatient group had a worse performance than the control group. After a significant decrease of their mean depression score, the patients still continued to show an outcome worse than the controls. We conclude that the variation of cognitive dysfunction with time in depression seems to be a phenomenon which does not depend on the kind of depressive sub-diagnosis. The results indicate that cognitive deficits might persist longer than the period of illness, but this seems to be true for all depressive sub-diagnoses. 䊚 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Depressive episode; Subtypes; Neuropsychological tests
1. Introduction Cognitive deficits are a common phenomenon during depressive episodes and always have been the object of considerable research interest. Most studies have been directed toward determining the areas of cognitive abilities which might be disturbed. Although primarily focused on memory U
ŽSternberg and Jarvik, 1976; Burt et al., 1995., more and more studies have shown deficits in other cognitive abilities like psychomotor skills ŽRaskin et al., 1982; Sobin and Sackeim, 1997., attention and vigilance ŽRush et al., 1983. and verbal skills ŽCaine et al., 1984. as well as a deficit in the central motivational state ŽCohen et al., 1981., thus suggesting that cognitive functioning in general might be disturbed rather than distinct abilities ŽRobbins et al., 1996; Tarbuck and Paykel, 1995.. But it has also been stated that the mechanisms leading to these disabilities remain un-
Corresponding author. Tel.: q49-30-8445-8673; fax: q4930-8445-8388. E-mail address: [email protected] ŽP. Neu.. 0165-1781r01r$ - see front matter 䊚 2001 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 1 6 5 - 1 7 8 1 Ž 0 1 . 0 0 2 8 6 - 4
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known. Because of widely reported but generally modest correlations between symptom severity and neuropsychologic deficits in depressed patients ŽCronholm and Ottoson, 1961; Stroemgren, 1977., as well as studies showing improvement in function after treatment ŽGoldberg et al., 1993., it has traditionally been accepted that cognitive deficits in mood disorders are related to the acute state of illness, but this point is considered controversial since some authors found cognitive disabilities in euthymic depressive patients which led to the hypothesis that cognitive deficits might persist longer than the period of illness. Considerable effort has made to identify subgroups or biological markers that might predict a risk of occurrence of cognitive deficits during depression. Cognitive deficits have been linked to a dysregulation of the hypothalam ic ᎐ pituitary᎐adrenal ŽHPA. axis, believed to result from adverse stress hormone effects on the hippocampus ŽBemelmans et al., 1996.. But the alteration of the HPA system seems to be a nonspecific phenomenon in psychiatric diseases ŽHeuser et al., 1994.. Since older depressives often suffer from both vascular diseases and major depression with cognitive deficits, another hypothesis suggested that small silent cortical or basal ganglia infarcts seen as white matter hyperintensities on MRI might cause cognitive deficits in depression ŽAlexopoulos et al., 1997.. As far as the problem of sub-groups is concerned, it is astonishing that very few studies have dealt with the comparison of cognitive impairments in different diagnostic sub-groups of depressive illness. There is considerable uncertainty about the differences in the time-dependence of cognitive deficits for different kinds of depressive sub-diagnoses Že.g. unipolar or bipolar depression, schizoaffective disorder.. In different depressive diagnoses, there are multiple factors, such as frequency, sexual distribution, age of onset ŽMcMahon et al., 1994., family history, and number ŽWinokur et al., 1993. and duration of episodes ŽAngst and Preisig, 1995., which help to differentiate between the diagnoses and possible indicators Žamong others. for further prognosis. It would therefore appear to be reasonable to as-
sume that there may also be differences in cognitive functioning which, in addition to those factors mentioned above, could be used for differentiating between depressive sub-diagnoses. Therefore, the aim of this study was to explore whether there is a difference of cognitive impairment in time-course between different types of depression. In order to verify this hypothesis, a sample of depressive patients suffering from different sub-diagnoses was neuropsychologically tested at the beginning and at the end of clinical treatment.
2. Patients and methods 2.1. Patients Consecutively admitted inpatients ŽDepartment of Psychiatry of Freie Universitat ¨ Berlin. were included, provided that they fulfilled the following criteria: Ža. age between 30 and 60 years; Žb. one of the following DSM-IV diagnoses, depressive episode, melancholic sub-type unipolar or bipolar or schizoaffective disorder, depressive type or dysthymia; and Žc. patient’s verbal informed consent. The following criteria led to exclusion from the sample: Ža. acute intoxication; Žb. delirium; Žc. heavy sensory or motor handicap; Žd. other than German native language Ždue to use of verbal tests.; Že. electroconvulsive therapy during the last 12 months; Žf. current or recent substance abuse; and Žg. history of CNS disease Že.g. multiple sclerosis or stroke.. From winter 1996 to summer 1997, 156 patients with a depressive syndrome were admitted to the hospital, of which 112 fulfilled the inclusion criteria. Diagnoses were made by the treating doctors and then confirmed or rejected by a senior consultant. Afterwards, the patients were invited to participate by the study doctor. Eleven patients refused to participate; 101 were included. Thirtyfive patients suffered from unipolar, 31 from bipolar depression. Seventeen patients had dysthymia and 18 had schizodepressive psychosis. Ž63.4%.. Most patients were already being treated with antidepressants at the time of admission, but
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36.6% were free of any drugs. At the time of the second testing, nine patients refused to be tested again, and 12 patients had been treated with electroconvulsive therapy and were excluded. So, a total of 80 patients were tested the second time. Among these patients 27 had a unipolar, 24 a bipolar depression, 14 patients had dysthymia and 15 patients had a schizodepressive episode. 2.2. Controls Healthy volunteers were included as controls, provided that they fulfilled the following criteria: Ža. aged between 30 and 60 years; Žb. no history of psychiatric or CNS disease; Žc. German native language; Žd. no experience with the tests applied; Že. verbal informed consent. Eighty-two controls were included, and 62 were able to be retested a second time. The majority of the controls were non-medical staff of the University of Berlin. A small number were recruited among nurses at the university clinics. 2.3. Procedure The patients included were neuropsychologically assessed and their depression scores were rated twice: the first time after admission to the department of psychiatry; and the second time before discharge from the clinic. The patients were discharged when the treating doctors decided that they were fully remitted and the patients felt ready to return to their normal lives. Then they were retested and depression was scored. The tests employed are of good reliability and validity and are in frequent international use. The tests were the same at both times of measurement except for the verbal memory test, for which an alternate form ŽCrawford et al., 1989. was used. The testing took approximately 20 min. The brief assessment was chosen for a special reason, on one hand, in order not to over-tax the patients and, on the other hand, because depressive illness may cause a decrease in motivation. A poor test outcome may then incorrectly be attributed to a reduction in cognitive abilities, when in fact it may have resulted from a decrease in motivation
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during a prolonged series of tests. At both times of neuropsychological assessment, the depression score was rated. The ratings and the testing were done by the same psychiatrist. Time between the two testings was 3.2 Žmean. months ŽS.D. 1.2.. Patients were compared to a sample of healthy volunteers who were assessed twice with the same series of tests. Time between testings was 3.4 Žmean. months ŽS.D. 1.5.. Patients and controls were tested by the same rater. Testing was performed between 14.00 and 16.00 h in order to control the influence of diurnal variation of mood. 2.4. Neuropsychological and clinical assessment 2.4.1. Rey auditory ¨ erbal learning test (RAVLT) The purpose of this test is to assess verbal learning and memory. A list of 15 words is read to the patient and he is then asked to repeat as many words as possible. Then the same list is reread and the patient again has to repeat as many words as he can. In the original version the list is reread five times. But, as mentioned above, we wanted to keep the testing as short as possible. After a delay of 10 min, the patient is asked to repeat as many words as he remembers without rereading the list. The score is the number of words correctly recalled ŽRey, 1964.. 2.4.2. Reitan trail-making test (part A) This test requires the connection, by pencil lines, between 25 encircled numbers randomly arranged on a page in proper order. Scoring is expressed as time required ŽReitan and Wolfson, 1985.. 2.4.3. Verbal fluency (animal naming) The patient is asked to name as many animals as possible within 90 s. The score is the sum of all admissible words. The purpose is to test speech abilities and semantic memory ŽSpreen and Benton, 1977.. 2.4.4. Wechsler memory sub-scale, ¨ isual memory This test provides aspects of visual memory. A geometric figure on a sheet of paper is presented to the patient. After 10 s it is taken away and the patient is asked to draw the figure on a piece of
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paper. Then another figure is shown and again the patient has to draw it following the same procedure. Finally, two figures on a sheet of paper are shown and the patient has to draw them after having seen both for 10 s. Scoring criteria are applied for the correctness of details ŽWechsler, 1987.. 2.4.5. Depression-ratings Depression was scored by the Bech᎐Rafaelsen Melancholia Scale ŽBRMS., a widely used depression scale which was derived from the Hamilton Depression Rating Scale ŽHAMD.. A score of 0 means no depressive symptoms; a score of 44 severe depressive symptoms ŽBech and Rafaelsen, 1980.. The lowest interrater reliability mentioned in literature for the BRMS was r s 0.67 ŽGjerris et al., 1983.; the highest was r s 0.97 ŽBallus and Marcos, 1986.. 2.5. Antidepressant medication Approximately two-thirds of the patients included were being treated with drugs at the time of admission. The following antidepressants and benzodiazepines were used: amitriptyline 100᎐150 mg; clomipramine 100᎐150 mg; serotonin-reuptake inhibitors 20᎐60 mg; monoamine oxidase inhibitors 20᎐60 mg; lithium 12᎐36 mmol; and diazepam 10᎐20 mg. Diazepam was not given on the day before the tests. One-third of the patients were drug-free at the time of admission. All patients were treated with one or more of the antidepressants mentioned above during their stay in the hospital. None of the patients were treated with antipsychotic drugs. 2.6. Statistical and ethical aspects To check the normal distribution of the investigated sample, the Kolmogorov᎐Smirnov test was employed. For group comparisons, the general linear model was used. For correlation of variables, the Spearman correlation coefficient was used. For all tests the significance was set at 0.05, two-tailed. All significant differences were Bonferroni-corrected; the ␣-level was divided by the
number of tests Ž0.05r6s 0.008.. For all statistical analyses, SPSS for Windows was applied. The study was approved by the ethical committee of Freie Universitat ¨ Berlin.
3. Results 3.1. Socio-economic and clinical data In Table 1 the socio-economic data of all patients and controls who were tested the second time are compared. The groups did not differ significantly in age and education. Among the bipolar patients there were more males than in the other groups. In Table 2 the test performance of all patients Ždivided into diagnostic sub-groups. and controls who were tested twice are compared in a fivegroup two-way ANOVA. 3.2. Baseline test scores of patient groups and controls At the first assessment, controls remembered significantly more words ŽRAVLT. than either patient group. In the second trial, controls repeated two additional words Žmean 2.35.. All patient groups repeated two additional words too Žunipolar mean 1.96, bipolar mean 2.33, dysthymic mean 2.17, schizoaffective mean 2.54.. In the third delayed recall, the controls named significantly more words than any patient group. In the Reitan Trailmaking Test, all patient groups needed significantly more time than the controls Ža higher score means a poorer performance.. In verbal fluency, the patient groups named significantly fewer animal names than the controls. In visual memory, all patient groups performed worse than the controls. This difference was not significant after Bonferroni-correction. In order to find out which patient group was most responsible for the significant difference from the control group, we directly compared each patient group to the healthy group. While the unipolars showed a significant difference Žafter Bonferroni-correction. in verbal memory only, and the bipolars in verbal fluency only, the dys-
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Table 1 Socio-economic and clinical data of all patients Ždivided into diagnostic sub-groups. and all controls who could be tested twice Controls Ž n s 62.
Unipolar Ž n s 27.
Bipolar Ž n s 24.
Dysthymic Ž n s 14.
Schizoaffective Ž n s 15.
Age ŽMeanrS.D..
52.30r7.15
49.81r8.75
49.58r7.72
46.29r8.26
47.27r9.91
Education Žschool and additional professional education in years. Median MeanrS.D.
13.0 12.97r2.83
13.0 14.19r3.37
13.0 14.67r3.62
13.0 13.21r3.56
13.0 13.60r2.50
Sex in% Femalermale
70.7r29.3
66.7r33.3
41.7r58.3
71.4r28.6
66.7r33.3
Episodes of illness ŽMedian.
3.0
4.0
2.0
4.0
Number of inpatient hospitalization ŽMedian.
2.0
4.0
1.0
3.0
Age at onset ŽMeanrS.D..
41.38r12.96
31.62r10.38
31.14r9.07
28.36r6.80
S.D.s standard deviation.
Table 2 Comparison of the neuropsychological assessment and depression scores of all four diagnostic groups and the control group in time-course Unipolar Ž n s 27 .
Bipolar Ž n s 24 .
Dysthymic Ž n s 14 .
Schizoaffective Ž n s 15 .
Controls Ž n s 62 .
1st test 2nd test 1st test 2nd test 1st test 2nd test 1st test 2nd test 1st test 2nd test MeanrS.D. MeanrS.D. MeanrS.D. MeanrS.D. MeanrS.D. MeanrS.D. MeanrS.D. MeanrS.D. MeanrS.D. MeanrS.D. RAVLT 1 5.81r1.81
6.81r1.71
6.25r1.67
6.91r1.76
6.16r1.19
7.58r1.78
5.30r1.65
5.53r1.94
7.27r1.51
7.38r1.66
RAVLT 2 7.77r2.51
8.85r2.01
8.58r2.48
9.33r2.33
8.33r1.77
9.33r2.53
7.84r2.03
8.61r2.14
9.62r1.91
9.91r2.10
RAVLT delayed
5.74r2.04
6.00r2.84
8.83r3.27
6.50r2.15
7.50r2.50
5.53r2.22
5.23r2.42
7.38r2.29
7.91r3.27
5.74r2.50
Trail44.61r20.22 40.48r20.01 43.03r17.71 40.24r17.73 35.36r9.61 making Verbal 27.44r9.32 fluency
30.29r8.65
25.04r6.36
29.04r6.81
26.58r7.41
WMS
7.81r3.77
8.40r4.21
8.91r3.36
9.66r2.86
8.75r2.34
BRMS
19.74r4.86
5.03r2.32
21.87r4.60
4.20r3.70
17.08r3.57
31.72r8.03 52.03r20.15 48.92r22.50 34.08r15.75 34.01r15.31
28.16r5.04 22.15r8.62
23.07r7.55
32.81r8.60
34.38r9.22
7.15r3.05
8.23r3.96
9.48r3.31
10.53r2.78
5.58r3.75 18.84r6.24
4.61r1.44
0.24r0.53
0.32r0.69
10.33r2.46
P. Neu et al. r Psychiatry Research 103 (2001) 237᎐247
242 Table 2
Ž Continued . Main effect Group
Time
Inter-action effect Group by time
RAVLT 1
SS d.f. F F-sig.
99.08 4 5.45 0.000 HHH
21.91 1 22.03 0.000 HHH
12.99 4 3.26 0.014
RAVLT 2
SS d.f. F F-sig.
111.86 4 3.70 0.007 HHH
29.56 1 16.47 0.000 HHH
7.35 4 1.02 0.39
RAVLT delayed
SS d.f. F F-sig.
210.95 4 5.13 0.001
8.30 1 4.25 0.04
10.24 4 1.31 0.26
Trailmaking
SS d.f. F F-sig.
8139.03 4 4.23 0.003 qqq
370.00 1 3.59 0.06
208.08 4 0.50 0.73
Verbal fluency
SS d.f. F F-sig.
WMS
SS d.f. F F-sig.
3690.43 4 7.35 0.000 HHH 205.97 4 2.73 0.03
BRMS
SS d.f. F F-sig.
9964.41 4 225.46 0.000 HHH
233.16 1 18.37 0.000 HHH 51.67 1 24.65 0.000 HHH 6598.43 1 946.25 0.000 HHH
70.61 4 1.39 0.24 5.67 4 0.67 0.60 4073.62 4 146.04 0.000 HHH
BRMS, Bech-Rafaelsen Melancholia-Scale; d.f., degrees of freedom; F-sig., significance of F ; RAVLT 1, first trial of Rey Auditory Verbal Learning Test; RAVLT 2, second trial of Rey Auditory Verbal Learning Test; S.D., standard deviation; SS, sum of squares; WMS, Wechsler Memory Sub-test, visual memory; and qqq, significant after Bonferroni correction.
thymic patients showed no significant difference at all and the schizoaffectives showed significant differences in the first trial of verbal memory, the Trail-making test and in verbal fluency. No diagnostic sub-group differed significantly from any other patient group in any test. When the depression score was used as a covariate in a four-group Ždepressive sub-groups. ANCOVA of the tests from the first assessment, the depression score did not turn out to be a significant influencing factor on any test outcome.
When comparing the first neuropsychological assessment of those 21 patients who later dropped out and a matched Žage, gender, education, diagnosis. group of patients who were tested twice, we did not find a significant difference. 3.3. Impro¨ ement in time-course At the time of the second assessment the control group had improved significantly ŽBonferronicorrected. in visual memory.
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The unipolar group had improved significantly in the first two trials of verbal memory ŽRAVLT., verbal fluency and depression score. The bipolar group had improved significantly in the first trial of verbal memory, verbal fluency and depression score. The dysthymic and schizoaffective groups had improved in depression score only. The patients who had been treated with electroconvulsive therapy ŽECT. were retested all the same, but excluded from the sample. Compared to a matched Žage, gender, education, diagnosis. group of patients who had not received ECT Žnot in Table 2., they showed a significantly worse performance in all memory tasks. In order to elucidate the influence of antidepressant drugs on cognitive abilities, we computed equivalent dosage levels using the so-called DDD system Ždefined daily dose. which is recommended by the World Health Organisation ŽWHO. for international drug utilisation studies. ‘One DDD’ is the assumed average maintenance dose per day for a drug used for its main indication in adults. Comparing to the accumulated dose that has been given to an individual patient over a period of time, one can compute the equivalent dose according to the DDD system. The details have been described elsewhere ŽRonning et al., 1999.. We correlated test abilities at each time point and equivalent dosage levels and did not find a significant difference.
teraction ANOVA and did not find a significant difference between the groups. When we co-varied years of education in a five-group Žsub-groups, controls. two-way group = time interaction ANOVA, the findings remained unaltered.
4. Discussion 4.1. Comparison of different kinds of depressi¨ e diagnosis Our main results are: 䢇
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3.4. Time by group interactions The four patient groups and the control group did not show any significant differences of test abilities in time course. When we correlated the degree of improvement in depression scores with the degree of improvement in test abilities Ždepressive groups only., we did not find a significant correlation either. Furthermore, there was no correlation with the number of prior periods of illness, age at onset or length of inpatient hospitalisation and cognitive abilities at either time point. We covaried medication-equivalent dosage levels, depression score and test᎐retest interval in a four-Ždepression.group two-way group= time in-
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Comparison of all four diagnostic groups did not reveal a significant difference in any of the tests, but the dysthymic group tended to perform best. At the time of admission to the clinic, our depressed patients differed significantly in tests of verbal memory, psychomotor speed and verbal fluency, compared to healthy controls. After having been treated for 3.4 months and after a clinically relevant decrease of their depression, the patients still performed worse than the controls. The degree of improvement of the depression score did not show a correlation with the degree of improvement in the test abilities. Furthermore, there was no correlation with number of prior periods of illness, age at onset or length of inpatient hospitalisation and cognitive abilities at either time point. Our results remain unaltered by adjusting for multiple comparisons using a Bonferronicorrection to guard against type 1 error.
The few studies which have previously dealt with cognitive functions in different groups of depressive patients led to contradictory findings. This might also be due to the fact that different studies used different classifications of sub-groups of depression. Austin et al. Ž1992. compared an endogenous depressive group and a group of neurotic-depressive patients, and found the neurotic group to be more impaired in Digit span and Trail-making tests but not in Auditory Verbal
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Learning and Verbal Fluency. Fromm and Schopflocher Ž1983. compared neurotic and psychotic depressives and found a greater impairment in the processing of visuospatial material and retention of verbal and non-verbal material shown by the latter group. Comparing unipolar and bipolar affective disorder, some older studies had found a better outcome of the unipolar patients ŽBlackburn, 1975; Savard et al., 1980.. But there were some problems such as not having rated the depression score or not having matched the groups for age. There are no studies to date which compare schizoaffective disorder with other depressive illnesses. This might be due to the fact that the distinction between schizophrenia and schizoaffective disorder was controversial for a long time. When comparing schizophrenics, schizoaffectives and patients with affective disorders, Pope et al. Ž1980. did not find significant differences between affective disorders and schizoaffectives concerning family history, treatment response and long-term outcome. Walker Ž1981. did not assess neuropsychological but neuromotor and attentional functions in three groups of schizophrenic, affective and schizoaffective disorder and found the latter to be distinguishable from schizophrenics but not from patients with affective disorder. Therefore, today schizoaffective syndrome is often regarded as being an affective disease. In this trial, we did not find a significant difference which could be helpful in reliably differentiating between the four kinds of diagnoses. Regarding the fact that the diagnosis of a certain kind of depression, for example, unipolar depression, has to be temporary, because 5᎐18% of unipolar depressives fall ill with mania during their lifetime ŽClayton, 1981. and then are diagnosed as a bipolar type of depression, it would be quite plausible to assume that there is no difference in cognitive abilities between unipolar and bipolar depression. Therefore, it seems possible that cognitive deficits in depression are a nonspecific phenomenon, which can be present in any kind of depressive sub-diagnosis. There may be factors other than sub-diagnosis, as yet unknown, which determine whether cognitive deficits occur in depression or not.
Furthermore, our findings suggest that cognitive deficits might persist longer than the depressive episode itself. Although the mean depression score decreased significantly, the patient group as a whole did not improve significantly in their cognitive abilities except for one test. It has to be noted that the duration of inpatient hospitalization is long compared to other studies. When the study was done, the university clinic in Berlin was the only institution where there were no insurance restrictions. This policy was to alleviate the performance of scientific work. We therefore could keep patients in the hospital until they were recovered even though in other settings they would have been discharged after some weeks and followed up as outpatients for financial reasons. But the university is not a specialized center for refractory depression; instead, we are responsible for all psychiatric patients living in our county Žand other counties if we have vacancies., so the patients were recruited from a general population. It is still discussed, controversially, whether cognitive deficits disappear at the end of the depressive episode. In an earlier study we already had found that cognitive deficits continued after successful treatment ŽReischies and Neu, 2000.. But one has to admit that our patients possibly improve some months later after having returned to their work and normal life. But there are also reports of patients with cognitive deficits in an euthymic phase several months after their last episode of illness ŽO’Brien et al., 1993; Tham et al., 1997.. Furthermore, the fact that we did not find a significant correlation between depression scores and test abilities could indicate that cognitive deficits are determined by factors other than mood. So it seems to be plausible that there might be at least a sub-group of patients who continue to show poorer cognitive abilities for a reason we do not yet know. This sub-group, however, seems not to be determined by sub-diagnosis. As mentioned earlier, one possible hypothesis which is currently discussed in the literature is that subtle brain damage caused by, for example, slight vascular infarcts could be responsible for cognitive impairment ŽDrevets et al., 1997.; this could be potentially true for every sub-diagnosis.
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Therefore, further studies dealing with the question of sub-groups have to take MRI investigations into account. 4.2. Practice effect It has to be discussed whether improvement of test abilities was simply due to a practice effect. There certainly was such an influence, because in most of the tests applied, identical tests at both time points were used. But if the improvement was due to a practice effect only, both groups Žpatients and controls. would have shown a similar improvement, which in fact was not the case. The significant improvement of controls in visual memory possibly was due to a practice effect Žwhereas in the other tests there was no such improvement., but the patients did not show a similar pattern of improvement, which strongly suggests that there are other more important factors. 4.3. Influence of psychotic symptoms Cognitive functions may have been affected by the presence of psychotic symptoms. The only group presenting such features were the patients suffering from schizoaffective disorder. Schatzberg et al. Ž2000. had compared non-psychotic vs. psychotic major depression using a battery of neuropsychological tests. Among others, they used the Trail-making Test and Wechsler Memory Sub-scale, visual reproduction as in our study and did not find a significant difference in either tests which would confirm our findings. However, there might be tests other than those used by us that are more sensitive to the neuropsychological deficits correlated with psychotic symptoms and that would have revealed significant differences; therefore the influence of psychotic symptoms might not be entirely controlled in this investigation. 4.4. Sensiti¨ ity of tests It has to be further critically considered whether the tests may not have been sensitive enough to detect changes in cognitive function. However,
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the Rey Auditory Verbal Learning Test ŽRAVLT. and the Wechsler Memory Scale are used in dementia research to demonstrate decline in performance ŽBigler et al., 1989; Welsh et al., 1994.. The Reitan Trail-making Test A is sensitive with regard to monitoring improvement in patients with brain lesions ŽEson et al., 1978.. The RAVLT and Reitan Trail-making Test are recommended for clinical neuropsychological investigation by the Therapeutics and Technology Assessment Subcommittee of the American Academy of TTASAAN Ž1996.. Verbal fluency has been a useful measure in differentiating between demented, depressed and healthy persons ŽGeffen et al., 1993; Monsch et al., 1993; Welsh et al., 1994.. 4.5. Drop-outs When comparing the first neuropsychological assessment of those 21 patients who later dropped out and a matched group of patients who were tested twice, we did not find a significant difference. This might indicate that the drop-outs were neuropsychologically comparable to the rest of the population as far as baseline assessment was concerned. The patients who had been treated with ECT were retested but excluded from the sample. Compared to a matched group of patients who had not received ECT, they showed significantly worse performance in all memory tasks. This is in agreement with earlier studies investigating the influence of ECT on neuropsychological performance ŽCalev et al., 1989., and therefore these patients had to be excluded. 4.6. Influence of medication Since not all of our patients had been treated with the same antidepressant drugs, it may have been possible that different medication status confounded the comparison between the sub-diagnoses. The issue of whether or not and to what extent antidepressants might influence cognitive functions remains a subject of discussion. Some authors reported cognitive impairment during antidepressant medication ŽLamping et al., 1984; Branconnier et al., 1982., but there are also re-
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ports of improvement of cognitive functions during antidepressant medication. Glass et al. Ž1981. reported an improvement of cognitive abilities among depressives taking imipramine, while the depression itself did not improve. Therefore, it might be possible that antidepressants have a positive influence on cognitive functions as well. We did not find a significant influence on test outcome in our sample. However, medication is a factor that cannot be entirely controlled. For ethical reasons it is not possible to let depressed patients be unmedicated for long periods of time.
Acknowledgements We wish to express our thanks to Mrs Frances May for critically reviewing our manuscript. Furthermore, we wish to thank all patients and controls who participated in this study. References Alexopoulos, G.S., Meyers, B.S., Young, R.C., Campell, S., Silbersweig, D., Charlson, M., 1997. Vascular depression hypothesis. Archives of General Psychiatry 54, 915᎐922. Angst, J., Preisig, M., 1995. Course of a clinical cohort of unipolar, bipolar and schizoaffective patients. Results of a prospective study from 1959 to 1985. Schweizer Archiv fur ¨ Neurologie und Psychiatrie 146 Ž1., 5᎐15. Austin, M.-P., Ross, M., Murray, C., O’Carroll, R.E., Ebmeier, K.P., Goodwin, G.M., 1992. Cognitive function in major depression. Journal of Affective Disorders 25, 21᎐30. Ballus, C., Marcos, T., 1986. The Melancholia Rating Scale: a useful instrument for the assessment of affective disorders. Validity and reliability of the spanish adaptation. Pharmakopsychiatry 19, 48᎐51. Bech, P., Rafaelsen, O.J., 1980. The use of rating scales exemplified by a comparison of the Hamilton and the Bech᎐Rafaelsen Melancholia Scale. Acta Psychiatrica Scandinavica 285, 128᎐131. Bemelmans, K.J., Goekoop, J.G., van Kempen, G.M., 1996. Recall performance in acutely depressed patients and plasma cortisol. Biological Psychiatry 39, 750᎐752. Bigler, E.D., Rosa, L., Schulz, F., 1989. Rey auditory verbal learning and Rey-Osterrieth complex figure design test performance in Alzheimer’s disease and closed head injury. Journal of Clinical Psychology 45, 277᎐280. Blackburn, I.M., 1975. Mental and psychomotor speed in depression and mania. British Journal of Psychiatry 126, 329᎐335.
Branconnier, R.J., Devitt, D.R., Cole, J.O., Spera, D.F., 1982. Amitriptyline selectively disrupts verbal recall from secondary memory of the normal aged. Neurobiology of Aging 3, 55᎐59. Burt, D.B., Zembar, M.J., Niederehe, G., 1995. Depression and memory impairment: a meta-analysis of the association, its pattern, and specificity. Psychological Bulletin 117, 285᎐305. Caine, E.D., Yerevanian, B.I., Bamford, K.A., 1984. Cognitive function and the dexamethasone suppression test in depression. American Journal of Psychiatry 141, 116᎐118. Calev, A., Ben-Tzvi, W., Shapira, B., Drexler, H., Carasso, R., Lerer, B., 1989. Distinct memory impairments following electroconvulsive therapy and imipramine. Psychological Medicine 19, 111᎐119. Clayton, P.J., 1981. The epidemiology of bipolar affective disorder. Comprehensive Psychiatry 22, 31. Cohen, R.M., Weingartner, H., Smallberg, S.A., Pickar, D., Murphy, D.L., 1981. Effort and cognition in depression. Archives of General Psychiatry 39, 59᎐597. Crawford, J.R., Stewart, L.E., Moore, J.W., 1989. Demonstration of savings on the AVLT and development of a parallel form. Journal of Clinical and Experimental Neuropsychology 11, 975᎐981. Cronholm, B., Ottoson, J.-O., 1961. Memory function in endogenous depression. Archives of General Psychiatry 5, 101᎐107. Drevets, W.C., Price, J.L., Simpson, J.R., 1997. Sub-genual prefrontal cortex abnormalities in mood disorders. Nature 386, 824᎐827. Eson, M.E., Yen, J.K., Bourke, R.S., 1978. Assessment of recovery from serious head injury. Journal of Neurology, Neurosurgery and Psychiatry 41, 1036᎐1042. Fromm, D., Schopflocher, D., 1983. Neuropsychological test performance in depressed patients before and after drug therapy. Biology Psychiatry 19 Ž1., 55᎐70. Geffen, G., Bate, A., Wright, M., Rozenbilds, U., Geffen, L., 1993. A comparison of cognitive impairments in dementia of the Alzheimer type and depression in the elderly. Dementia 4, 294᎐300. Gjerris, A., Bech, P., Bojholm, S., Bolwig, T.G., Kramp, P., Clemmensen, L., Andersen, J., Jensen, E., Rafaelsen, O.J., 1983. The Hamilton Anxiety Scale. Evaluation of homogenity and inter-observer reliability in patients with depressive disorders. Journal of Affective Disorders 5, 163᎐170. Glass, R.M., Uhlenhuth, E.H., Hartel, F.W., Matuzas, W., Fischman, M.W., 1981. Cognitive dysfunction and imipramine in outpatient depressives. Archives of General Psychiatry 38, 1048᎐1051. Goldberg, T.E., Gold, J.M., Greenberg, R., Griffin, S., Schulz, S.C., Pickar, D., 1993. Contrasts between patients with affective disorders and patients with schizophrenia on a neuropsychological test battery. American Journal of Psychiatry 159, 1355᎐1362. Heuser, I., Yassouridis, A., Holsboer, F., 1994. The combined dexamethasonerCRH test: a refined laboratory test for
P. Neu et al. r Psychiatry Research 103 (2001) 237᎐247 psychiatric disorders. Journal of Psychiatric Research 28 Ž4., 341᎐356. Lamping, D.L., Spring, B., Gelenberg, A.J., 1984. Effects of two antidepressants on memory performance in depressed outpatients: a double-blind study. Psychopharmacology 84, 254᎐261. McMahon, F.J., Stine, O.C., Chase, A., Meyers, D.A., Simpson, S.G., DePaulo Jr., J.R., 1994. Influence of clinical subtype, sex and lineality on age at onset of major affective disorder in a family sample. American Journal of Psychiatry 151 Ž2., 210᎐215. Monsch, A., Bondi, M., Butters, M., Salmon, D., Katzman, R., Thal, L., 1993. Comparison of verbal fluency tasks in the detection of dementia of the Alzheimer type. Archives of Neurology 49, 1253᎐1258. O’Brien, J.T., Sahakian, B.J., Checkley, S.A., 1993. Cognitive impairments in patients with seasonal affective disorder. British Journal of Psychiatry 163, 338᎐343. Pope, H.G., Lipinski, J.F., Cohen, B.M., 1980. Schizoaffective disorder: an invalid diagnosis? A comparison of schizoaffective disorder, schizophrenia and affective disorder. American Journal of Psychiatry 137, 815᎐817. Raskin, A., Friedman, A.S., DeMascio, A., 1982. Cognitive performance deficits in depression. Psychopharmacology Bulletin 18, 196᎐202. Reischies, F.M., Neu, P., 2000. Comorbidity of mild cognitive disorder and depression: a neuropsychological analysis. European Archives of Psychiatry and Clinical Neuroscience 250, 186᎐193. Reitan, R.M., Wolfson, D., 1985. The Halstead᎐Reitan Neuropsychological Test Battery. Neuropsychology Press, Tucson. Rey, A., 1964. L’Examen Clinique en Psychologie. Press Universitaire de France, Paris. Robbins, T.W., Elliot, R., Sahakian, B.F., 1996. Neuropsychology-dementia and affective disorders. British Medical Bulletin 52, 627᎐643. Rush, A.J., Wessenburger, J., Vinson, D.B., 1983. Neuropsychological dysfunction in unipolar nonpsychotic major depressions. Journal of Affective Disorders 5, 281᎐287. Savard, R.J., Rey, A.C., Post, R., 1980. Halstead-Reitan Category test in bipolar and unipolar affective disorders. Journal of Nervous and Mental Disease 168 Ž5., 297᎐304. Schatzberg, A.G., Posener, J.A., DeBattista, C., Kalehzan,
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B.M., Rothschild, A.J., Shear, P.K., 2000. Neuropsychological deficits in psychotic vs. nonpsychotic major depression and no mental illnesss. American Journal of Psychiatry 157, 1095᎐1100. Sobin, C., Sackeim, H.A., 1997. Psychomotor symptoms of depression. American Journal of Psychiatry 154, 4᎐17. Spreen, O., Benton, A.L., 1977. Neurosensory Center Comprehensive Examination for Aphasia ŽNCCEA., Revised Edition, University of Victoria, Neuropsychology Laboratory, Victoria. Sternberg, D.E., Jarvik, M.E., 1976. Memory function in depression: improvement with antidepressant medication. Archives of General Psychiatry 33, 219᎐244. Stroemgren, L.S., 1977. The influence of depression on memory. Acta Psychiatrica Scandinavica 56, 109᎐128. Tarbuck, A.F., Paykel, E.S., 1995. Effects of major depression on the cognitive function of younger and older subjects. Psychological Medicine 25, 285᎐296. Tham, A., Engelbrektson, K., Mathe, ´ A.A., Johnson, L., ˚ Olsson, E., Aberg-Wistedt, A., 1997. Impaired neuropsychological performance in euthymic patients with recurring mood disorders. Journal of Clinical Psychiatry 58 Ž1., 26᎐29. Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology, 1996. Assessment: neuropsychological testing of adults. Neurology 47, 592᎐599. Walker, E., 1981. Attentional and neuromotor functions of schizophrenics, schizoaffectives, and patients with other affective disorders. Archives of General Psychiatry 38, 1355᎐1358. Welsh, K.A., Butters, N., Mohs, R.C., Beekly, B.S., Edland, S., Fillenbaum, G., Heyman, A., 1994. The consortium to establish a registry for Alzheimer’s disease ŽCERAD.. Part V, a normative study of the neuropsychological battery. Neurology 44, 609᎐614. Welsh, K.A., Butters, N., Mohs, R.C., Beekly, B.S., Edland, S., Fillenbaum, G., Heyman, A., 1994. The consortium to establish a registry for Alzheimer’s disease ŽCERAD.. Part V, a normative study of the neuropsychological battery. Neurology 44, 609᎐614. Winokur, G., Coryell, W., Keller, M., Endicott, J., Akiskal, H., 1993. A prospective follow-up of patients with bipolar and primary unipolar affective disorder. Archives of General Psychiatry 50 Ž6., 457᎐465.
Time-related cognitive deficiency in four different types of depression Peter NeuU , Ursula Kiesslinger, Peter Schlattmann, Friedel M. Reischies Department of Psychiatry, Freie Uni¨ ersitat ¨ Berlin, Eschenallee 3, 14050 Berlin, Germany Received 28 June 2000; received in revised form 15 December 2000; accepted 21 January 2001
Abstract Mild cognitive impairment often occurs in depressive illness. But it is unknown whether the occurrence or severity of cognitive deficits has diagnostic specificity. It is of interest to investigate whether there are time-related differences in cognitive functions characteristic of different kinds of depressive diagnoses, and therefore whether such differences might help to distinguish between types of depressive disorder. Eighty inpatients with a DSM-IV depressive episode Žunipolar, bipolar, dysthymic and schizoaffective disorder, depressive type. were assessed with a series of neuropsychological tests at the beginning and at the end of their hospital stays. A group of 62 matched healthy controls were assessed with the same series of tests at comparable intervals. The diagnostic sub-groups could not be distinguished by cognitive parameters in the time-course. At the time of admission the inpatient group had a worse performance than the control group. After a significant decrease of their mean depression score, the patients still continued to show an outcome worse than the controls. We conclude that the variation of cognitive dysfunction with time in depression seems to be a phenomenon which does not depend on the kind of depressive sub-diagnosis. The results indicate that cognitive deficits might persist longer than the period of illness, but this seems to be true for all depressive sub-diagnoses. 䊚 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Depressive episode; Subtypes; Neuropsychological tests
1. Introduction Cognitive deficits are a common phenomenon during depressive episodes and always have been the object of considerable research interest. Most studies have been directed toward determining the areas of cognitive abilities which might be disturbed. Although primarily focused on memory U
ŽSternberg and Jarvik, 1976; Burt et al., 1995., more and more studies have shown deficits in other cognitive abilities like psychomotor skills ŽRaskin et al., 1982; Sobin and Sackeim, 1997., attention and vigilance ŽRush et al., 1983. and verbal skills ŽCaine et al., 1984. as well as a deficit in the central motivational state ŽCohen et al., 1981., thus suggesting that cognitive functioning in general might be disturbed rather than distinct abilities ŽRobbins et al., 1996; Tarbuck and Paykel, 1995.. But it has also been stated that the mechanisms leading to these disabilities remain un-
Corresponding author. Tel.: q49-30-8445-8673; fax: q4930-8445-8388. E-mail address: [email protected] ŽP. Neu.. 0165-1781r01r$ - see front matter 䊚 2001 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 1 6 5 - 1 7 8 1 Ž 0 1 . 0 0 2 8 6 - 4
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known. Because of widely reported but generally modest correlations between symptom severity and neuropsychologic deficits in depressed patients ŽCronholm and Ottoson, 1961; Stroemgren, 1977., as well as studies showing improvement in function after treatment ŽGoldberg et al., 1993., it has traditionally been accepted that cognitive deficits in mood disorders are related to the acute state of illness, but this point is considered controversial since some authors found cognitive disabilities in euthymic depressive patients which led to the hypothesis that cognitive deficits might persist longer than the period of illness. Considerable effort has made to identify subgroups or biological markers that might predict a risk of occurrence of cognitive deficits during depression. Cognitive deficits have been linked to a dysregulation of the hypothalam ic ᎐ pituitary᎐adrenal ŽHPA. axis, believed to result from adverse stress hormone effects on the hippocampus ŽBemelmans et al., 1996.. But the alteration of the HPA system seems to be a nonspecific phenomenon in psychiatric diseases ŽHeuser et al., 1994.. Since older depressives often suffer from both vascular diseases and major depression with cognitive deficits, another hypothesis suggested that small silent cortical or basal ganglia infarcts seen as white matter hyperintensities on MRI might cause cognitive deficits in depression ŽAlexopoulos et al., 1997.. As far as the problem of sub-groups is concerned, it is astonishing that very few studies have dealt with the comparison of cognitive impairments in different diagnostic sub-groups of depressive illness. There is considerable uncertainty about the differences in the time-dependence of cognitive deficits for different kinds of depressive sub-diagnoses Že.g. unipolar or bipolar depression, schizoaffective disorder.. In different depressive diagnoses, there are multiple factors, such as frequency, sexual distribution, age of onset ŽMcMahon et al., 1994., family history, and number ŽWinokur et al., 1993. and duration of episodes ŽAngst and Preisig, 1995., which help to differentiate between the diagnoses and possible indicators Žamong others. for further prognosis. It would therefore appear to be reasonable to as-
sume that there may also be differences in cognitive functioning which, in addition to those factors mentioned above, could be used for differentiating between depressive sub-diagnoses. Therefore, the aim of this study was to explore whether there is a difference of cognitive impairment in time-course between different types of depression. In order to verify this hypothesis, a sample of depressive patients suffering from different sub-diagnoses was neuropsychologically tested at the beginning and at the end of clinical treatment.
2. Patients and methods 2.1. Patients Consecutively admitted inpatients ŽDepartment of Psychiatry of Freie Universitat ¨ Berlin. were included, provided that they fulfilled the following criteria: Ža. age between 30 and 60 years; Žb. one of the following DSM-IV diagnoses, depressive episode, melancholic sub-type unipolar or bipolar or schizoaffective disorder, depressive type or dysthymia; and Žc. patient’s verbal informed consent. The following criteria led to exclusion from the sample: Ža. acute intoxication; Žb. delirium; Žc. heavy sensory or motor handicap; Žd. other than German native language Ždue to use of verbal tests.; Že. electroconvulsive therapy during the last 12 months; Žf. current or recent substance abuse; and Žg. history of CNS disease Že.g. multiple sclerosis or stroke.. From winter 1996 to summer 1997, 156 patients with a depressive syndrome were admitted to the hospital, of which 112 fulfilled the inclusion criteria. Diagnoses were made by the treating doctors and then confirmed or rejected by a senior consultant. Afterwards, the patients were invited to participate by the study doctor. Eleven patients refused to participate; 101 were included. Thirtyfive patients suffered from unipolar, 31 from bipolar depression. Seventeen patients had dysthymia and 18 had schizodepressive psychosis. Ž63.4%.. Most patients were already being treated with antidepressants at the time of admission, but
P. Neu et al. r Psychiatry Research 103 (2001) 237᎐247
36.6% were free of any drugs. At the time of the second testing, nine patients refused to be tested again, and 12 patients had been treated with electroconvulsive therapy and were excluded. So, a total of 80 patients were tested the second time. Among these patients 27 had a unipolar, 24 a bipolar depression, 14 patients had dysthymia and 15 patients had a schizodepressive episode. 2.2. Controls Healthy volunteers were included as controls, provided that they fulfilled the following criteria: Ža. aged between 30 and 60 years; Žb. no history of psychiatric or CNS disease; Žc. German native language; Žd. no experience with the tests applied; Že. verbal informed consent. Eighty-two controls were included, and 62 were able to be retested a second time. The majority of the controls were non-medical staff of the University of Berlin. A small number were recruited among nurses at the university clinics. 2.3. Procedure The patients included were neuropsychologically assessed and their depression scores were rated twice: the first time after admission to the department of psychiatry; and the second time before discharge from the clinic. The patients were discharged when the treating doctors decided that they were fully remitted and the patients felt ready to return to their normal lives. Then they were retested and depression was scored. The tests employed are of good reliability and validity and are in frequent international use. The tests were the same at both times of measurement except for the verbal memory test, for which an alternate form ŽCrawford et al., 1989. was used. The testing took approximately 20 min. The brief assessment was chosen for a special reason, on one hand, in order not to over-tax the patients and, on the other hand, because depressive illness may cause a decrease in motivation. A poor test outcome may then incorrectly be attributed to a reduction in cognitive abilities, when in fact it may have resulted from a decrease in motivation
239
during a prolonged series of tests. At both times of neuropsychological assessment, the depression score was rated. The ratings and the testing were done by the same psychiatrist. Time between the two testings was 3.2 Žmean. months ŽS.D. 1.2.. Patients were compared to a sample of healthy volunteers who were assessed twice with the same series of tests. Time between testings was 3.4 Žmean. months ŽS.D. 1.5.. Patients and controls were tested by the same rater. Testing was performed between 14.00 and 16.00 h in order to control the influence of diurnal variation of mood. 2.4. Neuropsychological and clinical assessment 2.4.1. Rey auditory ¨ erbal learning test (RAVLT) The purpose of this test is to assess verbal learning and memory. A list of 15 words is read to the patient and he is then asked to repeat as many words as possible. Then the same list is reread and the patient again has to repeat as many words as he can. In the original version the list is reread five times. But, as mentioned above, we wanted to keep the testing as short as possible. After a delay of 10 min, the patient is asked to repeat as many words as he remembers without rereading the list. The score is the number of words correctly recalled ŽRey, 1964.. 2.4.2. Reitan trail-making test (part A) This test requires the connection, by pencil lines, between 25 encircled numbers randomly arranged on a page in proper order. Scoring is expressed as time required ŽReitan and Wolfson, 1985.. 2.4.3. Verbal fluency (animal naming) The patient is asked to name as many animals as possible within 90 s. The score is the sum of all admissible words. The purpose is to test speech abilities and semantic memory ŽSpreen and Benton, 1977.. 2.4.4. Wechsler memory sub-scale, ¨ isual memory This test provides aspects of visual memory. A geometric figure on a sheet of paper is presented to the patient. After 10 s it is taken away and the patient is asked to draw the figure on a piece of
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paper. Then another figure is shown and again the patient has to draw it following the same procedure. Finally, two figures on a sheet of paper are shown and the patient has to draw them after having seen both for 10 s. Scoring criteria are applied for the correctness of details ŽWechsler, 1987.. 2.4.5. Depression-ratings Depression was scored by the Bech᎐Rafaelsen Melancholia Scale ŽBRMS., a widely used depression scale which was derived from the Hamilton Depression Rating Scale ŽHAMD.. A score of 0 means no depressive symptoms; a score of 44 severe depressive symptoms ŽBech and Rafaelsen, 1980.. The lowest interrater reliability mentioned in literature for the BRMS was r s 0.67 ŽGjerris et al., 1983.; the highest was r s 0.97 ŽBallus and Marcos, 1986.. 2.5. Antidepressant medication Approximately two-thirds of the patients included were being treated with drugs at the time of admission. The following antidepressants and benzodiazepines were used: amitriptyline 100᎐150 mg; clomipramine 100᎐150 mg; serotonin-reuptake inhibitors 20᎐60 mg; monoamine oxidase inhibitors 20᎐60 mg; lithium 12᎐36 mmol; and diazepam 10᎐20 mg. Diazepam was not given on the day before the tests. One-third of the patients were drug-free at the time of admission. All patients were treated with one or more of the antidepressants mentioned above during their stay in the hospital. None of the patients were treated with antipsychotic drugs. 2.6. Statistical and ethical aspects To check the normal distribution of the investigated sample, the Kolmogorov᎐Smirnov test was employed. For group comparisons, the general linear model was used. For correlation of variables, the Spearman correlation coefficient was used. For all tests the significance was set at 0.05, two-tailed. All significant differences were Bonferroni-corrected; the ␣-level was divided by the
number of tests Ž0.05r6s 0.008.. For all statistical analyses, SPSS for Windows was applied. The study was approved by the ethical committee of Freie Universitat ¨ Berlin.
3. Results 3.1. Socio-economic and clinical data In Table 1 the socio-economic data of all patients and controls who were tested the second time are compared. The groups did not differ significantly in age and education. Among the bipolar patients there were more males than in the other groups. In Table 2 the test performance of all patients Ždivided into diagnostic sub-groups. and controls who were tested twice are compared in a fivegroup two-way ANOVA. 3.2. Baseline test scores of patient groups and controls At the first assessment, controls remembered significantly more words ŽRAVLT. than either patient group. In the second trial, controls repeated two additional words Žmean 2.35.. All patient groups repeated two additional words too Žunipolar mean 1.96, bipolar mean 2.33, dysthymic mean 2.17, schizoaffective mean 2.54.. In the third delayed recall, the controls named significantly more words than any patient group. In the Reitan Trailmaking Test, all patient groups needed significantly more time than the controls Ža higher score means a poorer performance.. In verbal fluency, the patient groups named significantly fewer animal names than the controls. In visual memory, all patient groups performed worse than the controls. This difference was not significant after Bonferroni-correction. In order to find out which patient group was most responsible for the significant difference from the control group, we directly compared each patient group to the healthy group. While the unipolars showed a significant difference Žafter Bonferroni-correction. in verbal memory only, and the bipolars in verbal fluency only, the dys-
P. Neu et al. r Psychiatry Research 103 (2001) 237᎐247
241
Table 1 Socio-economic and clinical data of all patients Ždivided into diagnostic sub-groups. and all controls who could be tested twice Controls Ž n s 62.
Unipolar Ž n s 27.
Bipolar Ž n s 24.
Dysthymic Ž n s 14.
Schizoaffective Ž n s 15.
Age ŽMeanrS.D..
52.30r7.15
49.81r8.75
49.58r7.72
46.29r8.26
47.27r9.91
Education Žschool and additional professional education in years. Median MeanrS.D.
13.0 12.97r2.83
13.0 14.19r3.37
13.0 14.67r3.62
13.0 13.21r3.56
13.0 13.60r2.50
Sex in% Femalermale
70.7r29.3
66.7r33.3
41.7r58.3
71.4r28.6
66.7r33.3
Episodes of illness ŽMedian.
3.0
4.0
2.0
4.0
Number of inpatient hospitalization ŽMedian.
2.0
4.0
1.0
3.0
Age at onset ŽMeanrS.D..
41.38r12.96
31.62r10.38
31.14r9.07
28.36r6.80
S.D.s standard deviation.
Table 2 Comparison of the neuropsychological assessment and depression scores of all four diagnostic groups and the control group in time-course Unipolar Ž n s 27 .
Bipolar Ž n s 24 .
Dysthymic Ž n s 14 .
Schizoaffective Ž n s 15 .
Controls Ž n s 62 .
1st test 2nd test 1st test 2nd test 1st test 2nd test 1st test 2nd test 1st test 2nd test MeanrS.D. MeanrS.D. MeanrS.D. MeanrS.D. MeanrS.D. MeanrS.D. MeanrS.D. MeanrS.D. MeanrS.D. MeanrS.D. RAVLT 1 5.81r1.81
6.81r1.71
6.25r1.67
6.91r1.76
6.16r1.19
7.58r1.78
5.30r1.65
5.53r1.94
7.27r1.51
7.38r1.66
RAVLT 2 7.77r2.51
8.85r2.01
8.58r2.48
9.33r2.33
8.33r1.77
9.33r2.53
7.84r2.03
8.61r2.14
9.62r1.91
9.91r2.10
RAVLT delayed
5.74r2.04
6.00r2.84
8.83r3.27
6.50r2.15
7.50r2.50
5.53r2.22
5.23r2.42
7.38r2.29
7.91r3.27
5.74r2.50
Trail44.61r20.22 40.48r20.01 43.03r17.71 40.24r17.73 35.36r9.61 making Verbal 27.44r9.32 fluency
30.29r8.65
25.04r6.36
29.04r6.81
26.58r7.41
WMS
7.81r3.77
8.40r4.21
8.91r3.36
9.66r2.86
8.75r2.34
BRMS
19.74r4.86
5.03r2.32
21.87r4.60
4.20r3.70
17.08r3.57
31.72r8.03 52.03r20.15 48.92r22.50 34.08r15.75 34.01r15.31
28.16r5.04 22.15r8.62
23.07r7.55
32.81r8.60
34.38r9.22
7.15r3.05
8.23r3.96
9.48r3.31
10.53r2.78
5.58r3.75 18.84r6.24
4.61r1.44
0.24r0.53
0.32r0.69
10.33r2.46
P. Neu et al. r Psychiatry Research 103 (2001) 237᎐247
242 Table 2
Ž Continued . Main effect Group
Time
Inter-action effect Group by time
RAVLT 1
SS d.f. F F-sig.
99.08 4 5.45 0.000 HHH
21.91 1 22.03 0.000 HHH
12.99 4 3.26 0.014
RAVLT 2
SS d.f. F F-sig.
111.86 4 3.70 0.007 HHH
29.56 1 16.47 0.000 HHH
7.35 4 1.02 0.39
RAVLT delayed
SS d.f. F F-sig.
210.95 4 5.13 0.001
8.30 1 4.25 0.04
10.24 4 1.31 0.26
Trailmaking
SS d.f. F F-sig.
8139.03 4 4.23 0.003 qqq
370.00 1 3.59 0.06
208.08 4 0.50 0.73
Verbal fluency
SS d.f. F F-sig.
WMS
SS d.f. F F-sig.
3690.43 4 7.35 0.000 HHH 205.97 4 2.73 0.03
BRMS
SS d.f. F F-sig.
9964.41 4 225.46 0.000 HHH
233.16 1 18.37 0.000 HHH 51.67 1 24.65 0.000 HHH 6598.43 1 946.25 0.000 HHH
70.61 4 1.39 0.24 5.67 4 0.67 0.60 4073.62 4 146.04 0.000 HHH
BRMS, Bech-Rafaelsen Melancholia-Scale; d.f., degrees of freedom; F-sig., significance of F ; RAVLT 1, first trial of Rey Auditory Verbal Learning Test; RAVLT 2, second trial of Rey Auditory Verbal Learning Test; S.D., standard deviation; SS, sum of squares; WMS, Wechsler Memory Sub-test, visual memory; and qqq, significant after Bonferroni correction.
thymic patients showed no significant difference at all and the schizoaffectives showed significant differences in the first trial of verbal memory, the Trail-making test and in verbal fluency. No diagnostic sub-group differed significantly from any other patient group in any test. When the depression score was used as a covariate in a four-group Ždepressive sub-groups. ANCOVA of the tests from the first assessment, the depression score did not turn out to be a significant influencing factor on any test outcome.
When comparing the first neuropsychological assessment of those 21 patients who later dropped out and a matched Žage, gender, education, diagnosis. group of patients who were tested twice, we did not find a significant difference. 3.3. Impro¨ ement in time-course At the time of the second assessment the control group had improved significantly ŽBonferronicorrected. in visual memory.
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The unipolar group had improved significantly in the first two trials of verbal memory ŽRAVLT., verbal fluency and depression score. The bipolar group had improved significantly in the first trial of verbal memory, verbal fluency and depression score. The dysthymic and schizoaffective groups had improved in depression score only. The patients who had been treated with electroconvulsive therapy ŽECT. were retested all the same, but excluded from the sample. Compared to a matched Žage, gender, education, diagnosis. group of patients who had not received ECT Žnot in Table 2., they showed a significantly worse performance in all memory tasks. In order to elucidate the influence of antidepressant drugs on cognitive abilities, we computed equivalent dosage levels using the so-called DDD system Ždefined daily dose. which is recommended by the World Health Organisation ŽWHO. for international drug utilisation studies. ‘One DDD’ is the assumed average maintenance dose per day for a drug used for its main indication in adults. Comparing to the accumulated dose that has been given to an individual patient over a period of time, one can compute the equivalent dose according to the DDD system. The details have been described elsewhere ŽRonning et al., 1999.. We correlated test abilities at each time point and equivalent dosage levels and did not find a significant difference.
teraction ANOVA and did not find a significant difference between the groups. When we co-varied years of education in a five-group Žsub-groups, controls. two-way group = time interaction ANOVA, the findings remained unaltered.
4. Discussion 4.1. Comparison of different kinds of depressi¨ e diagnosis Our main results are: 䢇
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3.4. Time by group interactions The four patient groups and the control group did not show any significant differences of test abilities in time course. When we correlated the degree of improvement in depression scores with the degree of improvement in test abilities Ždepressive groups only., we did not find a significant correlation either. Furthermore, there was no correlation with the number of prior periods of illness, age at onset or length of inpatient hospitalisation and cognitive abilities at either time point. We covaried medication-equivalent dosage levels, depression score and test᎐retest interval in a four-Ždepression.group two-way group= time in-
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Comparison of all four diagnostic groups did not reveal a significant difference in any of the tests, but the dysthymic group tended to perform best. At the time of admission to the clinic, our depressed patients differed significantly in tests of verbal memory, psychomotor speed and verbal fluency, compared to healthy controls. After having been treated for 3.4 months and after a clinically relevant decrease of their depression, the patients still performed worse than the controls. The degree of improvement of the depression score did not show a correlation with the degree of improvement in the test abilities. Furthermore, there was no correlation with number of prior periods of illness, age at onset or length of inpatient hospitalisation and cognitive abilities at either time point. Our results remain unaltered by adjusting for multiple comparisons using a Bonferronicorrection to guard against type 1 error.
The few studies which have previously dealt with cognitive functions in different groups of depressive patients led to contradictory findings. This might also be due to the fact that different studies used different classifications of sub-groups of depression. Austin et al. Ž1992. compared an endogenous depressive group and a group of neurotic-depressive patients, and found the neurotic group to be more impaired in Digit span and Trail-making tests but not in Auditory Verbal
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Learning and Verbal Fluency. Fromm and Schopflocher Ž1983. compared neurotic and psychotic depressives and found a greater impairment in the processing of visuospatial material and retention of verbal and non-verbal material shown by the latter group. Comparing unipolar and bipolar affective disorder, some older studies had found a better outcome of the unipolar patients ŽBlackburn, 1975; Savard et al., 1980.. But there were some problems such as not having rated the depression score or not having matched the groups for age. There are no studies to date which compare schizoaffective disorder with other depressive illnesses. This might be due to the fact that the distinction between schizophrenia and schizoaffective disorder was controversial for a long time. When comparing schizophrenics, schizoaffectives and patients with affective disorders, Pope et al. Ž1980. did not find significant differences between affective disorders and schizoaffectives concerning family history, treatment response and long-term outcome. Walker Ž1981. did not assess neuropsychological but neuromotor and attentional functions in three groups of schizophrenic, affective and schizoaffective disorder and found the latter to be distinguishable from schizophrenics but not from patients with affective disorder. Therefore, today schizoaffective syndrome is often regarded as being an affective disease. In this trial, we did not find a significant difference which could be helpful in reliably differentiating between the four kinds of diagnoses. Regarding the fact that the diagnosis of a certain kind of depression, for example, unipolar depression, has to be temporary, because 5᎐18% of unipolar depressives fall ill with mania during their lifetime ŽClayton, 1981. and then are diagnosed as a bipolar type of depression, it would be quite plausible to assume that there is no difference in cognitive abilities between unipolar and bipolar depression. Therefore, it seems possible that cognitive deficits in depression are a nonspecific phenomenon, which can be present in any kind of depressive sub-diagnosis. There may be factors other than sub-diagnosis, as yet unknown, which determine whether cognitive deficits occur in depression or not.
Furthermore, our findings suggest that cognitive deficits might persist longer than the depressive episode itself. Although the mean depression score decreased significantly, the patient group as a whole did not improve significantly in their cognitive abilities except for one test. It has to be noted that the duration of inpatient hospitalization is long compared to other studies. When the study was done, the university clinic in Berlin was the only institution where there were no insurance restrictions. This policy was to alleviate the performance of scientific work. We therefore could keep patients in the hospital until they were recovered even though in other settings they would have been discharged after some weeks and followed up as outpatients for financial reasons. But the university is not a specialized center for refractory depression; instead, we are responsible for all psychiatric patients living in our county Žand other counties if we have vacancies., so the patients were recruited from a general population. It is still discussed, controversially, whether cognitive deficits disappear at the end of the depressive episode. In an earlier study we already had found that cognitive deficits continued after successful treatment ŽReischies and Neu, 2000.. But one has to admit that our patients possibly improve some months later after having returned to their work and normal life. But there are also reports of patients with cognitive deficits in an euthymic phase several months after their last episode of illness ŽO’Brien et al., 1993; Tham et al., 1997.. Furthermore, the fact that we did not find a significant correlation between depression scores and test abilities could indicate that cognitive deficits are determined by factors other than mood. So it seems to be plausible that there might be at least a sub-group of patients who continue to show poorer cognitive abilities for a reason we do not yet know. This sub-group, however, seems not to be determined by sub-diagnosis. As mentioned earlier, one possible hypothesis which is currently discussed in the literature is that subtle brain damage caused by, for example, slight vascular infarcts could be responsible for cognitive impairment ŽDrevets et al., 1997.; this could be potentially true for every sub-diagnosis.
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Therefore, further studies dealing with the question of sub-groups have to take MRI investigations into account. 4.2. Practice effect It has to be discussed whether improvement of test abilities was simply due to a practice effect. There certainly was such an influence, because in most of the tests applied, identical tests at both time points were used. But if the improvement was due to a practice effect only, both groups Žpatients and controls. would have shown a similar improvement, which in fact was not the case. The significant improvement of controls in visual memory possibly was due to a practice effect Žwhereas in the other tests there was no such improvement., but the patients did not show a similar pattern of improvement, which strongly suggests that there are other more important factors. 4.3. Influence of psychotic symptoms Cognitive functions may have been affected by the presence of psychotic symptoms. The only group presenting such features were the patients suffering from schizoaffective disorder. Schatzberg et al. Ž2000. had compared non-psychotic vs. psychotic major depression using a battery of neuropsychological tests. Among others, they used the Trail-making Test and Wechsler Memory Sub-scale, visual reproduction as in our study and did not find a significant difference in either tests which would confirm our findings. However, there might be tests other than those used by us that are more sensitive to the neuropsychological deficits correlated with psychotic symptoms and that would have revealed significant differences; therefore the influence of psychotic symptoms might not be entirely controlled in this investigation. 4.4. Sensiti¨ ity of tests It has to be further critically considered whether the tests may not have been sensitive enough to detect changes in cognitive function. However,
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the Rey Auditory Verbal Learning Test ŽRAVLT. and the Wechsler Memory Scale are used in dementia research to demonstrate decline in performance ŽBigler et al., 1989; Welsh et al., 1994.. The Reitan Trail-making Test A is sensitive with regard to monitoring improvement in patients with brain lesions ŽEson et al., 1978.. The RAVLT and Reitan Trail-making Test are recommended for clinical neuropsychological investigation by the Therapeutics and Technology Assessment Subcommittee of the American Academy of TTASAAN Ž1996.. Verbal fluency has been a useful measure in differentiating between demented, depressed and healthy persons ŽGeffen et al., 1993; Monsch et al., 1993; Welsh et al., 1994.. 4.5. Drop-outs When comparing the first neuropsychological assessment of those 21 patients who later dropped out and a matched group of patients who were tested twice, we did not find a significant difference. This might indicate that the drop-outs were neuropsychologically comparable to the rest of the population as far as baseline assessment was concerned. The patients who had been treated with ECT were retested but excluded from the sample. Compared to a matched group of patients who had not received ECT, they showed significantly worse performance in all memory tasks. This is in agreement with earlier studies investigating the influence of ECT on neuropsychological performance ŽCalev et al., 1989., and therefore these patients had to be excluded. 4.6. Influence of medication Since not all of our patients had been treated with the same antidepressant drugs, it may have been possible that different medication status confounded the comparison between the sub-diagnoses. The issue of whether or not and to what extent antidepressants might influence cognitive functions remains a subject of discussion. Some authors reported cognitive impairment during antidepressant medication ŽLamping et al., 1984; Branconnier et al., 1982., but there are also re-
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ports of improvement of cognitive functions during antidepressant medication. Glass et al. Ž1981. reported an improvement of cognitive abilities among depressives taking imipramine, while the depression itself did not improve. Therefore, it might be possible that antidepressants have a positive influence on cognitive functions as well. We did not find a significant influence on test outcome in our sample. However, medication is a factor that cannot be entirely controlled. For ethical reasons it is not possible to let depressed patients be unmedicated for long periods of time.
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