抑郁症对记忆的影响,8229,2周

Am J Psychiatry 165:6, June 2008 731 Article ajp.psychiatryonline.org This article is featured in this month’s AJP Audio. Toxic Effects of Depression on Brain Function: Impairment of Delayed Recall and the Cumulative Length of Depressive Disorder in a Large Sample of Depressed Outpatients Philip Gorwood, M.D., Ph.D. Emmanuelle Corruble, M.D., Ph.D. Bruno Falissard, M.D., Ph.D. Guy M. Goodwin, D.Phil., F.Med.Sci. Objective: An important current hypoth- esis suggests that the relationship be- tween severe depression and the hippo- campus is essentially toxic. The purpose of this study was to assess the generaliz- ability of the impact of depression on hippocampal function. Method: Participants were 8,229 outpa- tients who 1) fulfilled DSM-IV criteria for major depressive disorder based on clini- cal assessment and 2) were tested for de- layed recall, a memory function that is particularly related to hippocampal integ- rity in humans, during two visits several weeks apart. Results: As expected, at presentation with depression, the subjects’ current ill- ness severity was the major determinant of performance, as opposed to the inten- sity of their previous depressive history (the number and length of past episodes). However, following clinical response at the second visit, the length of previous de- pressive history became more significant than current symptoms. The following fac- tors had significant, independent impact: age, education level, and profession. Conclusions: Previous studies of small samples assessed for memory function, more or less specific to the hippocampus, have shown great variability in age, gen- der, education level, and the length and intensity of depressive episode. Hence, a very large sample was required to disen- tangle the central effect of previous de- pressive history. As demonstrated in a general practice sample in this study, the hypothesis that the length of past depres- sion impairs memory performance is sup- ported, suggesting that there is a toxic link between the burden of depression and cognition. This finding has important implications for public health. (Am J Psychiatry 2008; 165:731–739) It is a widely accepted current hypothesis that the rela- tionship between severe depression and the hippocampus is essentially toxic. Hence, the more intense the history of depression, the smaller the hippocampus. However, there is currently little evidence to consider this to be a general effect that is present across the spectrum of depression di- agnoses, which are regarded as highly heterogeneous. This is particularly true in primary care, in which there is often skepticism that depression represents anything more than normal human distress. Accordingly, we have sought to provide evidence of the generalizability of depression’s impact on hippocampal function. A large sample size would be required to account for many potentially major confounds, with an assessment that could be repeated be- fore and after treatment in order to control for the impact of the acute depressive state and provide a simple assay of hippocampal function. The majority of studies linking the hippocampus and major depressive illness have employed quantitative structural magnetic resonance imaging (MRI), functional MRI (fMRI), or positron emission tomography (PET), methods that are not easy to access in ordinary clinical practice. However, hippocampal size has usually corre- lated inversely with illness duration. This was demon- strated in a chronically depressed sample (1) and in pa- tients with variable illness durations seen in secondary care (2). Hippocampal size may also be related to other measures of illness intensity, such as the number of past hospitalizations (3) and recurrence of the disorder (4). Moreover, hippocampal abnormalities have been ob- served in the early years after illness onset (5). Meta-anal- yses have confirmed hippocampal volume reduction, and the total number of depressive episodes may be particu- larly correlated with right hippocampal volume (6, 7). The samples in imaging studies have often been rather small and potentially unrepresentative of the majority of outpatients with depression. We have been interested in measures of cognitive function that assay the function of the hippocampus but are much easier to conduct on a very large scale in everyday medical care. The choice of measures can be informed by imaging evidence of funda- mental hippocampal involvement. Thus, activation of the YYL 加亮 YYL 加亮 YYL 加亮 732 Am J Psychiatry 165:6, June 2008 TOXIC EFFECTS OF DEPRESSION ON BRAIN FUNCTION ajp.psychiatryonline.org hippocampus has been observed with tasks such as word- stem completion (8–10), success of word retrieval (11–14), emotional valence (15), and encoding (16–22). Even more consistent hippocampal activations have been shown in healthy subjects with a paragraph encoding task (23) that involves the encoding of complex and integrated informa- tion, which is hypothesized to be a core role for the hip- pocampus (24) and classically impaired in patients with known hippocampal lesions. Thus, there is considerable evidence to suggest that delayed paragraph recall is par- ticularly related to hippocampal function in humans (e.g., 9, 25, 26). While memory impairment may reasonably be taken to assay hippocampal function, its relationship to any current depressive episode has at least two (nonexclusive) aspects. 1) If the characteristics of the present depressive episode (such as symptom severity) predominate, memory func- tion is likely to be simply a “state marker,” reflecting the di- rect cognitive impact of current mood. 2) Alternatively, if the dominant factor is a lifetime cumulative impact of mood disorder (such as the total length or number of past episodes), memory impairment will act as a “trait marker” of enduring toxic effects of depression on brain function. In depressed individuals, both would potentially contrib- ute. In recovered individuals, deficits would most likely re- flect the enduring brain changes seen with brain imaging. The present study is of a large sample of outpatients who fulfilled DSM-IV criteria for major depressive disor- der and were assessed for memory function during two visits several weeks apart. We anticipated that some clini- cal factors, such as mood state markers (the length and se- verity of current depressive episode), choice of antide- pressant, and variation of testing methodology in a nonspecialist setting (as well as other factors such as older age, lower education level, and unemployment), would potentially confound the results at both visits. We hypoth- esized that the length and number of past episodes would also be involved in correct delayed recall but were much more likely to be discernible at a second clinic visit after symptom resolution, when the severity of current depres- sion would be reduced. Method Participants A list of 4,849 medical doctors were contacted via mail in France and asked to participate in a short-term follow-up protocol of de- pressed patients. Of these, 3,375 physicians (69.6%) agreed to par- ticipate. At least two contacts (usually via telephone) were made to each participating investigator: at the beginning of the protocol (in order to ensure that the protocol was clear and to explain how to assess memory recall) and at the close of trial entry (in order to verify the data received). By the end of the study, 1,844 clinicians (38.0%) had included at least one patient (a maximum number of five patients was requested to avoid center effects), who was fol- lowed up with a delay of at least 6 weeks between the two visits. The participating clinicians were experienced (mean age=49.9 years [SD=11.8]), with 7.8% practicing in a hospital, 46.6% in pri- vate practice, and 45.6% in a group practice. Clinicians were asked to include consecutive patients for whom a new (or different) antidepressant had to be prescribed for a major depressive episode. In addition, the patients were re- quired to be older than 18 years, speak fluent French, possess a social security number, and give informed consent. Patients had to be included by their clinicians during a 3-month interval. After complete description of the study was given to the subjects, writ- ten informed consent was obtained. A total of 9,515 patients were included in the study. Exclusion criteria were a diagnosis of bipolar disorder and the use of a mood stabilizer during treatment. All antidepressants (in accordance with the French Food and Drug Administration) were accepted in order to reflect usual clinical practice. Any change of antidepressant, an increase in the dosage, or the addition of a benzodiazepine was recorded at the second visit. Instruments The Hospital Anxiety and Depression Scale was chosen as a self- report instrument to measure symptom severity because of its ra- pidity and simplicity of rating. The scale was completed by all pa- tients at the first and second visits. A score above 8 for the depres- sion domain was required as an inclusion criterion. Hospital Anxiety and Depression Scale anxiety scores (score above 8 also re- quired for inclusion) were analyzed separately because anxiety may also have an impact on hippocampal volumes, according to animal models (27, 28) as well as studies in humans (29). The criteria for a major depressive episode were examined by the clinician, and the duration of each symptom was recorded during the two face-to-face visits. The presence of five or more symptoms (i.e., a DSM-IV diagnosis of major depressive disorder) was required for inclusion. The initial assessment also included the number of past depressive episodes, either treated or not treated with an antidepressant, and the cumulative length of past mood disorder. The delayed paragraph recall index from the Wechsler Memory Scale—Revised (30) was employed as a valid (8), sensitive (31, 32) measure of verbal declarative memory and a surrogate marker of hippocampal function. This subtest was administered according to the standardized protocol outlined in the Wechsler Memory Scale–Revised Manual (1987). A different story at each visit was read aloud to the subject by the clinician. After hearing the story, the subject was asked to repeat it using as many of the same words as he or she could recall from memory. One point was given for each verbatim or acceptable alternative response phrase. After at least a 10-minute delay (when the subject was distracted to complete the Hospital Anxiety and Depression Scale and provide other information), the subject was asked to recall the story again. The clinician tabulated the scores for each story as well as the to- tal score for the immediate and delayed trials. The existence of a practice effect was indirectly assessed in the subgroup of patients with identical levels of depression at both visits (the same Hospital Anxiety and Depression Scale global scores and number of DSM-IV symptoms of major depressive ep- isodes). In this subgroup of 33 patients, the difference between the number of correct delayed recall responses for the two visits (mean=0.029 [SD=3.6967]) was not significantly different from 0 (t=0.046, p=0.963). The level of memory impairment can be stratified according to the original description by Russel (33), who suggested that de- layed recall can be classified, out of the initial 25 elements, as fol- lows: 24 to 25=“better than normal,” 20 to 23=“normal,” 15 to 19= “mild,” 9 to 14=“mild to moderate,” 4 to 8=“moderate to severe,” and 0 to 3=“severe.” An age-corrected standard score can be com- puted on the basis of the Wechsler delayed paragraph recall in- dex, but we preferred to treat age as one of several potential con- Am J Psychiatry 165:6, June 2008 733 GORWOOD, CORRUBLE, FALISSARD, ET AL. ajp.psychiatryonline.org founding factors in our analysis. Nevertheless, age-corrected versus age-uncorrected scores of the Russel classification were very similar and identified the same group three standard devia- tions below the mean (kappa=0.829, var[kappa]<0.001). Statistics Variables were examined for the normality of distribution be- fore using parametric statistics. Given the sample size, rejection of a normal distribution (Kolmogorov-Smirnov test) for the fac- tors analyzed was expected for all variables. However, even if sig- nificantly different from 0 (p<0.001), the statistic was small for major covariables such as age (0.048), Hospital Anxiety and De- pression Scale depression score at visit 1 (0.085) and visit 2 (0.057), Hospital Anxiety and Depression Scale anxiety score at visit 1 (0.075) and visit 2 (0.089), and the number of correct de- layed recall responses at visit 1 (0.076) and visit 2 (0.073). A graph- ical appreciation was used to assess the normality of distribution of delayed recall (at the first and second visits). Thus, Q-Q (quan- tile) plots showing that dependent variables were close enough to the normal distribution were created. Parametric correlation (Pearson test) was used to compare two continuous variables, and analysis of variance was used to ana- lyze the role of a qualitative factor to explain continuous parame- ters. Since some parameters directly influenced correct recall in our sample (such as age and Hospital Anxiety and Depression Scale scores), we further analyzed the correlation between the number of potential recall responses and past episodes (their nonindependence being our main hypothesis) in different ranges. Structural equation modeling was used on the basis of SPSS and SAS PROC CALIS to disentangle the respective role of clus- tered variables, including state-dependent variables (such as the number of symptoms and Hospital Anxiety and Depression Scale scores) and state-independent variables (such as the total length of depressive history and number of past major depressive epi- sodes) (34). Patients with “severe” impairment (according to the Russel [33] classification) are at higher risk of neurological defects, and thus structural equation modeling analyses at the first and second vis- its were conducted, omitting this subgroup of patients. A further structural equation modeling analysis separated anxiety and de- pression scores on the Hospital Anxiety and Depression Scale and omitted the number of DSM-IV symptoms in order to avoid rein- forcing the role of depression versus anxiety. Last, we further investigated our main finding, the relationship between delayed recall and the number of past major depressive episodes in patients with treatment response, using a linear re- gression analysis. Results Sample A total of 9,515 depressed patients entered the study. The final sample for analysis consisted of 8,229 patients (86.48%). Subjects were excluded if the Hospital Anxiety and Depression Scale score was below 8 for depression or anxiety (644 patients) or data characterizing the patient were not correctly or completely saved. The subsample of subjects excluded 1) had fewer DSM-IV symptoms of de- pression (t=4.25, df=9512, p<0.0001); 2) had a shorter length of the present episode (t=2.15, df=6798, p=0.0159); 3) were more frequently men (χ2=172.9, df=8, p<0.0001); and 4) had better final Hospital Anxiety and Depression Scale scores for depression (t=3.974, df=9512, p<0.0001) and anxiety (t= 5.212, df=9512, p<0.0001), and thus they were more fre- quently responders (χ2=3.71, df=1, p=0.0124). Women comprised 70.37% of the final sample, and the average age of the sample was 48.02 years (SD=14.09). In this population, 1,115 patients were 65 years old or older, and 407 patients were over 75 years old. Civil status among these patients was as follows: married, 48.37%; single, 15.41%; divorced, 15.57%; and widowed, 7.31%. Education levels (middle=high school graduate) were as follows: low, 49.10%; middle, 30.06%; and high, 20.84%. Employment status was as follows: active employment, 57.86%; unem- TABLE 1. Clinical and Cognitive Characteristics of Patients With Major Depressive Disorder Before and After Antidepressant Treatment Characteristic Assessment AnalysisVisit 1 Visit 2 Mean SD Mean SD t df p Number of DSM-IV criteria for depression 6.62 1.14 3.25 1.77 142.86 16, 456 <0.0001 Hospital Anxiety and Depression Scale score for depression 14.62 3.24 9.94 4.22 79.83 16, 456 <0.0001 Hospital Anxiety and Depression Scale score for anxiety 14.12 3.01 8.92 3.40 103.86 16, 456 <0.0001 Number of correct delayed recall responses 9.98 4.57 12.04 4.85 27.63 16, 456 <0.0001 TABLE 2. Level of Memory Impairment for Delayed Recall in Patients With Major Depressive Disorder Before Visit 1 and 6 Weeks After Antidepressant Treatment (visit 2)a Classification Assessment Visit 1 (N=8,221) Visit 2 (N=8,221) Visit 2 Responders (N=1,895)b N % N % N % Better than normal (24–25 elements) 19 0.24 74 0.93 26 1.37 Normal (20–23 elements) 180 2.25 520 6.52 162 8.55 Mild (15–19 elements) 1,239 15.47 1,961 24.61 554 29.23 Mild to moderate (9–14 elements) 3,267 40.80 3,279 41.13 754 39.79 Moderate to severe (4–8 elements) 2,793 34.88 1,979 24.82 340 17.94 Severe (0–3 elements) 510 6.37 160 2.01 14 0.74 a According to Russel classification (33). b Subsample of patients after 6 weeks of treatment who had treatment response (i.e., at least a 50% decrease of their initial Hospital Anxiety and Depression Scale score for depression and less than five diagnostic criteria). 734 Am J Psychiatry 165:6, June 2008 TOXIC EFFECTS OF DEPRESSION ON BRAIN FUNCTION ajp.psychiatryonline.org ployed, 12.43%; retired, 19.07%; student, 0.11%; and an- other type of professional activity, 10.53%. The Hospital Anxiety and Depression Scale score for de- pression was below 11 in only 10.48% of patients. The du- ration of current major depressive episode was on average 8.37 weeks (SD=10.84). Among the patients, 18.38% ful- filled five DSM-IV criteria for depression, 31.82% fulfilled six criteria, 27.76% fulfilled seven criteria, 15.44% fulfilled eight criteria, and 6.60% fulfilled nine criteria (Table 1). This was the first episode of depression for 49.64% of pa- tients, the second episode for 25.30%, the third episode for 6.05%, and between the fourth and 13th episode for the re- maining patients (4.67%). The length of unipolar depres- sion, except the present episode, was on average 12.55 weeks (SD=34.91), and the lifetime duration (or number of weeks depressed) was 21.23 weeks (SD=33.91). The second visit was on average 42 days (SD=8.93) after the first visit (between 3 and 20 weeks). At the second visit, the number of depressive symptoms from the list of DSM- IV criteria decreased (Table 1). According to these criteria, 76.39% of patients no longer fulfilled the diagnosis of ma- jor depressive episode (i.e., fulfilled less than five criteria). According to Hospital Anxiety and Depression Scale self- rating, 76.44% of patients were responders (i.e., patients who had at least a 50% decrease of the depression score between the two visits). The number of correct answers for immediate recall of the Weschler paragraph recall index tested at the first visit was between one and 24, with an average of 11.75 appro- priate answers (SD=4.72) (see the table in the data supple- ment accompanying the online version of this article). The delay between immediate and delayed recall was on aver- age 14.15 minutes (SD=7.73; range=5–56). Accordingly, the delay between immediate and delayed recall was intro- duced into multivariate analyses, as was the delay be- tween the first and second visits. The patients recalled ap- proximately 10 correct details of the paragraph (i.e., 85.89% of the initial immediate recall) (Table 1). During the second visit, a global improvement of imme- diate recall was observed (13.24 correct answers; [SD= 4.79; range=1–24]) (see the table in the data supplement accompanying the online version of this article). On aver- age, 13.58 minutes later