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Long-lasting cognitive impairment in unipolar major depression: a 6-month follow-up study
Psychiatry Research 118 (2003) 189–196
Long-lasting cognitive impairment in unipolar major depression: a 6-month follow-up study ˚ Hammara,*, Anders Lundb, Kenneth Hugdahla,b Asa a
Department of Biological and Medical Psychology, Division of Cognitive Neuroscience, University of Bergen, Aarstadveien 21, 5009 Norway b Department of Psychiatry, Haukeland University Hospital and University of Bergen, Bergen, Norway Received 3 June 2002; received in revised form 6 February 2003; accepted 19 February 2003
Abstract The aim of the study was to investigate cognitive impairment in major depression both acutely and after 6 months. All patients were investigated within a neurocognitive experimental setting at two testing sessions: at inclusion and after 6 months. Automatic and effortful information processing was investigated with a visual search paradigm. Twenty-one patients with recurrent major depression according to DSM-IV and a Hamilton Depression Rating Scale score )18 were included in the study. Healthy subjects, matched for age and gender, were used as a control group. The results showed that the depressed patients performed equal to the control group on trials requiring automatic information processing at both sessions. However, the patients were impaired compared to the control group on trials requiring effortful information processing, also at both sessions. The depressed patients showed no improvement in cognitive performance from test 1 to test 2. The results indicate that the depressed patients had an impaired performance for effortful, but not automatic, visual search performance, and that the impairment remained after 6 months, despite significant improvement in their depression scores. 䊚 2003 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Effortful information processing; Automatic information processing; Visual search; Attention
1. Introduction Major depression is associated with cognitive dysfunction during periods of acute illness (Veiel, 1997; Elliot, 1998; Austin et al., 2001). A large number of patients with major depression have recurrent multiple episodes of depression between periods of symptom reduction and nonsymptomatic phases. *Corresponding author. Fax: q47-5589874. ˚ Hammar). E-mail address: [email protected] (A.
However, a major issue is whether cognitive impairment manifested during periods of depression is long lasting or improves during remission and recovery (see Austin et al., 2001, for an overview). There is a growing consensus in the literature that cognitive impairment seen during episodes of illness persists during episodes of remission (Trichard et al., 1995; Beats et al., 1996; Paradiso et al., 1997; Reischies and Neu, 2000), although not all studies have shown this (Calev et al., 1986; Bazin et al., 1994; Elliot et al., 1996).
0165-1781/03/$ - see front matter 䊚 2003 Elsevier Science Ireland Ltd. All rights reserved. doi:10.1016/S0165-1781(03)00075-1
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˚ Hammar et al. / Psychiatry Research 118 (2003) 189–196 A.
It has been suggested that cognitive impairment worsens for every episode of depression (Brown et al., 1999; Sweeney et al., 2000) and that cognitive impairment observed in a nonsymptomatic phase is related to number of previous episodes (Kessing, 1998). The risk for a relapse after a first episode is estimated at 50%. For patients having a history of three episodes or more, the estimated relapse risk is increased to 90% (Kasper and Eder, 1994). Knowledge about cognitive functioning in phases of remission can have implications for treatment, rehabilitation and risk of relapse. There is, however, no evidence that symptom reduction is followed by reduction in cognitive impairment to a similar degree. Hartlage et al. (1993) have proposed a ‘cognitive effort hypothesis’, suggesting that cognitive deficit in depression is dependent on the difficulty of the task to be performed, with impairment increasing in accord with the cognitive effort the task requires. Demanding tasks, no matter what cognitive function they assess, will have serious detrimental effects in depressed patients. In this context, automatic processing of information is defined as a stimulus-driven process without invoking attention, while effortful processing is an instruction-driven process that requires attention and allocation of cognitive capacity. This view is supported by other findings, which have shown that depressed patients are more impaired on tasks that require more effortful information processing compared to tasks that require more automatic information processing (Hashler and Zacks, 1979; Weingartner et al., 1981; Cohen et al., 1982; Roy-Byrne et al., 1986; Georgieff et al., 1998; Thomas et al., 1999). However, it is still unsettled whether this also holds true in patients tested longitudinally, during periods of symptom reduction as well as during acute phases of the illness. The aim of the present study was therefore to investigate if impairment in effortful information processing shown in an acute phase of depression still existed in a period of symptom reduction at a 6-month follow-up. A visual search paradigm was chosen in order to experimentally manipulate effortful and auto-
matic information processing. In this task, the subject has to detect a target stimulus on a computer screen, where the target is surrounded by distractor stimuli. Visual search time is dependent on how basic stimulus features (i.e. color, orientation, size) are shared by the target and the distractors. When the target shares many features with the surrounding distractors, search for a target becomes more demanding and effortful (Duncan and Humphreys, 1989; Wolfe, 1998), with an increased search and response time. The time it takes to respond from the onset of the stimulus display (reaction time, RT) is presumed to indicate the level of cognitive effort involved. Using a paradigm with different levels of cognitive effort, we predicted that depressed patients would: (a) show increased RTs on trials requiring effortful but not automatic information processing, and compared to a healthy control group, (b) this would prevail at a second test after 6 months in the patient group, despite symptom reduction, and (c) that the healthy control group would perform equally at the two test occasions. 2. Methods Twenty-one patients (10 males and 11 females: 18 inpatients and 3 outpatients) who met the DSMIV criteria for recurrent unipolar depression and with a minimum score of 18 on the Hamilton Depression Rating Scale (HDRS) were included in the study. The mean score on the HDRS at inclusion was 21.9 (S.D.s3.7). The age range was 20–56 years (mean 42 year, S.D.s10). Inclusion criteria were a history of recurrent major depression, with at least one previous episode requiring psychiatric treatment, no central nervous system (CNS) damage or disease, and no somatic condition that could interfere with cognitive functioning. The depressed patients were recruited from psychiatric institutions and clinics in Bergen, Norway. The patients were treated with the newer antidepressant medication (predominantly selective serotonin reuptake inhibitors; SSRIs). None of the patients received tricyclic antidepressants or benzodiazepines. One patient was drug-naive. The healthy control subjects were individually matched
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for age, gender, and level of education, and had no history of psychiatric illness or CNS damagey disease. All subjects were tested on two occasions: at inclusion (test 1) and at a 6-month follow-up (test 2). At 6-month follow-up, data were lost for one female patient. The mean HDRS score was 8.45 (S.D.s5.5) on the second testing session. See Table 1 for further details. All patients went through a diagnostic assessment by a senior psychiatrist at both sessions. The psychiatrists were blind to the cognitive deficit information. All patients, but one, were still treated with antidepressants at the follow-up test. The study was performed in accordance with the Helsinki Declaration of the World Medical Association Assembly. The University of Bergen Regional Medical Ethics Committee and The Norwegian Data Inspectorate had approved of the study. 2.1. Apparatus, stimuli and procedure The stimulus material was presented on a PC screen. The target stimulus was a black rectangle in a vertical position. One type of distractor stimuli were horizontal black rectangles (Fig. 1a and b). The other type of distractor stimuli were black horizontal rectangles and gray vertical rectangles (Fig. 1c and d). For half of the trials, a target stimulus was presented together with the distractors. For the other half of the trials, only distractors were presented. In half of the trials there was one type
Fig. 1. Examples of the stimulus conditions. (a) One type of distractor, no target presented; (b) one type of distractor, target presented; (c) two types of distractors, no target presented; (d) two types of distractors, target presented.
of distractors. In the other half of the trials both types of the distractors were presented. The idea was that trials with both types of distractors presented would be a cognitively more demanding condition, requiring effortful information processing.
Table 1 Average reaction times (in ms) for the patient and control groups for the different conditions at the two test sessions Depressed patients One-distractor With target Test 1 Test 2
Control group Two-distractor
One-distractor
Mean Two-distractor
1380.14 (S.D.s644.14) 2279.73 (S.D.s862.11) 1122.67 (S.D.s378.56) 1801.73 (S.D.s495.37 1435.62 (S.D.s111.67) 2313.74 (S.D.s1343.67) 954.50 (S.D.s358.56) 1610.97 (S.D.s599.53)
1646.07 1578.71
Without target Test 1 1511.61 (S.D.s519.5) 3798.18 (S.D.s1757.59) 1355.93 (S.D.s426.04) 2809.46 (S.D.s1001.09) 2368.80 Test 2 1463.99 (S.D.s806.03) 3451.66 (S.D.s2323.23) 1190.49 (S.D.s450.52) 2430.41 (S.D.s974.79) 2134.14 Mean
1447.84
2960.83
1155.90
2163.14
1931.93
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The experiment consisted of two blocks of 20 trials each; 10 trials with target and one distractor type; 10 trials without target and one distractor type; 10 trials with target and two distractor types; and 10 trials without target and two distractor types. There was a break of 30 s between the blocks. Before each trial, a fixation cross was presented and lasted for 1.5 s. The visual search display stayed on, on each trial, until a response was made. The different displays were presented in randomized order across trials. The subject was instructed to press the ‘A’ key on the PC keyboard with the left hand if the screen only consisted of distractors and to press the ‘L’ key with the right hand if a target was present. The ‘A’ and the ‘L’ keys are the last keys on the left and right, respectively of the middle row of the PC keyboard. The stimulus presentation and recording of responses was programmed in the MEL2programming language platform. The stimulus material was stored in digitized graphics format and imported into the MEL program. The experiment was presented on a portable Compaq Armada 1100 PC, Pentium with a 12.1-inch high contrast SVGA display with a resolution of 800=600 pixels. All patients and control subjects were given information about the study and that participation was voluntary. After written informed consent was obtained, the patients were tested on the visual search task, which was part of a larger neuropsychological test battery. All subjects were seated in front of the PC, approximately 40 cm away from the screen. They first performed a series of ‘familiarization trials’ where they had to respond by pressing the specified keyboard keys without any data being recorded. The subjects were instructed to respond as quickly and accurately as they could. 2.2. Data scoring and analysis The data were automatically collected by the program and scored as mean response latency for each condition, and statistically analyzed in a repeated-measures analysis of variance (ANOVA). The basic design was a 2=2=2=2 factorial design with Group (depressed patients and control subjects)=Target (present or absent)=Distractors
MEL2
(one or two distractors)=Test (test 1 and test 2). The first factor was treated as a between-groups factor and the second, third and the fourth factors were treated as within-group factors. Only trials with a correct response were included in the statistical analyses. The total errors across subjects and trials were less than 8%. 3. Results There was a significant main effect of Group: F(1, 40)s5.21 P-0.01. Tukey’s HSD post-hoc test showed that the depressed group was significantly impaired in their RTs compared to the control group both at test 1 and test 2. There were no significant effects for the Test factor, neither as a main effect, nor as an interaction with the group factor. Thus, the three-way and four-way interactions were not significant. There was, however, a significant main effect of Target: F(1, 40)s54.22 P-0.01, which showed longer RTs on trials when the target was absent. There was also a significant main effect of Distractors: F(1, 40)s139.19 P-0.01, with longer RTs in the two-distractor condition. See Table 1 for further details. The two-way interaction between Group and Distractor was also significant: F(1, 40)s5.61 P-0.01. Tukey’s HSD post-hoc test showed that the depressed group differed significantly from the control group on trials with two distractors, but not on trials with one distractor (Fig. 2). There was also a significant two-way interaction between Target and Distractor: F(1, 40)s36.71 P-0.01. This showed that the subjects had significantly longer RTs when a target was absent compared to when it was present in the two-distractor condition, while there was no difference in the one-distractor condition. In order to further probe group differences, an interference score was calculated by subtracting the scores in the effortful conditions (two-distractor condition, with and without target) from the scores in the automatic conditions (one-distractor condition, with and without target). A two-way ANOVA was carried out with Group (depressed patients and control group)=Interference score (test 1 and test 2). This
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Fig. 2. Mean RT for the depression and control group for the different conditions. *Significant difference P-0.05.
showed a significant main effect of Group F(1, 40)s5.61 P-0.01. Again, as predicted, there were no significant main or interaction effects involving test session. Further probing with Tukey’s HSD post-hoc test showed that the patient group still differed significantly from the control group at the 6-month follow-up (Fig. 3). At the second test session, the patient group consisted of two subgroups with 10 patients with HDRS scores )8 and 10 patients with HDRS scores -8. Performing a separate ANOVA on these two groups did not change any of the results between patients and controls, nor did comparing the patients with HDRS scores )8 and -8. Thus, the patient group still differed significantly from the control group, and there were no significant differences between the two patient subgroups. 4. Discussion These results support the hypothesis of longlasting cognitive impairment in major depression. The depressed patients did not show any significant improvement from test 1 to test 2 on any of the experimental conditions, despite symptom reduction as reflected by lower HDRS scores. Furthermore, they had significantly longer RTs on
effortful trials compared to the control group, on both test occasions. These findings are therefore consistent with the cognitive effort hypothesis, which argues that depressed patients are impaired on tasks requiring effortful information processing (Hartlage et al., 1993; see also Hashler and Zacks, 1979; Weingartner et al., 1981; Cohen et al., 1982; Roy-Byrne et al., 1986; Thomas et al., 1999). All patients went through a diagnostic assessment by a senior psychiatrist. By using, for example, the Structured Clinical Interview for DSM-IV, the study possibly could have been strengthened regarding diagnosis and symptom reduction. Thus, although the patients did improve their HDRS scores significantly from test 1 to test 2 (mean 21.9 and 8.45, respectively), it could still be argued that some of the patients scored in a subclinical range. If so, it could further be argued that the reason they did not improve on test 2 was that their HDRS scores were not down to zero. Therefore, a Pearson product-moment correlation was calculated to examine if severity of HDRS score could explain the interference score differences between the groups at the second test occasion. The correlation (rs12) was, however, nonsignificant.
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Fig. 3. Mean interference scores for the depression and control groups. *Significant difference P-0.05.
The significantly prolonged RTs in the depression group could not be explained as a general psychomotor slowing (cf. Parker et al., 1993; King, 1975). A comparison between trials requiring a more automatic information processing and trials requiring a more effortful information processing showed that the depressed patients only differed from the control group on the more effortful trials. Moreover, the interference score analysis would eliminate possible motor slowing by subtracting RTs from the less demanding trials from the more demanding trials. This still showed a significant difference in performance between the groups, which was present for both test sessions. Duration of the illness may be a critical factor when trying to explain the lack of improvement in the patient group. As previously mentioned, it has been argued that cognitive impairment increases with every episode of depression (Brown et al., 1999; Sweeney et al., 2000; Kessing, 1998). Most studies concerning number of episodes and cognitive performance in depression have, however, mainly been related to memory performance rather than to attention or executive functions (Austin et al., 2001). Another possible limitation in the present study is the lack of information on number of episodes and duration. However, since all patients had experienced at least one previous depressive episode with high HDRS scores, and several patients had experienced more episodes, this could
have affected the results. A comparison with a group of first episode patients in a longitudinal study could perhaps further clarify whether duration of illness is a critical factor for cognitive performance in the kind of experimental paradigms used in the present study. The main finding was a long-lasting cognitive impairment in recurrent major depression. However, the results give no indication concerning the pathogenesis. Several authors have suggested that there is a relation between duration of illness and structural changes in the brain, e.g. stress-induced glucocorticoids, which can cause reversible and irreversible brain atrophies and alter cognitive performance (see Kandel, 1999, for an overview; Sheline et al., 1999; Goodwin, 1997). Still, even if this could be a possible explanation for the present findings, there are inconsistent findings in the literature related to age, methods of assessment, treatment, diagnostic subtypes, etc. (Austin et al., 2001). Effects of antidepressant medication on cognitive functioning have been suggested as a possible confounding factor (for a review, see AmadoBoccara et al., 1995). However, this has been found to a lesser degree for selective serotonin reuptake inhibitors (SSRIs) (Peretti et al., 2000), which were prescribed for the majority of our patients. Since all patients in our study, except for one drug-naive patient, were treated with SSRIs, a
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medication explanation for the results seems unlikely. Further studies are, however, needed on this issue, including in drug-naive patients, to resolve the impact of medication treatment on cognitive functioning, particularly in a longitudinal perspective. The unimproved performance during the 6month period despite of an average reduction of the HDRS score of 13.42 points (from 21.9 to 8.45) points to a trait effect for cognitive impairment. There was no correlation between RTs and HDRS scores at the follow-up test. Thus, severity of depression did not predict severity of cognitive impairment and vice versa, ruling out state effects. Kuny and Stassen (1995) reported that cognitive and clinical improvement were relatively independent. However, trait factors that may indicate illness may be operative even in a recovery phase. There is a great need for further longitudinal studies addressing the issue of cognitive impairment in recurrent major depression, with a focus on long-lasting effects despite symptom reduction. In addition, more studies are needed for the investigation of the cognitive effort hypothesis across cognitive domains (e.g. memory, attention, executive function). Acknowledgments We are grateful for the help of the following students and colleagues for the data collection and analysis: Lin Sørensen, Jenny Linn Torgersen, Guro Vigestad, Inger Tonette van der Wel, Randi Hopsdal, Eva Aaker, Kirsten Stordal, Ketil Ødegaard, Rune Kroken and Atle Roness. References Amado-Boccara, I., Gougoulis, N., Poirier Littre, M.F., Galinowski, A., Loo, H., 1995. Effects of antidepressants on cognitive functions: a review. Neuroscience and Biobehavioral Reviews 19 (3), 479–493. Austin, M.-P., Mitchell, P., Goodwin, G.M., 2001. Cognitive deficits in depression. British Journal of Psychiatry 178, 200–2006. Bazin, N., Perruchet, P., De Bonis, M., Feline, A., 1994. The dissociation of explicit and implicit memory in depressed patients. Psychological Medicine 24 (1), 239–245. Beats, B.C., Sahakian, B.J., Levy, R., 1996. Cognitive performance in tests sensitive to frontal lobe dysfunction in the elderly depressed. Psychological Medicine 26, 591–603.
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Brown, E.S., Rush, A.J., McEvan, B.S., 1999. Hippocampal remodeling and damage by corticosteroids: implications for mood disorders. Neuropsychopharmacology 21 (4), 474–480. Calev, A., Korin, Y., Shapira, B., Kugelmass, S., Lerer, B., 1986. Verbal and non-verbal recall by depressed and euthymic affective patients. Psychological Medicine 16, 789–794. Cohen, R.M., Weingarten, H., Smallberg, S.A., Pickar, D., Murphy, D.L., 1982. Effort and cognition in depression. Archives of General Psychiatry 39, 805–807. Duncan, J., Humphreys, G.W., 1989. Visual search and stimulus similarity. Psychological Review 96, 433–458. Elliot, R., 1998. The neuropsychological profile in unipolar depression. Trends in Cognitive Sciences 2 (11), 447–454. Elliot, R., Sahakian, B.J., McKay, A.P., Herrod, J.J., Robbins, T.W., Paykel, E.S., 1996. Neuropsychological impairments in unipolar deression: the role of perceived failure on subsequent performance. Psychological Medicine 26, 975–989. Georgieff, N., Dominey, P.F., Michel, F., Marie-Cardine, M., ´ J., 1998. Semantic priming in major depressive state. Dalery, Psychiatry Research 78, 29–44. Goodwin, G.M., 1997. Neuropsychological and neuroimaging evidence for the involvement of the frontal lobes in depression. Journal of Psychopharmacology 11 (2), 115–122. ´ Hartlage, S., Alloy, L.B., Vazquez, C., Dykman, B., 1993. Automatic and effortful processing in depression. Psychological Bulletin 113 (2), 247–278. Hashler, L., Zacks, R.T., 1979. Automatic and effortful processes in memory. Journal of Experimental Psychology General 108, 356–388. Kandel, E., 1999. Biology and the future of psychoanalysis: a new intellectual framework for psychiatry revisited. American Journal of Psychiatry 156, 505–524. Kasper, S., Eder, H., 1994. Who should benefit from longterm antidepressant therapy? In: Mendlewicz, J., Glassmann, A. (Eds.), Depression as a Lifetime Disorder. Proceedings of the XIX CINP Congress, Washington, DC, pp. 17–28. Kessing, L.V., 1998. Cognitive impairment in the euthymic phase of affective disorder. Psychological Medicine 28, 1027–1038. King, H.E., 1975. Psychomotor correlates of behavior disorder. In: Kietzman, M.L., Sutton, S., Zubin, J. (Eds.), Experimental Approaches to Psychopathology. Academic Press, New York, pp. 421–450. Kuny, S., Stassen, H.H., 1995. Cognitive performance in patients recovering from depression. Psychopathology 2, 190–207. Paradiso, S., Lamberty, G.J., Garvey, M.J., Robinson, R.G., 1997. Cognitive impairment in the euthymic phase of chronic unipolar depression. Journal of Nervous and Mental Disease 185 (12), 748–754. Parker, G., Hadzi-Pavlovic, D., Brodaty, H., Boyse, P., Mitchell, P., Wilhelm, K., Hickie, I., Eyers, K., 1993. Psychomotoric disturbance in depression: defining the constructs. Journal of Affective Disorder 27 (4), 255–265.
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Peretti, S., Judge, R., Hindmarch, I., 2000. Safety and tolerability considerations: tricyclic antidepressants vs. selective serotonin reuptake inhibitors. Acta Psychiatrica Scandinavica Suppl 403, 17–25. 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. Roy-Byrne, P.P., Weingartner, H., Bierer, L.M-., Thompson, K., Post, R.M., 1986. Effortful and automatic cognitive processes in depression. Archives of General Psychiatry 43, 265–267. Sheline, Y., Sanghavi, M., Mintun, M., Gado, M.H., 1999. Depression duration but not age predicts hippocampal volume loss in medically healthy women with recurrent major depression. Journal of Neuroscience 19 (12), 5034–5043. Sweeney, J.A., Kmiec, J.A., Kupfer, D.J., 2000. Neuropsychologic impairment in bipolar and unipolar mood disorder
on the CANTAB neurocognitive battery. Biological Psychiatry 48 (7), 674–684. Thomas, P., Goudemand, M., Rousseaux, M., 1999. Attentional resources in major depression. European Archives of Clinical Neuroscience 249, 79–85. Trichard, C., Martinot, J.L., Alagille, M., Masure, M.C., Hardy, ´ P., Ginestet, D., Feline, A., 1995. Time course of prefrontal lobe dysfunction in severely depressed in-patients: a longitudinal neuropsychological study. Psychological Medicine 25, 79–85. Veiel, H.O.F., 1997. A preliminary profile of neuropsychological deficits associated with major depression. Journal of Clinical and Experimental Neuropsychology 19 (4), 587–603. Weingartner, H., Cohen, R.M., Martello, J., Gerdt, C., 1981. Cognitive processes in depression. Archives of General Psychiatry 38, 42–47. Wolfe, J.M., 1998. Visual search. In: Pashler, H. (Ed.), Attention. Psychology Press Ltd, Hove, pp. 13–73.
Long-lasting cognitive impairment in unipolar major depression: a 6-month follow-up study ˚ Hammara,*, Anders Lundb, Kenneth Hugdahla,b Asa a
Department of Biological and Medical Psychology, Division of Cognitive Neuroscience, University of Bergen, Aarstadveien 21, 5009 Norway b Department of Psychiatry, Haukeland University Hospital and University of Bergen, Bergen, Norway Received 3 June 2002; received in revised form 6 February 2003; accepted 19 February 2003
Abstract The aim of the study was to investigate cognitive impairment in major depression both acutely and after 6 months. All patients were investigated within a neurocognitive experimental setting at two testing sessions: at inclusion and after 6 months. Automatic and effortful information processing was investigated with a visual search paradigm. Twenty-one patients with recurrent major depression according to DSM-IV and a Hamilton Depression Rating Scale score )18 were included in the study. Healthy subjects, matched for age and gender, were used as a control group. The results showed that the depressed patients performed equal to the control group on trials requiring automatic information processing at both sessions. However, the patients were impaired compared to the control group on trials requiring effortful information processing, also at both sessions. The depressed patients showed no improvement in cognitive performance from test 1 to test 2. The results indicate that the depressed patients had an impaired performance for effortful, but not automatic, visual search performance, and that the impairment remained after 6 months, despite significant improvement in their depression scores. 䊚 2003 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Effortful information processing; Automatic information processing; Visual search; Attention
1. Introduction Major depression is associated with cognitive dysfunction during periods of acute illness (Veiel, 1997; Elliot, 1998; Austin et al., 2001). A large number of patients with major depression have recurrent multiple episodes of depression between periods of symptom reduction and nonsymptomatic phases. *Corresponding author. Fax: q47-5589874. ˚ Hammar). E-mail address: [email protected] (A.
However, a major issue is whether cognitive impairment manifested during periods of depression is long lasting or improves during remission and recovery (see Austin et al., 2001, for an overview). There is a growing consensus in the literature that cognitive impairment seen during episodes of illness persists during episodes of remission (Trichard et al., 1995; Beats et al., 1996; Paradiso et al., 1997; Reischies and Neu, 2000), although not all studies have shown this (Calev et al., 1986; Bazin et al., 1994; Elliot et al., 1996).
0165-1781/03/$ - see front matter 䊚 2003 Elsevier Science Ireland Ltd. All rights reserved. doi:10.1016/S0165-1781(03)00075-1
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It has been suggested that cognitive impairment worsens for every episode of depression (Brown et al., 1999; Sweeney et al., 2000) and that cognitive impairment observed in a nonsymptomatic phase is related to number of previous episodes (Kessing, 1998). The risk for a relapse after a first episode is estimated at 50%. For patients having a history of three episodes or more, the estimated relapse risk is increased to 90% (Kasper and Eder, 1994). Knowledge about cognitive functioning in phases of remission can have implications for treatment, rehabilitation and risk of relapse. There is, however, no evidence that symptom reduction is followed by reduction in cognitive impairment to a similar degree. Hartlage et al. (1993) have proposed a ‘cognitive effort hypothesis’, suggesting that cognitive deficit in depression is dependent on the difficulty of the task to be performed, with impairment increasing in accord with the cognitive effort the task requires. Demanding tasks, no matter what cognitive function they assess, will have serious detrimental effects in depressed patients. In this context, automatic processing of information is defined as a stimulus-driven process without invoking attention, while effortful processing is an instruction-driven process that requires attention and allocation of cognitive capacity. This view is supported by other findings, which have shown that depressed patients are more impaired on tasks that require more effortful information processing compared to tasks that require more automatic information processing (Hashler and Zacks, 1979; Weingartner et al., 1981; Cohen et al., 1982; Roy-Byrne et al., 1986; Georgieff et al., 1998; Thomas et al., 1999). However, it is still unsettled whether this also holds true in patients tested longitudinally, during periods of symptom reduction as well as during acute phases of the illness. The aim of the present study was therefore to investigate if impairment in effortful information processing shown in an acute phase of depression still existed in a period of symptom reduction at a 6-month follow-up. A visual search paradigm was chosen in order to experimentally manipulate effortful and auto-
matic information processing. In this task, the subject has to detect a target stimulus on a computer screen, where the target is surrounded by distractor stimuli. Visual search time is dependent on how basic stimulus features (i.e. color, orientation, size) are shared by the target and the distractors. When the target shares many features with the surrounding distractors, search for a target becomes more demanding and effortful (Duncan and Humphreys, 1989; Wolfe, 1998), with an increased search and response time. The time it takes to respond from the onset of the stimulus display (reaction time, RT) is presumed to indicate the level of cognitive effort involved. Using a paradigm with different levels of cognitive effort, we predicted that depressed patients would: (a) show increased RTs on trials requiring effortful but not automatic information processing, and compared to a healthy control group, (b) this would prevail at a second test after 6 months in the patient group, despite symptom reduction, and (c) that the healthy control group would perform equally at the two test occasions. 2. Methods Twenty-one patients (10 males and 11 females: 18 inpatients and 3 outpatients) who met the DSMIV criteria for recurrent unipolar depression and with a minimum score of 18 on the Hamilton Depression Rating Scale (HDRS) were included in the study. The mean score on the HDRS at inclusion was 21.9 (S.D.s3.7). The age range was 20–56 years (mean 42 year, S.D.s10). Inclusion criteria were a history of recurrent major depression, with at least one previous episode requiring psychiatric treatment, no central nervous system (CNS) damage or disease, and no somatic condition that could interfere with cognitive functioning. The depressed patients were recruited from psychiatric institutions and clinics in Bergen, Norway. The patients were treated with the newer antidepressant medication (predominantly selective serotonin reuptake inhibitors; SSRIs). None of the patients received tricyclic antidepressants or benzodiazepines. One patient was drug-naive. The healthy control subjects were individually matched
˚ Hammar et al. / Psychiatry Research 118 (2003) 189–196 A.
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for age, gender, and level of education, and had no history of psychiatric illness or CNS damagey disease. All subjects were tested on two occasions: at inclusion (test 1) and at a 6-month follow-up (test 2). At 6-month follow-up, data were lost for one female patient. The mean HDRS score was 8.45 (S.D.s5.5) on the second testing session. See Table 1 for further details. All patients went through a diagnostic assessment by a senior psychiatrist at both sessions. The psychiatrists were blind to the cognitive deficit information. All patients, but one, were still treated with antidepressants at the follow-up test. The study was performed in accordance with the Helsinki Declaration of the World Medical Association Assembly. The University of Bergen Regional Medical Ethics Committee and The Norwegian Data Inspectorate had approved of the study. 2.1. Apparatus, stimuli and procedure The stimulus material was presented on a PC screen. The target stimulus was a black rectangle in a vertical position. One type of distractor stimuli were horizontal black rectangles (Fig. 1a and b). The other type of distractor stimuli were black horizontal rectangles and gray vertical rectangles (Fig. 1c and d). For half of the trials, a target stimulus was presented together with the distractors. For the other half of the trials, only distractors were presented. In half of the trials there was one type
Fig. 1. Examples of the stimulus conditions. (a) One type of distractor, no target presented; (b) one type of distractor, target presented; (c) two types of distractors, no target presented; (d) two types of distractors, target presented.
of distractors. In the other half of the trials both types of the distractors were presented. The idea was that trials with both types of distractors presented would be a cognitively more demanding condition, requiring effortful information processing.
Table 1 Average reaction times (in ms) for the patient and control groups for the different conditions at the two test sessions Depressed patients One-distractor With target Test 1 Test 2
Control group Two-distractor
One-distractor
Mean Two-distractor
1380.14 (S.D.s644.14) 2279.73 (S.D.s862.11) 1122.67 (S.D.s378.56) 1801.73 (S.D.s495.37 1435.62 (S.D.s111.67) 2313.74 (S.D.s1343.67) 954.50 (S.D.s358.56) 1610.97 (S.D.s599.53)
1646.07 1578.71
Without target Test 1 1511.61 (S.D.s519.5) 3798.18 (S.D.s1757.59) 1355.93 (S.D.s426.04) 2809.46 (S.D.s1001.09) 2368.80 Test 2 1463.99 (S.D.s806.03) 3451.66 (S.D.s2323.23) 1190.49 (S.D.s450.52) 2430.41 (S.D.s974.79) 2134.14 Mean
1447.84
2960.83
1155.90
2163.14
1931.93
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The experiment consisted of two blocks of 20 trials each; 10 trials with target and one distractor type; 10 trials without target and one distractor type; 10 trials with target and two distractor types; and 10 trials without target and two distractor types. There was a break of 30 s between the blocks. Before each trial, a fixation cross was presented and lasted for 1.5 s. The visual search display stayed on, on each trial, until a response was made. The different displays were presented in randomized order across trials. The subject was instructed to press the ‘A’ key on the PC keyboard with the left hand if the screen only consisted of distractors and to press the ‘L’ key with the right hand if a target was present. The ‘A’ and the ‘L’ keys are the last keys on the left and right, respectively of the middle row of the PC keyboard. The stimulus presentation and recording of responses was programmed in the MEL2programming language platform. The stimulus material was stored in digitized graphics format and imported into the MEL program. The experiment was presented on a portable Compaq Armada 1100 PC, Pentium with a 12.1-inch high contrast SVGA display with a resolution of 800=600 pixels. All patients and control subjects were given information about the study and that participation was voluntary. After written informed consent was obtained, the patients were tested on the visual search task, which was part of a larger neuropsychological test battery. All subjects were seated in front of the PC, approximately 40 cm away from the screen. They first performed a series of ‘familiarization trials’ where they had to respond by pressing the specified keyboard keys without any data being recorded. The subjects were instructed to respond as quickly and accurately as they could. 2.2. Data scoring and analysis The data were automatically collected by the program and scored as mean response latency for each condition, and statistically analyzed in a repeated-measures analysis of variance (ANOVA). The basic design was a 2=2=2=2 factorial design with Group (depressed patients and control subjects)=Target (present or absent)=Distractors
MEL2
(one or two distractors)=Test (test 1 and test 2). The first factor was treated as a between-groups factor and the second, third and the fourth factors were treated as within-group factors. Only trials with a correct response were included in the statistical analyses. The total errors across subjects and trials were less than 8%. 3. Results There was a significant main effect of Group: F(1, 40)s5.21 P-0.01. Tukey’s HSD post-hoc test showed that the depressed group was significantly impaired in their RTs compared to the control group both at test 1 and test 2. There were no significant effects for the Test factor, neither as a main effect, nor as an interaction with the group factor. Thus, the three-way and four-way interactions were not significant. There was, however, a significant main effect of Target: F(1, 40)s54.22 P-0.01, which showed longer RTs on trials when the target was absent. There was also a significant main effect of Distractors: F(1, 40)s139.19 P-0.01, with longer RTs in the two-distractor condition. See Table 1 for further details. The two-way interaction between Group and Distractor was also significant: F(1, 40)s5.61 P-0.01. Tukey’s HSD post-hoc test showed that the depressed group differed significantly from the control group on trials with two distractors, but not on trials with one distractor (Fig. 2). There was also a significant two-way interaction between Target and Distractor: F(1, 40)s36.71 P-0.01. This showed that the subjects had significantly longer RTs when a target was absent compared to when it was present in the two-distractor condition, while there was no difference in the one-distractor condition. In order to further probe group differences, an interference score was calculated by subtracting the scores in the effortful conditions (two-distractor condition, with and without target) from the scores in the automatic conditions (one-distractor condition, with and without target). A two-way ANOVA was carried out with Group (depressed patients and control group)=Interference score (test 1 and test 2). This
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Fig. 2. Mean RT for the depression and control group for the different conditions. *Significant difference P-0.05.
showed a significant main effect of Group F(1, 40)s5.61 P-0.01. Again, as predicted, there were no significant main or interaction effects involving test session. Further probing with Tukey’s HSD post-hoc test showed that the patient group still differed significantly from the control group at the 6-month follow-up (Fig. 3). At the second test session, the patient group consisted of two subgroups with 10 patients with HDRS scores )8 and 10 patients with HDRS scores -8. Performing a separate ANOVA on these two groups did not change any of the results between patients and controls, nor did comparing the patients with HDRS scores )8 and -8. Thus, the patient group still differed significantly from the control group, and there were no significant differences between the two patient subgroups. 4. Discussion These results support the hypothesis of longlasting cognitive impairment in major depression. The depressed patients did not show any significant improvement from test 1 to test 2 on any of the experimental conditions, despite symptom reduction as reflected by lower HDRS scores. Furthermore, they had significantly longer RTs on
effortful trials compared to the control group, on both test occasions. These findings are therefore consistent with the cognitive effort hypothesis, which argues that depressed patients are impaired on tasks requiring effortful information processing (Hartlage et al., 1993; see also Hashler and Zacks, 1979; Weingartner et al., 1981; Cohen et al., 1982; Roy-Byrne et al., 1986; Thomas et al., 1999). All patients went through a diagnostic assessment by a senior psychiatrist. By using, for example, the Structured Clinical Interview for DSM-IV, the study possibly could have been strengthened regarding diagnosis and symptom reduction. Thus, although the patients did improve their HDRS scores significantly from test 1 to test 2 (mean 21.9 and 8.45, respectively), it could still be argued that some of the patients scored in a subclinical range. If so, it could further be argued that the reason they did not improve on test 2 was that their HDRS scores were not down to zero. Therefore, a Pearson product-moment correlation was calculated to examine if severity of HDRS score could explain the interference score differences between the groups at the second test occasion. The correlation (rs12) was, however, nonsignificant.
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Fig. 3. Mean interference scores for the depression and control groups. *Significant difference P-0.05.
The significantly prolonged RTs in the depression group could not be explained as a general psychomotor slowing (cf. Parker et al., 1993; King, 1975). A comparison between trials requiring a more automatic information processing and trials requiring a more effortful information processing showed that the depressed patients only differed from the control group on the more effortful trials. Moreover, the interference score analysis would eliminate possible motor slowing by subtracting RTs from the less demanding trials from the more demanding trials. This still showed a significant difference in performance between the groups, which was present for both test sessions. Duration of the illness may be a critical factor when trying to explain the lack of improvement in the patient group. As previously mentioned, it has been argued that cognitive impairment increases with every episode of depression (Brown et al., 1999; Sweeney et al., 2000; Kessing, 1998). Most studies concerning number of episodes and cognitive performance in depression have, however, mainly been related to memory performance rather than to attention or executive functions (Austin et al., 2001). Another possible limitation in the present study is the lack of information on number of episodes and duration. However, since all patients had experienced at least one previous depressive episode with high HDRS scores, and several patients had experienced more episodes, this could
have affected the results. A comparison with a group of first episode patients in a longitudinal study could perhaps further clarify whether duration of illness is a critical factor for cognitive performance in the kind of experimental paradigms used in the present study. The main finding was a long-lasting cognitive impairment in recurrent major depression. However, the results give no indication concerning the pathogenesis. Several authors have suggested that there is a relation between duration of illness and structural changes in the brain, e.g. stress-induced glucocorticoids, which can cause reversible and irreversible brain atrophies and alter cognitive performance (see Kandel, 1999, for an overview; Sheline et al., 1999; Goodwin, 1997). Still, even if this could be a possible explanation for the present findings, there are inconsistent findings in the literature related to age, methods of assessment, treatment, diagnostic subtypes, etc. (Austin et al., 2001). Effects of antidepressant medication on cognitive functioning have been suggested as a possible confounding factor (for a review, see AmadoBoccara et al., 1995). However, this has been found to a lesser degree for selective serotonin reuptake inhibitors (SSRIs) (Peretti et al., 2000), which were prescribed for the majority of our patients. Since all patients in our study, except for one drug-naive patient, were treated with SSRIs, a
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medication explanation for the results seems unlikely. Further studies are, however, needed on this issue, including in drug-naive patients, to resolve the impact of medication treatment on cognitive functioning, particularly in a longitudinal perspective. The unimproved performance during the 6month period despite of an average reduction of the HDRS score of 13.42 points (from 21.9 to 8.45) points to a trait effect for cognitive impairment. There was no correlation between RTs and HDRS scores at the follow-up test. Thus, severity of depression did not predict severity of cognitive impairment and vice versa, ruling out state effects. Kuny and Stassen (1995) reported that cognitive and clinical improvement were relatively independent. However, trait factors that may indicate illness may be operative even in a recovery phase. There is a great need for further longitudinal studies addressing the issue of cognitive impairment in recurrent major depression, with a focus on long-lasting effects despite symptom reduction. In addition, more studies are needed for the investigation of the cognitive effort hypothesis across cognitive domains (e.g. memory, attention, executive function). Acknowledgments We are grateful for the help of the following students and colleagues for the data collection and analysis: Lin Sørensen, Jenny Linn Torgersen, Guro Vigestad, Inger Tonette van der Wel, Randi Hopsdal, Eva Aaker, Kirsten Stordal, Ketil Ødegaard, Rune Kroken and Atle Roness. References Amado-Boccara, I., Gougoulis, N., Poirier Littre, M.F., Galinowski, A., Loo, H., 1995. Effects of antidepressants on cognitive functions: a review. Neuroscience and Biobehavioral Reviews 19 (3), 479–493. Austin, M.-P., Mitchell, P., Goodwin, G.M., 2001. Cognitive deficits in depression. British Journal of Psychiatry 178, 200–2006. Bazin, N., Perruchet, P., De Bonis, M., Feline, A., 1994. The dissociation of explicit and implicit memory in depressed patients. Psychological Medicine 24 (1), 239–245. Beats, B.C., Sahakian, B.J., Levy, R., 1996. Cognitive performance in tests sensitive to frontal lobe dysfunction in the elderly depressed. Psychological Medicine 26, 591–603.
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