Chinese Medical Journal 2013;126(6):1144-1149
A distinct pattern of memory and attention deficiency in patients with depression

Correspondence to:Dr. CHEN Xin,Department of Neurosurgery, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin 300052, China (Tel: 86-22-60814472. Fax:86-22-60817449. E-mail:xinchentianjin@me.com)
Keywords
cognitive deficits; anti-depressive drugs; depression; attention; memory
Abstract
Background  Depression related cognitive deficits are frequently considered as simple epiphenomena of the disorder. However, whether or not the depression might directly bring about cognitive deficits is still under investigation. This study was to investigate the distinctpattern of cognitive deficits in patients with depression by comparing the cognitive function before and after anti-depressive drug therapy.
Methods  Sixty cases of patients, first-time diagnosed with depression, were assessed by 17-item Hamilton Rating Scale for Depression (HAMD17scale). The memory ability was tested by quantitatively clinical memory scale, while the attention ability by modified Ruff 2&7 Selective Attention Test. Forty-two healthy volunteers were recruited as controls. The depressive patients were treated with Venlafaxine (75–300 mg/d), Fluoxetine (20–40 mg/d), Paroxetine (20–40 mg/d), and Sertraline (50–150 mg/d). After 12 weeks treatment, patients were tested again by HAMD17scale, quantitatively clinical memory scale, and modified Ruff 2&7 selective attention test to assess the effect of anti-depressive drugs on cognitive deficits.
Results  The memory quotient (MQ) was significantly lowered in depressive patients. The selection speed was also significantly decreased and the number of missing and error hits increased in the depression group as compared to control. However, there was no significant difference in clinical memory scale and Ruff 2&7 selective attention test between mild-to-moderate and severe depression group. Importantly, after anti-depressive drug therapy, the HAMD17 scale scores in depressive patients were significantly decreased, but the MQ, directional memory (DM), free recall (FR), associative learning (AL), and face recognition were comparable with those before the treatment. Furthermore, the selection speed and the number of missing and error hits were also not significantly different after anti-depressive drugs treatment.
Conclusions  Depressive patients suffer from short-term memory deficits, and attention extent, stability and rearrangement deficiency. Even though anti-depressive drugs sufficiently relieve the cardinal presentation of depression, they could not successfully alleviate the accompanying cognitive deficits. This might indicate a distinct pattern of cognitive deficits in patients with depression.
Depression is one of the most common psychiatric disorders in patients with mental disease. Previous studies showed patients with depression presenting with not only depressed mood, loss of interest or pleasure, feelings of guilt or low self-esteem, disturbed sleep or appetite, low energy, poor concentration, but also cognitive deficits,1 among which attention and memory impairment are the most common type.2,3 Furthermore, a great amount of depressive patients still complain having difficulty memorizing and concentrating, and could not be able to afford daily works, even though their clinical manifestation of depression has been significantly relieved.
 
Depression is believed to be associated with reduced levels of Serotonin (5-hydroxytryptamine, 5-HT) in the brain, which presents in various structures of the central nervous system and plays an important role in a great variety of behaviors.4 The selective serotonin reuptake inhibitors (SSRIs) are believed to replenish the levels of 5-HT in the synaptic cleft by binding at the 5-HT re-uptake transporter preventing the re-uptake and subsequent degradation of 5-HT. This action of SSRIs is thought to contribute to the alleviation of the symptoms of depression.5 Although the efficacy of SSRIs for the treatment of depression has been disputed, SSRIs are considered as front-line anti-depressive drugs.6
 
Interestingly, previous studies suggested that 5-HT could also interact with the cholinergic, glutamatergic, dopaminergic or GABAergic systems, and exert its effects on cognitive functions.7 Thus the depression related cognitive deficits are frequently considered as simple epiphenomena of the disorder.2 However, whether or not the clinical manifestation of depression might directly bring about cognitive deficits is still under investigation. On the other hand, whether the improvement of depression related clinical manifestation could lead to the improvement of cognitive deficits remains unknown.
 
This study is designed to compare the cognitive deficits before and after anti-depressive drug treatment, to investigate whether the cognitive deficits might be improved after depression-related clinical manifestation has been resolved, to investigate a distinct feature of cognitive deficits in depressive patients.
 
METHODS
 
Study design and participants
Sixty outpatients, first diagnosed with depression in the Psychiatric Clinic at Tianjin Huanhu Hospital from May 2007 to June 2010, were enrolled in this study. Inclusion criteria are as follows: (1) patients are first diagnosed with depression in the clinic, and never take any anti-depressive or other psychiatric drug; (2) the diagnosis of depression is made according to DSNM-IV criteria; (3) patients are from 17 to 60 years old; (4) depressive patients are allocated into two groups: mild-to-moderate and severe-depression groups, according to 17-item Hamilton Depression Scale (HAMD17scale); (5) patients sign the consent form for enrolling in this study. Exclusion criteria are as follows: (1) patients have other accompanying psychiatric disorders or are dependent on drugs; (2) patients have other medical complications or server drug allergy history; (3) patients recently have suffered severe infections or undergone surgical operation; (4) patients are pregnant or breast feeding; (5) patients are participating other clinical trials.
 
In the total enrolled 60 patients, 20 cases are male, and 40 are female. Fifty cases are from metropolitan and 10 from countryside. The age ranges from 17 to 60 (36±13) years old. The duration of education ranges from 8 to 19 (12±3) years. The course of the depression ranges from 3 to 43 (18±3) weeks.
 
Forty-two healthy controls are the physicians and nurses from Tianjin Huanhu Hospitals, and all these controls do not have any background knowledge of cognitive tests. Inclusion criteria are as follows: (1) have no severe medical conditions; (2) are currently in a good mood, and have no medical history of any psychiatric disorder; (3) deny familial psychiatric disorder in two generations.
 
In these 42 healthy controls, 18 cases are male, 24 are female; 38 cases are from metropolitan and 4 from countryside. The age ranges from 17 to 60 (34±14) years old, and the duration of education ranges from 8 to 21 (12±4) years. There is no significant difference in gender, residential location, age, and duration of education between patients and healthy controls (P >0.05).
 
HAMD17scale
The Hamilton Depression Rating Scale is a 17-item scale that evaluates depressed mood, vegetative and cognitive symptoms of depression, and comorbid anxiety symptoms.8 The 17 items are rated on 5-point (0–4). In general, mild to moderate depression is defined as total item scores between 17 and 23, while severe depression more than 23.
 
Quantitatively clinical memory scale
Quantitatively clinical memory scale was introduced by Psychology Institute of Chinese Academy of Science to evaluate patients’ memory ability.9 The scale is composed of 5 subtests: directional memory (DM), associative learning (AL), graphic free recall (FR), meaningless graphics recognition and portrait memory (PM). Each patient was assessed individually in a quiet and comfortable room with soft light. The test is performed once without any interruption. The detailed procedure and scaling score were performed according to the clinical memory scale form.9
 
Modified Ruff 2&7 selective attention test
The modified Ruff 2&7 test was developed to measure two aspects of visual attention: sustained attention (ability to maintain consistent performance level over time) and selective attention (ability to select relevant stimuli while ignoring distracters).10 The test consists of a series of 20 trials of visual search and cancellation task. The respondent detects and marks through all occurrences of the two target digits: “2” and “7”. In the 10 automatic detection trials, the target digits are embedded among alphabetical letters that serve as distracters. In the 10 controlled search trials, the target digits are embedded among other numbers that serve as distracters. Correct hits and errors are counted for each trial and serve as the basis for scoring the test.
 
Attention assessment
Each patient was assessed individually in a quiet and comfortable room with soft light. The test is performed once without any interruption.
 
Instructions under normal condition: please cross out the number “2” and “7” in each line of numbers or letters, from left to right. The total time is 150 seconds. When hearing the bell ring, please stop writing. Instructions under non-relevant interference condition: please cross out the number “2” and “7” in each line of numbers or letters, from left to right. In doing so, tape recorder will play a conversation or article; you must ignore the interference and to complete the task. The total time is 150 seconds. When hearing the bell ring, please stop writing. Instructions under relevant interference condition: please cross out the number “2” and “7” in each line of numbers or letters, from left to right. In doing so, tape recorder will play some questions regarding addition, subtraction, multiplication and division within number 10. You are required to answer these questions loudly and at the same time doing the crossing out task. The total time is 150 seconds. When hearing the bell ring, please stop writing.
 
The test indices were calculated as follows: the selection speed=the number of right hits within limited times. Under normal condition, the selection speed=first time score + last time score. Under non-relevant interference condition, the selection speed=original scores ×2. Under relevant interference condition, the selection speed =original scores ×2.
 
Anti-depressive drug therapy
Venlafaxine, Fluoxetine, Paroxetine, and Sertraline were used individually to treat patients according to depression severity. The dose of Venlafaxine is 75–225 mg/d, average dose is (101±31) mg/d; the dose of Fluoxetine is 20–40 mg/d, average dose is (21±3) mg/d; the dose of Paroxetine is 20–40 mg/d, average dosing (21±4) mg/d; the dose of Sertraline is 50–150 mg/d, average dosing (57±4) mg/d. The treatment cycle is 12 weeks.6
 
Statistical analyses
Data were analyzed by using SPSS 16.0 (SPSS Inc., USA). All the data were presented by mean±standard deviation (SD), and analyzed by independent-sample t test. A P value of <0.05 was considered to be statistically significant.
 
RESULTS
 
Memory deficiencies in patients with depression
To assess changes in memory function, the quantitatively clinical memory scale was used. As expected, the memory quotient (MQ) was significantly lowered in the depression group (t=7.014, P=0.000) as compared to control group. More importantly, the DM, AL, graphic FR and PM were also found significantly worsened in the depressive patients (P <0.05; Figure 1A), suggesting that depressive patients develop memory deficiency.
 
Further, there was no significant difference in MQ and clinical memory scale between mild-to-moderate and severe depression groups (P >0.05; Figure 1B), indicating that severity of depression does not correlate with that of memory deficits.
 
Attention deficits in patients with depression
The modified Ruff 2&7 selective attention test is a well-characterized and extensively used assessment to evaluate attention function. With our expectancy, the selection speed was significantly decreased and the number of missing and error hits increased in the depression group as compared to control (P <0.05; Figure 2A and 2B). This implies attention deficits indeed occurred in depressive patients.
 
Similar to memory function, the selection speed and the number of missing and error hits were comparable between mild-to-moderate and severe depression groups (P >0.05; Figure 2C and 2D). This demonstrates the aggravation of depression could not be able to exacerbate attention deficiency.
 

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Figure 1. Memory impairments in depressive patients. 1A: The DM, AL, FR, and PM were significantly lowered in the depression group, while meaningless graphic memory (MGM) was comparable between depression and control group. 1B: There is no significant difference in DM, AL, FR, MGM, and PM between mild-to-moderate and severe depression group. n=60 in depression group, n=42 in control group, n=30 in mild-to-moderate depression group, and n=30 in severe depression group. *P <0.05. Bars represent group mean±SD.
Figure 2. Attention deficits in depressive patients. 2A: The selection speed of 2 and 7 selective attention test was significantly decreased in depression patients under normal condition (NL), non-relevant noise interference (Non-RI), and relevant calculation interference (RI); 2B: The number of missing and error hits were significantly higher in depression patients under NL, Non-RI, and RI. 2C and 2D: There is no significant difference in selection speed and number of missing and error hits between mild-to-moderate and severe depression group. n=60 in depression group, n=42 in control group, n=30 in mild-to-moderate depression group, and n=30 in severe depression group. *P <0.05. Bars represent group mean±SD.
Figure 3. Cognitive deficits in patients with depression after anti-depressive drug therapy. 3A: The total score (O/R), anxiety score (AX), block score (BL), sleep disorder score (SD), and body weight score (BW) were significantly decreased after anti-depressive drug treatment. 3B: After anti-depressive drug treatment, there is no significant difference in any sub-test of clinical memory scale. 3C and 3D: There is also no significant difference in selection speed and number of missing and error hits before and after anti-depressive drug treatment. n=60 in both pre-treatment and post-treatment group. *P <0.05. Bars represent group mean±SD. NL: normal condition; Non-RI: non-relevant noise interference; RI: relevant calculation interference.
 
 
 
Cognitive deficits in depressive patients after anti-depressive drug therapy
In order to comprehensively study the therapeutic effects of anti-depression drugs, HAMD17scale was adopted. After the 12-week-cycle of treatment, the HAMD17scale was significantly decreased as compared to pre-treatment, indicating the depression has been successfully relieved by medication (P <0.05; Figure 3A; Table 1). However, there was no significant difference in clinical memory scale, selection speed, and the number of missing and error hits after anti-depressive drug treatment (Figure 3B–3D; Table 2). This suggests that both of attention and memory deficits could not be alleviated as the depression has been relieved.
 

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Table 1. Comparison of HAMD17scale for patients before and after anti-depressive drugs treatment
 

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Table 2. Comparison of subtests of quantitatively clinical memory scale before and after anti-depressive drugs treatment
 
DISCUSSION
 
Whereas depression is known to involve a disturbance of mood, movement and cognition, its associated cognitive deficits are usually considered as simple epiphenomena of the disorder.1-3 In the present study, using well-characterized tools for assessing cognitive function in patients with depression, we compared changes in attention and memory function in depressive patients before and after anti-depressive drug therapy. We found that (1) depressive patients develop not only the memory deficits but also the attention impairments; (2) the severity of depression does not correlate with that of memory and attention deficits; (3) the front-line anti-depressive drugs sufficiently alleviate clinical manifestation of depression; but (4) have slightly affects on memory and attention functions. These might suggest cognitive deficits have a distinct pattern and a unique pathogenesis in patients with depression.
 
Depression is a state of low mood and repulsion to activity exerting a harmful influence on a person’s thoughts, behavior, feelings, worldview and physical well-being. Serotonin appears to be one of the key players in mood and a variety of other disorders.11 A longitudinal study found that people with one or two short alleles of the serotonin transporter gene likely to suffer from depression after stressful life events.4,5 Serotonin has also been demonstrated to facilitate regulating other neurotransmitter systems,12 and decreased serotonin activity may “permit” these systems to act in unusual and unreliable ways to yield a series of clinical manifestation.8
 
Memory deficits in depressive patients
Given the fact that the underlying biochemical mechanism of memory formation partially coincide with the pathogenesis of depression, it is commonly accepted that depression is highly associated with a number of memory deficits.13 Brand and colleagues demonstrated that by testing depressive subjects in word learning tests, depressive patients were characterized by inferior memory recall, and not only retrieval but also encoding of information into memory might also be impaired.14 By using quantitatively clinical memory scale to study the memory deficits in depression patients, we found that MQ, DM, associative memory, FR, and PM were significantly lowered in depressive patients as compared to healthy controls. These suggest depressive patient could suffer from memory deficits.
 
The exact underlying mechanism of memory deficits after depression remains poorly understand. Hypofunction of the 5-HT system has emerged as a leading candidate cause for memory deficits. A previous study reports that depletion of tryptophan, a precursor of 5-HT, is associated with lower performance on episodic memory retention tests in humans.4,15 This also represents findings in depression, which is accompanied by moderate to severe memory deficits. However, receptor agonist studies in both humans and animals show that manipulations that increase 5-HT concentration or 5-HT receptor activation also lower memory performance.16,17 Until now, why both increased and decreased 5-HT activation have adverse effects on memory remains unclear.
 
Attention deficits in depression patients
The attention ability is an imperative process throughout sensation, perception, memory, and intelligence, and its normal function might be imperative to maintain the intact cognitive functions in human.18 In this study, in order to exclude the interference of the impact of fatigue or learning on attention assessment, the scores of Ruff 2&7 selective attention test were calculated by the summation of first time and last time scores. We have showed the selection speed, the number of missing and error hits in the Ruff 2&7 selective attention test were significantly decreased in depressive patients under normal condition. This indicates that the depressive patients undergo slow response and impairments of attention, which are consistent with previous studies.19 Under non-relevant circumstance, the depressive patients were interfered by the surrounding noise, and had lowered selection scores, indicating the impaired anti-jamming ability. Furthermore, under relevant interference condition, patients were asked to perform selection test, while simultaneously carrying out simple summation, subtraction, multiplication, and division. These required patients fully concentrate and reasonably rearrange attention, and perform two tasks simultaneously. The decreased speed of selection and increased number of missing and error hits suggest the impaired attention rearrangement and stability.
 
Many studies have applied the cognitive-behavioral theories of motivation and response bias to explain the neurocognitive impairments in depressive patients.18 Previous studies showed that impaired motivation in depressed patients could be measured as a lack of an appropriate response to explicit reward.17 Also, it has been suggested that response bias to negative feedback with the testing paradigm is related with impaired cognitive performance.12,20 That is to say, an individual’s awareness of failure on one problem dramatically increased the chance of failure on the subsequent problem, probably by either adequate response to negative feedback or a stronger negative reaction to negative feedback.
 
Distinct pattern of cognitive deficits in patients with depression
In the present study, even though patients with mild-to-moderate depression had slightly better performances of cognitive function than those with severe one, there is no significant difference. This suggests that the severity of depression does not affect cognitive function, which is also demonstrated by Wu et al.21 In the current study, the cardinal presentations of depressive patients were almost relieved by the 12-week-cycle anti-depression treatments. The overall HAMD17score was significantly decreased after treatment. However, both the speed of 2 and 7 selection either under normal condition, non-relevant interference or relevant interference, and the number of missing and error hits were slightly better after anti-depressive drugs treatment, but with no statistical significance. This demonstrates that anti-depressive drugs could efficiently alleviate depression, but not lessen the cognitive deficits.
 
SSRIs are a class of compounds typically used as antidepressants in the treatment of depression, anxiety disorders, and some personality disorders. Even though SSRIs would interfere with the 5-HT re-uptaking and probably interfere with cognitive function, recently studies clearly show that Venlafaxine, Fluoxetine, Paroxetine, and Sertraline have no effect on quantitative ECG and cognitive functions in healthy individuals.22-25 Furthermore, even depressive patients are successfully treated with SSIRs, some are still complaining having the cognitive deficits.
 
Whether or not the cognitive deficits are caused by depression still remains unknown. Right after the unveiling of adult neurogenesis, by which neurons replenish themselves in sub-granular zone of the dentate gyrus of hippocampus in the adult brain of humans,26 the “neurogenic hypothesis” is becoming one of the prevailing pathogenesis of depression. Small and colleagues27 showed that humans with depression had decreased hippocampal volume and Fotuhi et al28 found that decreased neurogenesis could lead to a smaller hippocampus. Accordingly, the novel neurons in the adult brain are necessary for proper mood control and for antidepressant efficacy.29 Consequently, the underlying pathological changes of hippocampus might be one of the fundamental basis for developing both depression and cognitive deficits, which might divert the current 5-HT based treating regimen to neurogenesis-based therapy for depression.
 
In this study, we found that improvement of cognitive deficits might not be accomplished by resolving depression per se. This suggests depression might not directly yield cognitive deficits, which might have a distinct pathogenesis after depression. However, these results might be caused by limited case number and different depression duration to yield negative results, in spite of a study reporting the duration of depression correlates with cognitive dysfunction.30,31 Consequently, in future study, more attention should be paid on depression duration and its related structural alteration of hippocampus.
 
In sum, cognitive deficiency could not be improved by treating depression alone, which accounts for the phenomenon that many patients still complain about poor memory and low working efficiency after depression was completely relieved. In clinical practice, psychiatrists not only need to treat the depressed mood, but also the accompanying cognitive deficiency. These results, therefore, call for more studies regarding the distinct pathogenesis and early treatment of cognitive deficits in depressive patients.
 
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