Effect of escitalopram on cognitive function in depression A mismatch negativity potentials study*

Department of Psychology, Wuxi Mental Health Center, Wuxi 214151, Jiangsu Province, China

INTRODUCTION

The clinical symptoms of depression are paralleled by typical neurocognitive deficits, including verbal memory, attention processing and executive function[1-3].In a study assessing cognitive disturbances among newly diagnosed depression cases and healthy controls using the McNair and Kahn auto-evaluation scale[4], 63.3% depressed patients had cognitive difficulties compared to 3.3% of healthy controls.Cognitive dysfunction is a core syndrome,but is also correlated with functional impairment in depression.As for schizophrenia patients, as persistent impairment of work and social functioning has been demonstrated in individuals with depression[5-6].Poor outcome in schizophrenia has been associated with core cognitive deficits as well as residual positive and negative symptoms[7].Thus, the assessment of the level of cognitive function is crucial determining treatment outcomes in depression.

Selective serotonin reuptake inhibitors(SSRI) are used clinically as first-line agents for the treatment of depression.Escitalopram is the therapeutically active S-enantiomer of RS-citalopram, a commonly prescribed SSRI.In a recent study assessing the efficacy, acceptability, and tolerability of escitalopram in comparison with tricyclics,other selective serotonin reuptake inhibitors,heterocyclics, and newer agents in the acute-phase treatment of major depression[8], escitalopram scored better than other antidepressants in terms of efficacy (citalopram and fluoxetine) and acceptability (duloxetine).However, the efficacy of escitalopram compared to other antidepressants in the early response to treatment (after two weeks of treatment) remains unclear[8].

Information processing deficits in depressive disorder are infrequently examined using electrophysiology.Studies employing a mismatch field elicited in response to duration and frequency changes of pure-tone stimuli in response to a vowel across-category change demonstrated that the magnetic global field power of the mismatch field was significantly smaller in depressive disorder patients than in healthy volunteers[9-10].Information processing at the preattentive level is impaired functionally in depressive disorder, and this dysfunction is not due to the dysfunction at the lower level of information processing.

The event-related potential (ERP) mismatch negativity (MMN) is an effective measure of preattentive information processing by auditory change detection[11].MMN is a negative ERP component elicited by deviant stimulus;i.e., the standard sounds changed by frequency, duration, intensity,or location.The MMN is believed to be the outcome of a comparison process commonly elicited when an incoming stimulus differs from the memory of repetitive tones(standards) occurring in the recent acoustic past.As no MMN is generated in the absence of such a memory trace, MMN generation indexes auditory sensory memory and reflects context-dependent information processing at the level of the auditory sensory cortex.Patients with depression have been reported to exhibit preattentive information processing auditory ERP MMN.For example, in a study investigating the relationship between auditory sensory memory and attention orienting in treatment-naive children with major depression by auditory MMN, the children with major depression had shorter MMN than the controls, while ERP findings indicated enhanced sensory sensitivity and attentional distractibility in these children[12].This increased distractibility might underlie the concentration difficulties that compromise school performance in children with major depression.Another study used MMN to investigate cognitive dysfunction among patients with treatment-resistant depression, borderline personality disorder, or treatment-resistant depression comorbid borderline personality disorder[13], and found no significant intergroup difference for the N1 latencies/amplitudes to either standard or deviant stimuli, and no significant intergroup difference for MMN latencies.However, MMN amplitudes were higher in the treatment-resistant depression group than the other three groups (including the control group).Further, Plutchik-van Praag depression inventory scores were highest in the treatment-resistant depression comorbid borderline personality disorder group, and lowest in healthy subjects, while the higher MMN was not correlated with the Plutchik-van Praag depression inventory score or with the duration of life-long depression, which is considered a neurophysiological marker for treatment-resistant depression[13].By contrast, MMN deficits were not observed in other major mental illnesses such as bipolar disorder or major depression, indicating that MMN may be fairly specific to schizophrenia[14].A previous study reported that patients with first-episode psychosis schizophrenia-spectrum and first-episode psychosis affective-spectrum exhibited a similar impairment in MMN and P3a, suggesting potential biomarkers for schizophrenia, while first-episode psychosis subgroups showed impairments in fronto-central MMN consistent with chronic patients[15].These findings suggest that first-episode psychosis patients with both affective and schizophrenia spectrum diagnoses share common neurobiological disturbances in deviance detection/orienting processes in the early phase of illness.As MMN changes reflect abnormalities of early auditory processing in depression, we hypothesized that treatment with escitalopram may improve MMN.Thus, in the present study we investigated whether the effects of escitalopram on abnormalities of early auditory processing in patients with depression were reflected by auditory MMN.

RESULTS

Quantitative analysis of subjects

A total of 30 healthy controls and 30 patients with depression were recruited, and all were included in the final analysis.

Demographic characteristics of subjects

The demographic characteristics of all subjects are detailed in Table 1.There were no differences in sex ratio,mean age, mean education years, and handedness between the two groups (P＞ 0.05).

Table 1 Demographic characteristics of the subjects

Comparison of MMN at baseline between depression patients and healthy controls

Depression patients showed smaller mean amplitudes of frequency and duration MMN at baseline compared with controls (frequency MMN:t=2.895,P=0.004; duration MMN,t=3.153,P=0.007;dffor all electrodes=29).No differences in latencies were observed between patients and controls (Table 2; Figure 1).

Table 2 Amplitudes and latencies of mismatch negativity of healthy controls and patients at baseline and 8 weeks of treatment

Effects of escitalopram treatment on Hamilton Rating Scale for Depression (HAMD) scores in patients with depression

HAMD scores[17]were 34±7 and 20±4 at baseline and after 8 weeks of treatment, respectively.There was a significant decrease in HAMD scores after 8 weeks of escitalopram treatment in the depression patient group(t=2.374,P=0.030).

Effects of escitalopram treatment on MMN in patients with depression

A repeated measure analysis of variance with session(baselinevs.8-week treatment) and MMN type (frequencyvs.duration) as within-subject factors revealed no significant MMN type or MMN type × session main effect for MMN amplitudes (MMN type:F=0.965,df=1,P=0.365; MMN type × session:F=0.658,df=2,P=0.614).However, there was a session main effect (F=7.506,df=1,P=0.028).LSD tests were performed aspost hocanalyses and demonstrated that MMN amplitudes at 8 weeks of treatment were higher than those at baseline (P=0.021) (Table 2; Figure 1).

Figure 1 Grand averages of frequency and duration mismatch negativity (MMN) at Fz in controls, and patients at baseline and 8 weeks of escitalopram treatment.MMN waveforms were obtained by subtracting waveforms elicited by standards from waveforms elicited by frequency- or duration-deviant stimuli.The patient group showed smaller mean amplitudes of frequency and duration MMN at baseline than the control group, while MMN amplitudes at 8 weeks were higher in the patient group than those at baseline.A1, A2 served as waveform control.

Correlation between MMN and HAMD scores in patients with depression

There was no significant correlation between changes in amplitudes of frequency and duration MMN and changes in HAMD scores at baseline (r=0.12, 0.23,P=0.79,0.65) and after 8 weeks of treatment (r=0.19, 0.29,P=0.71, 0.85).

Comparisons of HAMD scores and MMN between antidepressant-naive and antidepressant-free patients

There were no differences in HAMD between antidepressant-naive (35±8) and antidepressant-free patients (34±5), and no differences in mean amplitudes and latencies of frequency and duration MMN at baseline and 8 weeks of treatment between antidepressant-naive and antidepressant-free patients (P＞ 0.05; Table 3).

DISCUSSION

In the present study, we employed electrophysiological indices of automatic auditory information processing (i.e.,MMN) to assess cognitive improvement in patients with depression treated by escitalopram.Our results support previous hypotheses that treatment with escitalopram leads to the improvement of MMN in patients with depression.

Table 3 Amplitudes and latencies of mismatch negativity of antidepressant-naive and antidepressant-free patients at baseline and 8 weeks of treatment

Depression is associated with significant functional impairment and reduced quality of life.Disruptions occur both globally and in specific functional areas such as work, interpersonal relationships, and cognitive function.Clinical and experiment studies have largely focused on the resolution of symptoms associated with depression,while functional improvements have been largely ignored[18-19].In the present study, depression patients showed smaller mean amplitudes of frequency and duration MMN at baseline than controls, indicating that patients with depression present abnormalities of early auditory processing.

Current treatment outcomes of depression in adolescents remain suboptimal.Discriminating between state and trait markers of depression in adolescents would help identify markers that facilitate choice of appropriate interventions and help improve longer-term outcome.A recent study compared neurocognitive performance in executive function, sustained attention, and short-term memory in patients with depression in acute episode (DA), in remission (DS), and healthy control participants[20], and found a difference in executive function with increasing task difficulty.In that study, patients with DA showed impaired executive function, as assessed by measuring numbers of moves to solve 4-move problems on a forward planning task, relative to DS and healthy control subjects.The DA group also showed more impulsivity, as measured by lower response bias on a sustained attention task, than DS and healthy control subjects.Further, higher impulsivity was associated with more severe depression and earlier age of onset of depression, and there was a trend for a correlation between more executive dysfunction and more severe depression in DA and DS combined groups.Finally, there was no difference in short-term memory or target detection on the sustained attention task between the three groups, indicating that executive dysfunction and impulsivity appear to be state-specific markers of depression that are related to depression severity, and are not present in remission.SSRIs are widely used in treatment of major depression because of their efficacy, safety, and tolerability.The SSRI escitalopram was previously reported to decrease oxidative stress in a chronic stress animal model[21].Preand post-treatments with escitalopram also protected against ischemia-induced neuronal death in the gerbil hippocampal CA1 region induced by transient cerebral ischemia,viaincreased brain-derived neurotrophic factor and decreased microglial activation and oxidative stress[22].In the present study, escitalopram decreased HAMD scores, while MMN amplitudes at 8 weeks were higher than those at baseline, demonstrating that MMN might be a state-specific marker of depression.

At present, the definition of remission in depression is most frequently based on achieving a cut-off score on clinical rating scales of depressive symptoms.However,results of clinical rating scales often display subjectivity.Consistent with a previous report[23], our data suggest that MMN may be a useful tool for evaluation of cognitive function and treatment effects.We also found that during presentation of the auditory test paradigm, the attention of the subjects was diverted from the tones.These results may exclude a practice effect, although we did not retest the validity in the control group at 8 weeks.

In conclusion, we found that escitalopram was useful for the treatment of depression patients, especially for improvement of abnormalities of early auditory processing, as assessed by MMN, a non-invasive technique with good temporal resolution.MMN offers the ability to map the neuroelectrophysiological response to treatment intervention within the brain, and may enable improved understanding of the neuropharmacology of depression.

SUBJECTS AND METHODS

Design

A case-controlled observational experiment.

Time and setting

The experiment was performed in the Department of Psychology, Wuxi Mental Health Center, China, from July 2010 to May 2011.

Subjects

A total of 30 patients (30 years of age) with depression as diagnosed using a Diagnostic and Statistical Manual of Mental Disorders (4thed, DSM-IV)[24]diagnosis criteria,with age and gender matched controls with no personal or family history of depression or other mental disorders were recruited.Patients with depression were recruited from Wuxi Mental Health of Nanjing Medical University,China.Controls were recruited from the employees and relatives of Wuxi Mental Health Center of Nanjing Medical University.Subjects and controls were excluded from the study if they were smokers or had a diagnosis of alcohol or substance dependence, neurological disorders, all kinds of head injury, or had received electroconvulsive therapy in the last 6 months.All participants were Chinese.All participants received $15 for participation, and underwent a clinical assessment by a psychiatrist to collect information on medication and socio-demographic data.Written informed consent was obtained from all participants.

Methods

Clinical assessment

On the day of the ERP recording, severity was rated in patients using HAMD.Handedness was assessed using the Annett handedness scale[16].Ratings on this scale were recorded using the following definitions of handedness: Annett score (1)=right, (2-7)=mixed,(8)=left.

Stimulation protocol and procedure

ERP recordings were acquired during the presentation of auditory stimuli.Auditory stimuli consisted of 100 ms/1 000 Hz standards intermixed with 100 ms/1 500 Hz frequency deviants and 250 ms/1 000 Hz duration deviants.All stimuli had a rise/fall time of 5 ms.Stimuli were presented in a fixed order (four standards, one frequency deviant, four standards, one duration deviant)with a stimulus onset asynchrony of 300 ms.The stimuli were presented through foam insert earphones at a nominal intensity of 75 dB.Stimuli were presented in four blocks with 1 000 stimuli each, totaling 4 000 stimuli including 3 200 standards, 400 frequency deviants, and 400 duration deviants[7].During presentation of the auditory test paradigm, subjects watched a silent self-selected video film to divert attention from the tones,and to minimize boredom and reduce eye movement artifacts.Subjects were constantly monitored.Short breaks were offered to ensure full alertness and comfort during the recording session.

In order to detect the treatment effects on MMN, auditory ERPs were recorded at baseline and 8 weeks of escitalopram treatment.For healthy controls, ERPs were recorded once.At baseline, 20 patients were antidepressant naive and 10 patients were antidepressant free (four patients for at least half a year,and six patients for at least 1 month).After 2 weeks follow-up, patients received only escitalopram 10-20 mg(mean, 13.7±1.5 mg) per day (Austin Chemical Company, Inc., Chicago, IL, USA).

Electroencephalographic recordings

The majority of previous reports typical measured MMN at the Fz site[7], according to the 10/20 International System[25].We recorded electroencephalography (EEG)with the Stellate Harmonie EEG device (Physiotec Electronics Ltd.Ontario, Canada) from Fz, A1, and A2 sites using the Electro-Cap Electrode System (ECITMElectro-Caps; Electro-cap International, INL, Chicago, IL,USA).Ear electrodes served as a reference and the ground electrode was attached to the forehead.Eye movement artifacts were monitored by recording vertical and horizontal electro-oculogram from electrodes placed above and below the right eye and at the left outer canthus.Electrode impedance was kept below 5 kΩ.System band pass was 0.1-30 Hz and data was digitalized continuously at a sampling rate of 250 Hz.Digital tags were obtained for all auditory stimuli.

Data analysis

Brain Electrical Source Analysis program (BESA 5.2.0 software, Graefelfing, Germany) was used for data analysis.Epochs were constructed that consisted of a 100 ms pre-stimulus baseline and a 500 ms post-stimulus interval.All epochs with amplitudes exceeding±75 μV at any electrode were excluded automatically.Epochs were averaged offline for each subject and stimulus type and digitally filtered with a low-pass filter of 15 Hz (24 dB down).MMN waveforms were obtained by subtracting waveforms elicited by standards, or from waveforms elicited by frequency- or duration-deviant stimuli.Inspection of the grand-average waveforms indicated that frequency MMN amplitude was defined as the peak negativity within a 100-225 ms latency window, and duration MMN amplitude was defined as the peak negativity within the 125-250 ms latency window.

Statistical analysis

Data were analyzed using SPSS 10.0 (SPSS, Chicago,IL, USA).Comparisons of amplitudes of MMN between healthy controls and patients were performed using paired samplet-test.Comparisons of HAMD scores between baseline and 8 weeks of treatment were performed using paired samplet-test.The effects of escitalopram treatment on MMN amplitudes were analyzed by repeated measure analysis of variance with session (baseline and 8 weeks of treatment) and MMN type (frequencyvs.duration) as within-subject factors.Least square difference tests were performed aspost hocanalyses if indicated.Correlation coefficients between MMN and HAMD scores were calculated by Pearson test.A value ofP＜0.05 was considered statistically significant.

Author contributions:Zhenhe Zhou designed the study, acquired data, performed data analyses and interpretation, drafted the manuscript, and critically revised the results.Guozhen Yuan,Jianjun Yao, and Zaohuo Cheng were responsible for the design of the study, data acquisition, and interpretation.All authors read and approved the final manuscript.

Conflicts of interest:none declared.

Funding:This study was supported by the Medical Research Foundation of Jiangsu Provincial Department of Public Health,No.H201043.

Ethical approval:The protocol was approved by the Ethics Committee of Nanjing Medical University, China.

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