Inflammatory markers are associated with decreased psychomotor speed in patients with major depressive disorder

Previous data have demonstrated that administration of inflammatory cytokines or their inducers leads to altered basal ganglia function associated with reduced psychomotor speed. Decreased psychomotor speed, referred to clinically as psychomotor retardation, is a cardinal symptom of major depressive disorder (MDD) and has been associated with poor antidepressant treatment response. We therefore examined the association between plasma inflammatory markers and psychomotor speed in ninety-three un-medicated patients with MDD. Psychomotor speed was assessed by a range of neuropsychological tests from purely motor tasks (e.g. movement latency and finger tapping) to those that involved motor activity with increasing cognitive demand and cortical participation (e.g. Trails A and Digit Symbol Substitution Task (DSST)). Linear regression analyses were performed to determine the relationship of inflammatory markers and psychomotor task performance controlling for age, race, sex, education, body mass index, and severity of depression. MDD patients exhibited decreased psychomotor speed on all tasks relative to normative standards. Increased IL-6 was associated with decreased performance on simple and choice movement time tasks, whereas MCP-1 was associated with decreased performance on the finger tapping task and DSST. IL-10 was associated with increased performance on the DSST. In an exploratory principle component analysis including all psychomotor tasks, IL-6 was associated with the psychomotor speed factor. Taken together, the data indicate that a peripheral inflammatory profile including increased IL-6 and MCP-1 is consistently associated with psychomotor speed in MDD. These data are consistent with data demonstrating that inflammation can affect basal ganglia function, and indicate that psychomotor speed may be a viable outcome variable for anti-inflammatory therapies in depression and other neuropsychiatric disorders with increased inflammation.     

Low serum HDL‐cholesterol levels are associated with long symptom duration in patients with major depressive disorder

Aims: The purpose of the present study was to examine whether the association between depression and the serum high‐density lipoprotein cholesterol (HDL‐C) is modified by symptom duration. Methods: Depressed patients (n = 88) and an age‐ and sex‐matched group of healthy general population controls (n = 88) underwent a Structured Clinical Interview for DSM‐IV (SCID), and depressed participants reported the duration of their symptoms. The serum levels of total cholesterol (TC), HDL‐C, low‐density lipoprotein cholesterol (LDL‐C), triglycerides (TG) and non‐HDL, and the ratios of LDL‐C/HDL and TC/HDL‐C were assessed. Results: Major depressive disorder (MDD) subjects with a long symptom duration (≥3 years) had lower levels of HDL‐C compared with healthy controls or MDD subjects with a symptom duration <3 years. The likelihood for long symptom duration doubled for each 0.5‐mmol/L decrease in HDL‐C levels in regression models adjusted for age, gender, marital status, overweight, symptom severity, alcohol consumption, smoking, physical exercise, medication use, and non‐HDL‐C (P < 0.05). Conclusions: These findings suggest that a low serum HDL‐C level, a risk factor for coronary heart disease, is specifically associated with long‐term depressive symptomatology.     

Selective neurocognitive impairments in adolescents with major depressive disorder

This study investigated whether major depression in adolescence is characterized by neurocognitive deficits in attention, affective decision making, and cognitive control of emotion processing. Neuropsychological tests including the Wechsler Abbreviated Scale of Intelligence, the Continuous Performance Test-Identical Pairs, the Attention Network Test, the Iowa Gambling Task, the Emotional Go-NoGo Task, and the Face Go-NoGo Task were administered to adolescents with Major Depressive Disorder (MDD) (n = 31) and psychiatric diagnosis free controls (n = 30). Findings indicated that compared with controls, depressed adolescents exhibited impaired sustained attention; a gender by group interaction on affective decision making such that depressed males tended to make less advantageous choices on the IGT; and an inverse pattern of correlations between depressive symptom counts and reaction time to affective stimuli, characterizing greater affective reactivity in depressed adolescents. Findings demonstrate that adolescents with MDD display selective neurocognitive impairments on tasks capturing 'cool' and 'hot' executive functioning.     

重性抑郁障碍患者认知功能损害的研究进展

重性抑郁障碍（Major Depressive Disorder,MDD）是以持久自发性的情绪低落为主的二系列抑郁症状,常导致患者心理、生理和社会功能紊乱。     

Serum high-sensitivity C-reactive protein levels are positively associated with cognitive impairments in patients with first-episode schizophrenia

BackgroundTo clarify the controversy regarding the relationship between serum high-sensitivity C-reactive protein (hs-CRP) levels and cognitive impairments in first-episode schizophrenic patients and examine whether hs-CRP is a potential objective biological indicator for evaluating cognitive impairment in first-episode schizophrenic patients.MethodsSerum hs-CRP levels were measured in 58 first-episode schizophrenic patients and 31 healthy controls using immunofluorescence. The Brief Psychiatric Rating Scale (BPRS) and the P300 event-related potential were assessed. The relationship between serum hs-CRP levels and both BPRS scores and P300 were analyzed.ResultsSerum hs-CRP levels and BPRS scores were significantly higher in the study group than in the control group. The incubation period of P3 was longer, and the amplitude of P3 was larger in the study group than in the control group. Correlation analysis showed that in the study group, serum hs-CRP levels were positively correlated with BPRS total scores. Serum hs-CRP levels were also positively correlated with the incubation period of P3 and negatively correlated with P3 amplitudes.ConclusionsSerum hs-CRP levels were positively associated with cognitive impairment in first-episode schizophrenic patients and potentially represent an objective biological indicator for the rapid evaluation of cognitive impairment in first-episode schizophrenic patients.     

Plasma kynurenine levels are elevated in suicide attempters with major depressive disorder

Background

Inflammation has been linked to depression and suicide risk. One inflammatory process that has been minimally investigated in this regard is cytokine-stimulated production of kynurenine (KYN) from tryptophan (TRP). Recent data suggest that KYN increases in cerebrospinal fluid (CSF) are associated with depressive symptoms secondary to immune activation. KYN may alter dopaminergic and glutamatergic tone, thereby contributing to increased arousal, agitation and impulsivity - important risk factors in suicide. We hypothesized that patients with major depressive disorder (MDD) and a history of suicide attempt would have higher levels of KYN than depressed nonattempters, who in turn would have higher levels than healthy volunteers.

Methods

Plasma KYN, TRP, and neopterin were assayed by high performance liquid chromatography in three groups: healthy volunteers (n = 31) and patients with MDD with (n = 14) and without (n = 16) history of suicide attempt. Analysis of variance tested for group differences in KYN levels.

Results

KYN levels differed across groups (F = 4.03, df = (2,58), and p = 0.023): a priori planned contrasts showed that KYN was higher in the MDD suicide attempter subgroup compared with MDD non-attempters (t = 2.105, df = 58, and p = 0.040), who did not differ from healthy volunteers (t = 0.418, df = 58, and p = 0.677). In post hoc testing, KYN but not TRP was associated with attempt status, and only suicide attempters exhibited a positive correlation of the cytokine activation marker neopterin with the KYN:TRP ratio, suggesting that KYN production may be influenced by inflammatory processes among suicide attempters.

Conclusion

These preliminary results suggest that KYN and related molecular pathways may be implicated in the pathophysiology of suicidal behavior.     

Quality of life among bipolar disorder patients misdiagnosed with major depressive disorder

Objective: Bipolar disorder is frequently misdiagnosed as major depressive disorder (MDD). We aim to quantify the prevalence of misdiagnosed bipolar disorder among the depression population and evaluate the quality-of-life (QOL) impact of misdiagnoses.Method: Data were collected from 2 self-administered, cross-sectional studies in 2003. Patients participating in The Bipolar Disorder Misdiagnosis Study (N = 1156) were previously diagnosed with depression, experienced a depressive episode within the past year, and had no previous diagnosis of bipolar disorder or schizophrenia. Patients who experienced a manic episode in the past year, based on DSM-IV criteria, were classified as misdiagnosed. Patients participating in The Bipolar Disorder Project (N = 1214) self-reported a diagnosis of bipolar disorder and were recruited through community mental health centers and support groups. Quality of life was assessed via the Psychological General Well-Being (PGWB) Index and Medical Outcomes Study 8-Item Short-Form Health Survey (SF-8). Demographic differences between groups were controlled using linear regression models.Results: Of the diagnosed MDD sample, 14.3% met criteria for misdiagnosed bipolar disorder. When controlling for demographic differences, the PGWB overall score for the misdiag-nosed averaged 12.77 (p < .001) points lower than that of MDD patients and 9.55 (p < .001) points lower than that of diagnosed bipolar disorder patients. The average SF-8 mental component summary score for the misdiagnosed was 5.85 (p < .001) points lower than that of MDD patients and 3.18 (p = .002) points lower than that of diagnosed bipolar disorder patients.Conclusion: Misdiagnosis is associated with poorer QOL than MDD or diagnosed bipolar disorder, which are recognized as having a considerable impact on QOL.     

Neurocognitive impairments and quality of life in unemployed patients with remitted major depressive disorder

Quality of life (QOL) has been reported to be impaired in patients with major depressive disorder (MDD), even after remission according to symptom rating scales. Although a relationship between QOL and neurocognitive dysfunction has been reported during depressive episodes, little is known about this relationship in remitted MDD patients. The aim of the present study was to investigate the relationship between QOL and neurocognitive dysfunction in patients with remitted MDD while controlling for confounding factors. Forty-three remitted MDD patients were assessed with neuropsychological tests and QOL, which was measured by a short-form 36-item health survey. The neurocognitive performances of the patients were compared with those of 43 healthy controls. We next evaluated the relationships between neurocognitive impairments, clinical factors, and QOL. Remitted MDD patients had poorer neurocognitive performances than healthy controls for psychomotor speed, attention, and verbal memory. Residual depressive symptoms were strongly associated with QOL. Delayed verbal recall was associated with general health perceptions, which are part of the QOL assessment, even after the effects of the residual depressive symptoms were considered. The results may indicate that clinicians should try to detect neurocognitive dysfunctions that may interfere with QOL using neurocognitive assessments in their daily practice.     

Elevated peripheral inflammation is associated with attenuated striatal reward anticipation in major depressive disorder

BackgroundMajor depressive disorder (MDD) is the leading cause of years lived with disability worldwide, and up to 40% of individuals with MDD do not respond to current treatments. Studies suggest that peripheral inflammation plays an important role in the striatal mesolimbic dopamine pathway and corticostriatal reward circuitry in MDD. Although MDD patients show blunted striatal responses to reward, the link between degree of inflammation and attenuation of reward processing is unclear. We investigated whether MDD patients with elevated peripheral inflammation exhibit attenuated reward responses to enhance our understanding of MDD pathophysiology and develop more effective treatments for current non-responders.MethodsMDD subjects varying on serum C-reactive protein (CRP) concentrations (MDD-High CRP, >3 mg/L, n = 44; MDD-Low CRP, <3 mg/L, n = 44) and healthy comparisons (HC, n = 44) completed a monetary incentive delay (MID) task and provided blood samples to measure inflammation-related markers. MDD-High and MDD-Low were propensity score-matched on age, sex, body mass index (BMI), smoking status, exercise and MID task head motion. Percent change in blood oxygen level-dependent (BOLD) signal during anticipation of wins and losses was extracted from bilateral nucleus accumbens, dorsal caudate and dorsolateral putamen regions of interest (ROIs). A linear mixed-effects model was used to test group (MDD-High, MDD-Low and HC), condition (large-win, small-win and no win), and their interaction for these ROIs as well as whole-brain voxelwise data. Analyses also tested group differences in inflammatory mediators. Correlations were used to explore the relationship between inflammatory mediators and brain regions showing differences between MDD-High and MDD-Low.ResultsMDD-High exhibited: (a) lower BOLD signal change in dorsal caudate, thalamus, left insula and left precuneus during anticipation of small wins than MDD-Low; and (b) higher serum soluble intercellular adhesion molecule 1 (sICAM-1) and interleukin 6 (IL-6) concentrations than MDD-Low and HC. MDD as a whole, regardless of CRP-based inflammation, exhibited: (a) lower precuneus BOLD signal change to large wins than HC; and (b) higher Interleukin 1 receptor antagonist (IL-1ra), macrophage-derived chemokine (MDC) and macrophage inflammatory protein-1 alpha (MIP-1α) concentrations than HC. Higher serum sICAM-1 concentrations were associated with lower caudate BOLD signal change to small wins only within the MDD-High group.ConclusionWithin MDD patients, high inflammation (CRP, sICAM-1) was linked to reduced striatal activation recruited to discriminate intermediate reward magnitudes. These findings support an association between levels of peripheral inflammation and the degree of reward-related activation in individuals with MDD.Registration of clinical trialsThe ClinicalTrials.gov identifier for the clinical protocol associated with data published in this current paper is NCT02450240, “Latent Structure of Multi-level Assessments and Predictors of Outcomes in Psychiatric Disorders.”     

Blood levels of cytokines in elderly patients with major depressive disorder

Plasma concentrations of interleukin-iβ (IL-lβ), interleukin-6 (IL-6) and tumour necrosis factor a (TNFα) were measured in 10 elderly women with major depressive disorder (MDD) and in two groups of controls, one consisting of 10 age-matched healthy female volunteers and one consisting of 10 young healthy female volunteers. The cytokine concentrations were measured in MDD patients before and after 30 days of treatment with phosphatidylserine (BC-PS), 600 mg daily p.o. The plasma IL-1β IL-6 and TNFα concentrations did not differ significantly in young controls, elderly controls and MDD patients. BC-PS therapy, while significantly improving the depressive symptoms, did not alter the cytokine concentrations.     

Suicidal ideation and attempts among psychiatric patients with major depressive disorder

BACKGROUND: Few studies have investigated risk factors for suicidal ideation and attempts, or possible variations in them, among representative samples of psychiatric patients with major depressive disorder. METHOD: As part of the Vantaa Depression Study in Vantaa, Finland, 269 patients with DSM-IV major depressive disorder (MDD), diagnosed by interview using semistructured World Health Organization Schedules for Clinical Assessment in Neuropsychiatry, version 2.0, and Structured Clinical Interview for DSM-III-R Personality Disorders, were thoroughly investigated. Information was gathered on patients' levels of depression, anxiety, hopelessness, perceived social support, social and occupational functioning, and alcohol use. Suicidal behavior was assessed by interviews, including the Scale for Suicidal Ideation, and by information from psychiatric records. Data were gathered from Feb. 1, 1997, to May 31, 1998. RESULTS: During the current MDD episode, 58% of all patients had experienced suicidal ideation; among the 15% of the total who had attempted suicide, almost all (95%) had also had suicidal ideation. In nominal regression models predicting suicidal ideation, hopelessness, alcohol dependence or abuse, low level of social and occupational functioning, and poor perceived social support were found to be significant (p < .05) independent risk factors. High severity of depression and current alcohol dependence or abuse in particular, but also younger age and low level of social and occupational functioning, predicted suicide attempt. CONCLUSION: Suicidal ideation is prevalent and appears to be a precondition for suicide attempts among psychiatric patients with MDD. The risk factors for suicidal ideation and attempts locate in several clinical and psychosocial domains. While these risk factors largely overlap, the overall level of psychopathology of suicide attempters is higher compared with that in patients with ideation, and substance use disorders and severity of depression may be of particular importance in predicting suicide attempts.     

Interleukin 10 family gene polymorphisms are not associated with major depressive disorder and panic disorder phenotypes

Genetic regulation of immune system and inflammatory response may be related to the pathogenesis and manifestations of mood and anxiety disorders. In the present study we examined a range of single-nucleotide polymorphisms (SNP) in chromosomal region 1q32, the locus of interleukin 10 (IL10) gene, in patients with major depressive disorder (n = 312) and panic disorder (n = 210), and matched healthy controls (n = 356). We found no significant associations of the SNPs in IL10 family genes with either diagnostic group. Haplotype analysis revealed seven haplotype blocks, but their frequencies did not differ between patients and controls. Significant associations were detected for SNP rs1539243 in IKBKE (inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase epsilon) gene showing different allelic and genotypic distributions in the total as well as in separate diagnostic groups as compared to controls. IKBKE emerged as a candidate for further studies of genetic factors associated with panic disorder and major depressive disorder.     

Disrupted reward circuits is associated with cognitive deficits and depression severity in major depressive disorder

Neuroimaging studies have demonstrated that major depressive disorder (MDD) patients show blunted activity responses to reward-related tasks. However, whether abnormal reward circuits affect cognition and depression in MDD patients remains unclear. Seventy-five drug-naive MDD patients and 42 cognitively normal (CN) subjects underwent a resting-state functional magnetic resonance imaging scan. The bilateral nucleus accumbens (NAc) were selected as seeds to construct reward circuits across all subjects. A multivariate linear regression analysis was employed to investigate the neural substrates of cognitive function and depression severity on the reward circuits in MDD patients. The common pathway underlying cognitive deficits and depression was identified with conjunction analysis. Compared with CN subjects, MDD patients showed decreased reward network connectivity that was primarily located in the prefrontal-striatal regions. Importantly, distinct and common neural pathways underlying cognition and depression were identified, implying the independent and synergistic effects of cognitive deficits and depression severity on reward circuits. This study demonstrated that disrupted topological organization within reward circuits was significantly associated with cognitive deficits and depression severity in MDD patients. These findings suggest that in addition to antidepressant treatment, normalized reward circuits should be a focus and a target for improving depression and cognitive deficits in MDD patients.     

CSF-hypocretin-1 levels in patients with major depressive disorder compared to healthy controls

Depressive patients exhibit symptoms of impaired regulation of wakefulness with hyperarousal and agitation as well as difficulties to falling asleep and preserving sleep continuity. Changes in hypocretin (hcrt) levels as polypeptides with impact on arousal and sleep-wake-regulation have been discussed in affective disorders but have not been investigated in patients with solely unipolar depression in comparison to healthy controls. In the present study, cerebrospinal fluid (CSF) levels of hcrt-1 for the first time were analyzed in patients with major depressive disorder (MDD) without psychiatric comorbidities and compared with levels in healthy controls. In 17 inpatients with MDD (mean Hamilton Depression Rating Scale 13.9 ± 7.4) and 10 healthy controls, CSF-hcrt-1 levels were measured using a fluorescence immunoassay (FIA). The mean hcrt-1 CSF levels in patients with MDD (74.3 ± 17.8pg/ml) did not differ compared to that of healthy controls (82.8 ± 22.1pg/ml). Hcrt-1 levels did not correlate with the severity of depressive episode, the symptoms of depression or the number of episodes. Although autonomic and neurohumoral signs of hyperarousal are common in MDD, hcrt-1 levels in CSF were not found to be altered in MDD compared to healthy controls. Whether hcrt-1 levels are altered in depressive patients exhibiting impaired vigilance regulation has to be investigated in further studies combining measures of CSF-hcrt-1 with electroencephalography.     

Birth-cohort trends in rates of major depressive disorder among relatives of patients with affective disorder

As part of the National Institute of Mental Health-Clinical Research Branch Collaborative Program on the Psychobiology of Depression Clinical Study, 2,289 relatives of 523 probands with affective disorder were interviewed with the Schedule for Affective Disorders and Schizophrenia and diagnosed for major depressive disorder by the Research Diagnostic Criteria. Data were analyzed using life-table and survival methods. The findings suggest a progressive increase in rates of depression in successive birth cohorts through the 20th century and an earlier age at onset of depression in each birth cohort. A predominance of female depressives was found in all birth cohorts but the magnitude of female-male differences fluctuated over the decades. The existence of these trends is reported to stimulate further research. These findings are discussed in terms of possible gene-environment interactions. However, no conclusive causal inferences can be drawn pending further investigation.