Walter Swardfager

A Meta-Analysis of Cytokines in Major Depression

BACKGROUND Major depression occurs in 4.4% to 20% of the general population. Studies suggest that major depression is accompanied by immune dysregulation and activation of the inflammatory response system (IRS). Our objective was to quantitatively summarize the data on concentrations of specific cytokines in patients diagnosed with a major depressive episode and controls. METHODS We performed a meta-analysis of studies measuring cytokine concentration in patients with major depression, with a database search of the English literature (to August 2009) and a manual search of references. RESULTS Twenty-four studies involving unstimulated measurements of cytokines in patients meeting DSM criteria for major depression were included in the meta-analysis; 13 for tumor necrosis factor (TNF)-alpha, 9 for interleukin (IL)-1beta, 16 for IL-6, 5 for IL-4, 5 for IL-2, 4 for IL-8, 6 for IL-10, and 4 for interferon (IFN)-gamma. There were significantly higher concentrations of TNF-alpha (p < .00001), weighted mean difference (WMD) (95% confidence interval) 3.97 pg/mL (2.24 to 5.71), in depressed subjects compared with control subjects (438 depressed/350 nondepressed). Also, IL-6 concentrations were significantly higher (p < .00001) in depressed subjects compared with control subjects (492 depressed/400 nondepressed) with an overall WMD of 1.78 pg/mL (1.23 to 2.33). There were no significant differences among depressed and nondepressed subjects for the other cytokines studied. CONCLUSIONS This meta-analysis reports significantly higher concentrations of the proinflammatory cytokines TNF-alpha and IL-6 in depressed subjects compared with control subjects. While both positive and negative results have been reported in individual studies, this meta-analytic result strengthens evidence that depression is accompanied by activation of the IRS.

A Meta-Analysis of Cytokines in Alzheimer's Disease

BACKGROUND Studies suggest that inflammation is involved in the neurodegenerative cascade leading to Alzheimers disease (AD) pathology and symptoms. This study sought to quantitatively summarize the clinical cytokine data. METHODS Original English language peer-reviewed studies measuring cytokine concentrations in AD and healthy control subjects were included. Mean (± standard deviation) cytokine concentrations for AD and control subjects were extracted. RESULTS Forty studies measuring peripheral blood cytokine concentrations and 14 measuring cerebrospinal fluid (CSF) cytokine concentrations were included. In peripheral blood, there were significantly higher concentrations (weighted mean difference [95% confidence interval]) of interleukin (IL)-6 (2.86 [1.68, 4.04] pg/mL, p < .00001, N[AD/control subjects] = 985/680, 14 studies), tumor necrosis factor (TNF)-α (3.25 [.76, 5.74] pg/mL, p = .01, N = 680/447, 14 studies), IL-1β (.55 [.32, .78] pg/mL, p < .00001, N = 574/370, 10 studies), transforming growth factor (TGF)-β (67.23 [28.62, 105.83] pg/mL, p = .0006, N = 190/158, 5 studies), IL-12 (7.60 [5.58, 9.62] pg/mL, p < .00001, N = 148/106, 5 studies), and IL-18 (15.82 [1.98, 29.66] pg/mL, p = .03, N = 131/94, 4 studies) but not of IL-4, IL-8, IL-10, interferon-γ, or C-reactive protein in AD subjects compared with control subjects. There were significantly higher concentrations of TGF-β (7.81 [2.27, 13.35] pg/mL, p =.006, N = 113/114, 5 studies) but not IL-6, TNF-α, and IL-1β in the CSF of AD subjects compared with control subjects. CONCLUSIONS These results strengthen the clinical evidence that AD is accompanied by an inflammatory response, particularly higher peripheral concentrations of IL-6, TNF-α, IL-1β, TGF-β, IL-12 and IL-18 and higher CSF concentrations of TGF-β.

Effects of omega-3 fatty acids on cognitive performance: a meta-analysis

BACKGROUND Higher intake of omega-3 fatty acids (n-3 FAs) is associated with a reduced risk of Alzheimers disease (AD) and milder forms of cognitive impairment (e.g. cognitive impairment no dementia [CIND]); however, findings from interventional trials are inconsistent. This meta-analysis examined the neuropsychological benefit of n-3 FAs in randomized double-blind placebo-controlled studies (RCTs) including healthy, CIND, or AD subjects. METHODS Literature was searched using Medline, Embase, PsycInfo, Cochrane Library, Allied and Complementary Medicine Database (AMED), and Cumulative Index to Nursing and Allied Health Literature (CINAHL) up to September 2011. Treatment effects were summarized across cognitive subdomains, and effect sizes were estimated using Hedges g and random effects modeling. RESULTS Ten RCTs were combined quantitatively. There was no effect of n-3 FAs on composite memory (g = 0.04 [95% CI: -0.06-0.14], N = 934/812, p = 0.452). When examined by domain, no overall benefit for immediate recall (0.04 [-0.05-0.13], N = 934/812, p = 0.358) was detected; however, an effect in CIND subjects (0.16 [0.01-0.31], N = 349/327, p = 0.034) was found. A benefit for attention and processing speed was also detected in CIND (0.30 [0.02-0.57], N = 107/86, p = 0.035), but not healthy subjects. Benefits for delayed recall, recognition memory, or working memory and executive function were not observed. Treatment did not benefit AD patients as measured by the Mini-Mental State Examination (MMSE) or Alzheimers Disease Assessment Scale-Cognitive Subscale (ADAS-cog). No differences in adverse events (AE), dropout, or dropout due to AE between groups were observed. CONCLUSIONS These results suggest an effect of n-3 FAs within specific cognitive domains in CIND, but not in healthy or AD subjects.

Zinc in Depression: A Meta-Analysis

BACKGROUND Zinc is an essential micronutrient with diverse biological roles in cell growth, apoptosis and metabolism, and in the regulation of endocrine, immune, and neuronal functions implicated in the pathophysiology of depression. This study sought to quantitatively summarize the clinical data comparing peripheral blood zinc concentrations between depressed and nondepressed subjects. METHODS PubMed, Cumulated Index to Nursing and Allied Health Literature, and PsycINFO were searched for original peer-reviewed studies (to June 2012) measuring zinc concentrations in serum or plasma from depressed subjects (identified by either screening or clinical criteria) and nondepressed control subjects. Mean (±SD) zinc concentrations were extracted, combined quantitatively in random-effects meta-analysis, and summarized as a weighted mean difference (WMD). RESULTS Seventeen studies, measuring peripheral blood zinc concentrations in 1643 depressed and 804 control subjects, were included. Zinc concentrations were approximately -1.85 µmol/L lower in depressed subjects than control subjects (95% confidence interval: [CI]: -2.51 to -1.19 µmol/L, Z17 = 5.45, p < .00001). Heterogeneity was detected (χ(2)17 = 142.81, p < .00001, I(2) = 88%) and explored; in studies that quantified depressive symptoms, greater depression severity was associated with greater relative zinc deficiency (B = -1.503, t9 = -2.82, p = .026). Effect sizes were numerically larger in studies of inpatients (WMD -2.543, 95% CI: -3.522 to -1.564, Z9 = 5.09, p < .0001) versus community samples (WMD -.943, 95% CI: -1.563 to -.323, Z7 = 2.98, p = .003) and in studies of higher methodological quality (WMD -2.354, 95% CI: -2.901 to -1.807, Z7 = 8.43, p < .0001). CONCLUSIONS Depression is associated with a lower concentration of zinc in peripheral blood. The pathophysiological relationships between zinc status and depression, and the potential benefits of zinc supplementation in depressed patients, warrant further investigation.

Novel therapeutic targets in depression: Minocycline as a candidate treatment

Mood disorders are marked by high rates of non-recovery, recurrence, and chronicity, which are insufficiently addressed by current therapies. Several patho-etiological models have been proposed that are not mutually exclusive and include but are not limited to the monoamine, inflammatory, neurotrophic, gliotrophic, excitatory, and oxidative stress systems. A derivative of these observations is that treatment(s) which target one or more of these mechanistic steps may be capable of mitigating, or preventing, disparate psychopathological features. Minocycline is an agent with pleiotropic properties that targets multiple proteins and cellular processes implicated in the patho-etiology of mood disorders. Moreover, preclinical and preliminary clinical evidence suggests that minocycline possesses antidepressant properties. Herein, we provide the rationale for conducting a randomized, controlled trial to test the antidepressant properties of minocycline.

Major Depressive Disorder Predicts Completion, Adherence, and Outcomes in Cardiac Rehabilitation: A Prospective Cohort Study of 195 Patients With Coronary Artery Disease

OBJECTIVE To compare completion, adherence, and cardiac rehabilitation (CR) outcomes between participants with and without major depressive disorder (MDD) undertaking CR. METHOD In a prospective cohort study of consecutive patients with coronary artery disease (n = 195) entering 1-year outpatient CR between January 2006 and August 2008, rates of noncompletion (comprehensive CR criteria), nonadherence (< 70% attendance at scheduled CR visits), and CR outcomes were compared between patients with and without MDD based on the Structured Clinical Interview for DSM-IV criteria. RESULTS Major depressive disorder was diagnosed in 22.1% of participants. Rates of noncompletion were 44.2% and 28.9%, and rates of nonadherence were 53.0% and 34.9% for those with and without MDD, respectively. Major depressive disorder was associated with increased risks of noncompletion (multivariate hazard ratio [HR], 2.5; 95% confidence interval [CI], 1.3-4.7) and nonadherence (multivariate HR, 2.4; 95% CI, 1.3-4.2). More participants with MDD failed to complete CR for medical reasons than those without MDD (25.6% vs 12.3%, respectively; P = .031) in post hoc comparisons. Participants with MDD achieved poorer cardiopulmonary fitness increases (change in mean ± SD peak oxygen uptake of 3.3 ± 3.2 vs 6.6 ± 5.7 mL/kg/min; P = .021) and poorer body fat outcomes (a mean ± SD increase of 2.1% ± 4.5% vs a decrease of 0.4% ± 3.4%, P = .009) than those without MDD. CONCLUSIONS Major depressive disorder was associated with poorer rates of completion and adherence in CR, and it mitigated improvements in clinical outcomes. Despite depression screening and psychosocial support as structured components of care, MDD remained a significant barrier to effective CR.

Potential roles of zinc in the pathophysiology and treatment of major depressive disorder

Incomplete response to monoaminergic antidepressants in major depressive disorder (MDD), and the phenomenon of neuroprogression, suggests a need for additional pathophysiological markers and pharmacological targets. Neuronal zinc is concentrated exclusively within glutamatergic neurons, acting as an allosteric modulator of the N-methyl D-aspartate and other receptors that regulate excitatory neurotransmission and neuroplasticity. Zinc-containing neurons form extensive associational circuitry throughout the cortex, amygdala and hippocampus, which subserve mood regulation and cognitive functions. In animal models of depression, zinc is reduced in these circuits, zinc treatment has antidepressant-like effects and dietary zinc insufficiency induces depressive behaviors. Clinically, serum zinc is lower in MDD, which may constitute a state-marker of illness and a risk factor for treatment-resistance. Marginal zinc deficiency in MDD may relate to multiple putative mechanisms underlying core symptomatology and neuroprogression (e.g. immune dysfunction, monoamine metabolism, stress response dysregulation, oxidative/nitrosative stress, neurotrophic deficits, transcriptional/epigenetic regulation of neural networks). Initial randomized trials suggest a benefit of zinc supplementation. In summary, molecular and animal behavioral data support the clinical significance of zinc in the setting of MDD.

relationship between hair cortisol concentrations and depressive symptoms in patients with coronary artery disease

Objective Concentrations of cortisol in hair, a novel marker of longer-term cortisol status, were compared in depressed versus nondepressed patients with coronary artery disease (CAD). Methods 20 mg hair samples of 3 cm length were collected from 121 patients attending a cardiac rehabilitation program, 34 of whom suffered from depressive symptoms. Results Controlling for age, gender, coronary artery bypass grafting, history of depression, and time since most recent acute coronary syndrome, cortisol concentrations (P = 0.162) did not predict severity of depression. Younger age (P = 0.003) was a significant predictor of depressive symptoms. Perceived stress was not associated with long-term cortisol concentrations (P = 0.161). Conclusions Cortisol concentrations in hair do not predict depressive symptoms in CAD patients attending cardiac rehabilitation.

The relationship between indoleamine 2,3-dioxygenase activity and post-stroke cognitive impairment

BackgroundActivation of indoleamine 2,3-dioxygenase (IDO) and higher concentrations of several kynurenine metabolites have been observed post-stroke, where they have been associated with increased mortality. While lower tryptophan or a higher ratio of kynurenine/tryptophan (K/T) in peripheral blood have been associated with dementia and the severity of cognitive symptoms in Alzheimers disease, the association between K/T ratios and post-stroke cognitive impairment (PSCI) has not been investigated.MethodsPatients were recruited from the acute stroke unit of a general hospital within 1 month post-stroke. Assessments included the Standardized Mini-Mental State Examination (sMMSE) for cognition, the National Institutes of Health Stroke Scale (NIHSS) for stroke severity, and the Center for Epidemiological Studies-Depression Scale (CES-D) for depressive symptoms. Tryptophan and kynurenine concentrations were determined by high-performance liquid chromatography.ResultsA total of 41 patients with ischemic stroke ([mean ± SD] age 72.3 ± 12.2 years, 53.7% male, sMMSE 25.6 ± 4.1, NIHSS 7.27 ± 5.55) were recruited. Higher K/T ratios were associated with lower post-stroke global cognition (i.e. sMMSE scores; β = -.327, P = .037). A backward stepwise elimination linear regression (F1,40=6.15, P=.005, adjusted R2=.205) showed that the highest K/T ratio tertile (β = -.412, P = .006) predicted lower sMMSE scores, controlling for age (β = -.253, p = .081), with NIHSS (β = -.027, P = 0.859), and lesion volume (β = -.066, P = 0.659) removed from the model. In receiver operating characteristic analysis, a K/T ratio of 78.3 μmol/mmol (top tertile) predicted significant cognitive impairment (sMMSE score ≤ 24) with 67% sensitivity and 86% specificity (area under the curve = 0.730, p = .022).ConclusionsThese data suggest an inflammatory response characterized by IDO activation may be relevant to the development of PSCI. Since the neuroactivity of kynurenine metabolites may be amenable to pharmacotherapeutic intervention, the K/T ratio may be a clinically important biomarker.

Exercise intervention and inflammatory markers in coronary artery disease: A meta-analysis

BACKGROUND Inflammatory activity plays a role in the development and progression of coronary artery disease (CAD), and exercise confers survival benefit. We performed a meta-analysis of changes in inflammatory biomarkers over the course of exercise interventions in patients with CAD. METHODS We searched MEDLINE, Embase, the Cochrane Collaboration, AMED, and CINAHL for studies reporting peripheral inflammatory biomarker concentrations before and after exercise interventions of ≥ 2 weeks in patients with CAD. Data were summarized using standard mean differences (SMD) and 95% CIs. RESULTS Twenty-three studies were included. Concentrations of C-reactive protein (CRP; SMD -0.345, 95% CI -0.444 to -0.246, n = 1,466, P < .001), interleukin 6 (SMD -0.546, 95% CI -0.739 to -0.353, n = 280, P < .001), fibrinogen (SMD -0.638, 95% CI -0.953 to -0.323, n = 247, P < .001), and vascular cell adhesion molecule 1 (SMD -0.413, 95% CI -0.778 to -0.048, n = 187, P = .027) were lower postintervention. Higher total cholesterol (B = -0.328, 95% CI -0.612 to -0.043, P = .026) and higher total/high-density lipoprotein cholesterol ratios (B = -0.250, 95% CI -0.425 to -0.076, P = .008) at baseline were associated with greater reductions in CRP. In controlled studies, follow-up concentrations of CRP (SMD -0.500, 95% CI -0.844 to -0.157, n(exercise/control) = 485/284, P = .004), and fibrinogen (SMD -0.544, 95% CI -1.058 to -0.030, n(exercise/control) = 148/100, P = .038) were lower in subjects who exercised compared with controls. CONCLUSION Exercise training is associated with reduced inflammatory activity in patients with CAD. C-reactive protein and fibrinogen have provided the strongest evidence. Higher baseline CRP and adverse baseline lipid profiles predicted greater reductions in CRP.