Yekta Dowlati

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.

Does inclusion of a placebo arm influence response to active antidepressant treatment in randomized controlled trials? Results from pooled and meta-analyses.

OBJECTIVE To determine if the inclusion of a placebo arm and/or the number of active comparators in antidepressant trials influences the response rates of the active medication and/or placebo. DATA SOURCES Searches of MEDLINE, PsycINFO, and pharmaceutical Web sites for published trials or trials conducted but unpublished between January 1996 and October 2007. STUDY SELECTION 2,275 citations were reviewed, 285 studies were retrieved, and 90 were included in the analysis. Trials reporting response and/or remission rates in adult subjects treated with an antidepressant monotherapy for unipolar major depression were included. DATA EXTRACTION The primary investigator recorded the number of responders and/or remitters in the intent-to-treat population of each study arm or computed these numbers using the quoted rates. DATA SYNTHESIS Poisson regression analyses demonstrated that mean response rate for the active medication was higher in studies comparing 2 or more active medications without a placebo arm than in studies comparing 2 or more active medications with a placebo arm (65.4% vs 57.7%, P < .0001) or in studies comparing only 1 active medication with placebo (65.4% vs 51.7%, P = .0005). Mean response rate for placebo was significantly lower in studies comparing 1 rather than 2 or more active medications (34.3% vs 44.6%, P = .003). Mean remission rates followed a similar pattern. Meta-analysis confirmed results from the pooled analysis. CONCLUSIONS These data suggest that antidepressant response rates in randomized control trials may be influenced by the presence of a placebo arm and by the number of treatment arms and that placebo response rates may be influenced by the number of active treatment arms in a study.

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.

Efficacy and tolerability of antidepressants for treatment of depression in coronary artery disease: a meta-analysis.

Objective: Depression occurs in 18% to 45% of patients with coronary artery disease (CAD) where it is associated with an increased risk of acute coronary events and mortality. Our objective was to quantitatively summarize the data on the efficacy and tolerability of antidepressant (AD) treatment for depression in CAD. Methods: We performed a meta-analysis of randomized, placebo-controlled, double-blind trials with a database search of the English literature (to March 2008) and manual search of references. Results: Four clinical trials with ADs (mirtazapine, citalopram, fluoxetine, and sertraline) of a 9- to 24-week duration involving 798 subjects (402 ADs, 396 placebo) with documented CAD and meeting the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria for depression were included. ADs were superior to placebo for decreasing Hamilton Depression Rating Scale (HDRS) scores (402 ADs, 396 placebo; weighted mean difference 1.41, 95% CI 0.53 to 2.29, P = 0.002) and Beck Depression Inventory (BDI) scores (373 ADs, 369 placebo; weighted mean difference 2.27, 95% CI 0.60 to 3.94, P = 0.008). The proportion of patients (216 ADs, 213 placebo) who responded (a 50% or more reduction in HDRS scores, OR 1.72, 95% CI 1.17 to 2.54) and remitted (HDRS of 8 or less at final assessment, OR 1.80, 95% CI 1.18 to 2.74), were also significantly higher with AD, compared with placebo, with no significant differences between the 2 groups for overall dropouts (OR 0.84, 95% CI 0.42 to 1.68) or dropout owing to adverse events (OR 1.30, 95% CI 0.75 to 2.25). The combined studies were homogeneous except for overall dropout rate (P = 0.01). Conclusion: Treatment with ADs for depression in CAD results in significant therapeutic effects without substantially increased rates of discontinuation.

Indoleamine 2,3-dioxygenase activation and depressive symptoms in patients with coronary artery disease

An increase in immune-stimulated synthesis of kynurenine from tryptophan by indoleamine 2,3-dioxygenase (IDO) has been observed in patients with coronary artery disease (CAD). However, neuropsychiatric correlates of IDO activation remain unexplored. We hypothesize that IDO activation, as measured by the kynurenine to tryptophan (K/T) ratio, is associated with depressive symptoms in those with CAD. This cross-sectional study recruited subjects with CAD (n=95) from a cardiac rehabilitation facility. Demographic, anthropometric and cardiac data were obtained by chart review. Patients using an antidepressant were excluded. The presence of a major depressive episode or minor depression was assessed using a structured clinical interview for depression based on Diagnostic and Statistical Manual 4th edition criteria. The Center for Epidemiological Studies-Depression Scale (CES-D) was used to quantify depressive symptoms. A standardized exercise stress test was used to assess cardiopulmonary fitness as summarized using the peak volume of oxygen consumption (Peak VO(2)). Kynurenine and tryptophan were assayed from fasting plasma samples to obtain the K/T ratio. Higher K/T ratios were significantly associated with higher CES-D scores (beta=.322, p=.002) in a linear regression controlling for time since most recent acute coronary syndrome (tACS), age and sex. Twenty-four patients met criteria for depression (16 major depression; 8 minor depression). There was a trend towards higher K/T ratios in depressed vs. non-depressed patients (45.6+/-20.0 micromol/mmol vs. 38.5+/-15.7 micromol/mmol, F=3.778, p=.055) when controlling for age, sex and tACS. Activation of IDO is associated with the severity of depressive symptoms among patients with CAD.

Relationship between cardiopulmonary fitness and depressive symptoms in cardiac rehabilitation patients with coronary artery disease.

OBJECTIVE To identify independent predictors of depressive symptoms in a cohort of patients with coronary artery disease entering cardiac rehabilitation. DESIGN Cross-sectional cohort study. PATIENTS AND METHODS Consecutive patients entering a cardiac rehabilitation and secondary prevention programme underwent screening for depressive symptoms using the Center for Epidemiological Studies Depression (CES-D) scale and cardiopulmonary fitness testing to quantify peak oxygen consumption. RESULTS Of the 366 patients with coronary artery disease, 22.3% reported at least mild (CES-D > or = 16) and 10.4% reported significant (CES-D > or = 23) depressive symptoms. Antidepressant medications were being used by 6.3% of patients. Sociodemographic, cardiopulmonary and cardiac characteristics, and medical co-morbidities previously associated with depression accounted for 14.7% of the variance in a multiple linear regression model (F = 8.713, p < 0.001) predicting CES-D scores. Significant independent predictors of CES-D scores were lower peak oxygen consumption, younger age, female sex, lower maximum diastolic blood pressure, angina pectoris and antidepressant use. CONCLUSION Reduced physical fitness, younger age, female sex and ischaemic symptoms of coronary artery disease predict higher depressive symptoms in patients entering cardiac rehabilitation.

Selective dietary supplementation in early postpartum is associated with high resilience against depressed mood

Significance Postpartum blues is a healthy range of sadness that peaks on day 5 after giving birth in most women. Severe postpartum blues is a high-risk state for postpartum depression. A dietary supplement was designed to compensate for a temporary rise in a brain protein, monoamine oxidase A, which occurs on postpartum day 5. This study tested whether this dietary supplement reduces the sadness associated with the postpartum blues. Total levels of tryptophan and tyrosine in breast milk are not affected by this dietary supplement. Women received the dietary supplement over postpartum days 3–5 or received no supplement. This dietary supplement dramatically reduced the vulnerability to sadness on postpartum day 5, the peak of the postpartum blues, eliminating the prodrome of postpartum depression. Medical research is moving toward prevention strategies during prodromal states. Postpartum blues (PPB) is often a prodromal state for postpartum depression (PPD), with severe PPB strongly associated with an elevated risk for PPD. The most common complication of childbearing, PPD has a prevalence of 13%, but there are no widespread prevention strategies, and no nutraceutical interventions have been developed. To counter the effects of the 40% increase in monoamine oxidase A (MAO-A) levels that occurs during PPB, a dietary supplement kit consisting of monoamine precursor amino acids and dietary antioxidants was created. Key ingredients (tryptophan and tyrosine) were shown not to affect their total concentration in breast milk. The aim of this open-label study was to assess whether this dietary supplement reduces vulnerability to depressed mood at postpartum day 5, the typical peak of PPB. Forty-one healthy women completed all study procedures. One group (n = 21) received the dietary supplement, composed of 2 g of tryptophan, 10 g of tyrosine, and blueberry juice with blueberry extract. The control group (n = 20) did not receive any supplement. PPB severity was quantitated by the elevation in depressed mood on a visual analog scale following the sad mood induction procedure (MIP). Following the MIP, there was a robust induction of depressed mood in the control group, but no effect in the supplement group [43.85 ± 18.98 mm vs. 0.05 ± 9.57 mm shift; effect size: 2.9; F(1,39) = 88.33, P < 0.001]. This dietary supplement designed to counter functions of elevated MAO-A activity eliminates vulnerability to depressed mood during the peak of PPB.

No effect of oral L-tryptophan or alpha-lactalbumin on total tryptophan levels in breast milk.

Postpartum depression (PPD) is the most common complication of childbearing with a 13% prevalence rate. Sleep disturbances are also common, particularly during early postpartum. In theory, l-tryptophan could improve sleep and reduce depressed mood in early postpartum; however, the first step in clinical development of tryptophan for use in postpartum is to measure the effect of oral l-tryptophan on its concentrations in breast milk, which is presently unknown. The aims were to investigate the effect of oral l-tryptophan and alpha-lactalbumin, a protein with high tryptophan concentration, on total and free tryptophan levels in breast milk and plasma, and to compare free tryptophan levels in breast milk with those in common infant formulas. Thirty healthy breastfeeding women were randomly allocated to receive 2g or 4g of l-tryptophan, or, 20g or 40g of alpha-lactalbumin or no supplement. Free tryptophan levels were also measured in 12 different infant formulas. Total tryptophan in breast milk was unaffected by oral administration of l-tryptophan or alpha-lactalbumin (repeated measures of ANOVA (rANOVA), group effect: p=0.93). Both l-tryptophan and alpha-lactalbumin were associated with greater free tryptophan levels in breast milk (rANOVA, group effect: p<0.001) (representing 2% of total tryptophan), but these concentrations were within the range of commonly used infant formulas. In contrast to most sleep inducing medications, l-tryptophan does not affect its total concentration in breast milk. These results support further investigation of dietary l-tryptophan and alpha-lactalbumin as part of a dietary supplementation approach to address sleep disturbances in postpartum and reduce risk of PPD.

Effect of dysfunctional attitudes and postpartum state on vulnerability to depressed mood.

BACKGROUND Postpartum depression (PPD) is the most common complication of childbearing with a 13% prevalence. Vulnerability to depressed mood has an important role in the onset of major depressive episodes (MDE), but has not been investigated in postpartum. The aim is to assess whether day-5 postpartum blues and severity of dysfunctional attitudes predicts vulnerability to depressed mood. METHODS About 45 healthy women were recruited: group 1 (n=12) was day-5 postpartum during the typical peak of postpartum blues. Group 2 (n=11) was within 18 months postpartum and reported a vulnerability to cry (and had elevated dysfunctional attitudes but no MDE). Group 3 (n=11) was within 18 months postpartum and no vulnerability to cry. Group 4 (n=11) was not recently postpartum. Vulnerability to depressed mood was measured by the change in the visual analog scale from the sad mood induction procedure (MIP). RESULTS Univariate analysis of covariance demonstrated that day-5 postpartum blues and level of dysfunctional attitudes were highly predictive of change in sad mood (postpartum blues: F(1,41)=12.9, p<0.005, dysfunctional attitudes scale score: F(1,41)=11.49, p<0.005). LIMITATIONS Although the effects were robust, sample sizes were 11-12 within each group. CONCLUSION Two factors (day-5 postpartum and severity of dysfunctional attitudes) predicted vulnerability to sad mood. Since the severity of postpartum blues predicts PPD, MIP on day-5 postpartum represents a quantitative measure that can be applied to screen novel, early interventions for preventing PPD. Interventions to prevent PPD through increasing resilience against mood induction should target postpartum women with greater severity of dysfunctional attitudes.