Supplementation with eicosapentaenoic omega-3 fatty acid does not influence serum brain-derived neurotrophic factor in diabetes mellitus patients with major depression: a randomized controlled pilot study.

BACKGROUND: Low brain-derived neurotrophic factor (BDNF) levels are observed in both depressed and diabetes patients. Animal research has shown that omega-3 polyunsaturated fatty acids increase BDNF levels. In this exploratory randomized double-blind placebo-controlled study in diabetes patients with major depression, we tested whether (a) omega- 3 ethyl-eicosapentaenoic acid (E-EPA) leads to increased serum BDNF levels and (b) whether changes in BDNF levels are associated with corresponding changes in depression. METHODS: Patients received 1 g/day E-EPA (n = 13) or placebo (n = 12) for 12 weeks, in addition to ongoing antidepressant therapy. At baseline and 12-week follow-up, we determined serum BDNF levels and depression severity, using the Montgomery-Åsberg Depression Rating Scale. RESULTS: We found no effect of E-EPA on BDNF levels (t = -0.144, p = 0.887), and changes in BDNF levels and depression severity were not significantly associated (Spearman's ρ = -0.115, p = 0.593). CONCLUSION: Our study does not provide evidence that supplementation with E-EPA improves BDNF levels in depressed diabetes patients already using antidepressants.

Metabolic features of recurrent major depressive disorder in remission, and the risk of future recurrence.

Recurrent major depressive disorder (rMDD) is a relapsing-remitting disease with high morbidity and a 5-year risk of recurrence of up to 80%. This was a prospective pilot study to examine the potential diagnostic and prognostic value of targeted plasma metabolomics in the care of patients with rMDD in remission. We used an established LC-MS/MS platform to measure 399 metabolites in 68 subjects with rMDD (n = 45 females and 23 males) in antidepressant-free remission and 59 age- and sex-matched controls (n = 40 females and 19 males). Patients were then followed prospectively for 2.5 years. Metabolomics explained up to 43% of the phenotypic variance. The strongest biomarkers were gender specific. 80% of the metabolic predictors of recurrence in both males and females belonged to 6 pathways: (1) phospholipids, (2) sphingomyelins, (3) glycosphingolipids, (4) eicosanoids, (5) microbiome, and (6) purines. These changes traced to altered mitochondrial regulation of cellular redox, signaling, energy, and lipid metabolism. Metabolomics identified a chemical endophenotype that could be used to stratify rrMDD patients at greatest risk for recurrence with an accuracy over 0.90 (95%CI = 0.69-1.0). Power calculations suggest that a validation study of at least 198 females and 198 males (99 cases and 99 controls each) will be needed to confirm these results. Although a small study, these results are the first to show the potential utility of metabolomics in assisting with the important clinical challenge of prospectively identifying the patients at greatest risk of recurrence of a depressive episode and those who are at lower risk.

Omega-3 Fatty Acid Supplementation for Perinatal Depression: A Meta-Analysis.

OBJECTIVE: Several randomized controlled trials (RCTs) investigated omega-3 polyunsaturated fatty acids (PUFAs) (ie, fish oil) in perinatal depression, but their efficacy remains unclear. We performed a meta-analysis of RCTs on omega-3 PUFAs for perinatal depression, comparing a priori defined subgroups: pregnant women vs postpartum women and prevention vs treatment of perinatal depression. METHODS: We searched Web of Science, Embase, PsycINFO, and the Cochrane Library, combining omega-3 PUFAs and perinatal depression terms and including publications up to February 18, 2019, for RCTs on omega-3 PUFAs compared to placebo or any active comparator. RESULTS: Data from 18 RCTs on 4,052 participants showed an overall significant small beneficial effect of omega-3 PUFAs on depressive symptoms compared to placebo (-0.236 standardized difference in means [SDM]; 95% CI = -0.463 to -0.009; P = .042). Heterogeneity was considerable (I² = 88.58; P < .001), with significant subgroup differences explaining 55% of between-study variance (P = .001). In depressed women, omega-3 PUFAs showed a medium effect (SDM = -0.545; 95% CI = -1.182 to 0.093; P = .094) vs no effect in nondepressed women (SDM = -0.073). Moreover, the effect was medium to large in postpartum women (SDM = -0.656; 95% CI = -1.690 to 0.378; P = .214) compared to a negligible effect during pregnancy (SDM = -0.071). RCTs specifically studying postpartum depression showed the largest effect (SDM = -0.886; 95% CI = -2.088 to 0.316; P = .149). CONCLUSIONS: Omega-3 PUFAs have an overall significant small beneficial effect on perinatal depression, with important subgroup differences. We advise against prescribing omega-3 PUFAs for the treatment or prevention of depressive symptoms during pregnancy, given a lack of effect with low heterogeneity. In contrast, omega-3 PUFA supplementation may be a promising (add-on) treatment for postpartum depression.

Changes in cortisol and DHEA plasma levels after psychotherapy for PTSD.

Post-traumatic stress disorder (PTSD) has been associated with dysregulation of the neuroendocrine system. In this study we examine the effects of psychotherapy in 21 PTSD patients, with and without coexisting depression, on the levels of six stress-related hormones: cortisol, dehydroepiandrosterone (DHEA), and dehydroepiandrosterone-sulfate (DHEA-S), prolactin, thyrotropin (TSH) and free thyroxin (fT4). The results show that after brief eclectic psychotherapy (BEP) significant changes occurred in levels of cortisol and DHEA. Responders showed an increase in cortisol and DHEA levels, while in non-responders both hormone levels decreased. Differences were only found after controlling for depressive symptoms. In conclusion, effective psychotherapy for PTSD may alter dysregulations in the Hypothalamus-pituitary-adrenal (HPA)-axis, but comorbid depressive symptoms should be taken into account.

Plasma lipoproteins in posttraumatic stress disorder patients compared to healthy controls and their associations with the HPA- and HPT-axis.

BACKGROUND: Based on studies among primarily male veteran subjects, lipoproteins are thought to mediate the association of posttraumatic stress disorder (PTSD) with cardiovascular disease (CVD). However, recent civilian studies with female samples or samples with both sexes represented provide little evidence for this association. Gender, diet and sex-specific effects of stress hormones on lipoproteins may explain this dissociation in findings. METHOD: Cross-sectional analysis of plasma concentrations of total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL) and triglycerides (TG) in a male and female sample of 49 PTSD-patients due to civilian trauma and 45 healthy controls. Second, we related these lipoproteins to several stress hormones (prolactin, cortisol, DHEA(S), TSH, T4). RESULTS: Patients showed lower LDL (p=0.033) and LDL:HDL ratio (p=0.038) compared to controls, also when adjusting for diet. Sex influenced the effect of having PTSD on LDL with only male patients having lower values than male controls (p=0.012). All stress hormones were associated with several lipoproteins, mostly in a sex-dependent manner. For LDL, a significant sex-by-cortisol effect (p<0.001), having PTSD-by-sex-by-DHEA (p<0.001), having PTSD-by-sex-by-DHEAS (p=0.016) and having PTSD-by-sex-by-prolactin (p=0.003) was found. CONCLUSION: In this male and female civilian sample we found a somewhat more favorable lipoprotein profile in PTSD-patients in contrast to evidence from strictly male veteran samples exhibiting a less favorable lipoprotein profile. Male patients did not exhibit a worse lipoprotein profile than female patients and therefore gender cannot explain the contradiction in evidence. Additionally, we found that PTSD-related stress hormones are associated with lipoproteins levels in patients in a sex-specific manner. Specific configurations of stress hormones may contribute to CVD in male patients or protect in female patients. Further research on these configurations could indicate which PTSD-patients are especially at risk for CVD and which are not. This could guide future precision medicine efforts to prevent and treat the still growing burden of CVD morbidity and mortality in PTSD.

HPA- and HPT-axis alterations in chronic posttraumatic stress disorder.

Posttraumatic stress disorder (PTSD) has been associated with dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis as well as of the hypothalamus-pituitary-thyroid (HPT) axis. Findings have not been consistent and may depend on methodological issues like controlling for relevant variables. This study examines the levels of six HPA and HPT-axis related hormones in civilian PTSD patients without psychotropic medication. In a cross sectional study, 39 chronic PTSD patients and 44 healthy volunteers were included. Psychometric instruments included SCID, SI-PTSD, IES-R and BDI. The plasma hormones levels assessed were cortisol, dehydroepiandrosterone (DHEA), and dehydroepiandrosterone sulfate (DHEA-S), prolactin, thyrotropin (TSH), and free thyroxin (fT4). Results showed that patients had significantly lower plasma cortisol, prolactin and TSH levels compared to the comparison group. The difference between TSH levels in patients and comparison subjects only emerged after controlling for relevant background variables. Furthermore, the severity of PTSD symptoms was negatively related to cortisol levels. Secondary analyses revealed no statistically significant effect of comorbid depression (26% of patients) on any of the hormone levels. Complex feedback mechanisms are likely to result in altered levels of stress related hormones in PTSD, and results depend on controlling for relevant variables. Further research with longitudinal designs is needed to find out whether these lower hormone levels are preexisting risk factors or consequence of trauma and whether these alterations are deleterious or adaptive.

Fatty acid concentrations in patients with posttraumatic stress disorder compared to healthy controls.

BACKGROUND: Although fatty acid (FA)-supplementation studies are currently being implemented, in fact little is known about FA-profiles in posttraumatic stress disorder (PTSD). Therefore, the present study aimed at comparing FA-concentrations between PTSD-patients and healthy controls. METHODS: A cross-sectional study comparing a mixed-gender sample of 49 patients with PTSD due to civilian trauma to 46 healthy controls regarding erythrocyte FAs including docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), arachidonic acid (AA), and nervonic acid (NA). RESULTS: DHA was found to be significantly lower in PTSD-patients compared to controls after adjusting for sociodemographic and dietary factors (p =0.043). Additionally, exploratory analyses showed lower vaccenic acid (p =0.035) and eicosatrienoic acid (p =0.006), but higher erucic acid (p =0.032) in PTSD-patients. The effect of erucic acid remained after adjustment for sociodemographic factors (p =0.047); with the additional adjustment for dietary factors none of these FAs were found to be significant. LIMITATIONS: Statistical power for differences with small effect sizes was limited, and dietary assessment could be optimized. CONCLUSIONS: We found little evidence for a considerable role of FA-metabolism in PTSD. Apart from lower DHA after adjusting for confounders, no differences were observed in the hypothesized long-chained polyunsaturated FA-concentrations. Additionally, we found few alterations in the long-chained monounsaturated FAs, which may be explained by dietary factors. Nevertheless, the observed small effect sizes and limited extent of the alterations emphasize the importance of further investigating the assumed role of FA-metabolism and its underlying mechanisms in PTSD, before implementing further FA-supplementation studies.

Vulnerability for new episodes in recurrent major depressive disorder: protocol for the longitudinal DELTA-neuroimaging cohort study.

INTRODUCTION: Major depressive disorder (MDD) is widely prevalent and severely disabling, mainly due to its recurrent nature. A better understanding of the mechanisms underlying MDD-recurrence may help to identify high-risk patients and to improve the preventive treatment they need. MDD-recurrence has been considered from various levels of perspective including symptomatology, affective neuropsychology, brain circuitry and endocrinology/metabolism. However, MDD-recurrence understanding is limited, because these perspectives have been studied mainly in isolation, cross-sectionally in depressed patients. Therefore, we aim at improving MDD-recurrence understanding by studying these four selected perspectives in combination and prospectively during remission. METHODS AND ANALYSIS: In a cohort design, we will include 60 remitted, unipolar, unmedicated, recurrent MDD-participants (35-65 years) with ≥ 2 MDD-episodes. At baseline, we will compare the MDD-participants with 40 matched controls. Subsequently, we will follow-up the MDD-participants for 2.5 years while monitoring recurrences. We will invite participants with a recurrence to repeat baseline measurements, together with matched remitted MDD-participants. Measurements include questionnaires, sad mood-induction, lifestyle/diet, 3 T structural (T1-weighted and diffusion tensor imaging) and blood-oxygen-level-dependent functional MRI (fMRI) and MR-spectroscopy. fMRI focusses on resting state, reward/aversive-related learning and emotion regulation. With affective neuropsychological tasks we will test emotional processing. Moreover, we will assess endocrinology (salivary hypothalamic-pituitary-adrenal-axis cortisol and dehydroepiandrosterone-sulfate) and metabolism (metabolomics including polyunsaturated fatty acids), and store blood for, for example, inflammation analyses, genomics and proteomics. Finally, we will perform repeated momentary daily assessments using experience sampling methods at baseline. We will integrate measures to test: (1) differences between MDD-participants and controls; (2) associations of baseline measures with retro/prospective recurrence-rates; and (3) repeated measures changes during follow-up recurrence. This data set will allow us to study different predictors of recurrence in combination. ETHICS AND DISSEMINATION: The local ethics committee approved this study (AMC-METC-Nr.:11/050). We will submit results for publication in peer-reviewed journals and presentation at (inter)national scientific meetings. TRIAL REGISTRATION NUMBER: NTR3768.

Altered one-carbon metabolism in posttraumatic stress disorder.

BACKGROUND: Posttraumatic stress disorder (PTSD) is associated with increased morbidity and mortality through somatic conditions, particularly cardiovascular disease. The one-carbon metabolism in connection with the hypothalamic-pituitary-adrenal (HPA)-axis may be an important mediator of this increased cardiovascular risk. METHODS: In a mixed-gender sample of 49 PTSD patients and 45 healthy controls we therefore investigated: (1) alterations in the one-carbon metabolism as reflected in fasting plasma concentrations of homocysteine, folate, vitamins B6 and B12, and (2) associations of these one-carbon metabolites with the HPA-axis hormones cortisol, dehydroepiandrosterone (DHEA) and its sulfate (DHEA-S). RESULTS: After correction for confounders, PTSD patients had significantly elevated homocysteine (z = 2.963, p = .003) compared to controls, but normal levels of folate, vitamin B6 and B12. Comorbid depression did not explain the observed higher homocysteine levels. Patients showed increased risk for moderate hyperhomocysteinemia (OR = 7.0, χ(2) = 7.436, p = .006). Additionally, homocysteine was associated with PTSD severity (z = 2.281, p = .005). Moreover, all HPA-axis hormones were associated with folate in both patients and controls (all p's ≤ .011), while DHEA-S influenced folate in patients (z = 2.089, p = .037). LIMITATIONS: Our clinical sample is relatively small and therefore small-sized effects may have remained undetected. CONCLUSIONS: Our study indicates that: (1) the one-carbon metabolism is altered in PTSD patients, (2) earlier findings of higher homocysteine in male PTSD patients are generalized to female patients, (3) homocysteine is negatively associated with PTSD severity, and (4) HPA-axis alterations are associated with the one-carbon metabolism. Longitudinal studies are needed to determine whether elevated homocysteine levels reflect preexisting risk factors and/or consequences of psychological trauma.

Erythrocyte fatty acid profiles and plasma homocysteine, folate and vitamin B6 and B12 in recurrent depression: Implications for co-morbidity with cardiovascular disease.

Oxidative stress induced interactions between fatty acid (FA) and one-carbon metabolism may be involved in co-occurrence of major depressive disorder (MDD) and cardiovascular disease (CVD), which have been scarcely studied together. In 137 recurrent MDD-patients vs. 73 age- and sex-matched healthy controls, we simultaneously measured key components of one-carbon metabolism in plasma (homocysteine, folate, vitamins B6 and B12), and of FA-metabolism in red blood cell membranes [main polyunsaturated fatty acids (PUFAs) eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and arachidonic acid (AA) and structural FA-indices (chain length, unsaturation, peroxidation)]. Results show significant positive associations of folate with EPA, DHA, and the peroxidation index, which were similar in patients and controls. After correction for confounders, these associations were lost except for EPA. Associations between B-vitamins and FA-parameters were non-significant, but also similar in patients and controls. Homocysteine and DHA were significantly less negatively associated in patients than in controls. In conclusion, these data indicate similarities but also differences in associations between parameters of one-carbon and FA-metabolism in recurrent MDD patients vs. controls, which may reflect differences in handling of oxidative stress. Further research should test the consequences of these differences, particularly the premature development of CVD in MDD.

Fatty acid metabolism and its longitudinal relationship with the hypothalamic-pituitary-adrenal axis in major depression: Associations with prospective antidepressant response.

BACKGROUND: Metabolism of dietary fatty acids (FAs), and its relationship with the hypothalamic-pituitary-adrenal (HPA)-axis, have been found to be altered in major depressive disorder (MDD). Moreover, indications exist that these factors are associated with antidepressant-response. If we better understand these associations, we might identify novel targets for add-on therapy to increase antidepressant-response, and/or early indicators to improve response prediction. OBJECTIVE: To determine whether alterations in FA-metabolism, and their relationship with the HPA-axis, are associated with prospective response to the antidepressant paroxetine in MDD. DESIGN: We first compared 70 initially unmedicated MDD-patients with 51 age- and gender-matched controls at study-entry, regarding salivary cortisol and erythrocyte membrane FAs [omega-3 docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), FA-chain length, -unsaturation and -peroxidizability]. Subsequently, we treated patients with 6 weeks 20mg/day selective serotonin reuptake inhibitor paroxetine. After 6 weeks, we continued this treatment in responders (i.e. showing ≥50% decrease in Hamilton depression rating scale-score), and randomized non-responders to a 6-week, double-blind, placebo-controlled dose-escalation up to 50mg/day. We repeated cortisol and FA-measures in patients after 6 and 12 weeks. RESULTS: Compared to controls, patients showed higher FA-chain length, FA-unsaturation and FA-peroxidation, and more negative relationships of FA-unsaturation and FA-peroxidation with cortisol. Moreover, these negative relationships were associated with paroxetine nonresponse. Nonresponse was also associated with low DHA, which was related to low fatty fish intake. Furthermore, early responders showed initial low FA-chain length, FA-peroxidation and EPA that increased during the study, while non-responders exhibited opposite patterns. CONCLUSIONS: FA-metabolism alterations, and their relationship with cortisol, are associated with prospective paroxetine response in MDD, and may therefore form an early indicator of treatment effectiveness. Moreover, dietary fatty fish intake may improve antidepressant response through an effect on FA-metabolism.

Elevated salivary dehydroepiandrosterone-sulfate but normal cortisol levels in medicated depressed patients: preliminary findings.

Major depression is often associated with dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. In contrast to cortisol, dehydroepiandrosterone-sulfate (DHEA-S) has been less extensively studied in depressed patients. This study examined salivary morning and evening levels of cortisol and DHEA-S in 13 medicated, unipolar, non-psychotic depressed patients and 13 healthy volunteers. Diurnal declines in cortisol and DHEA-S levels were found in both depressed and control groups. In patients compared with controls, DHEA-S was significantly elevated, in conjunction with normal cortisol levels. Based on DHEA-S at 22:00 h only, 77% of the subjects were correctly classified in a discriminant analysis as depressed or control. When simultaneously entered in a multiple regression analysis, DHEA-S (morning and evening) and cortisol (evening only) predicted symptom severity in depressed patients. These preliminary results suggest that DHEA-S may be a more sensitive indicator of depression and symptom severity than cortisol in medicated but still clinically depressed patients.

Relationship between the hypothalamic-pituitary-adrenal-axis and fatty acid metabolism in recurrent depression.

Alterations in hypothalamic-pituitary-adrenal (HPA)-axis activity and fatty acid (FA)-metabolism have been observed in (recurrent) major depressive disorder (MDD). Through the pathophysiological roles of FAs in the brain and cardiovascular system, a hypothesized relationship between HPA-axis activity and FA-metabolism could form a possible missing link accounting for the association of HPA-axis hyperactivity with recurrence and cardiovascular disease in MDD. In 137 recurrent MDD-patients and 73 age- and sex-matched controls, we therefore investigated associations between salivary cortisol (morning and evening) and the following indicators of FA-metabolism measured in the red blood cell membrane: (I) three main FAs [eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and arachidonic acid (AA)], and (II) structural FA indices (unsaturation, chain length, peroxidation) calculated from concentrations of 29 FAs to delineate overall FA-characteristics. In addition, we compared these associations in patients with those in controls. In patients, evening cortisol concentrations were significantly negatively associated with DHA (B=-1.358; SE=0.499; t=-2.72; p=.006), the unsaturation index (B=-0.021; SE=0.009; t=-2.42; p=.018), chain length index (B=-0.060; SE=0.025; t=-2.41; p=.019), and peroxidation index (B=-0.029; SE=0.012; t=-2.48; p=.015). The relations between cortisol and the latter three variables were significantly negative in patients relative to controls. Significance remained after correction for confounders. Our results suggest a relationship between HPA-axis activity and FA-metabolism in recurrent MDD. Future randomized experimental intervention studies using clinical outcome measures could help to further elucidate the suggested effects of hypercortisolemia in the brain and cardiovascular system in recurrent MDD.

Ala54Thr fatty acid-binding protein 2 (FABP2) polymorphism in recurrent depression: associations with fatty acid concentrations and waist circumference.

BACKGROUND: Fatty acid (FA)-alterations may mediate the mutual association between Major Depressive Disorder (MDD) and cardiovascular disease (CVD). However, etiology of observed FA-alterations in MDD and CVD remains largely unclear. An interesting candidate may be a mutation in the fatty acid-binding protein 2 (FABP2)-gene, because it regulates dietary FA-uptake. Therefore, we aimed to test the hypotheses that in MDD-patients the FABP2 Ala54Thr-polymorphism would be (I) more prevalent than in sex- and age-matched controls, (II) associated with observed alterations in FA-metabolism, and (III) associated with CVD-risk factor waist circumference. METHODS: We measured concentrations of 29 different erythrocyte FAs, FABP2-genotype, and waist circumference in recurrent MDD-patients and matched never-depressed controls. RESULTS: FABP2-genotype distribution did not significantly differ between the 137 MDD-patients and 73 matched controls. However, patients with the Ala54Thr-polymorphism had (I) higher concentrations of especially eicosadienoic acid (C20:2ω6; P=.009) and other 20-carbon FAs, and associated (II) lower waist circumference (P=.019). In addition, FABP2-genotype effects on waist circumference in patients seemed (I) mediated by its effect on C20:2ω6, and (II) different from controls. CONCLUSIONS: Although Ala54Thr-polymorphism distribution was not associated with recurrent MDD, our results indicate that FABP2 may play a role in the explanation of observed FA-alterations in MDD. For Ala54Thr-polymorphism patients, potentially adaptive conversion of increased bioavailable dietary precursors into eicosadienoic acid instead of arachidonic acid might be related to a low waist circumference. Because this is the first investigation of these associations, replication is warranted, preferably by nutrigenetic studies applying lipidomics and detailed dietary assessment.

Sustained medically unexplained physical symptoms in euthymic patients with recurrent depression: predictive value for recurrence and associations with omega 3- and 6 fatty acids and 5-HTTLPR?

BACKGROUND: Identification of potentially modifiable risk factors for recurrence in recurrent depression could provide opportunities to improve preventive interventions. In this study we aimed to examine the predictive value of medically unexplained physical symptoms (MUPS) on time to recurrence in recurrent depression. Additionally, to elucidate pathophysiological mechanisms that could explain the relations between MUPS and depression, we investigate the association between a sustained high level of MUPS, and (I) omega (ω)-3 and -6 fatty acid (FA)-status and (II) functional polymorphisms in the promoter region of the serotonin transporter gene (5-HTTLPR). METHODS: Based on three Physical Symptom Checklist (PCS) scores over 12 months, we defined two groups of remitted recurrently depressed patients: 41 patients with a sustained high number of MUPS and 34 patients with a sustained low number or no MUPS. Patients were followed-up for 3.5 years while recurrence of their depression was monitored. In addition, we analyzed patients' erythrocyte's FA-profiles and triallelically genotyped their 5-HTTLPR. RESULTS: A sustained high level of MUPS predicted consecutive depression recurrence over 3.5 years (adjusted relative risk 2.8). FA-status and distribution of 5-HTTLPR variant frequencies did not differ between patients with sustained high compared to low/absent MUPS-levels. LIMITATIONS: Our sample was relatively small. CONCLUSION: Remitted recurrently depressed patients with sustained MUPS have a considerably increased risk of recurrence. Having sustained MUPS is not associated with either erythrocyte ω-3 or -6 FA-levels or 5-HTTLPR polymorphism. Recognition and reducing MUPS in an early state could prevent a (depressive) relapse.

Biological effects of add-on eicosapentaenoic acid supplementation in diabetes mellitus and co-morbid depression: a randomized controlled trial.

BACKGROUND: Eicosapentaenoic acid (EPA) may reduce increased risks for (cardiovascular) morbidity and mortality in patients with diabetes mellitus (DM) and comorbid major depressive depression (MDD). Yet, effects of EPA-supplementation on biological risk factors for adverse outcomes have not been studied in DM-patients with MDD. METHODS: We performed a randomized, double-blind trial (n = 25) comparing add-on ethyl-EPA-supplementation to placebo on (I) oxidative stress, (II) inflammatory, (III) hypothalamic-pituitary-adrenal (HPA)-axis, (IV) one-carbon-cycle, (V) fatty acid metabolism and (VI) lipoprotein parameters during 12-weeks' follow-up. RESULTS: Besides increases in supplemented α-tocopherol [estimate (95% CI); 3.62 (1.14-6.11) µmol/l; p = 0.006] and plasma and erythrocyte EPA, the intervention did not influence other oxidative stress, inflammatory or one-carbon-cycle parameters compared to placebo. HPA-axis reactivity significantly decreased in the EPA-group (N = 12) [AUC(i): -121.93 (-240.20--3.47) min×nmol/l; p = 0.045], not in the placebo-group (N = 12). Furthermore, EPA-supplementation increased erythrocyte and plasma docosapentaenoic acid, and decreased plasma arachidonic acid (AA) concentrations [-1.61 (-3.10--0.11) %; p = 0.036]. Finally, EPA had a multivariate influence on lipoprotein concentrations (p = 0.030), reflected by relative increases in high density lipoprotein [HDL; 0.30 (0.02-0.58) mmol/l; p = 0.039] and total cholesterol concentrations [1.01 (0.29-1.72) mmol/l; p = 0.008]. CONCLUSION: Overall, add-on EPA-supplementation had limited effects on biological risk factors for adverse outcome in this sample of DM-patients with comorbid MDD. Besides increases in concentrations of supplemented α-tocopherol and EPA, AA decreased, and inconclusive effects on HPA-axis (re)activity and lipoprotein concentrations were observed. Therefore, further studies on the alleged beneficial effects of EPA-supplementation on biological risk factors for adverse outcome in DM-patients with comorbid MDD seem warranted, preferably using clinical outcomes such as (cardiovascular) DM-complications.

Lower cortisol levels predict recurrence in remitted patients with recurrent depression: a 5.5 year prospective study.

Major Depressive Disorder (MDD) is a highly recurrent disease. Stress-responsive system dysfunction seems to persist after remission. In patients with more chronic and recurrent depressive episodes, state related HPA-axis dysregulation might be a risk factor for prospective recurrence. This study examines the predictive effect of cortisol on consecutive episodes in remitted recurrently depressed patients. Cortisol was assessed in saliva in remitted recurrently depressed patients (n=55) that were followed up prospectively for 5.5 years after remission. Recurrence was assessed using a well validated structured interview. Lower mean morning cortisol levels predicted earlier time to recurrence over 5.5 year after correction for residual symptoms (p=0.015). Residual symptoms and childhood trauma slightly confounded the association between cortisol and recurrence. Lower cortisol levels were associated with having experienced traumatic childhood life events (42.3% in patients with lower cortisol versus 19.2% in patients with higher cortisol). Our study provides further support for the predictive role over 5.5 year of HPA axis dysregulation, i.e. lower morning cortisol levels, of recurrence in recurrently depressed patients. Childhood trauma is associated to having lower cortisol levels. It might have long term consequences for dealing with stress and the HPA-axis.