Roel J. T. Mocking

Plasma and erythrocyte fatty acid patterns in patients with recurrent depression: a matched case-control study.

Background The polyunsaturated fatty acid (PUFA) composition of (nerve) cell membranes may be involved in the pathophysiology of depression. Studies so far, focussed mainly on omega-3 and omega-6 PUFAs. In the present study, saturated fatty acids (SFAs), monounsaturated fatty acids (MUFAs) and PUFAs of the omega-3, -6 and -9 series in plasma and erythrocytes of patients with recurrent major depressive disorder (MDD-R) were compared with controls. Methodology and Principal Findings We carried out a case-control study. The sample consisted of 137 patients with MDD-R and 65 matched non-depressed controls. In plasma and erythrocytes of patients with MDD-R the concentrations of most of the SFAs and MUFAs, and additionally erythrocyte PUFAs, all with a chain length >20 carbon (C) atoms, were significantly lower than in the controls. In contrast, the concentrations of most of the shorter chain members (≤18C) of the SFAs and MUFAs were significantly higher in the patients. Estimated activities of several elongases in plasma of patients were significantly altered, whereas delta-9 desaturase activity for C14∶0 and C18∶0 was significantly higher. Conclusions/Significance The fatty acid status of patients with MDD-R not only differs with regard to omega-3 and omega-6 PUFAs, but also concerns other fatty acids. These alterations may be due to: differences in diet, changes in synthesizing enzyme activities, higher levels of chronic (oxidative) stress but may also result from adaptive strategies by providing protection against enhanced oxidative stress and production of free radicals.

Meta-analysis and meta-regression of omega-3 polyunsaturated fatty acid supplementation for major depressive disorder.

Omega-3 polyunsaturated fatty acid (PUFA) supplementation has been proposed as (adjuvant) treatment for major depressive disorder (MDD). In the present meta-analysis, we pooled randomized placebo-controlled trials assessing the effects of omega-3 PUFA supplementation on depressive symptoms in MDD. Moreover, we performed meta-regression to test whether supplementation effects depended on eicosapentaenoic acid (EPA) or docosahexaenoic acid dose, their ratio, study duration, participants’ age, percentage antidepressant users, baseline MDD symptom severity, publication year and study quality. To limit heterogeneity, we only included studies in adult patients with MDD assessed using standardized clinical interviews, and excluded studies that specifically studied perinatal/perimenopausal or comorbid MDD. Our PubMED/EMBASE search resulted in 1955 articles, from which we included 13 studies providing 1233 participants. After taking potential publication bias into account, meta-analysis showed an overall beneficial effect of omega-3 PUFAs on depressive symptoms in MDD (standardized mean difference=0.398 (0.114–0.682), P=0.006, random-effects model). As an explanation for significant heterogeneity (I2=73.36, P<0.001), meta-regression showed that higher EPA dose (β=0.00037 (0.00009–0.00065), P=0.009), higher percentage antidepressant users (β=0.0058 (0.00017–0.01144), P=0.044) and earlier publication year (β=−0.0735 (−0.143 to 0.004), P=0.04) were significantly associated with better outcome for PUFA supplementation. Additional sensitivity analyses were performed. In conclusion, present meta-analysis suggested a beneficial overall effect of omega-3 PUFA supplementation in MDD patients, especially for higher doses of EPA and in participants taking antidepressants. Future precision medicine trials should establish whether possible interactions between EPA and antidepressants could provide targets to improve antidepressant response and its prediction. Furthermore, potential long-term biochemical side effects of high-dosed add-on EPA supplementation should be carefully monitored.

Effects of oxidative stress on fatty acid- and one-carbon-metabolism in psychiatric and cardiovascular disease comorbidity

Cardiovascular disease (CVD) is the leading cause of death in severe psychiatric disorders (depression, schizophrenia). Here, we provide evidence of how the effects of oxidative stress on fatty acid (FA) and one‐carbon (1‐C) cycle metabolism, which may initially represent adaptive responses, might underlie comorbidity between CVD and psychiatric disorders.

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.

Statistical methodological issues in handling of fatty acid data: percentage or concentration, imputation and indices.

Basic aspects in the handling of fatty acid-data have remained largely underexposed. Of these, we aimed to address three statistical methodological issues, by quantitatively exemplifying their imminent confounding impact on analytical outcomes: (1) presenting results as relative percentages or absolute concentrations, (2) handling of missing/non-detectable values, and (3) using structural indices for data-reduction. Therefore, we reanalyzed an example dataset containing erythrocyte fatty acid-concentrations of 137 recurrently depressed patients and 73 controls. First, correlations between data presented as percentages and concentrations varied for different fatty acids, depending on their correlation with the total fatty acid-concentration. Second, multiple imputation of non-detects resulted in differences in significance compared to zero-substitution or omission of non-detects. Third, patients’ chain length-, unsaturation-, and peroxidation-indices were significantly lower compared to controls, which corresponded with patterns interpreted from individual fatty acid tests. In conclusion, results from our example dataset show that statistical methodological choices can have a significant influence on outcomes of fatty acid analysis, which emphasizes the relevance of: (1) hypothesis-based fatty acid-presentation (percentages or concentrations), (2) multiple imputation, preventing bias introduced by non-detects; and (3) the possibility of using (structural) indices, to delineate fatty acid-patterns thereby preventing multiple testing.

Interaction between the MTHFR C677T polymorphism and traumatic childhood events predicts depression

Childhood trauma is associated with the onset and recurrence of major depressive disorder (MDD). The thermolabile T variant of the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism (rs1801133) is associated with a limited (oxidative) stress defense. Therefore, C677T MTHFR could be a potential predictor for depressive symptomatology and MDD recurrence in the context of traumatic stress during early life. We investigated the interaction between the C677T MTHFR variant and exposure to traumatic childhood events (TCEs) on MDD recurrence during a 5.5-year follow-up in a discovery sample of 124 patients with recurrent MDD and, in an independent replication sample, on depressive symptomatology in 665 healthy individuals from the general population. In the discovery sample, Cox regression analysis revealed a significant interaction between MTHFR genotype and TCEs on MDD recurrence (P=0.017). Over the 5.5-year follow-up period, median time to recurrence was 191 days for T-allele carrying patients who experienced TCEs (T+ and TCE+); 461 days for T− and TCE+ patients; 773 days for T+ and TCE− patients and 866 days for T− and TCE− patients. In the replication sample, a significant interaction was present between the MTHFR genotype and TCEs on depressive symptomatology (P=0.002). Our results show that the effects of TCEs on the prospectively assessed recurrence of MDD and self-reported depressive symptoms in the general population depend on the MTHFR genotype. In conclusion, T-allele carriers may be at an increased risk for depressive symptoms or MDD recurrence after exposure to childhood trauma.

State-Dependent Differences in Emotion Regulation Between Unmedicated Bipolar Disorder and Major Depressive Disorder

IMPORTANCE Major depressive disorder (MDD) and bipolar disorder (BD) are difficult to distinguish clinically during the depressed or remitted states. Both mood disorders are characterized by emotion regulation disturbances; however, little is known about emotion regulation differences between MDD and BD. Better insight into these differences would be helpful for differentiation based on disorder-specific underlying pathophysiological mechanisms. Previous studies comparing these disorders often allowed medication use, limiting generalizability and validity. Moreover, patients with MDD and BD were mostly compared during the depressed, but not the remitted, state, while state might potentially modulate differences between MDD and BD. OBJECTIVE To investigate positive and negative emotion regulation in medication-free patients with MDD and BD in 2 mood states: depressed or remitted. DESIGN, SETTING, AND PARTICIPANTS A cross-sectional study conducted from May 2009 to August 2013 comparing behavioral and functional magnetic resonance imaging emotion regulation data of 42 patients with MDD, 35 with BD, and 36 healthy control (HC) participants free of psychotropic medication recruited from several psychiatric institutions across the Netherlands. INTERVENTION A voluntary emotion regulation functional magnetic resonance imaging task using positive and negative pictures. MAIN OUTCOMES AND MEASURES Behavioral and functional magnetic resonance imaging blood oxygen level-dependent responses during emotion regulation. RESULTS In the remitted state, only patients with BD showed impaired emotion regulation (t = 3.39; P < .001; Cohen d = 0.70), irrespective of emotion type and associated with increased dorsolateral prefrontal cortex activity compared with those with MDD and healthy control participants (P = .008). In the depressed state, patients with MDD and BD differed with regard to happy vs sad emotion regulation (t = 4.19; P < .001; Cohen d = 1.66) associated with differences in rostral anterior cingulate activity (P < .001). Patients with MDD regulated sad and happy emotions poorly compared with those with BD and healthy control participants, while they demonstrated no rostral anterior cingulate difference between happy and sad emotion regulation. In contrast, patients with BD performed worse than those with MDD on sad emotion regulation but normal on happy emotion regulation, and they demonstrated significantly less rostral anterior cingulate activity while regulating happy compared with sad emotions. CONCLUSIONS AND RELEVANCE Medication-free patients with MDD vs BD appear to differ in brain activations during emotion regulation, both while depressed and in remission. These different neuropathophysiological mechanisms between MDD and BD may be useful for further development of additional diagnostic tools.

Effects of short-term varenicline administration on emotional and cognitive processing in healthy, non-smoking adults: a randomized, double-blind, study.

Varenicline is an effective and increasingly prescribed drug for smoking cessation, but has been associated with depressive symptoms and suicidal behavior. However, it remains unclear whether those changes in mood and behavior are directly related to varenicline use, or caused by smoking cessation itself or reflects depression and suicidality rates in smokers, independent of treatment. To investigate the influence of varenicline on mood and behavior independent of smoking and smoking cessation, we assessed the effects of varenicline on emotional processing (a biomarker of depressogenic effects), emotion-potentiated startle reactivity, impulsivity (linked with suicidal behavior), and cognitive performance in non-smoking subjects. We used a randomized, double-blind design, in which we administered varenicline or placebo to healthy subjects over 7 days (0.5 mg/day first 3 days, then 1 mg/day). Cognitive and emotional processing was assessed by a battery of computerized tasks and recording of emotion-potentiated startle response. A total of 41 subjects were randomized, with 38 subjects included in the analysis. The varenicline group did not differ from placebo in terms of negative biases in emotional processing or mood. However, compared with placebo, the varenicline group scored higher on working and declarative memory. In conclusion, short-term varenicline use did not influence negative biases in emotional processing or impulsivity in non-smoking subjects, thereby not supporting direct depressogenic or suicidal risk behavior-inducing effects. In contrast, varenicline may have cognitive-enhancing effects.

Therapygenetics: the 5HTTLPR as a biomarker for response to psychological therapy?

Psychiatric illnesses are under polygenic influence and are associated with interactions between genetic variants and environmental exposures.1 Gene–environment interactions might not only predict onset of disease, but genetic biomarkers might also help the clinician to select the optimal treatment for patients.2 However, there is a lack of studies on therapygenetics for psychological treatment of psychiatric diseases.

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.