Gilles Bertschy

Decreased serum brain-derived neurotrophic factor levels in major depressed patients.

Recent findings with animal models have suggested a possible role for brain-derived neurotrophic factor (BDNF) in depression. We have therefore hypothesized that depression could be characterized by low levels of serum BDNF. Major depressed patients (15F + 15M) diagnosed according to DSM-IV criteria and healthy controls (15F + 15M) participated in the study. Serum BDNF was assayed with the ELISA method and the severity of depression was evaluated with Montgomery-Asberg-Depression Rating Scale (MADRS). BDNF levels were significantly lower in patients than in controls: 22.6 +/- 3 and 26.5 +/- 7 ng/ml (t-test = 2.7; d.f. = 58; P < 0.01). They were negatively correlated to the MADRS scores (r = -0.55; P < 0.02). Female patients were more depressed and released less BDNF than men. Analysis of covariance (MADRS and gender as independent variable vs. BDNF as dependent variable) indicated that depression severity mainly accounted for the negative correlation. These results suggest that major depression is characterized by low serum BDNF levels and support the hypothesis of neurotrophic factor involvement in affective disorders.

Low brain-derived neurotrophic factor (BDNF) levels in serum of depressed patients probably results from lowered platelet BDNF release unrelated to platelet reactivity.

BACKGROUND Recent reports have suggested a role for brain-derived neurotrophic factor (BDNF) in psychiatric disorders. Decreased serum BDNF levels have been reported in major depression, but the cause of this decrease has not yet been investigated. The goal of this study was to assess blood BDNF and a platelet activation index, PF4. METHODS Forty-three drug-free patients (27 female, 16 male) diagnosed with major depression and 35 healthy control subjects (18 female, 17 male) were assessed for plasma, serum, and blood BDNF content. Brain-derived neurotrophic factor and PF4 were assayed with enzyme-linked immunosorbent assay methods, and severity of depression was evaluated with the Montgomery-Asberg Depression Rating Scale. RESULTS Serum and plasma BDNF levels were decreased in depressed patients compared with control subjects. In whole blood, BDNF levels were unaltered in the depressed subjects compared with control subjects. The serum/blood BDNF ratio was lower in patients with major depression. Increased plasma but not serum PF4 levels were observed in depressed subjects compared with control subjects. CONCLUSIONS Our results suggest that an alteration of serum or plasma BDNF is not due to the change in blood BDNF but rather is probably related to mechanisms of BDNF release. Secretion of BDNF seems to be independent of platelet reactivity; other mechanisms are therefore probably involved and need to be elucidated.

Partial normalization of serum brain-derived neurotrophic factor in remitted patients after a major depressive episode.

We had previously reported decreased serum brain-derived neurotrophic factor (BDNF) levels in depressed patients. In the present study, we tested the hypothesis that antidepressant treatment would normalize serum BDNF levels, at least in a subgroup of patients. Major depressed patients (15 females and 11 males) diagnosed according to DSM-IV criteria and healthy controls (13 females and 13 males) participated in this study. Serum BDNF was assayed with the ELISA method for depressed and remitted patients and the severity of depression was evaluated with the Montgomery-Asberg Depression Rating Scale. An analysis of variance showed that treatment had an effect [F(1, 24) = 4.46, p = 0.045] on the normalization of serum BDNF levels. We also found a correlation between the severity of depression (r = 0.51, p = 0.008), the pretreatment BDNF levels (r = 0.62, p = 0.001) and the difference in serum BDNF levels after antidepressant treatment. These results suggest that antidepressant treatment has a positive effect on serum BDNF levels and support the hypothesis of neurotrophic factor involvement in affective disorders.

Depression relapse prophylaxis with Mindfulness-Based Cognitive Therapy: replication and extension in the Swiss health care system.

Background Mindfulness-Based Cognitive Therapy (MBCT) is a group intervention that integrates elements of Cognitive Behavioural Therapy (CBT) with components of mindfulness training to prevent depressive relapse. The efficacy of MBCT compared to Treatment As Usual (TAU), shown in two randomized controlled trials indicates a significant decrease in 1-year relapse rates for patients with at least three past depressive episodes. The present study is the first independent replication trial comparing MBCT + TAU to TAU alone across both language and culture (Swiss health care system). Methods Sixty unmedicated patients in remission from recurrent depression (≥ 3 episodes) were randomly assigned to MBCT + TAU or TAU. Relapse rate and time to relapse were measured over a 60 week observation period. The frequency of mindfulness practices during the study was also evaluated. Results Over a 14-month prospective follow-up period, time to relapse was significantly longer with MBCT + TAU than TAU alone (median 204 and 69 days, respectively), although both groups relapsed at similar rates. Analyses of homework adherence revealed that following treatment termination, the frequency of brief and informal mindfulness practice remained unchanged over 14 months, whereas the use of longer formal meditation decreased over time. Limitations Relapse monitoring was 14 months in duration and prospective reporting of mindfulness practice would have yielded more precise frequency estimates compared to the retrospective methods we utilized. Conclusions Further studies are required to determine which patient characteristics, beyond the number of past depressive episodes, may predict differential benefits from this therapeutic approach.

CYP2D6 and ABCB1 Genetic Variability : Influence on Paroxetine Plasma Level and Therapeutic Response

Paroxetine is characterized by large interindividual pharmacokinetic variability and heterogeneous response patterns. The present study investigates plasma concentration and therapeutic response to paroxetine for the influence of age, sex, and CYP2D6 and ABCB1 polymorphisms, the latter gene encoding for the permeability glycoprotein. Genotyping for CYP2D6 (alleles *3, *4, *5, *6, and *xN) and ABCB1 polymorphisms (61A>G, 2677G>T, and 3435C>T) was performed in 71 depressed patients who started 20 mg paroxetine per day and had plasma concentration measured after 2 weeks at a fixed dose. A dose increase to 30 mg per day was possible starting at week 2. For 63 patients, severity of depression (Montgomery-Åsberg Depression Rating Scale) was assessed at weeks 0, 2, and 4 and every 2 weeks thereafter until discontinuation. Persistent response was defined as 50% improvement from baseline score sustained from the first occurrence to study end point. Paroxetine concentration significantly differed between female and male patients (median, 28 versus 16 ng/mL; P = 0.001). Differences were not significant between CYP2D6 heterozygous and homozygous extensive metabolizers (median, 27 versus 22 ng/mL; P = 0.074) and between ABCB1 genotypes (P > 0.10). When considered in a multivariate model, CYP2D6 heterozygous extensive metabolizer phenotype (P = 0.062) and female gender (P = 0.001) predicted 1.3-fold and 1.6-fold higher paroxetine concentration, respectively, but fraction of explained variability was modest (21%). Frequency of persistent response at study end point did not significantly differ according to CYP2D6 heterozygous extensive metabolizer versus homozygous extensive metabolizer phenotype and ABCB1 polymorphisms in univariate analyses. After adjusting for age, sex, paroxetine concentration at week 2, and daily dose at study end point, ABCB1 genotype contributed to improving the model significantly for 61A>G (P = 0.043), but not 2677G>T (P = 0.068) and 3435C>T (P = 0.11). None of two poor metabolizers and four ultrarapid metabolizers showed persistent response to paroxetine. The hypothesis that permeability glycoprotein activity might be a relevant predictor of therapeutic response deserves to be further investigated while controlling for pharmacokinetic variability.

Fluvoxamine and fluoxetine do not interact in the same way with the metabolism of the enantiomers of methadone.

Six and seven addicts treated with racemic methadone (MTD) were comedicated with fluvoxamine (FLV) and fluoxetine (FLX), respectively. The plasma concentrations of both (R)- (the active enantiomer) and (S)-MTD were increased by FLV, whereas only (R)-MTD concentrations were increased by the addition of FLX. This suggests that cytochrome P450IID6 (CYP2D6), an enzyme that is strongly inhibited by FLX, preferentially metabolizes (R)-MTD, whereas CYP1A2, which is strongly inhibited by FLV, metabolizes both enantiomers. The choice of a selective serotonin reuptake inhibitor in depressive addicted patients treated with MTD and the possible use of FLX or FLV to potentiate the effects of MTD in some cases of therapeutic failure are discussed.

Wearable monitoring for mood recognition in bipolar disorder based on history-dependent long-term heart rate variability analysis.

Current clinical practice in diagnosing patients affected by psychiatric disorders such as bipolar disorder is based only on verbal interviews and scores from specific questionnaires, and no reliable and objective psycho-physiological markers are taken into account. In this paper, we propose to use a wearable system based on a comfortable t-shirt with integrated fabric electrodes and sensors able to acquire electrocardiogram, respirogram, and body posture information in order to detect a pattern of objective physiological parameters to support diagnosis. Moreover, we implemented a novel ad hoc methodology of advanced biosignal processing able to effectively recognize four possible clinical mood states in bipolar patients (i.e., depression, mixed state, hypomania, and euthymia) continuously monitored up to 18 h, using heart rate variability information exclusively. Mood assessment is intended as an intrasubject evaluation in which the patients states are modeled as a Markov chain, i.e., in the time domain, each mood state refers to the previous one. As validation, eight bipolar patients were monitored collecting and analyzing more than 400 h of autonomic and cardiovascular activity. Experimental results demonstrate that our novel concept of personalized and pervasive monitoring constitutes a viable and robust clinical decision support system for bipolar disorders recognizing mood states with a total classification accuracy up to 95.81%.

Probable metabolic interaction between methadone and fluvoxamine in addict patients

Summary We report five cases where fluvoxamine (FLVX) was added to maintenance treatment with methadone (MTD) in addict patients with affective disorders. In view of the implication of FLVX in several metabolic drug interactions, MTD plasma levels were measured before and after treatment with FLVX. A slight increase (∼20% of the MTD plasma level/dose ratio) occurred in two cases. In the remaining three patients, the interaction was more pronounced (40–100% increase of the MTD plasma level/dose ratio), with clinical manifestations of opiate withdrawal after stopping FLVX therapy in one case. Caution is needed when starting or stopping treatment with FLVX in patients receiving maintenance treatment with methadone.

No human tryptophan hydroxylase-2 gene R441H mutation in a large cohort of psychiatric patients and control subjects

BACKGROUND It was recently reported that a rare functional variant, R441H, in the human tryptophan hydroxylase-2 gene (hTPH2) could represent an important risk factor for unipolar major depression (UP) since it was originally found in 10% of UP patients (vs. 1.4% in control subjects). METHODS We explored the occurrence of this variation in patients with affective disorders (n = 646), autism spectrum disorders (n = 224), and obsessive-compulsive disorder (OCD) (n = 201); in healthy volunteers with no psychiatric disorders (n = 246); and in an ethnic panel of control individuals from North Africa, Sub-Saharan Africa, India, China, and Sweden (n = 277). RESULTS Surprisingly, we did not observe the R441H variant in any of the individuals screened (3188 independent chromosomes). CONCLUSIONS Our results do not confirm the role of the R441H mutation of the hTPH2 gene in the susceptibility to UP. The absence of the variant from a large cohort of psychiatric patients and control subjects suggests that the findings reported in the original study could be due to a genotyping error or to stratification of the initial population reported. Additional data by other groups should contribute to the clarification of the discrepancy between our results and those previous published.

Complex interaction of circadian and non-circadian effects of light on mood: Shedding new light on an old story

In addition to its role in vision, light exerts strong effects on behavior. Its powerful role in the modulation of mood is well established, yet remains poorly understood. Much research has focused on the effects of light on circadian rhythms and subsequent interaction with alertness and depression. The recent discovery of a third photoreceptor, melanopsin, expressed in a subset of retinal ganglion cells, allows major improvement of our understanding of how photic information is processed. Light affects behavior in two ways, either indirectly through the circadian timing system, or directly through mechanisms that are independent of the circadian system. These latter effects have barely been studied in regard to mood, but recent investigations on the direct effects of light on sleep and alertness suggest additional pathways through which light could influence mood. Based on our recent findings, we suggest that light, via melanopsin, may exert its antidepressant effect through a modulation of the homeostatic process of sleep. Further research is needed to understand how these mechanisms interplay and how they contribute to the photic regulation of mood. Such research could improve therapeutic management of affective disorders and influence the management of societal lighting conditions.