Romain Colle

Treating major depressive episodes with antidepressants can induce or worsen metabolic syndrome: results of the METADAP cohort

Recent data (1–4) show a high comorbidity between major depressive disorder and metabolic syndrome (MetS) (5), a cluster of risk factors for cardiovascular diseases and type 2 diabetes including high waist circumference, high blood pressure, hypertriglyceridemia, low high-density lipoprotein (HDL) cholesterol, and high fasting plasma glucose. In a context of increasing prescription of antidepressant medication (6) and evidence of weight gain induced by antidepressants (7), the impact of antidepressant treatment on MetS has to be clarified. Indeed, there has been no prospective study of reasonable sample size and duration addressing the incidence of MetS in patients with major depressive episode treated with antidepressants. This question was addressed in the METADAP, a 6-month prospective, multicentric, real-world treatment observational cohort study of 624 patients with a diagnosis of major depressive disorder and a current major depressive episode. Data were collected from November 2009 to March 2013 in six university psychiatry departments in France. Consecutive in- or out-patients, aged 18 to 65 years, with a current major depressive episode in a context of major depressive disorder (with a minimum score of 18 at the Hamilton Depression Rating Scale-17, HDRS-17) were assessed for MetS at the start of the index antidepressant treatment (M0), and one (M1), three (M3) and six (M6) months later. All of them provided their written informed consent. Patients with psychotic symptoms, bipolar disorders, psychotic disorders, eating disorders, current substance abuse or dependence, pregnancy, organic brain syndromes or severe unstable medical conditions were not included. Patients receiving antipsychotics or mood stabilizers before inclusion and/or for 4 months or more during the last year were also excluded. Antipsychotics, mood stabilizers and stimulants were not permitted during the study, because of their metabolic effects. Benzodiazepines at the minimum effective dose and for the minimum time period and psychotherapies were allowed. The index antidepressant treatment had to be a monotherapy. The drug and its dose were left to the treating psychiatrist, using “real world” treatment options. MetS was diagnosed according to the International Diabetes Federation definition (8). Participants had to have fasted and abstained from strenuous physical activity for 8 hours before examination. Triglycerides, HDL cholesterol and fasting plasma glucose levels were assessed using routine standardized laboratory methods. Thereafter, an assistant investigator blind to the major depression assessment measured waist circumference and blood pressure. Mixed-effects multivariate models were used, because they are a well-accepted method for analyzing longitudinal clinical data in which missing or mistimed observations are present (9). All regression models included main effects for time since initiation of current antidepressant treatment, age, gender, HDRS-17 score at baseline, lifetime duration of prior major depressive disorder, lifetime duration of prior antidepressant medication, antidepressant-free period before inclusion, and current antidepressant classes. Of 689 pre-included patients, 643 were included, of whom 19 had major deviations to the protocol. Thus, 624 patients were analyzed. Six had missing data for MetS at baseline. Patients’ mean age was 45.6±13.2 years; 68.7% were women, 87.5% were inpatients at baseline. Their mean HDRS-17 score at baseline was 24.7±5.0. Their mean number of previous major depressive episodes was 1.9±2.1. The average lifetime duration of major depressive disorder before inclusion was 11.5±12.2 years. The lifetime duration of antidepressant drug treatment before inclusion was 2.3±4.1 years. Upon inclusion, 22.7% of patients were antidepressant naive. The administered antidepressant was a selective serotonin reuptake inhibitor (SSRI) in 38.9% of cases, a serotonin norepinephrine reuptake inhibitor (SNRI) in 38.3%, a tricyclic antidepressant (TCA) in 8.8%, and another one in 14.0%. The mean duration of follow-up was 4.9±4.6 months. The drop-out rate was 25.9% before M1, 21.8% between M1 and M3, and 14.3% later. The main reasons for drop-out were antidepressant change (28.4%), prescription of antipsychotics or mood stabilizers (29.4%), and lost to follow-up (20.4%). In patients without MetS at baseline (N=442, 70.8%), the incidence of MetS was 11.7% at M3 and 16.5% at M6. This increase was significant (mixed-effect multivariate logistic regression: OR=2.29, 95% CI: 1.69-3.10, p<0.0001). It was observed within both the SSRI (0% to 16.2%, p<0.001) and the SNRI group (0% to 16.1%, p=0.001). This increase was independent from other factors, such as age, lifetime duration of prior antidepressant medication, and presence of an antidepressant-free period at baseline. The number of altered components of MetS significantly increased with time (M0: 1.2±0.9, M3: 1.3±1.1, M6: 1.5±1.2; mixed-model multivariate Poisson regression: incident risk ratio, IRR=1.06, 95% CI: 1.02-1.09, p<0.0001). It was significantly higher in patients treated with SNRIs than in those treated with SSRIs (IRR=1.45, 95% CI: 1.16-1.80, p=0.001), and it was lower amongst patients who were antidepressant-free at baseline (IRR=0.81, 95% CI: 0.65-0.99, p=0.03). These effects were independent from each other, from age and gender. In patients with MetS at baseline, mixed-effect multivariate linear regressions showed significant increases over time of supine blood pressure (M0: 123.2±16.4 mmHg, M3: 124.8±13.9 mmHg, M6: 126.8±15.0 mmHg, p<0.05) and fasting plasma glucose (M0: 0.98±0.29 g/l, M3: 1.07±0.48 g/l, M6: 1.03±0.31 g/l, p<0.01), which were independent from other factors. The highlight of this study is the early and significant incidence of MetS after initiation of treatment with antidepressants. The majority of cases occurred in the first three months of treatment. A significant worsening of MetS was also observed in patients who already had the syndrome at baseline. Taken together, these results suggest that treating major depressive episodes with antidepressants can induce or worsen MetS. Specific recommendations for the prevention of MetS in patients with major depressive disorder receiving antidepressant medication are needed. Further studies assessing the underlying mechanisms of this phenomenon are warranted.

BDNF/TRKB/P75NTR polymorphisms and their consequences on antidepressant efficacy in depressed patients

We propose an extensive review of the literature about BDNF/TRKB/P75NTR polymorphisms and their consequences on antidepressant efficacy in depressed patients. Five genome-wide association studies and 30 association studies were included. Twenty seven studies focused on the Val66Met polymorphism (rs6265), the Met allele being associated with a higher antidepressant efficacy only in Asian patients. Other BDNF/TRKB/P75NTR polymorphisms (BDNF: rs7103411, rs7124442, rs908867, rs2049046, rs61888800, rs10501087, rs1491850; TRKB: rs10868223, rs11140778, rs1565445, rs1659412; P75NTR: rs2072446) were reported to be associated with antidepressant efficacy but these results were not replicated. Finally, there are 15 positive studies among 30 studies regarding BDNF/TRKB/P75NTR polymorphisms. The only SNP which benefits of at least three positive studies is the BDNF Val66Met polymorphism (rs6265). Consequently, with a lack of good and consistent studies, the clinical utility of BDNF in treatment selection is far from clear. We propose several recommendations for further studies.

Brain-derived neurotrophic factor Val66Met polymorphism and 6-month antidepressant remission in depressed Caucasian patients

BACKGROUND Whether the Brain Derived Neurotrophic Factor (BDNF) Val66Met polymorphism can predict antidepressant drug efficacy in depressed patients remains unclear, suggesting that it may depend on antidepressant classes. We assessed the impact of Val66Met polymorphism on antidepressant response and remission depending on antidepressant classes. METHODS In a 6-month prospective, real-world setting, treatment study, 345 Caucasian depressed patients requiring a new or different drug treatment with a selective serotonin reuptake inhibitor (SSRI), a serotonin and noradrenalin reuptake inhibitor (SNRI) or a tricyclic antidepressant (TCA), were genotyped and assessed for response and remission. RESULTS 231 (67%) patients were homozygous for the Val66 allele (Val/Val) and 114 (33%) were carriers of Met allele (Met). 152 (44.1%) patients were treated with SSRI, the others with SNRI/TCA. Both response and remission were explained by interactions between the Val66Met polymorphism and antidepressant drug classes (multivariate models adjusted for propensity-scores: p=0.02 and p=0.03 respectively). With SSRI, Val/Val patients had a higher response rate 3 months post-treatment than Met patients (68.1% versus 44%; adjusted-OR: 3.04, IC95% [1.05; 9.37], p=0.04). With SNRI/TCA, Val/Val patients had a lower remission rate 6 months post-treatment than Met patients (33.3% versus 60.9%, adjusted-OR: 0.27, IC95% [0.09; 0.76], p=0.02). LIMITATIONS Limited sample size. CONCLUSIONS This study argues for a personalized prescription of antidepressants in Caucasian patients with major depressive disorder, based on the BDNF Val66Met polymorphism: SSRI should be preferred for Val/Val patients and SNRI/TCA for Met patients. Further studies are required to confirm these data.

Depressed suicide attempters have smaller hippocampus than depressed patients without suicide attempts

BACKGROUND Despite known relationship between hippocampal volumes and major depressive episodes (MDE) and the increased suicidality in MDE, the links between hippocampal volumes and suicidality remain unclear in major depressive disorders (MDD). If the hippocampus could be a biomarker of suicide attempts in depression, it could be useful for prevention matters. This study assessed the association between hippocampal volumes and suicide attempts in MDD. METHODS Hippocampal volumes assessed with automatic segmentation were compared in 63 patients with MDD, with (n = 24) or without (n = 39) suicide attempts. Acute (one month) suicide attempts were studied. RESULTS Although not different in terms of socio-demographic, MDD and MDE clinical features, suicide attempters had lower total hippocampus volumes than non-attempters (4.61 (± 1.15) cm(3) vs 5.22 (± 0.99) cm(3); w = 625.5; p = 0.03), especially for acute suicide attempts (4.19 (± 0.81) cm(3) vs 5.22 (± 0.99) cm(3); w = 334; p = 0.005), even after adjustment on brain volumes, sex, age, Hamilton Depression Rating Scale (HDRS) scores and MDD duration. A ROC analysis showed that a total hippocampal volume threshold of 5.00 cm(3) had a 98.2% negative predictive value for acute suicide attempts. CONCLUSION Depressed suicide attempters have smaller hippocampus than depressed patients without suicide attempts, independently from socio-demographics and MDD characteristics. This difference is related to acute suicide attempts but neither to past suicide attempts nor to duration since the first suicide attempt, suggesting that hippocampal volume could be a suicidal state marker in MDE. Further studies are required to better understand this association.

Genetic dysfunction of serotonin 2A receptor hampers response to antidepressant drugs: A translational approach.

Pharmacological studies have yielded valuable insights into the role of the serotonin 2A (5-HT2A) receptor in major depressive disorder (MDD) and antidepressant drugs (ADs) response. However, it is still unknown whether genetic variants in the HTR2A gene affect the therapeutic outcome of ADs and the mechanism underlying the regulation of such response remains poorly described. In this context, a translational human-mouse study offers a unique opportunity to address the possibility that variations in the HTR2A gene may represent a relevant marker to predict the efficacy of ADs. In a first part of this study, we investigated in depressed patients the effect of three HTR2A single nucleotide polymorphisms (SNPs), selected for their potential functional consequences on 5-HT2A receptor (rs6313, rs6314 and rs7333412), on response and remission rates after 3 months of antidepressant treatments. We also explored the consequences of the constitutive genetic inactivation of the 5-HT2A receptor (i.e. in 5-HT2A(-/-) mice) on the activity of acute and prolonged administration of SSRIs. Our clinical data indicate that GG patients for the rs7333412 SNP were less prone to respond to ADs than AA/AG patients. In the preclinical study, we demonstrated that the 5-HT2A receptor exerts an inhibitory influence on the neuronal activity of the serotonergic system after acute administration of SSRIs. However, while the chronic administration of the SSRIs escitalopram or fluoxetine elicited a progressive increased in the firing rate of 5-HT neurons in 5-HT2A(+/+) mice, it failed to do so in 5-HT2A(-/-) mutants. These electrophysiological impairments were associated with a decreased ability of the chronic administration of fluoxetine to stimulate hippocampal plasticity and to produce antidepressant-like activities. Genetic loss of the 5-HT2A receptor compromised the activity of chronic treatment with SSRIs, making this receptor a putative marker to predict ADs response.

Pioglitazone could induce remission in major depression: a meta-analysis

Background Pioglitazone, a selective agonist of the nuclear transcription factor peroxisome proliferator-activated receptor-gamma (PPAR-γ), prescribed for the treatment of type 2 diabetes, could have antidepressant properties. However, its potential to induce remission of major depressive episodes, the optimal clinical target for an antidepressant drug, is a matter of concern. Indeed, only one out of four double-blind randomized controlled trials show higher remission rates with pioglitazone than with control treatments. Hence, the main aim of this study was to perform a meta-analysis of the efficacy of pioglitazone for the treatment of MDE, focusing on remission rates. Methods Four double-blind randomized controlled trials, comprising 161 patients with an MDE, were included in this meta-analysis. Pioglitazone was studied either alone (one study) or as add-on therapy to conventional treatments (antidepressant drugs or lithium salts). It was compared either to placebo (three studies) or to metformin (one study). Remission was defined by a Hamilton Depression Rating Scale score <8 after treatment. Results Pioglitazone could induce higher remission rates than control treatments (27% versus 10%, I2=17.3%, fixed-effect model: odds ratio [OR] =3.3, 95% confidence interval [95% CI; 1.4; 7.8], P=0.008). The OR was even higher in the subgroup of patients with major depressive disorder (n=80; 23% versus 8%, I2=0.0%; fixed-effect model: OR =5.9, 95% CI [1.6; 22.4], P=0.009) and in the subgroup of patients without metabolic comorbidities (n=84; 33% versus 10%, I2=0.0%; fixed-effect model: OR =5.1, 95% CI [1.5; 17.9], P=0.01). As compared to control treatments, results suggest six patients would need to be treated with pioglitazone in order to achieve the possibility of one more remission. Conclusion Pioglitazone, either alone or as add-on therapy to conventional treatments, could induce remission of MDE, suggesting that drugs with PPAR-γ agonist properties may be true and clinically relevant antidepressants, even in patients without metabolic comorbidities.

PPAR-γ Agonists for the Treatment of Major Depression: A Review

Introduction: Selective agonists of the nuclear transcription factor peroxisome proliferator-activated receptor-gamma (PPAR-γ) are used for the treatment of type 2 diabetes. We reviewed their efficacy and safety for the treatment of major depression and the association of their potential antidepressant effects with changes in biomarkers of metabolism and inflammation. Methods: From 8 studies, 4 open-label trials, and 4 randomized controlled trials (RCT) (3 vs. placebo and 1 vs. metformin), 448 patients with major depression were included, of which 209 patients received PPAR-γ agonists (pioglitazone or rosiglitazone) for 6-12 weeks, either alone or in add-on therapy to conventional treatments. Results: PPAR-γ agonists have antidepressant effects in the 4 open-label studies and in 3 out of 4 RCT. No major adverse event was reported. Improvement in depression scores was associated with improvement in 3 biomarkers of insulin resistance (homeostatic model assessment [HOMA-IR], oral glucose tolerance test, and fasting plasma glucose) and 1 biomarker of inflammation (interleukin-6) among 21 biomarkers studied. Conclusion: PPAR-γ agonists may have antidepressant properties, which need to be assessed in further studies of major depressive episodes.

The human plasma-metabolome: Reference values in 800 French healthy volunteers; impact of cholesterol, gender and age

Metabolomic approaches are increasingly used to identify new disease biomarkers, yet normal values of many plasma metabolites remain poorly defined. The aim of this study was to define the “normal” metabolome in healthy volunteers. We included 800 French volunteers aged between 18 and 86, equally distributed according to sex, free of any medication and considered healthy on the basis of their medical history, clinical examination and standard laboratory tests. We quantified 185 plasma metabolites, including amino acids, biogenic amines, acylcarnitines, phosphatidylcholines, sphingomyelins and hexose, using tandem mass spectrometry with the Biocrates AbsoluteIDQ p180 kit. Principal components analysis was applied to identify the main factors responsible for metabolome variability and orthogonal projection to latent structures analysis was employed to confirm the observed patterns and identify pattern-related metabolites. We established a plasma metabolite reference dataset for 144/185 metabolites. Total blood cholesterol, gender and age were identified as the principal factors explaining metabolome variability. High total blood cholesterol levels were associated with higher plasma sphingomyelins and phosphatidylcholines concentrations. Compared to women, men had higher concentrations of creatinine, branched-chain amino acids and lysophosphatidylcholines, and lower concentrations of sphingomyelins and phosphatidylcholines. Elderly healthy subjects had higher sphingomyelins and phosphatidylcholines plasma levels than young subjects. We established reference human metabolome values in a large and well-defined population of French healthy volunteers. This study provides an essential baseline for defining the “normal” metabolome and its main sources of variation.

Vortioxetine for the treatment of major depressive disorder

Vortioxetine (Brintellix®, 1-[2-(2,4-dimethylphenyl-sulfanyl)-phenyl]-piperazine) is a multimodal antidepressant targeting the 5-HT1A, 5-HT1B, 5-HT1D, 5-HT3, 5-HT7 receptors and the serotonin (5-HT) transporter (5-HTT). Vortioxetine administration induces antidepressant- and anxiolytic-like effects, and can enhance cognitive performance in rodents. Several clinical trials have reported the efficiency and a satisfactory tolerability of vortioxetine treatment in depressed patients. Remarkably, vortioxetine has a specific positive impact on cognitive symptoms in depressed patients. Overall, vortioxetine is an efficacious antidepressant drug for the treatment of patients with a major depressive episode and has a unique mechanism of action offering a new therapeutic option.

Differential Peripheral Proteomic Biosignature of Fluoxetine Response in a Mouse Model of Anxiety/Depression

The incorporation of peripheral biomarkers in the treatment of major depressive disorders (MDD) could improve the efficiency of treatments and increase remission rate. Peripheral blood mononuclear cells (PBMCs) represent an attractive biological substrate allowing the identification of a drug response signature. Using a proteomic approach with high-resolution mass spectrometry, the present study aimed to identify a biosignature of antidepressant response (fluoxetine, a Selective Serotonin Reuptake Inhibitor) in PBMCs in a mouse model of anxiety/depression. Following determination of an emotionality score, using complementary behavioral analysis of anxiety/depression across three different tests (Elevated Plus Maze, Novelty Suppressed Feeding, Splash Test), we showed that a 4-week corticosterone treatment (35 μg/ml, CORT model) in C57BL/6NTac male mice induced an anxiety/depressive-like behavior. Then, chronic fluoxetine treatment (18 mg/kg/day for 28 days in the drinking water) reduced corticosterone-induced increase in emotional behavior. However, among 46 fluoxetine-treated mice, only 30 of them presented a 50% decrease in emotionality score, defining fluoxetine responders (CORT/Flx-R). To determine a peripheral biological signature of fluoxetine response, proteomic analysis was performed from PBMCs isolated from the “most” affected corticosterone/vehicle (CORT/V), corticosterone/fluoxetine responders and non-responders (CORT/Flx-NR) animals. In comparison to CORT/V, a total of 263 proteins were differently expressed after fluoxetine exposure. Expression profile of these proteins showed a strong similarity between CORT/Flx-R and CORT/Flx-NR (R = 0.827, p < 1e-7). Direct comparison of CORT/Flx-R and CORT/Flx-NR groups revealed 100 differently expressed proteins, representing a combination of markers associated either with the maintenance of animals in a refractory state, or associated with behavioral improvement. Finally, 19 proteins showed a differential direction of expression between CORT/Flx-R and CORT/Flx-NR that drove them away from the CORT-treated profile. Among them, eight upregulated proteins (RPN2, HSPA9, NPTN, AP2B1, UQCRC2, RACK-1, TOLLIP) and one downregulated protein, TLN2, were previously associated with MDD or antidepressant drug response in the literature. Future preclinical studies will be required to validate whether proteomic changes observed in PBMCs from CORT/Flx-R mice mirror biological changes in brain tissues.