[Burnout, anxiety, insomnia and depressive symptoms among French outpatient physicians in the second wave of COVID-19: Comparison between general practitioners and specialists]. / Santé mentale des médecins libéraux français pendant la deuxième vague de COVID 19.

INTRODUCTION: The 2019 coronavirus (COVID-19) pandemic has caused a public health crisis worldwide. Concerns have been expressed about the rapid deterioration of mental health among primary care physicians among whom burnout already had a high prevalence prior to the pandemic. However, there is little data on private doctors during the pandemic. France experienced a second wave with a second lockdown. We aimed to assess and compare physicians' burnout, anxiety and depression symptoms and insomnia between general practitioners (GP) and all other private specialists during the second Covid-19 wave. METHODS: We conducted an online survey of private practitioners registered on Doctolib® (n=32,655), the interface software most used by private practitioners for booking medical appointments in France. Doctors were invited by email to complete an online survey in November 2020. Inclusions were closed on 1st December. The 2nd lockdown lasted from 30th October to 15th December 2020. We used the Copenhagen Burnout Inventory (CBI) to assess burnout syndrome. A mean score of>50 in at least one subscale defined burnout. The Hospital Anxiety and Depression Scale assessed anxiety and depression symptoms. We used two cut-offs, 8 (>7) and 11 (>10), as both are validated in the ability to find cases. The Insomnia Severity Index (ISI) measures sleep-related complaints among physicians (cut-off >7). To link variations in the psychological scales to the COVID-19 pandemic, one of the items asked explicitly whether participants considered that "the COVID-19 epidemic we are currently experiencing is a source of excess stress, psychological suffering or burnout". Approval for this study was obtained from the local institutional review board of the University of Paris-Saclay, France. The questionnaires were collected anonymously. Statistical significance was tested using the chi-square test and student's t-test to compare the prevalence between GPs and other specialities. Subsequently, logistic regression models were run for statistically significant associations. RESULTS: 1992 physicians replied, a response rate of 12.8% of those who received the invitation email. Among them, 79.4% suffered from psychological distress (symptoms of anxiety or depression or burnout), of which 71.3% suffered from burnout, 26.7% from depressive symptoms, 58.9% from anxiety symptoms and 45.8% from insomnia. There was no difference in gender between GPs and specialists, but there was an age difference (P<0.001). GPs had a higher prevalence of burnout (OR=1.33 CI95 [1.09;1.63]) and took more psychotropic drugs (1.38 CI95 [1.05;1.81]). They were also more likely to perceive their stress as work-related (OR=1.50 CI95 [1.23;1.81]) or COVID-19-related (OR=1.43 CI95 [1.16;1.77]). CONCLUSION: Our study is the first to assess the mental health of private practitioners in the second wave in association with COVID-19 stress. Firstly, GPs who provide primary care have a significantly higher burnout rate than other doctors. Secondly, COVID-19 stress is associated with more significant psychological distress. Thirdly, almost 80% of the private doctors surveyed suffer from psychological pain, and 71% suffer from burnout. This study has strengths and limitations. Firstly, this study assesses mental health and stress related to its COVID-19 association. Second, this is the largest population of private physicians during the COVID-19 pandemic. The low response rate is the main limit of this study. The alarming rates of psychological distress among private doctors and, in particular, GPs should lead to intervention to help doctors reduce stress, burnout and other mental disorders. This study gives a picture of the situation during the second wave and the lock-in, and we need to be cautious with the next waves.

The ERICH3 rs11580409 polymorphism is associated with 6-month antidepressant response in depressed patients.

INTRODUCTION: Major Depressive Disorder (MDD) is the current leading cause of disability worldwide. The effect of its main treatment option, antidepressant drugs (AD), is influenced by genetic and metabolic factors. The ERICH3 rs11580409(A > C) genetic polymorphism was identified as a factor influencing serotonin (5HT) levels in a pharmacometabolomics-informed genome-wide association study. It was also associated with response following AD treatment in several cohorts of depressed patients. OBJECTIVE: Our aim was to analyze the association of the ERICH3 rs11580409(A > C) genetic polymorphism with response following AD treatment and plasma 5HT levels in METADAP, a cohort of 6-month AD-treated depressed patients. METHODS: Clinical (n = 377) and metabolic (n = 150) data were obtained at baseline and after 3 (M3) and 6 months (M6) of treatment. Linear mixed-effects models and generalized logistic mixed-effects models were used to assess the association of the rs11580409 polymorphism with the Hamilton Depression Rating Scale (HDRS) score, response and remission rates, and plasma 5HT levels. RESULTS: The interaction between the ERICH3 rs11580409 polymorphism and time was an overall significant factor in mixed-effects models of the HDRS score (F3,870 = 3.35, P = 0.019). At M6, CC homozygotes had a significantly lower HDRS score compared to A allele carriers (coefficient = -3.50, 95%CI [-6.00--0.99], P = 0.019). No association between rs11580409 and 5HT levels was observed. CONCLUSION: Our results suggest an association of rs11580409 with response following long-term AD treatment. The rs11580409 genetic polymorphism may be a useful biomarker for treatment response in major depression.

Psychological distress among outpatient physicians in private practice linked to COVID-19 and related mental health during the second lockdown.

BACKGROUND: Outpatient physicians in private practice, as inpatient physicians, are on the frontline of the COVID-19 pandemic. Mental-health consequences of the pandemic on hospital staff have been published, but the psychological distress among outpatient physicians in private practice due to COVID-19 has never been specifically assessed. METHODS: A French national online cross-sectional survey assessed declared psychological distress among outpatient physicians in private practice linked to COVID-19, sociodemographic and work conditions, mental health (Copenhagen Burn-out Inventory, Hospital Anxiety and Depression Scale, and the Insomnia severity Index), consequences on alcohol, tobacco, and illegal substance misuse, and sick leave during the 2nd COVID-19 wave. FINDINGS: Among the 1,992 physicians who answered the survey, 1,529 (76.8%) declared psychological distress linked to COVID-19. Outpatient physicians who declared psychological distress linked to COVID-19 had higher rates of insomnia (OR = 1.4; CI95 [1.1-1.7], p = 0.003), burnout (OR = 2.7; CI95 [2.1; 3.2], p < 0.001), anxiety and depressive symptoms (OR = 2.4; CI95 [1.9-3.0], p < 0.001 and OR = 1.7; CI95 [1.3-2.3], p < 0.001) as compared to physicians who did not. They also had higher psychotropic drug use in the last twelve months, or increased alcohol or tobacco consumption due to work-related stress and were more frequently general practitioners. INTERPRETATION: The feeling of being in psychological distress due to COVID-19 is highly frequent among outpatient physicians in private practice and is associated with mental health impairment. There is a need to assess specific interventions dedicated to outpatient physicians working in private practice.

The olfactory deficits of depressed patients are restored after remission with venlafaxine treatment.

BACKGROUND: It is unclear whether olfactory deficits improve after remission in depressed patients. Therefore, we aimed to assess in drug-free patients the olfactory performance of patients with major depressive episodes (MDE) and its change after antidepressant treatment. METHODS: In the DEP-ARREST-CLIN study, 69 drug-free patients with a current MDE in the context of major depressive disorder (MDD) were assessed for their olfactory performances and depression severity, before and after 1 (M1) and 3 (M3) months of venlafaxine antidepressant treatment. They were compared to 32 age- and sex-matched healthy controls (HCs). Olfaction was assessed with a psychophysical test, the Sniffin' Sticks test (Threshold: T score; Discrimination: D score; Identification: I score; total score: T + D + I = TDI score) and Pleasantness (pleasantness score: p score; neutral score: N score; unpleasantness score: U score). RESULTS: As compared to HCs, depressed patients had lower TDI olfactory scores [mean (s.d.) 30.0(4.5) v. 33.3(4.2), p < 0.001], T scores [5.6(2.6) v. 7.4(2.6), p < 0.01], p scores [7.5(3.0) v. 9.8(2.8), p < 0.001)] and higher N scores [3.5(2.6) v. 2.1(1.8), p < 0.01]. T, p and N scores at baseline were independent from depression and anhedonia severity. After venlafaxine treatment, significant increases of T scores [M1: 7.0(2.6) and M3: 6.8(3.1), p < 0.01] and p scores [M1: 8.1(3.0) and M3: 8.4(3.3), p < 0.05] were evidenced, in remitters only (T: p < 0.01; P: p < 0.01). Olfaction improvement was mediated by depression improvement. CONCLUSIONS: The olfactory signature of MDE is restored after venlafaxine treatment. This olfaction improvement is mediated by depression improvement.

Lower plasma vascular endothelial growth factor A in major depressive disorder not normalized after antidepressant treatment: A case control study.

OBJECTIVE: Vascular endothelial growth factor A is a growth factor with pro-angiogenic and neurotrophic properties. Anti-vascular endothelial growth factor A treatments, used to treat cancers and opthalmic diseases, are known to induce depressive symptoms. Thus, we hypothesized that vascular endothelial growth factor A plasma levels are low in patients experiencing a major depressive episode in the context of major depressive disorder, which consequently increase after antidepressant treatment. The aim of this study was to compare plasma vascular endothelial growth factor A levels in patients with major depressive episode-major depressive disorder before and after antidepressant treatment. METHODS: Vascular endothelial growth factor A fasting plasma levels of 469 major depressive episode-major depressive disorder patients were compared with healthy controls. Depressed patients were assessed for remission after 3 and 6 months of antidepressant treatment. Bivariate and multivariate analyses adjusted for sex, age, body mass index and tobacco use were performed. RESULTS: As compared to healthy controls, major depressive episode patients had lower vascular endothelial growth factor A, 66.0 (38.3) pg/mL (standard deviation) vs 83.2 (49.2) pg/mL, p < 0.0001. Plasma vascular endothelial growth factor A levels did not change after antidepressant treatment, even in remitters, and remained lower than those of healthy controls, 64.9 (39.3) pg/mL vs 83.2 (49.2) pg/mL, p < 0.0001. CONCLUSION: Depressed patients with major depressive disorder have lower plasma vascular endothelial growth factor A levels than healthy controls during their major depressive episode and after remission following antidepressant treatment. New strategies targeting enhancement of plasma vascular endothelial growth factor A could be promising for the prevention and treatment of major depressive disorder.

Human Dermal Fibroblast: A Promising Cellular Model to Study Biological Mechanisms of Major Depression and Antidepressant Drug Response.

BACKGROUND: Human dermal fibroblasts (HDF) can be used as a cellular model relatively easily and without genetic engineering. Therefore, HDF represent an interesting tool to study several human diseases including psychiatric disorders. Despite major depressive disorder (MDD) being the second cause of disability in the world, the efficacy of antidepressant drug (AD) treatment is not sufficient and the underlying mechanisms of MDD and the mechanisms of action of AD are poorly understood. OBJECTIVE: The aim of this review is to highlight the potential of HDF in the study of cellular mechanisms involved in MDD pathophysiology and in the action of AD response. METHODS: The first part is a systematic review following PRISMA guidelines on the use of HDF in MDD research. The second part reports the mechanisms and molecules both present in HDF and relevant regarding MDD pathophysiology and AD mechanisms of action. RESULTS: HDFs from MDD patients have been investigated in a relatively small number of works and most of them focused on the adrenergic pathway and metabolism-related gene expression as compared to HDF from healthy controls. The second part listed an important number of papers demonstrating the presence of many molecular processes in HDF, involved in MDD and AD mechanisms of action. CONCLUSION: The imbalance in the number of papers between the two parts highlights the great and still underused potential of HDF, which stands out as a very promising tool in our understanding of MDD and AD mechanisms of action.

The TRKB rs2289656 genetic polymorphism is associated with acute suicide attempts in depressed patients: A transversal case control study.

INTRODUCTION: Suicide Attempts (SA) are the main complications of Major Depressive Episodes (MDE) and are difficult to predict. Suicide is associated with the expression of Receptor Tyrosin-Kinase B (TRKB), the receptor of the Brain Derived Neurotrophic Factor (BDNF) involved in MDE. However, the impact of its genetic polymorphisms as predictive factors of SA should be clarified. Our main aim is to assess the association of 8 TRKB genetic polymorphisms and SA in depressed patients. MATERIAL AND METHODS: In 624 patients currently experiencing an MDE in the context of Major Depressive Disorder (MDD) (METADAP study), we assessed the association between 8 TRKB genetic polymorphisms (rs1778933, rs1187352, rs2289658, rs2289657, rs2289656, rs3824519, rs56142442 and rs1439050) and acute (previous month) or past (older than one month) SA. Bonferroni corrections and multivariate analysis adjusted for age, sex, level of education, marital status, Hamilton Depression Rating Scale score and previous MDE were used. RESULTS: The rs2289656 was associated with acute SA (CC = 28.5%, CT = 15.0% and TT = 11.5%, p = 0.0008). However, the other SNPs were not. Patients with the CC genotype had a higher rate of acute SA (28.5%) as compared to T carriers (14.6%) (adjusted OR = 2.2, CI95% [1.4; 3.5], p<0.0001). CONCLUSION: The TRKB rs2289656 CC genotype is associated with a 2.2 fold higher risk of acute SA in depressed patients. If this result could be confirmed, this TRKB SNP may be assessed to contribute to the prediction of SA in depressed patients.

Level of agreement between physician and patient assessment of non-medical health factors.

Background: GPs need to consider assorted relevant non-medical factors, such as family or work situations or health insurance coverage, to determine appropriate patient care. If GPs' knowledge of these factors varies according to patients' social position, less advantaged patients might receive poorer care, resulting in the perpetuation of social inequalities in health. Objective: To assess social disparities in GPs' knowledge of non-medical factors relevant to patient care. Methods: Observational survey of GPs who supervise internships in the Paris metropolitan area. Each of the 52 enrolled GPs randomly selected 70 patients from their patient list. Their knowledge of five relevant factors (coverage by publicly funded free health insurance, or by supplementary health insurance, living with a partner, social support and employment status) was analysed as the agreement between the patients' and GPs' answers to matching questions. Occupational, educational and financial disparities were estimated with multilevel models adjusted for age, sex, chronic disease and GP-patient relationship. Results: Agreement varied according to the factor considered from 66% to 91%. The global agreement score (percentage of agreement for all five factors) was 72%. Social disparities and often gradients, disfavouring the less well-off patients, were observed for each factor considered. Social gradients were most marked according to perceived financial situation and for health insurance coverage. Conclusion: GPs must be particularly attentive toward their least advantaged patients, to be aware of the relevant non-medical factors that affect these patients' health and care, and thus provide management adapted to each individual's personal situation.

Smaller hippocampal volumes predict lower antidepressant response/remission rates in depressed patients: A meta-analysis.

OBJECTIVES: Whether hippocampal volume predicts response and/or remission after antidepressant treatment of major depressive episodes (MDE) in major depressive disorder (MDD) remains unclear. We meta-analysed prospective studies comparing baseline hippocampal volume in patients with or without response/remission after antidepressant treatment. METHODS: Pubmed, Embase and Google Scholar were searched for studies of patients with current MDE in MDD, with hippocampal volume assessments at baseline, initiation of antidepressant drug treatment, and prospective assessment of response/remission after treatment. RESULTS: Six studies (374 patients), of which two were positive and four negative, were meta-analysed. Compared to responders/remitters, patients who failed to achieve response/remission had smaller total hippocampus volumes at baseline (mean volume difference = 260 mm3, 95% CI [93; 427], P = 0.002). These results remained significant in patients under 60 years of age (P = 0.02), in those over 60 years old (P = 0.04), and for right (P = 0.006) and left (P = 0.02) hippocampi. The probability of non-response/non-remission was 68.6% for patients with a total hippocampal volume at least 10% lower than the average, and 47.1% for patients with a total hippocampal volume 10% higher than the average. CONCLUSIONS: In depressed patients treated with antidepressant drugs, smaller hippocampal volumes predict lower response/remission rates.

No impact of eight NTRK2 genetic polymorphisms on 6-month antidepressant efficacy in depressed patients.

AIM: NTRK2 is the main receptor of the brain derived neurotrophic factor, which is involved in antidepressant efficacy. We assessed the impact of eight NTRK2 SNPs pertaining to response and remission after antidepressant treatment in depressed patients. PATIENTS & METHODS: In a naturalistic study, 569 patients with a major depressive episode requiring a new antidepressant treatment were genotyped for eight NTRK2 SNPs (rs1187352, rs1439050, rs1778933 rs2289656, rs2289657, rs2289658, rs3824519, rs56142442) and prospectively assessed for response and remission after 6 months of treatment. RESULTS: No association was shown between the NTRK2 SNPs and response/remission. CONCLUSION: There is no benefit to assess these eight TRKB SNPs to predict response/remission after antidepressant treatment in depressed patients.

Hippocampal volume predicts antidepressant efficacy in depressed patients without incomplete hippocampal inversion.

BACKGROUND: Incomplete hippocampal inversion (IHI), also called malrotation, is a frequent atypical anatomical pattern of the hippocampus. Because of the crucial implication of the hippocampus in Major Depressive Disorder (MDD) and the neurodevelopmental hypothesis of MDD, we aimed to assess the prevalence of IHI in patients with MDD, the link of IHI with hippocampal volume (HV) and the impact of IHI on the predictive value of HV for response and remission after antidepressant treatment. METHODS: IHI (right and left, partial and total and IHI scores) and HV were assessed in 60 patients with a current Major Depressive Episode (MDE) in a context of MDD and 60 matched controls. Patients were prospectively assessed at baseline and after one, three and six months of antidepressant treatment for response and remission. RESULTS: The prevalence of IHI did not significantly differ between MDD patients (right = 23.3%; left = 38.3%) and controls (right = 16.7%; left = 33.3%). IHI was not significantly associated with MDD clinical characteristics. IHI alone did not predict response and remission after antidepressant treatment. However, an interaction between left HV and left IHI predicted six-month response (p = 0.04), HDRS score decrease (p = 0.02) and both three-month (p = 0.04) and six-month (p = 0.03) remission. A case-control design in 30 matched patients with or without left IHI confirmed that interaction. In patients without left IHI, left HV at baseline were smaller in six-month non-remitters as compared to remitters (2.2(± 0.43) cm3 vs 2.97(± 0.5) cm3 p = 0.02), and in six-month non-responders as compared to responders (2.18(± 0.42) cm3 vs 2.86(± 0.54) cm3, p = 0.03). In patients with left IHI, no association was found between left HV at baseline and antidepressant response and remission. CONCLUSION: IHI is not more frequent in MDD patients than in controls, is not associated with HV, but is a confounder that decreases the predictive value of hippocampal volume to predict response or remission after antidepressant treatment. IHI should be systematically assessed in future research studies assessing hippocampal volume in MDD.

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.