[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.

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.

Cerebrospinal fluid levels of monoamines among suicide attempters: A systematic review and random-effects meta-analysis.

BACKGROUND: It remains unclear whether the dopaminergic and noradrenergic systems may be implied in suicide attempt risk. In addition, although the serotonergic system has been extensively studied, no formal meta-analysis has been performed to examine its association with suicide attempt. METHODS: Using PRISMA methodology, we performed a systematic literature review and random-effects meta-analyses of the differences in cerebrospinal fluid (CSF) levels of 5-HIAA, HVA and MHPG between suicide attempters and individuals who never attempted suicide. RESULTS: We identified 30 studies including 937 suicide attempters and 1128 non-attempters; 29 of them measured CSF levels of 5-HIAA, 22 measured CSF levels of HVA and 14 measured CSF levels of MHPG. CSF levels of 5-HIAA and HVA were significantly lower in suicide attempters than in non-attempters [SMD = -0.43 (95% CI: -0.71 to -0.15; p < 0.01) and SMD = -0.45 (95% CI: -0.72 to -0.19; p < 0.01), respectively]. We did not find a significant association between CSF MHPG levels and suicide attempt. LIMITATIONS: Our analyses relied on a limited number of studies of good quality and most studies included small sample sizes. CONCLUSION: Both serotonin and dopamine systems may play a role in suicide attempt risk. Our findings suggest that a silo approach to biomarkers should be phased out in favor of the study of multiple systems in parallel and in the same populations to progress in the identification of the biological components independently associated with suicide risk, with the goal of identifying new treatment targets and improving suicide risk prediction.

Generalizability of pharmacologic and psychotherapy trial results for late-life unipolar depression.

OBJECTIVES: Despite evidence of low representativeness of clinical trial results for depression in adults, the generalizability of clinical trial results for late-life depression is unknown. This study sought to quantify the representativeness of pharmacologic and psychotherapy clinical trial results for late-life unipolar depression. METHOD: Data were derived from the 2004-2005 National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), a nationally representative sample of 34,653 adults from the United States population. To assess the generalizability of clinical trial results for late-life depression, we applied a standard set of eligibility criteria representative of pharmacologic and psychotherapy clinical trials to all individuals aged 65 years and older in NESARC with a DSM-IV diagnosis of MDE and no lifetime history of mania/hypomania (n = 273) and in a subsample of individuals seeking help for depression (n = 78). RESULTS: More than four of ten respondents and about two of ten respondents would have been excluded by at least one exclusion criterion in a typical pharmacologic and psychotherapy efficacy trial, respectively. Similar results (i.e.41.1% and 25.9%, respectively) were found in the subsample of individuals seeking help for depression. Excess percentage of exclusion in typical pharmacologic studies was accounted for by the criterion "significant medical condition". We also found that populations typically included in pharmacologic and psychotherapy clinical trials for late-life unipolar depression may substantially differ. CONCLUSION: Psychotherapy trial results may be representative of most patients with late-life unipolar depression in routine clinical practice. By contrast, pharmacologic clinical trials may not be readily generalizable to community samples.

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.

Blood NAD levels are reduced in very old patients hospitalized for heart failure.

BACKGROUND: Age-associated decline in nicotinamide adenine dinucleotide (NAD) tissue levels has emerged as potential driving mechanism in the establishment of energy metabolism perturbations in the context of chronic diseases, notably heart failure. OBJECTIVE: The aim of this study was to measure the blood NAD levels in a healthy blood donor population and in a population of elderly patients hospitalized for decompensated heart failure. METHOD: Whole blood sample was collected from 151 healthy voluntary blood donors, aged 19 to 68 years, and from 19 patients aged 75 to 101 years and hospitalized for decompensated heart failure in a geriatric ward. Metabolites were extracted by the hot buffered ethanol procedure and NAD was quantified in triplicate for each sample. RESULTS: The mean concentration of NAD in blood of healthy donors was 23.4 (SD 4.05) µmol/L. There was no significant correlation between NAD levels and donors' age nor sex in the healthy population when studied as a whole. However, the linear regression curves of NAD concentration plotted against age differed between males and females (p = 0.0283) with a trend in males to decline with age that was not observed in females. The mean concentration of NAD in whole blood samples of the geriatric population was 20.7 (SD 3.6) µmol/L (p = 0.007 versus the healthy blood donor population). There were no differences between males and females (p = 0.7) nor between patients with ejection fraction inferior or superior to 50% (p = 0.86) in the geriatric population. CONCLUSION: This study highlighted a diminution of NAD blood levels for elderly patients hospitalized for decompensated heart failure in comparison to a healthy population, suggesting that new therapeutics to restore NAD stock and energy metabolism would be a major progress in the management of this type of geriatric patients.

Severe insomnia is associated with metabolic syndrome in women over 50 years with major depression treated in psychiatry settings: a METADAP report.

INTRODUCTION: Major depression is associated with metabolic syndrome and cardiovascular risk. We have previously shown that severe insomnia, a core symptom of major depression episode (MDE), is associated with hypertriglyceridemia, a component of metabolic syndrome, in women but not in men with major depression. Since insomnia is related to cardiovascular morbidity in the general population and major depression also, our objective was to assess the link between insomnia and metabolic syndrome, a marker syndrome of cardiovascular risk, during MDE, in women and in men. METHODS: In 624 patients with a current MDE cohort, both insomnia and metabolic syndrome were assessed in women and men. Insomnia was rated from 0 to 6 based on the HDRS corresponding items, severe insomnia being defined by a total insomnia score ≥4. RESULTS: severe insomnia was associated with metabolic syndrome in women but not in men. In multivariate logistic regressions, these results in women were independent from age, educational level, major depressive disorder duration and current smoking. These results were only significant in women aged ≥50 years, a cut-off age for menopausal status but not in women under 50 years. CONCLUSION: Women aged ≥50 years with a severe insomnia during MDE have an increased risk of metabolic syndrome. Severe insomnia may be a clinical marker of metabolic risk in this population. They should be particularly monitored for metabolic syndrome and may benefit from sleep recommendations and cardiovascular prevention.

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.

Comparison of burnout, anxiety and depressive syndromes in hospital psychiatrists and other physicians: Results from the ESTEM study.

AIMS: To compare prevalence and risk factors for burnout, anxiety and depression among hospital psychiatrists and non-psychiatrists. METHOD: Regional online survey of psychiatric and non-psychiatric hospital physicians was performed including: a job-stress scale, the Hospital Anxiety and Depression Scale (HADS), the Copenhagen Burnout Inventory (CBI), a stressful work relationships list and a six items scale about work-related psychosocial risk factors (PRFs). The client-related burnout scale of the CBI has been changed to an interpersonal burnout scale. Cases were defined by a score of 8+ for the HADS-A/HADS-D and 50+ for the three CBI subscales. RESULTS: 285 psychiatrists and 326 non-psychiatrists participated. The prevalence of depression, personal burnout and work-related burnout did not differ between physicians. Anxiety was lower in psychiatrists and interpersonal burnout was higher in senior psychiatrists. Multivariate analysis showed two main PRFs, common to both groups of physicians: "work intensity and time" was associated with four of the five syndromes and "emotional demands" with the three burnout syndromes. Interpersonal burnout was associated with stressful relationships with leaders, but not with patients. CONCLUSION: Reducing the workload, improving the management of emotions and increasing managerial skills are important approaches for prevention.

Psychiatric and physical outcomes of long-term use of lithium in older adults with bipolar disorder and major depressive disorder: A cross-sectional multicenter study.

OBJECTIVE: Although lithium is widely used in current practice to treat bipolar disorder (BD) and treatment-resistant major depressive disorder (MDD) among older adults, little is known about its efficacy and tolerability in this population, which is generally excluded from randomized clinical trials. The objective of this study was to evaluate the efficacy and tolerability of long-term use of lithium among older adults with BD and MDD. METHOD: Data from the Cohort of individuals with Schizophrenia and mood disorders Aged 55 years or more (CSA) were used. Two groups of patients with BD and MDD were compared: those who were currently receiving lithium versus those who were not. The effects of lithium on psychiatric (i.e., depressive symptoms severity, perceived clinical severity, rates of psychiatric admissions in the past-year), geriatric (overall and cognitive functioning) and physical outcomes (i.e., rates of non-psychiatric medical comorbidities and general hospital admissions in the past-year) were evaluated. All analyses were adjusted for age, sex, duration of disorder, diagnosis, smoking status, alcohol use, and use of antipsychotics, antiepileptics or antidepressants. RESULTS: Among the 281 older participants with BD or MDD, 15.7% were taking lithium for a mean duration of 12.5(SD = 11.6) years. Lithium use was associated with lower intensity of depressive symptoms, reduced perceived clinical global severity and lower benzodiazepine use (all p < 0.05), without being linked to greater rates of medical comorbidities, except for hypothyroidism. LIMITATIONS: Data were cross-sectional and data on lifetime history of psychotropic medications was not assessed. CONCLUSION: Our results suggest that long-term lithium use may be efficient and relatively well-tolerated in older adults with BD or treatment-resistant MDD.

Glycogen synthase kinase-3ß genetic polymorphisms and insomnia in depressed patients: A prospective study.

BACKGROUND: 80-90% of patients with Major Depressive Episode (MDE) experience insomnia and up-to 50% severe insomnia. Glycogen Synthase Kinase-3ß (GSK3B) is involved both in mood regulation and circadian rhythm. Since GSK3B polymorphisms could affect protein levels or functionality, we investigated the association of GSK3B polymorphisms with insomnia in a sample of depressed patients treated with antidepressants. METHODS: In this 6-month prospective real-world treatment study in psychiatric settings (METADAP), 492 Caucasian patients requiring a new antidepressant treatment were included and genotyped for five GSK3B Single Nucleotide Polymorphisms (SNPs) (rs6808874, rs6782799, rs2319398, rs13321783, rs334558). Insomnia and MDE severity were rated using the Hamilton Depression Rating Scale (HDRS). Bi- and multivariate analyses were performed to assess the association between GSK3B SNPs and insomnia (main objective). We also assessed their association with MDE severity and HDRS response/remission after antidepressant treatment. RESULTS: At baseline severe insomnia was associated with the GSK3B rs334558 minor allele (C+) [OR=1.81, CI95%(1.17-2.80), p=0.008]. GSK3B rs334558 C+ had greater insomnia improvement after 6 months of antidepressant treatment (p=0.007, ß=0.17, t=2.736). No association was found between GSK3B SNPs and MDE baseline severity or 6-month response/remission. CONCLUSION: GSK3B rs334558 was associated with insomnia but not with MDE severity in depressed patients. Targeting GSK3B in patients with MDE and a severe insomnia could be a way to improve their symptoms with greater efficiency. And it should be further studied whether the GSK3B-insomnia association may fit into the larger picture of mood disorders.

Neuroprotective effects of lithium: what are the implications in humans with neurodegenerative disorders?

Lithium is used as a first line treatment in bipolar disorder. The neuroprotective effects of lithium in this indication tend to be well known and are mediated by its action on two enzymes: glycogen synthase kinase-3 and inositol monophosphatase-1. Preclinical and clinical studies seek to evaluate the neuroprotective effect of lithium in neurodegenerative disorders. The aims of this literature review is to gather clinical studies that investigated the efficacy of lithium in neurodegenerative diseases, using a systematic method based on PubMed data. Results were found concerning Alzheimer's disease and related dementias, Huntington's disease, amyotrophic lateral sclerosis and spino-cerebellar ataxia. Lithium exposure showed a potential neuroprotective effect in studies on psychiatric populations with a lower prevalence of Alzheimer's disease in exposed patients. In patients with mild cognitive impairment, lithium would be associated with clinical improvement and a lower level of cerebrospinal phosphorylated tau protein. Lithium would allow at least a partial improvement in symptoms, including suicidal thoughts, in Huntington's disease. Despite several positive case reports and short studies, further controlled researches have failed to substantiate any positive effects of lithium exposure in amyotrophic lateral sclerosis. In spinocerebellar ataxia, introduction of lithium may be of benefits in terms of improvement of cerebellar symptoms. Large randomized controlled trials are required to asses the effect of early exposure lithium in these indications, based on reliable biological markers of disease.

Outpatient treatment engagement after suicidal attempt: A multisite prospective study.

After suicidal attempt, the rate of specialized out treatment engagement (SOTE) does not exceed 30-50%. We designed a multisite prospective naturalistic study, in order to investigate predictive factors of SOTE after emergency department discharge among 107 suicidal attempters without current psychiatric ambulatory care. Both bivariate and multivariate analyses highlighted that booking an appointment with a mental health professional before discharge was significantly associated with higher SOTE rate. Psychiatric caregivers of emergency departments should be informed that this approach is a simple, fast way to improve SOTE among this population.

Major depression and heart failure: Interest of monoamine oxidase inhibitors.

Several physiopathological hypotheses have been studied to explain the link between heart failure (HF) and major depression (MD). An increase of monoamine oxidase (MAO) has recently been found as a factor involved in the development of HF. The aim of this review is to provide a complete overview of the involvement of MAOs in HF comorbidity of MD and to discuss the pharmacological options. Our work highlights the scientific evidence of MAO involvement in the development of HF. Studies focusing on MAO-A seem to have reproducible results on HF, establishing the effect of this enzyme as well as the protective effect of its inhibition. Fewer studies addressed MAO-B; results are nonetheless encouraging. Based on this knowledge, the hypothesis of a rise of MAO activity in HF seems to be well established. The large prevalence of comorbid MD in HF could be due to the deamination of monoamines linked with MAOs activity. In addition, MAOIs are effective in MD and well tolerated among the elderly according to the literature. This original hypothesis provides a new perspective in the use of MAOIs in HF patients with MD.

Severe insomnia is associated with hypertriglyceridemia in women with major depression treated in psychiatry settings.

BACKGROUND: Hypertriglyceridemia (HTG) is a cardiovascular risk factor. In the general population, elevated fasting triglyceridemia (TG) is associated with insomnia. Since insomnia is a core symptom of Major Depressive Episodes (MDE), we studied the association of severe insomnia with HTG in major depression. METHODS: We used the baseline data of the METADAP cohort, comprising 624 patients with a current MDE in a context of Major Depressive Disorder treated in psychiatry settings, without current alcohol use disorders. Patients were screened for severe insomnia, defined by a score of four or more on the three Hamilton Depression Rating Scale (HDRS) sleep items, and for HTG characterised by TG≥200mg/dL. RESULTS: Severe insomnia was observed in 335(54%) patients with a current MDE, of whom 234(70%) were women; 49(8%) patients had HTG, of whom 25(51%) were women. 69(11%) patients were treated with lipid-lowering drugs. Severe insomnia was associated with a higher frequency of HTG in the whole sample (9.9% vs 5.6%, p=0.046) and in the subgroup of women (9.0% vs 2.0%, p=0.002). Multivariate logistic regression analyses adjusted for age, education levels, BMI and total HDRS scores confirmed the association between severe insomnia and HTG in the whole sample (OR=2.02, 95%CI [1.00-4.08], p=0.05) as well as in the subgroup of women (OR=4.82, 95%CI [1.5-15.5], p=0.008). No association was shown in men. PERSPECTIVES: HTG should be systematically investigated in depressed patients with severe insomnia and particularly in women. Further studies are needed to explain the association we observed between severe insomnia and HTG.