Evolution of Cognitive Impairments in Treatment-Resistant Depression: Results from the Longitudinal French Centers of Expertise for Treatment-Resistant Depression (FACE-DR) Cohort.

Previous studies set out profound cognitive impairments in subjects with treatment-resistant depression (TRD). However, little is known about the course of such alterations depending on levels of improvement in those patients followed longitudinally. The main objective of this study was to describe the course of cognitive impairments in responder versus non-responder TRD patients at one-year follow-up. The second aim was to evaluate the predictive aspect of cognitive impairments to treatment resistance in patients suffering from TRD. We included 131 patients from a longitudinal cohort (FACE-DR) of the French Network of Expert TRD Centers. They undertook comprehensive sociodemographic, clinical, global functioning, and neuropsychological testing (TMT, Baddeley task, verbal fluencies, WAIS-4 subtests, D2 and RLRI-16) at baseline (V0) and one-year follow-up (V1). Most patients (n = 83; 63.36%) did not respond (47 women, 49.47 ± 12.64 years old), while one-third of patients responded (n = 48, 30 women, 54.06 ± 12.03 years old). We compared the cognitive performances of participants to average theoretical performances in the general population. In addition, we compared the cognitive performances of patients between V1 and V0 and responder versus non-responder patients at V1. We observed cognitive impairments during the episode and after a therapeutic response. Overall, each of them tended to show an increase in their cognitive scores. Improvement was more prominent in responders at V1 compared to their non-responder counterparts. They experienced a more marked improvement in code, digit span, arithmetic, similarities, and D2 tasks. Patients suffering from TRD have significant cognitive impairments that persist but alleviate after therapeutic response. Cognitive remediation should be proposed after therapeutic response to improve efficiency and increase the daily functioning.

Long-term benzodiazepine prescription in treatment-resistant depression: A national FACE-TRD prospective study.

BACKGROUND: Benzodiazepine long-term use (BLTU) is a public health challenge. We lack data on the consequences of LBTU on the trajectory of treatment-resistant depression (TRD). OBJECTIVE: To determine the prevalence of BLTU in a nationwide non-selected population of patients with TRD, to determine the rate of patients succeeding at withdrawing benzodiazepines at one year and to determine if persistent BLTU is associated with poorer mental health outcomes. METHOD: The FACE-TRD cohort is a national cohort of TRD patients recruited in 13 resistant depression expert centers between 2014 and 2021 and followed-up at one year. A standardized one-day long comprehensive battery was carried out, including trained-clinician and patient-reported outcomes, and patients were reevaluated at one year. RESULTS: At baseline, 45.2% of the patients were classified in the BLTU group. In multivariate analysis, compared to patients without BLTU, patients with BLTU were more frequently classified in the "low physical activity" group (adjusted odds ratio (aOR) = 1.885, p = 0.036), and had higher primary healthcare consumption (B = 0.158, p = 0.031) independently of age, sex and antipsychotic consumption. We found no significant difference for personality traits, suicidal ideation, impulsivity, childhood trauma exposure, earlier age at first major depressive episode, anxiety and sleep disorders (all p > 0.05). Despite recommendations for withdrawal, <5% of BLTU patients withdraw benzodiazepines during the one-year follow-up. Persistent BLTU at one-year was associated with higher depression severity (B = 0.189, p = 0.029), higher clinical global severity (B = 0.210, p = 0.016), higher state-anxiety (B = 0.266, p = 0.003), impaired sleep quality (B = 0.249, p = 0.008), increased peripheral inflammation (B = 0.241, p = 0.027), lower functioning level (B = -0.240, p = 0.006), decreased processing speed (B = -0.195, p = 0.020) and verbal episodic memory (B = -0.178, p = 0.048), higher absenteeism and productivity loss (B = 0.595, p = 0.016) and lower subjective global health status (B = -0.198, p = 0.028). CONCLUSION: Benzodiazepines are over-prescribed in TRD (in almost a half of the patients). Despite recommendations for withdrawal and psychiatric follow-up, <5% of patients successfully stopped taking benzodiazepines at one-year. Maintaining BLTU may contribute to the worsening of clinical and cognitive symptoms and of daily functioning in TRD patients. Progressive and planed withdrawal of benzodiazepines seems therefore strongly recommended in TRD patients with BLTU. Pharmacological and non-pharmacological alternatives should be promoted when possible.

Diurnal symptoms of sleepiness and dysfunction predict future suicidal ideation in a French cohort of outpatients (FACE-DR) with treatment resistant depression: A 1-year prospective study about sleep markers.

BACKGROUND: Patients suffering from treatment-resistant depression (TRD) are at risk of suicide. Sleep and circadian rhythm alterations are widely recognized as core symptoms of major depressive disorder and are associated with suicidal ideation. Thus, sleep and circadian rhythm alterations may be targeted to prevent suicide. METHODS: Patients were recruited from a prospective cohort of the French network of TRD expert centers. Mood, sleep and circadian rhythms were assessed at baseline; suicidal risk was assessed both at baseline and during a one-year follow-up with standardized subjective questionnaires. RESULTS: Excessive daytime sleepiness (adjusted odds ratio aOR = 1.7(1-3.3), p = 0.04) and daytime dysfunction (aOR = 1.81(1.16-2.81), p = 0.0085) increased the risk of suicidal thoughts over the one-year follow-up period in patients with TRD after adjustment on age, gender, depression, trauma, anxiety, impulsivity, current daily tobacco smoking and body mass index. Hypnotics intake is associated with a reduced risk of suicidal ideation at one-year follow-up after the same adjustments (OR = 0.73(0.56-0.95), p = 0.019). Other associations between sleep quality or circadian rhythms and suicidal ideations at either baseline or one year did not remain significant in multivariate analyses after the same adjustments. LIMITATIONS: Sleep assessments were based on self-reported questionnaires rather than objective measures. CONCLUSIONS: Daytime sleepiness and dysfunction are predictors of suicidal ideations, whereas hypnotics intake is associated with a reduced risk of suicidal ideations. Diurnal symptoms of sleep disturbances are therefore red flags to target for preventing suicide in depressed patients, and hypnotics seem efficient in preventing suicide for patients with TRD.

Case Report: Use of Subcutaneous Midazolam During an Episode of Catatonia.

Midazolam is a benzodiazepine (BZD) mainly used in anesthetic induction due to its pharmacokinetic features. Its place in the therapeutic management of catatonia remains to be determined. Here we present the case of a 65-year-old man who presented with a first episode of catatonia with opposition to any form of oral treatment, where a single dose of 1 mg of subcutaneous (SC) Midazolam permitted clinical improvement allowing oral treatment to be given. The patient's history notably included a renal transplant linked to Polycystic Kidney Disease (PKD) and no history of psychiatric illness nor of any use of psychotropic drugs. As the patient refused to drink or eat and ceased answering basic questions, a psychiatric assessment was required. A diagnosis of Catatonic disorder due to a general medical condition [DSM 5-293.89/ ICD10 [F06.1]] was made. A Bush-Francis Catatonia Rating Scale (BFCRS) analysis returned a score of 15 out of 62, with stupor, mutism, negativism, staring, withdrawal, rigidity, and stereotypy. As the negativism prevented the patient from taking any form of oral treatment, after a brief discussion with the unit's physician, it was decided to administer 1 mg of SC Midazolam. One hour later, the patient was more responsive and compliant, and agreed to drink, eat, and take medication. Thus, the catatonic signs of mutism, negativism, staring, and withdrawal were resolved, but waxy flexibility and catalepsy appeared, leading to a new BFCRS score of 10 out of 62. Oral treatment with 2.5 mg Lorazepam, 4 times a day, was then initiated. Midazolam could be a safer choice compared with the other options available, such as other SC BZD, considering the complex safety profile of this patient with renal insufficiency. This situation represents the first report of using SC Midazolam as an injectable treatment for catatonia. More studies are needed to assess the clinical pertinence of SC Midazolam in the treatment of catatonia.