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.

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.

Cognitive change in breast cancer patients up to 2 years after diagnosis.

BACKGROUND: Using the large nationwide French, national, multicenter, prospective cancer and toxicities (CANTO) cohort, we assessed cognitive functioning change after cancer treatments in a subgroup of breast cancer (BC) patients. METHODS: We included patients with newly diagnosed invasive stage I-III BC enrolled in the CANTO substudy focused on cognitive evaluation and healthy control women matched for age and education. Episodic and working memory, executive functions, processing speed, attention, self-report cognitive difficulties (SRCD), fatigue, anxiety and depression were assessed with neuropsychological tests and self-report questionnaires before treatment (baseline) and approximately 1 (year 1) and 2 years (year 2) after diagnosis. We used linear mixed models to study changes in cognition and tested the effect of adjuvant chemotherapy. RESULTS: We studied 276 localized BC patients (62% chemotherapy) compared with 135 healthy controls (HC). After adjustment, patients had lower baseline working memory, processing speed, and attention scores than HC (P ≤ .001), and the difference remained statistically significant over follow-up for working memory and processing speed. Executive function scores were similar between groups at baseline but decreased at year 1 among patients compared with HC (Pchange = .006). This decrease in chemotherapy patients was statistically significant compared with HC scores (Pchange < .001). After adjustment, SRCD were similar between BC patients and HC at baseline but increased in patients after treatment at year 1 (Pchange = .002). CONCLUSIONS: Cognitive difficulties are an important concern in BC patients, starting at diagnosis. Cancer treatments induce executive function decline and SRCD, which decrease over follow-up.

Clinical characteristics of adults suffering from high-functioning autism and comorbid obsessive-compulsive disorder.

Autism spectrum disorder (ASD) is a very heterogeneous disorder. Obsessive compulsive disorder (OCD) comorbidity, frequent in ASD, could be useful to define a specific ASD subtype. Our objective was to explore if adults with ASD and comorbid OCD could present a specific clinical profile of ASD in 89 high functioning-adult ASD patients. We found that adults with ASD and comorbid OCD showed a lower verbal IQ and a more severe impairments in social cognition. ASD with comorbid OCD present a specific clinical profile which could constitute a possible subtype of ASD.

Relationship between neurocognition and theory of mind as a function of symptomatic profile in schizophrenia: results from the national FACE-SZ cohort.

INTRODUCTION: Deficits in theory of mind (ToM) can vary depending on the predominant schizophrenia symptoms, and though most neurocognitive functions are involved in ToM, all may not be associated with the same symptoms. With consideration to the relationships between symptoms, neurocognition and ToM, the aim of the present study is to identify the neurocognitive functions influencing ToM capacities according to symptomatic profile. METHODS: The study is based on a sample of 124 adults with schizophrenia from a French national cohort. Patients were divided into two groups according to their scores on the five Wallwork factors of the Positive and Negative Syndrome Scale using hierarchical clustering before carrying out multivariable analyses. RESULTS: The "disorganised group" (n = 89) showed high scores on the disorganised factor, and had a ToM associated with reasoning, visual recognition and speed of processing. The "positive group" (n = 35) showed high scores on the positive and depressive factors, and had a ToM associated with working memory. CONCLUSIONS: These results suggest that neurocognitive predictors of ToM in schizophrenia are different according to the predominant clinical dimension, thus refining our knowledge of the relationship between symptoms, neurocognition and ToM, and acknowledging their status as important predictors of patients' functional status.

Recommendations of the treatment-resistant depression expert center network for promoting tobacco smoking cessation based on the results from the real-world FACE-TRD national cohort.

BACKGROUND: Tobacco smoking has been associated with suicide, impulsivity and depression in non-clinical populations with differences across sexes. OBJECTIVE: To determine the role of tobacco smoking in Treatment-Resistant Depression (TRD) according to sex in a precision-medicine approach. 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 6 months. A standardized one-day long comprehensive battery was carried out, including trained-clinician and patient-reported outcomes, and patients were reevaluated at 6 months on their smoking and psychiatric hospitalization outcomes. RESULTS: 355 TRD participants were included (222 women). The smoking rate was much higher in TRD women compared to the French general population (34% vs 24%) while it was comparable for men (approximately 29%). In multivariate analyses, compared to non-smoking women, female smokers had significantly increased number of lifetime psychiatric hospitalizations (standardized beta B = 0.232, p = 0.014) and electro-convulsive therapy (adjusted odds ratio (aOR) = 2.748, p = 0.005), increased suicidal ideations (aOR = 4.047, p = 0.031), history of suicide attempt (aOR = 1.994, p = 0.033), and increased impulsivity (B = 0.210, p = 0.006) and were more frequently treated by benzodiazepines (aOR = 1.848, p = 0.035) and third- or fourth-line TRD treatments (antipsychotics aOR = 2.270, p = 0.006, mood stabilizers aOR = 2.067 p = 0.044). Tobacco smoking at baseline was predictive of psychiatric hospitalization within 6 months in persistent smoking women (aOR = 2.636, p = 0.031). These results were not replicated in men, for whom tobacco smoking was only associated with increased clinician-rated and self-reported depressive symptoms (respectively B = 0.207, p = 0.022 and B = 0.184, p = 0.048). The smoking cessation rate at 6 months was higher in women than in men (12% vs. 7%). No patient was administered nicotine substitute or varenicline at the two timepoints. INTERPRETATION: Combining these results and those of the literature, we recommend that active tobacco cessation should be promoted in TRD to improve depression, suicide and impulsivity especially in women. Female smokers appear as a specific population with heavier mental health outcomes that should be specifically addressed.

Occurrence of Side Effects in Treatment-Resistant Depression: Role of Clinical, Socio-Demographic and Environmental Characteristics.

Introduction: Treatment-resistant depression (TRD) is a disabling psychiatric condition characterized by the failure of two antidepressants (ADs). Since the occurrence of side effects (SEs) appears to be one of the main determinants of early discontinuation of pharmacological treatments contributing to a pseudo-resistance, the purpose of this study was to determine the parameters associated with the occurrence of SEs under ADs in a cohort of patients with TRD. Methods: An observational, cross-sectional, multicentre study was carried out using data from the French network of Expert Centers for TRD. For the 108 patients enrolled in the study, the statistical analyses focused on the overall occurrence and on the profile of the SEs (9 categories, 32 items). Results: SEs were influenced by age and sex and were positively associated with the intensity of anxious, depressive and suicidal symptoms, a history of childhood trauma (sexual abuse, emotional abuse and neglect), and negatively associated with self-esteem, and assessment of overall functioning. Conclusion: Using variables accessible in common practice, these results fall within the dynamic of a more tailored approach to medicine that could allow, through integrated pharmacological management, the continuation of antidepressant treatments, and therefore limit the risk of therapeutic failure.

Relationship between childhood physical abuse and clinical severity of treatment-resistant depression in a geriatric population.

INTRODUCTION: We assessed the correlation between childhood maltreatment (CM) and severity of depression in an elderly unipolar Treatment-Resistant Depression (TRD) sample. METHODS: Patients were enrolled from a longitudinal cohort (FACE-DR) of the French Network of Expert TRD Centres. RESULTS: Our sample included 96 patients (33% of the overall cohort) aged 60 years or above, with a mean age of 67.2 (SD = 5.7). The majority of the patients were female (62.5%). The Montgomery and Asberg Depression Rating Scale (MADRS) and Quick Inventory Depression Scale-Self Report (QIDS-SR) mean scores were high, 28.2 (SD = 7.49) [MADRS score range: 0-60; moderate severity≥20, high severity≥35] and 16.5 (SD = 4.94) [IDS-SR score range: 0-27; moderate severity≥11, high severity≥16], respectively. Mean self-esteem scores were 22.47 (SD = 6.26) [range 0-30]. In an age- and sex-adjusted model, we found a positive correlation between childhood trauma (CTQ scores) and depressive symptom severity [MADRS (ß = 0.274; p = 0.07) and QIDS-SR (ß = 0.302; p = 0.005) scores]. We detected a statistically significant correlation between physical abuse and depressive symptom severity [MADRS (ß = 0.304; p = 0.03) and QIDS-SR (ß = 0.362; p = 0.005) scores]. We did not observe any significant correlation between other types of trauma and depressive symptom severity. We showed that self-esteem (Rosenberg scale) mediated the effect of physical abuse (PA) on the intensity of depressive symptoms [MADRS: b = 0.318, 95% BCa C.I. [0.07, 0.62]; QIDS-SR: b = 0.177, 95% BCa C.I. [0.04, 0.37]]. Preacher & Kelly's Kappa Squared values of 19.1% (k2 = 0.191) and 16% (k2 = 0.16), respectively for the two scales, indicate a moderate effect. CONCLUSION: To our knowledge, this is the first study conducted in a geriatric TRD population documenting an association between childhood trauma (mainly relating to PA) and the intensity of depressive symptoms.

Childhood Trauma increases suicidal behaviour in a treatment-resistant depression population: a FACE-DR report.

OBJECTIVE: In addition to heredity, exposure to early-life adversity is an important predisposing risk factor of suicidal behaviour. Although the association between Childhood Trauma (CT) and suicide risk is well documented, interactions between CT and suicidal behaviour in Treatment-Resistant Depression (TRD) populations have received little coverage. This study aimed to evaluate i) association between CT and suicidal behaviour in a TRD population, and ii) the role of personality traits and impulsiveness as potential factors of mediation in these associations. METHODS: Patients were recruited from a cohort of the French network of TRD expert centers. Depressive symptom severity, CT, suicidal behaviour, personality traits, and impulsiveness were assessed with the Montgomery-Åsberg Depression Rating Scale (MADRS), the Childhood Trauma Questionnaire (CTQ), the Columbia Suicide Severity Rating Scale (CSSRS), the Structured Clinical Interview for DSM-IV, the Big Five Inventory, and the Barratt Impulsivness Scale (BIS) respectively. RESULTS: Among the 256 patients with a baseline CTQ, in relation to suicide risk for the current depressive episode, we found an association with the total CTQ scores mediated by the intensity of the current episode in a model adjusted for age and sex (total effect: ß = 0.171; p = 0.011, direct effect: ß = 0.135; p = 0.043; indirect effect: ß = 0.036; p = 0.048). Focusing on CT subtypes, we detected an association between suicide risk and physical neglect in a model adjusted for age and sex (ß = 0.301; p = 0.002), without any mediation by the intensity of the current episode. There was no mediation effect from personality traits nor impulsiveness. With regards to CSSRS to assess suicidal ideation, we did not find any association with the total CTQ score and CT subtype scores. CONCLUSION: We report a strong association between suicidal behaviour and CT (in particular childhood physical neglect) in a TRD population.

Differentiation of groups of patients with cognitive complaints at breast cancer diagnosis: Results from a sub-study of the French CANTO cohort.

OBJECTIVE: Cognitive complaints are more frequent in women with breast cancer (BC) than in healthy controls and can be present before any treatment. Findings regarding contributive factors remain inconsistent. This study aimed to identify different groups of patients with cognitive complaints at BC diagnosis and to determine whether these different groups were associated with demographic, medical, or psychological characteristics. METHODS: Cognitive complaints were assessed in a subset of 264 women from the French multicenter prospective CANTO cohort, at baseline before any treatment. Clustering analyzes were performed using the six-cognitive dimension Costa's scoring of the FACT-Cog V3. Univariable analyses were used to study how cognitive function (standardized neuropsychological tests, ICCTF), anxiety, depression, fatigue, and quality of life (HADS, FA12, QLQ-C30) were associated with specific cognitive complaints groups. RESULTS: Results included 263 women (54±11 years), newly diagnosed with BC (69% stages I-III). Four distinct groups emerged, ranged from "no complaints" (22.8%), "low complaints" (55.1), "mixed complaints" (14.5%), to "consistent complaints" (7.6%). No significant differences were found in terms of demographic and medical factors between the four groups. However, the groups with higher proportions of patients with complaints were found to have more impairment in executive function, higher scores of anxiety, depressive symptoms, and fatigue, and lower quality of life, than the groups with lower proportions of cognitive complaints. CONCLUSION: Using complete cognitive assessment prior to BC treatment, we identified four distinct cognitive complaints groups with specific characteristics. This work provides valuable clinical basis to further investigations for a better understanding of cognitive complaints and their associates.

Cognitive Impairment in Patients with Breast Cancer before Surgery: Results from a CANTO Cohort Subgroup.

BACKGROUND: Twenty to 30% of patients with breast cancer have cognitive impairment after surgery and before adjuvant treatment, but very few studies have focused on cognition before any treatment. This study used a subgroup of women with newly diagnosed breast cancer from the French cancer and toxicities (CANTO) cohort to describe cognition before any treatment in comparison with a group of healthy controls (HC). METHODS: Cognitive assessment was performed before any breast cancer treatment (surgery or neoadjuvant treatment) on women with newly diagnosed invasive stage I-III breast cancer and HCs. Objective cognitive performance, cognitive complaints, anxiety, depression, and fatigue were assessed. Objective cognitive impairment was defined according to International Cognition and Cancer Task Force recommendations. RESULTS: Of the 264 included patients with breast cancer (54 ± 11 years) and 132 age-matched HCs (53 ± 9 years), overall objective cognitive impairment was observed in 28% of patients with breast cancer and 8% of HCs (P < 0.001). Cognitive complaints were reported by 24% of patients versus 12% of HCs (P < 0.01). Patients reported significantly more anxiety and emotional and cognitive fatigue than HCs (P < 0.01). After adjustment, significantly more patients with breast cancer had overall objective cognitive impairment than HCs [OR = 3.01; 95% confidence interval (CI): 1.31-6.88] without significant difference between groups for cognitive complaints (OR = 1.38; 95% CI: 0.65-2.92). Cognitive complaints were positively associated with fatigue (OR = 1.03; 95% CI: 1.02-1.05). CONCLUSIONS: In this prospective study, compared with HCs, patients with localized breast cancer had more objective cognitive impairment before any treatment. Cognitive complaints were mostly related to fatigue. IMPACT: Baseline assessment before treatment is important to assess the impact of each cancer treatment on cognition.

Childhood maltreatment and clinical severity of treatment-resistant depression in a French cohort of outpatients (FACE-DR): One-year follow-up.

BACKGROUND: Childhood maltreatment is associated with major depressive disorder (MDD). It not only increases the risk of lifetime MDD, but it also aggravates its course. Among depressed patients, 20-30% of them experience treatment-resistance depression (TRD). We aimed to assess the association between childhood maltreatment, severity of depression in a unipolar TRD sample, and patient outcomes after one-year of follow-up. METHODS: Patients were recruited for a prospective cohort from the French network of TRD expert centers. Depressive symptom severity was assessed with the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Quick Inventory of Depressive Symptomatology self-report (QIDS-SR). Childhood maltreatment was evaluated with the Childhood Trauma Questionnaire (CTQ). RESULTS: In total, 256 patients filled in the CTQ at baseline between 2012 and 2019. At baseline, the MADRS score was associated with CTQ score (ß = .185; p = .004). QIDS was also associated with CTQ scores (ß = .27; p < .001). Regarding the different subtypes of childhood maltreatment, MADRS was associated with physical (ß = .21; p = .005) and sexual abuse (ß = .22; p = .002), while QIDS with physical abuse (ß = .304; p < .001) and physical neglect (ß = .254; p < .001). However, we did not find any significant association focusing on the other types of traumas. During a 1-year follow-up focusing on remission, CTQ scores (baseline) were less important in remittent patients [n = 38; CTQ score = 39.26 (9.68)] than in nonremittent ones [n = 92; CTQ score = 46.02 (17.53)] (p = .027). There was no significant difference among remitters and nonremitters based on trauma subtypes. At baseline, CTQ scores had a significant influence on remission at 1 year (χ2 (1) = 5.57; p < .05). We lost this influence adding MADRS scores at baseline in the model (p = .063). CONCLUSION: We highlighted a significant association between the severity of depressive disorders and childhood maltreatment in the TRD population. Information about a history of childhood maltreatment helps in identifying individuals who could be less likely to go into remission after treatment.