Esketamine-induced post-traumatic stress disorder flashbacks during treatment-resistant depression indication: is it just a side effect?

Background: Posttraumatic stress disorder (PTSD) is a severe and frequent affection that is highly comorbid to major depressive disorder. Comorbid PTSD and depression are usually treatment-resistant, with a high risk of functional impairment and suicide. Esketamine nasal spray is a recent validated treatment for treatment-resistant depression (TRD), but its efficacy on comorbid TRD-PTSD remains insufficiently documented. In particular, flashbacks can occur during esketamine administration and their influence on clinical outcomes is unknown. Objectives: Our main objective was to describe esketamine-induced traumatic flashbacks and their impact on clinical trajectories within a sample of patients with comorbid TRD-PTSD. Methods: We retrospectively collected clinical data of patients receiving esketamine nasal spray for TRD with comorbid PTSD who experienced at least one flashback of their trauma during esketamine sessions across 11 psychiatric departments. Results: Between February 2020 and March 2023, 22 adult patients with TRD met inclusion criteria. In sixteen patients (72.7%) flashbacks disappeared as the sessions progressed. In six patients (27.3%), esketamine treatment was stopped because of persistent flashbacks. When esketamine was continued, clinical response was observed both for depression and PTSD (depression response rate: 45.5% and remission rate: 22.7%; PTSD response rate: 45.5% and remission: 18.2%). Limitations: The retrospective design of the study and the absence of a comparator group are the main limitations of our study. Conclusions: Our results suggest that the occurrence of esketamine-induced traumatic flashbacks does not hinder clinical response. On the contrary, when managed appropriately and combined with targeted psychotherapy, it could even contribute to positive outcomes.

Early effects predict trajectories of response to esketamine in treatment-resistant depression.

BACKGROUND: The efficacy of esketamine in treatment-resistant depression (TRD) has been confirmed. However, its administration is expensive and restrictive, with limited knowledge on how long the treatment should be continued. Predicting the treatment outcome would benefit patients and alleviate the global treatment cost. We aimed to define distinct trajectories of treatment response and assess their predictability. METHODS: In this longitudinal study, two independent samples of patients with unipolar or bipolar TRD were treated with esketamine in real-world settings. Depression severity was assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS) before each esketamine administration. Latent class analyses were used to define trajectories of response. RESULTS: In the original sample (N = 50), we identified two classes whose trajectories depicted response and non-response, respectively. The model was validated in the confirmatory sample (N = 55). Class membership was influenced by a few baseline characteristics such as concomitant benzodiazepine medication, number of depressive episodes or polarity. On the other hand, after only two esketamine administrations, the MADRS score predicted the 90-day trajectory of response with an accuracy of 80 %. LIMITATIONS: This observational study is not placebo-controlled. Therefore, its results and their generalizability need to be confirmed in experimental settings. CONCLUSIONS: After the first administrations of esketamine, the MADRS score has a good capacity to predict the most plausible trajectory of response. While thresholds and their predictive values need to be confirmed, this finding suggests that clinicians could base on MADRS scores their decision to discontinue treatment because of poor remaining chances of treatment response.

Esketamine nasal spray in patients with treatment-resistant depression: the real-world experience in the French cohort early-access programme.

OBJECTIVE: To present the first real-world data of patients with treatment-resistant depression (TRD) treated with esketamine through a French cohort Temporary Authorisation for Use (ATUc) programme. METHODS: In 2019, the French Health Authorities exceptionally granted the first ATUc in psychiatry for TRD patients. Clinical characteristics, safety and efficacy data were reported by physicians. The ATUc ended ∼6 months after initiation. RESULTS: The cohort (n = 66; median age 53.0 years; 62.1% female; 78.8% with severe major depressive episodes; resistance to a mean of 4.2 previous antidepressants) received esketamine treatment for a median of 30 days. Among 46 analysed patients, 22 (47.8%) achieved response (Montgomery-Åsberg Depression Rating Scale [MADRS] total score reduction ≥50.0%) and 17 (37.0%) achieved remission (MADRS total score of ≤12) at least once at a median of 18.5 (2.0-77.0) and 21.0 (2.0-46.0) days after initiation, respectively. By Week 4, patients had a 31.6% probability of achieving remission (Kaplan-Meier method). Sedation, somnolence, dizziness, hypertension, anxiety and dissociation were the most frequently reported (>10.0%) adverse events. No new safety signals were identified. CONCLUSIONS: Patient characteristics of this cohort demonstrate high-level treatment resistance. The safety and efficacy of esketamine in patients with TRD in real-world clinical practice were consistent with Phase 3 trials.Key pointsPatients with treatment-resistant depression (TRD) exceptionally received esketamine nasal spray ahead of its launch through a French cohort Temporary Authorisation for Use (ATUc) programme.The clinical characteristics of 66 adult patients with TRD included in this cohort demonstrated a high-level of resistance to conventional treatments at the time of treatment request prior to esketamine initiation.No new safety signals were observed with esketamine initiation during the ATUc period compared with the Phase 3 clinical trials.The safety and efficacy of esketamine in the real world remain consistent with that established in Phase 3 clinical trials.The data collected during this ATUc also provide the first real-world data on the management and practical use of esketamine in a hospital setting in France.

Depressive-, Cognitive- or Stroke-Related Risk Factors of Post-Stroke Depression: Which One Could Better Help Clinicians and Patients?

PURPOSE: Post-stroke depression (PSD) affects one third of stroke survivors, with multiple severe negative consequences. We aim to assess the weight of four different types of clinical risk factors for PSD. PATIENTS AND METHODS: We conducted a prospective cohort study in a stroke centre. After stroke, patients were assessed for cognitive performances, psychiatric standardized questionnaires and socio-demographic features. They were called three months after and assessed for major depressive episode using DSM criteria. RESULTS: PSD was diagnosed in 8 of the 59 (13.6%) patients enrolled in the study. After multivariate analysis, only "previous history of depressive episode" remained a significant predictive factor for PSD, the model explaining 19% of the total variance (OR=18.0; p=0.002). Patients with a previous history of depression had a 10-fold increased risk for PSD. CONCLUSION: Previous history of depression is confirmed as a strong risk factor for PDS and allow the identification of an at-risk sub-group of patients.

A meta-analysis of poststroke depression risk factors comparing depressive-related factors versus others.

OBJECTIVES: Poststroke depression (PSD) is a public health issue, affecting one-third of stroke survivors, and is associated with multiple negative consequences. Reviews tried to identify PSD risk factors with discrepant results, highlighting the lack of comparability of the analyzed studies. We carried out a meta-analysis in order to identify clinical risk factors that can predict PSD. DESIGN: PubMed and Web of Science were searched for papers. Only papers with a strictly defined Diagnostic and Statistical Manual of Mental Disorders depression assessment, at least 2 weeks after stroke, were selected. Two authors independently evaluated potentially eligible studies that were identified by our search and independently extracted data using standardized spreadsheets. Analyses were performed using MetaWin®, the role of each variable being given as a risk ratio (RR). RESULTS: Eighteen studies were included in the meta-analysis. Identified risk factors for PSD with RR significantly above 1 were previous history of depression (RR 2.19, confidence interval (CI) 1.52-3.15), disability (RR 2.00, CI 1.58-2.52), previous history of stroke (RR 1.68, CI 1.06-2.66), aphasia (RR 1.47, CI 1.13-1.91), and female gender (RR 1.35, CI 1.14-1.61). Fixed effects model leads to identification of two more risk factors: early depressive symptoms with an RR of 2.32 (CI 1.43-3.79) and tobacco consumption (RR 1.40, CI 1.09-1.81). Time bias was found for alcohol consumption. Sample size was significantly involved to explain the role of "alcohol consumption" and "cognitive impairment." CONCLUSION: Five items were significantly predictive of PSD. It might be of clinical interest that depressive-related risk factors (such as past depressive episodes) were having the largest impact.

[Benefits and challenges of eHealth in depression]. / Intérêt et enjeux de la "e-santé" dans la dépression.

Depression is a common and debilitating pathology with a significant socioeconomic impact. Early and optimal treatment can help to reduce its progression towards chronicity and long-term cognitive disorders. In the context of falling numbers of medical professionals and the poor provision of validated tools, such as cognitive behavioural therapy, the use of eHealth in depression presents a clear benefit in terms of diagnostic efficacy, patient autonomy, prevention of relapse and health care costs. Innovation must however be associated with ethical deliberation, which respects the patients and their needs.

Endogenous retrovirus type W GAG and envelope protein antigenemia in serum of schizophrenic patients.

BACKGROUND: Recent and independent molecular studies have shown an association between human endogenous retroviruses type "W" family (HERV-W) and schizophrenia, mostly by polymerase chain reaction studies, but none has yet addressed specific antigen detection in living patients. METHODS: Forty-nine schizophrenic patients and an equivalent number of healthy control subjects were included in the present exploratory study. The HERV-W GAG and envelope (ENV) proteins were quantified in the serum with a dedicated immunoassay set-up with specific monoclonal antibodies to either antigen. RESULTS: In schizophrenic patients, positive antigenemia for ENV was found in 23 of 49 (47%) and for GAG in 24 of 49 (49%). Only 1 of 30 (3%) for ENV and 2 of 49 (4%) for GAG were positive in blood donors (p < .01 for ENV; p < .001 for GAG). Interestingly, bioclinical data analyses revealed significant correlation between GAG or ENV antigenemia (a protein causing dysimmune inflammatory effects) and C-reactive protein (CRP) levels (a systemic inflammation biomarker). CONCLUSIONS: Frequently elevated CRP has previously been described in schizophrenic patients and has been shown to match with an evolution toward cognitive deficit and neuronal loss. Elsewhere viruses such as influenza, long-associated with risk for schizophrenia through perinatal infections, have been shown to activate HERV-W elements in human cells. We therefore discuss a relationship between environment factors long-associated with early risk, genetic factors represented by this endogenous family, the production of its pro-inflammatory ENV protein and known "inflammation-mediated" neurotoxicity, as a possible hypothesis for a pathogenic cascade in association with HERV-W. Our present results thus confirm that HERV-W studies have opened a novel avenue of research in schizophrenia.

[Prophylactic treatment for recurrent major depression]. / Stratégies thérapeutiques prophylactiques dans la dépression unipolaire.

Approximately 80% of the patients who have a first episode of major depression will have at least one more. The lifetime average is 4 episodes. Nevertheless, despite this high risk of relapse, often severe and disabling, only half the patients with recurrent major depression receive prophylactic treatment. Long-term antidepressant treatment appears to be the most effective option for prophylactic treatment of recurrent major depression. The optimal duration of this treatment remains uncertain, in part because of the lack of long-term studies, that is, with a follow-up longer than 2 years. The interpretation of some of the controlled studies of the prophylactic efficacy of antidepressant treatment is limited by methodological issues: most antidepressants have not been studied in a purely prophylactic approach, but rather as a maintenance treatment after response during an acute episode. Lithium and carbamazepine may be prescribed as second-line preventive treatment. Although we lack controlled studies of the prophylactic efficacy of psychotherapies in recurrent depression, interpersonal, cognitive and behavioral psychotherapies have been shown to be effective in reducing the relapse rate, especially when associated with antidepressants. Treatment duration should be determined individually, taking into account the patient's risk profile and international and national guidelines.

Patients' health literacy in psychotic disorders.

Compliance and relapse are major issues in the treatment of psychotic disorders. About 50% of subjects with schizophrenia do not comply with treatment and relapse rates of 65% are reported after one year and 80% after two years. Drug treatments are effective against psychotic symptoms, but cannot promote functional recovery or prevent relapses when prescribed alone. The factors influencing compliance include side effects and the patients' awareness of their illness. Psychosocial interventions, cognitive remediation and psychotherapy have been proposed as adjuvant treatments to increase compliance and to decrease the rate of relapse. Most of these interventions have been shown to increase compliance and to decrease the rate of relapse, but the most robust results have been achieved with cognitive behavioral therapy.