Microglial production of quinolinic acid as a target and a biomarker of the antidepressant effect of ketamine.

Major depressive disorder is a complex multifactorial condition with a so far poorly characterized underlying pathophysiology. Consequently, the available treatments are far from satisfactory as it is estimated that up to 30% of patients are resistant to conventional treatment. Recent comprehensive evidence has been accumulated which suggests that inflammation may be implied in the etiology of this disease. Here we investigated ketamine as an innovative treatment strategy due to its immune-modulating capacities. In a murine model of LPS-induced depressive-like behavior we demonstrated that a single dose of ketamine restores the LPS-induced depressive-like alterations. These behavioral effects are associated with i/ a reversal of anxiety and reduced self-care, ii/ a decrease in parenchymal cytokine production, iii/ a modulation of the microglial reactivity and iv/ a decrease in microglial quinolinic acid production that is correlated with plasmatic peripheral production. In a translational approach, we show that kynurenic acid to quinolinic acid ratio is a predictor of ketamine response in treatment-resistant depressed patients and that the reduction in quinolinic acid after a ketamine infusion is a predictor of the reduction in MADRS score. Our results suggest that microglia is a key therapeutic target and that quinolinic acid is a biomarker of ketamine response in major depressive disorder.

Are participants in pharmacological and psychotherapy treatment trials for social anxiety disorder representative of patients in real-life settings?

BACKGROUND: The present study sought to quantify the generalizability of clinical trial results in individuals with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnosis of social anxiety disorder (SAD) to a large representative community sample. METHODS: Data were derived from the 2004-2005 National Epidemiologic Survey on Alcohol and Related Conditions, a large nationally representative sample of 34,653 adults from the US population. We applied a standard set of exclusion criteria representative of pharmacological and psychotherapy clinical trials to all adults with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnosis of SAD (n = 965) in the past 12 months and then to a subsample of participants seeking treatment (n = 363). Our aim was to assess how many participants with SAD would fulfill typical eligibility criteria. RESULTS: We found that more than 7 of 10 respondents from the overall SAD sample in a typical pharmacological efficacy trial and more than 6 of 10 participants in a typical psychotherapy efficacy trial would have been excluded by at least 1 criterion. In addition, more than 8 of 10 respondents seeking treatment for SAD would have been excluded from participation in a typical pharmacological or psychotherapy efficacy trial. Having a current major depression explained a large proportion of ineligibility. CONCLUSIONS: Clinical trials should carefully consider the impact of exclusion criteria on the generalizability of their results and explain the rationale for their use. For SAD treatment trials to adequately inform clinical practice, the eligibility rate must be increased through a general relaxation of overly stringent eligibility criteria.

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.

One-year mirror-image study of the impact of olanzapine long-acting injection on healthcare resource utilization and costs in severe schizophrenia.

Olanzapine long-acting injections (OLAIs) are often prescribed to patients with severe schizophrenia who are typically excluded from randomized clinical trials. To date, no mirror-image study has examined the impact of OLAIs on healthcare resource utilizations in these patients. We conducted a retrospective, one-year mirror-image study of OLAIs on 40 patients with severe schizophrenic disorder. Illness severity was defined by failure to respond to two sequential antipsychotics. Outcomes included: (i) healthcare resource utilizations via hospitalization admissions, bed days, outpatient visits, and inpatient service costs computations (ii) clinical efficacy through changes in the Brief Psychiatric Rating Scale (BPRS) and in the Clinical Global Impression-Schizophrenia Scale (CGI-SCH), and (iii) adverse effects. After one year, OLAIs were associated with significant decreases of 65.7%, 86.2% and 86.2% in hospitalization admissions, bed days, and inpatient service costs respectively. A significant mean change of -0.47 and -0.63 was determined the BPRS and the CGI-SCH scores, respectively. There were no significant differences in the number of outpatient visits and adverse effects, except for post-injection sedation/delirium syndrome whose incidence was 0.30% per injection. This mirror-image study provides the first evidence that prescribing OLAIs reduces in a cost-effective manner average bed days and hospital admissions in patients with severe schizophrenia.

Attention-deficit/hyperactivity disorder symptom expression: a comparison of individual age at onset using item response theory.

BACKGROUND: The DSM-IV age at onset criterion for attention-deficit/hyperactivity disorder (ADHD) has been a subject of debate. In DSM-5, the required age at onset (ie, the age by which impairing symptoms must have been present) has increased from 7 years to 12 years. The present study examined measurement properties of ADHD symptoms according to age at onset. METHOD: Data were derived from the 2004-2005 National Epidemiologic Survey on Alcohol and Related Conditions, which included 34,653 US participants. Among participants with a lifetime DSM-IV diagnosis of ADHD (assessed using the Alcohol Use Disorder and Associated Disabilities Interview Schedule-IV), we compared the psychometric properties of the 18 ADHD symptoms according to 3 categories of age at onset (≤ 7 years, > 7 and ≤ 12 years, and > 12 and ≤ 18 years). A 2-parameter item response model was used to estimate differential item functioning (DIF) between these groups. RESULTS: 364 participants with a lifetime DSM-IV diagnosis of ADHD had an age at onset ≤ 7 years, 252 had an age at onset > 7 and ≤ 12 years, and 148 had an age at onset > 12 and ≤ 18 years. In both dimensions of ADHD (ie, inattention and hyperactivity-impulsivity), there was no significant DIF between age at onset groups. CONCLUSIONS: Expression of DSM-IVADHD symptoms was not affected by age at onset in the 3 groups considered. This study provides psychometric support to the change in the age criterion introduced by DSM-5 and further suggests that the age at onset criterion could be extended to 18 years without changing the psychometric properties of the ADHD symptoms.

Novel routes to bipolar disorder drug discovery.

INTRODUCTION: Bipolar disorder (BD) is a severe and chronic medical condition typified by episodic recurrent mania (or hypomania) in addition to major depression. BD is associated with a number of negative outcomes including premature death, reduced quality of life and can also lead to other complications including impaired cognitive function. Unfortunately, the currently available pharmacological treatments for BD are insufficient for many with the condition. AREAS COVERED: This review focuses on known therapeutic targets of mood stabilizing drugs including: the glycogen synthase kinase-3 (GSK-3), the phosphoinositide pathway and protein kinase C (PKC), the brain-derived neurotrophic factor (BDNF), and histone deacetylases (HDACs). This article also presents new promising therapeutic targets including: the glutamatergic pathway, mitochondrial modulators, neuropeptide-converting endopeptidases, the insulin transduction pathway, the purinergic system and the melatoninergic system. EXPERT OPINION: Challenges in improving methods and tools to generate, integrate and analyze high-dimensional data are required to allow opening novel routes to BD drug discovery. Through the application of systems biology approaches and the use of bioinformatical tools to integrate all omics data, it will be possible in the near future to gain deeper insights into pathophysiology of BD. This will in turn lead to the identification and exploitation of new potential therapeutic approaches.

Are subjects in treatment trials of panic disorder representative of patients in routine clinical practice? Results from a national sample.

BACKGROUND: Research on the generalizability of clinical trials in panic disorder is limited. The present study sought to quantify the generalizability of clinical trials' results of individuals with DSM-IV panic disorder (PD) to a large community sample. METHODS: Data were derived from the National Epidemiological Survey on Alcohol and Related Conditions (NESARC), a large national representative sample of 43,093 adults of the United States population. We applied a standard set of eligibility criteria representative of PD clinical trials to all adults with past 12 months PD (n=907), and then to a subgroup of participants seeking treatment (n=105). Our aim was to determine the proportion of participants with PD who would have been excluded by typical eligibility criteria. RESULTS: We found that more than 8 out of ten participants (80.52%; 95% CI=77.13-83.52%) with PD were excluded by at least one criterion. In the subgroup of participants who sought treatment, the exclusion rate by at least one criterion was higher (92.40%; 95% CI=84.60-96.42%). For the full sample and the treatment-seeking subsample, having currently a depression and a diagnosis of alcohol or drug abuse/dependence were the criteria excluding the highest percentage of participants. Having a lifetime history of bipolar disorder and a current significant medical condition also excluded a substantial proportion of individuals in both samples. Exclusion rates were similar when considering panic disorder with and without agoraphobia. CONCLUSIONS: Clinical trials, that exclude a majority of adults with panic disorder, should carefully consider the impact of eligibility criteria on the generalizability of their results. As required by CONSORT guidelines, reporting exclusion rate estimate and reasons of eligibility should be mandatory in both clinical trials and meta-analyses.