A double-blind, randomized, placebo-controlled proof of concept study of the efficacy and safety of Lu AF11167 for persistent negative symptoms in people with schizophrenia.

Lu AF11167 is a selective, high-affinity inhibitor of PDE10A that modulates dopamine D1 and D2 receptor-mediated intraneuronal signalling without binding to these receptors. This randomized, double-blind, parallel-group, placebo-controlled study (NCT03793712) with open-label extension (NCT03929497) evaluated the efficacy of two fixed-flexible doses (1-2mg/day and 3-4mg/day) of Lu AF11167 in stable, non-acute patients with schizophrenia and persistent prominent negative symptoms. The studies were discontinued following a futility analysis of the double-blind study, and we report data collected up to study termination. Of the 210 patients screened, 162 were randomized, 111 completed the double-blind study and 96 entered the open-label study before early termination. The withdrawal rate due to impending relapse was low and comparable across treatment groups (n = 2-4 per group in the double-blind study and n = 1 in the open-label extension). Double-blind treatment with Lu AF11167 3-4mg was not superior to placebo in the reduction of Brief Negative Symptom Scale (BNSS) total scores from Baseline to Week 12 (primary endpoint); adjusted mean changes were -6.8 with placebo, -5.7 with Lu AF11167 1-2 mg group and -6.0 with Lu AF11167 3-4mg. Treatment with Lu AF11167 1-2mg also failed to separate from placebo on the primary endpoint. Neither dose group showed significant improvements versus placebo on any of the secondary efficacy measures exploring effect of treatment on overall symptomology, negative symptoms, positive symptoms, or functioning. Administration of Lu AF11167 was safe and well tolerated and adverse events were not a major reason for withdrawal from the study.

Predictors and trajectories of treatment response to SSRIs in patients suffering from PTSD.

Paroxetine and sertraline are the only FDA approved drugs for treatment of posttraumatic stress disorder (PTSD). Although both drugs show better outcomes than placebo, not all patients benefit from treatment. We examined predictors and latent classes of SSRI treatment response in patients with PTSD. Symptom severity was measured over a 12-week period in 390 patients suffering from PTSD treated with open-label sertraline or paroxetine and a double-blinded placebo. First, growth curve modeling (GCM) was used to examine population-level predictors of treatment response. Second, growth mixture modeling (GMM) was used to group patients into latent classes based on their treatment response trajectories over time and to investigate predictors of latent class membership. Gender, childhood sexual trauma, and sexual assault as index trauma moderated the population-level treatment response using GCM. GMM identified three classes: fast responders, responders with low pretreatment symptom severity and responders with high pretreatment symptom severity. Class membership was predicted based on time since index trauma, severity of depression, and severity of anxiety. The study shows that higher severity of comorbid disorders does not result in an inferior response to treatment and suggests that patients with longer time since index trauma might particularly benefit from treatment with sertraline or paroxetine.

A large-scale genome-wide gene expression analysis in peripheral blood identifies very few differentially expressed genes related to antidepressant treatment and response in patients with major depressive disorder.

A better understanding of the biological factors underlying antidepressant treatment in patients with major depressive disorder (MDD) is needed. We perform gene expression analyses and explore sources of variability in peripheral blood related to antidepressant treatment and treatment response in patients suffering from recurrent MDD at baseline and after 8 weeks of treatment. The study includes 281 patients, which were randomized to 8 weeks of treatment with vortioxetine (N = 184) or placebo (N = 97). To our knowledge, this is the largest dataset including both gene expression in blood and placebo-controlled treatment response measured by a clinical scale in a randomized clinical trial. We identified three novel genes whose RNA expression levels at baseline and week 8 are significantly (FDR < 0.05) associated with treatment response after 8 weeks of treatment. Among these genes were SOCS3 (FDR = 0.0039) and PROK2 (FDR = 0.0028), which have previously both been linked to depression. Downregulation of these genes was associated with poorer treatment response. We did not identify any genes that were differentially expressed between placebo and vortioxetine groups at week 8 or between baseline and week 8 of treatment. Nor did we replicate any genes identified in previous peripheral blood gene expression studies examining treatment response. Analysis of genome-wide expression variability showed that type of treatment and treatment response explains very little of the variance, a median of <0.0001% and 0.05% in gene expression across all genes, respectively. Given the relatively large size of the study, the limited findings suggest that peripheral blood gene expression might not be the best approach to explore the biological factors underlying antidepressant treatment.

Challenges and opportunities for the development of new antipsychotic drugs.

In spite of the significant impact that the serendipitous discovery of drugs with antipsychotic properties had on the care of patients with psychotic disorders, there are significant challenges when aiming at therapeutic goals such as remission, recovery, improved health-related quality of life and functioning. The efficacy and effectiveness of existing antipsychotic drugs fail to address the full spectrum of symptoms and functional deficits that currently prevent patients with psychotic disorders from achieving fulfilling lives. The study of the pharmacological mechanism of action has increased our knowledge on molecular targets and brain circuits related to the antipsychotic properties of this drug class. However, our understanding of how these molecular targets and brain circuits relate to other aspects of disease pathophysiology like cognitive impairment and negative symptoms is incomplete although these are significant clinical unmet needs. Currently, there is still an important knowledge gap between psychopathology and pathophysiology in schizophrenia research. This may have contributed to some recent costly failures of large clinical development programs for drugs targeted at glutamatergic function and nicotinic receptors. The lack of success of these pharmacological approaches to achieve clinical validation raises important questions concerning the underlying hypothesis that guided the choice of molecular targets, and about the predictive validity of translational models that supported the rationale for testing these drugs in clinical studies. From a clinical perspective there is a need to more strongly consider the disease heterogeneity linked to the use of the current diagnostic classification of subjects and to the validity of the psychopathological constructs and assessments that are used to assess clinical outcomes. A paradigm shift in the development of drugs for schizophrenia is needed. This will require among other addressing: the shortcomings of a single diagnostic entity; the needs for in depth clinical phenotyping to leverage the findings of schizophrenia genetics and advance the understanding of the disease biology; the symptom domains that are the major sources of disability in order to improve functional outcomes beyond current treatment options. In spite of the progress achieved during the last century the task ahead is still daunting and will require the efforts of scientists and clinicians through inclusive public-private partnerships and consortia to create the scientific basis for new therapeutic approaches to schizophrenia.

The cultural adaptability of intermediate measures of functional outcome in schizophrenia.

The Measurement and Treatment Research to Improve Cognition in Schizophrenia initiative was designed to encourage the development of cognitive enhancing agents for schizophrenia. For a medication to receive this indication, regulatory agencies require evidence of improvement in both cognition and functional outcome. Because medication trials are conducted across multiple countries, we examined ratings of the cross-cultural adaptability of 4 intermediate measures of functional outcome (Independent Living Scales, UCSD Performance-based Skills Assessment, Test of Adaptive Behavior in Schizophrenia, Cognitive Assessment Interview [CAI]) made by experienced clinical researchers at 31 sites in 8 countries. English-speaking research staff familiar with conducting medication trials rated the extent to which each subscale of each intermediate measure could be applied to their culture and to subgroups within their culture based on gender, geographic region, ethnicity, and socioeconomic status on the Cultural Adaptation Rating Scale. Ratings suggested that the CAI would be easiest to adapt across cultures. However, in a recent study, the CAI was found to have weaker psychometric properties than some of the other measures. Problems were identified for specific subscales on all the performance-based assessments across multiple countries. India, China, and Mexico presented the greatest challenges in adaptation. For international clinical trials, it would be important to use the measures that are most adaptable, to adapt subscales that are problematic for specific countries or regions, or to develop a battery composed of the subscales from different instruments that may be most acceptable across multiple cultures with minimal adaptation.

Current therapeutic strategies for anxious depressives.

Anxious depressives refers to a group of patients with a primary depressive disorder, who also have significant symptoms of anxiety. Despite the fact that this group of patients is widely recognized and understood to have a poorer prognosis, this group has been poorly studied to date. In this review, we briefly examine the pathophysiology and neurophysiology of this condition. We then reviewed in detail the relevant clinical studies which have been carried out in this condition and published over the last 5 years. Taken together, the results of published studies begin to suggest that patients with anxious depression may respond better to antidepressants that are dual action drugs (such as serotonin and noradrenaline re-uptake inhibitors), rather than single action drugs (such as specific serotonin re-uptake inhibitors). However, further controlled studies are warranted to test this hypothesis.

Novel treatments for anxiety and depression: hurdles in bringing them to the market.

Anxiety and depressive disorders are the most common psychiatric conditions. The medical need for newer, better-tolerated and more efficacious treatments remains high. However, drug development is time-consuming and has a high rate of failed or inconclusive trials. Improvements in study design, investigator training and early proof-of-concept studies are being discussed as means to decrease failure rates and the duration of development. So far, no uniformly applicable 'magic formulas' for success have been discovered. The most promising approach to overcome these hurdles appears to be a sound study design carried out by experienced professionals in the clinic and in industry.