A new era for schizophrenia drug development - Lessons for the future.

For many patients and their treating clinicians, the pharmacological management of psychotic symptoms centres on trying to find a regime that balances efficacy and quality of life-impairing side effects associated with dopamine antagonism. Recent reports of a positive Phase III study from Karuna Therapeutics indicate that the first primarily non-dopamine-based treatment for schizophrenia may come to market soon with the potential for substantially reduced or differentiated side effects. Against a background of repeated failures, Karuna's success promises a desperately needed new treatment option for patients. It also reflects some hard-won lessons about the methodology for schizophrenia drug development.

Emotional bias training as a treatment for anxiety and depression: evidence from experimental medicine studies in healthy and medicated samples.

BACKGROUND: Anxiety and depression are leading causes of disability worldwide, yet individuals are often unable to access appropriate treatment. There is a need to develop effective interventions that can be delivered remotely. Previous research has suggested that emotional processing biases are a potential target for intervention, and these may be altered through brief training programs. METHODS: We report two experimental medicine studies of emotional bias training in two samples: individuals from the general population (n = 522) and individuals currently taking antidepressants to treat anxiety or depression (n = 212). Participants, recruited online, completed four sessions of EBT from their own home. Mental health and cognitive functioning outcomes were assessed at baseline, immediately post-training, and at 2-week follow-up. RESULTS: In both studies, our intervention successfully trained participants to perceive ambiguous social information more positively. This persisted at a 2-week follow-up. There was no clear evidence that this change in emotional processing transferred to improvements in symptoms in the primary analyses. However, in both studies, there was weak evidence for improved quality of life following EBT amongst individuals with more depressive symptoms at baseline. No clear evidence of transfer effects was observed for self-reported daily stress, anhedonia or depressive symptoms. Exploratory analyses suggested that younger participants reported greater treatment gains. CONCLUSIONS: These studies demonstrate the effectiveness of delivering a multi-session online training program to promote lasting cognitive changes. Given the inconsistent evidence for transfer effects, EBT requires further development before it can be considered as a treatment for anxiety and depression.

Latent inhibition, aberrant salience, and schizotypy traits in cannabis users.

Aberrant salience processing may underlie the link between cannabis and psychosis, as posited in individuals with schizophrenia or high schizotypy. We investigated the relative effects of cannabis use, schizotypy status, and self-reported aberrant salience experiences on salience processing, measured using a latent inhibition (LI) task (Granger et al., 2016), in a non-clinical population. A university sample of 346 participants completed the Schizotypal Personality Questionnaire (SPQ), Aberrant Salience Inventory (ASI) the modified Cannabis Experience Questionnaire (CEQmv) and the LI task. Regression models and parallel (Bayesian and frequentist) t-tests or ANOVA (or non-parametric equivalents) examined differences in LI based on lifetime or current cannabis use (frequent use during previous year), as well as frequency of use. Mann-Whitney U tests assessed differences in SPQ and ASI scores based on current cannabis use. Neither lifetime nor current cannabis use was associated with significant change in LI scores. Current cannabis use was associated with both higher 'Disorganised' and 'Cognitive-perceptual' SPQ dimension scores and higher total and sub-scale ASI scores. No association was observed between LI score and SPQ total and dimension scores. Higher scores on 'Senses sharpening' and the 'Heightened cognition' ASI subscales predicted decreased LI scores. These data support previous findings of no association between cannabis use and abnormality in other associative learning tasks in young non-clinical populations, and elaborate the previously demonstrated association between self-reported cannabis use, schizotypy and aberrant salience. The association between dimensions of ASI and LI performance suggests this task may have potential as an experimental measure of aberrant salience.

Test-retest reliability on the Cambridge Neuropsychological Test Automated Battery: Comment on Karlsen et al. (2020).

Test-retest reliability is essential to the development and validation of psychometric tools. Here we respond to the article by Karlsen et al. (Applied Neuropsychology: Adult, 2020), reporting test-retest reliability on the Cambridge Neuropsychological Test Automated Battery (CANTAB), with results that are in keeping with prior research on CANTAB and the broader cognitive assessment literature. However, after adopting a high threshold for adequate test-retest reliability, the authors report inadequate reliability for many measures. In this commentary we provide examples of stable, trait-like constructs which we would expect to remain highly consistent across longer time periods, and contrast these with measures which show acute within-subject change in response to contextual or psychological factors. Measures characterized by greater true within-subject variability typically have lower test-retest reliability, requiring adequate powering in research examining group differences and longitudinal change. However, these measures remain sensitive to important clinical and functional outcomes. Setting arbitrarily elevated test-retest reliability thresholds for test adoption in cognitive research limits the pool of available tools and precludes the adoption of many well-established tests showing consistent contextual, diagnostic, and treatment sensitivity. Overall, test-retest reliability must be balanced with other theoretical and practical considerations in study design, including test relevance and sensitivity.

Effects of 7.5% Carbon Dioxide and Nicotine Administration on Latent Inhibition.

Stratified medicine approaches have potential to improve the efficacy of drug development for schizophrenia and other psychiatric conditions, as they have for oncology. Latent inhibition is a candidate biomarker as it demonstrates differential sensitivity to key symptoms and neurobiological abnormalities associated with schizophrenia. The aims of this research were to evaluate whether a novel latent inhibition task that is not confounded by alternative learning effects such as learned irrelevance, is sensitive to (1) an in-direct model relevant to psychosis [using 7.5% carbon dioxide (CO2) inhalations to induce dopamine release via somatic anxiety] and (2) a pro-cognitive pharmacological manipulation (via nicotine administration) for the treatment of cognitive impairment associated with schizophrenia. Experiment 1 used a 7.5% CO2 challenge as a model of anxiety-induced dopamine release to evaluate the sensitivity of latent inhibition during CO2 gas inhalation, compared to the inhalation of medical air. Experiment 2 examined the effect of 2 mg nicotine administration vs. placebo on latent inhibition to evaluate its sensitivity to a potential pro-cognitive drug treatment. Inhalation of 7.5% CO2 raised self-report and physiological measures of anxiety and impaired latent inhibition, relative to a medical air control; whereas administration of 2 mg nicotine, demonstrated increased latent inhibition relative to placebo control. Here, two complementary experimental studies suggest latent inhibition is modified by manipulations that are relevant to the detection and treatment of schizophrenia. These results suggest that this latent inhibition task merits further investigation in the context of neurobiological sub-groups suitable for novel treatment strategies.

Postoperative cognitive dysfunction: an acute approach for the development of novel treatments for neuroinflammation.

Inflammation within the central nervous system (CNS; neuroinflammation) is a major contributor to lasting symptoms of traumatic brain injury and stroke, and likely has a casual role Alzheimer's disease (AD) and other neurodegenerative conditions. Therapeutic modulation of the immune processes that initiate and maintain neuroinflammation is of growing scientific interest but neuroinflammatory drug development is hampered by limited reliability and availability of neuroimaging or other biomarkers in humans. Better means of establishing drug efficacy on human neuroinflammation would have great value in accelerating the development of neuroinflammatory compounds for many clinical indications. Here, we discuss the use of postoperative cognitive decline (POCD), which is hypothesised to have a neuroinflammatory basis, as an acute indication to demonstrate the efficacy of novel neuroinflammatory drugs.

The Use of Cognitive Screening in Pharmacotherapy Trials for Cognitive Impairment Associated With Schizophrenia.

There are currently no regulatory approved pharmacological treatments for cognitive impairment associated with schizophrenia (CIAS). One possibility is that trial methodology itself is hindering their development. Emerging evidence suggests that patients with schizophrenia may show limited benefit from pro-cognitive interventions if they already exhibit intact cognitive performance, relative to normative thresholds. The aim of this report was to examine the extent to which objectively assessed cognitive performance has been used as an eligibility and/or stratification criterion in CIAS pharmacotherapy trials. On 16th January 2019, we conducted a systematic search of studies listed on ClinicalTrials.gov to identify randomized, double-blind, placebo-controlled, add-on pharmacotherapy trials conducted in patients with a diagnosis of schizophrenia, in which a paper-and-pencil or computerized cognitive task (or battery) was specified as a primary outcome measure. Of the 87 trials that met our inclusion criteria, 10 (11.5%) required the presence of an objectively assessed cognitive deficit as part of their patient eligibility criteria. No studies reported stratifying patients according to the presence or degree of cognitive impairment they exhibited. These results suggest that the vast majority of CIAS trials may have been underpowered due to the inclusion of cognitively "normal" patients. Purposive screening for cognitive impairment could increase CIAS trial success.

Examining the effectiveness of acetylcholinesterase inhibitors and stimulant-based medications for cognitive dysfunction in multiple sclerosis: A systematic review and meta-analysis.

We sought to examine the effectiveness of acetylcholinesterase inhibitors (AChEIs) and stimulant-based medications for improving cognitive performance in patients with multiple sclerosis (MS). An electronic database search was conducted on 25th March 2017. Eligible studies were double-blind, randomised, placebo-controlled trials that examined the efficacy of compounds that act primarily as AChEIs or stimulants (administered daily for ≥1 week) on cognitive outcome measures in patients with MS. Where suitable data was reported, we generated effect sizes and corresponding 95% confidence intervals and performed meta-analyses using random-effects models to investigate the effectiveness of these drug types across cognitive domains. Sixteen trials were included in the systematic review, with eleven trials (N = 734 MS patients) providing sufficient data for meta-analysis. Whilst there was only a limited pool of relatively small trials and a number of different compounds, we found that collectively, both AChEIs (donepezil and rivastigmine) and stimulants (methylphenidate, modafinil, l-amphetamine sulfate and lisdexamfetamine dimesylate) offered no significant benefits over placebo on measures of processing speed, working memory, verbal fluency, verbal memory, visuospatial memory or executive functioning.

Social cognitive dysfunction as a clinical marker: A systematic review of meta-analyses across 30 clinical conditions.

Social cognition includes a range of cognitive processes that help individuals to understand how others think and feel. There is emerging evidence that social cognitive deficits may represent a transdiagnostic issue, potentially serving as a marker of neurological abnormality. We performed an electronic database search in order to identify published, peer-reviewed meta-analyses that compared facial emotion recognition or theory of mind task performance between individuals meeting clinical criteria for a psychiatric, neurological or developmental condition against healthy controls. We identified 31 meta-analyses eligible for inclusion that examined performance across relevant tasks among 30 different clinical populations. The results suggest that social cognitive deficits appear to be a core cognitive phenotype of many clinical conditions. Across the clinical groups, deficits in social cognitive domains were broadly similar in magnitude to those previously reported for more established aspects of cognition, such as memory and executive function. There is a need to clarify the 'real world' impact of these deficits, and to develop effective transdiagnostic interventions for those individuals that are adversely affected.