Evaluation of state and trait biomarkers in healthy volunteers for the development of novel drug treatments in schizophrenia

Abstract

Antipsychotic drugs are the mainstay of treatment for schizophrenia but they have little effect on core negative symptoms or cognitive impairment. To meet the deficiencies of current treatments, novel potential compounds are emerging from preclinical research but translation to clinical success has been poor. This article evaluates the possibility that cognitive and physiological abnormalities in schizophrenia can be used as central nervous system biomarkers to predict, in healthy volunteers, the likely efficacy of entirely new pharmacological approaches to treatment. Early detection of efficacy would focus resource on rapidly developing, effective drugs. We review the relevance of selected cognitive and physiological abnormalities as biomarkers in schizophrenia and three of its surrogate populations: (i) healthy volunteers with high trait schizotypy; (ii) unaffected relatives of patients; and (iii) healthy volunteers in a state of cortical glutamate disinhibition induced by low-dose ketamine. Several biomarkers are abnormal in these groups and in some instances there has been exploratory work to determine their sensitivity to drug action. They are generally insensitive to current antipsychotics and therefore their predictive validity cannot be established until novel, therapeutically useful drugs are discovered. Until then such biomarker studies can provide evidence of drugs engaging with the mechanism of interest and encouragement of the concept.

Cognition and Brain Function in Schizotypy: A Selective Review

“…The incomplete effectiveness of antipsychotic and procognitive drugs represent an area of clear unmet need in schizophrenia and the development of new compounds is likely to benefit from model systems with well validated biomarkers. 146,147 Applying the high schizotypy approach in an exploration of the validity of this model system it was recently shown that (1) WM impairments in high schizotypy were partly alleviated by amisulpride 148 and (2) risperidone impaired antisaccade performance in medium schizotypal controls, whereas high schizotypals showed a numeric trend towards improvement. 149 These recent data suggest that it may be possible to apply the schizotypy approach in drug development.…”

Baseline dependency of nicotine’s sensory gating actions: similarities and differences in low, medium and high P50 suppressors

“…As evident with our rP50 gating index, the average S 2 /S 1 % gating score of ~99% in low suppressors is well within 1 SD (24.3) of the mean ratio of 79% typically seen in patients with schizophrenia (Patterson et al, 2008). The pro-gating action of nicotine in these extreme low suppressor individuals suggests that this P50 strategy of segmenting healthy volunteers allows for selection of a more homogenous sample that closely models the gating pathophysiology of schizophrenia, which in turn reduces the variability of response to a drug candidate and may help to reveal pharmacological and pharmacodynamic activity in early phases of the drug discovery and development process (Koychev et al, 2011). Baseline-dependency, however, remains a description of a relationship, and not a cause of response to drugs.…”

Neurobiological basis of motivational deficits in psychopathology

“…Pharmacological induction of the full range of schizophrenia symptoms, including negative symptoms, in healthy volunteers has been proposed as a model that may facilitate early (i.e. Phase 1 clinical trials) evaluation of efficacy of novel agents (Koychev et al, 2011).…”