Innovative solutions to novel drug development in mental health

Abstract

There are many new advances in neuroscience and mental health which should lead to a greater understanding of the neurobiological dysfunction in neuropsychiatric disorders and new developments for early, effective treatments. To do this, a biomarker approach combining genetic, neuroimaging, cognitive and other biological measures is needed. The aim of this article is to highlight novel approaches for pharmacological and non-pharmacological treatment development. This article suggests approaches that can be taken in the future including novel mechanisms with preliminary clinical validation to provide a toolbox for mechanistic studies and also examples of translation and back-translation. The review also emphasizes the need for clinician-scientists to be trained in a novel way in order to equip them with the conceptual and experimental techniques required, and emphasizes the need for private-public partnership and pre-competitive knowledge exchange. This should lead the way for important new holistic treatment developments to improve cognition, functional outcome and well-being of people with neuropsychiatric disorders.

Keywords: Back-translation; Biomarkers; Cognitive and psychosocial treatments; Neurobiological mechanisms; Neuropsychiatric disorders; Novel drug development; Pharmacological tool box; Translation.

Fig. 1

Complex genetics of mental disorders: prevalence and risk. This figure outlines genetic risk factors and rare genetic aetiologies that may be appropriate for population based screening and translation into therapeutic approaches. Three categories are identified: highly penetrant or high risk but rarely identified; more commonly identified through genomic sequencing; and higher prevalence but low contribution to risk. The degrees of penetrance are defined as follows: highly penetrant (the trait or symptom will almost always be expressed in those carrying the allele); incomplete or reduced (some individuals fail to express the trait despite carrying the allele); low penetrance (an allele will only sometimes produce the symptom).

Fig. 2

Translation and back-translation: cognitive flexibility. Intra-dimensional and extra-dimensional (ID/ED) set shifting tasks assess reversal learning (response to shift in outcome contingency) and attentional set-shifting (response to shift in focus of attention within the same dimension (IDS) or a different dimension (EDS)). (A-C) Translational studies: Dissociation of reversal learning and extra-dimensional set shifting as a function of prefrontal cortical sectors has been demonstrated in 4 species: (A) human; (B) marmoset; (C) rat and (not illustrated) mouse. Graphs for the marmoset and rat show the number of trials to criterion for ID, ED and Reversal learning in control (white), orbitofrontal cortex (red) and rodent medial prefrontal cortex and marmoset lateral prefrontal cortex (green). Graph for human shows fMRI units for Reversal and EDS in orbitofrontal cortex (red) and ventrolateral prefrontal cortex (green). These images are adapted from (Brown and Bowman, 2002; Dias et al., 1997; Hampshire and Owen, 2006). (D) The graph shows the improvement in EDS (*p < 0.05) when patients with schizophrenia are given modafanil (yellow) versus placebo. This graph is adapted from Turner et al. (2004). (E) Back-translation: In rats, PCP (black) worsens EDS compared to vehicle (white). This deficit is ameliorated by modafanil (yellow). The effects of sertindole, risperidone and haloperidol are also shown. This graph is adapted from (Goetghebeur and Dias, 2009).