New drug developments in psychosis: Challenges, opportunities and strategies

Abstract

All currently approved drugs for schizophrenia work mainly by dopaminergic antagonism. While they are efficacious for psychotic symptoms, their efficacy is limited for negative symptoms and cognitive deficits which underlie the substantive disability in this illness. Recent insights into the biological basis of schizophrenia, especially in relation to non-dopaminergic mechanisms, have raised the efforts to find novel and effective drug targets, though with relatively little success thus far. Potential impediments to novel drug discovery include the continued use of symptom based disease definitions which leads to etiological and pathophysiological heterogeneity, lack of valid preclinical models for drug testing, and design limitations in clinical trials. These roadblocks can be addressed by (i) characterizing trans-diagnostic, translational pathophysiological dimensions as potential treatment targets, (ii) efficiency, accountability and , transparency in approaches to the clinical trials process, and (iii) leveraging recent advances in genetics and in vitro phenotypes. Accomplishing these goals is urgent given the significant unmet needs in the pharmacological treatment of schizophrenia. As this happens, it is imperative that clinicians employ optimal dosing, measurement-based care, and other best practices in utilizing existing treatments to optimize outcomes for their patients today.

Potential Role of Antipsychotic-Galantamine-Memantine Combination in the Treatment of Positive, Cognitive, and Negative Symptoms of Schizophrenia

“…It is important to note that single-site studies are limited by small sample size because of the recruitment and retention challenge. Rather than adjusting the inclusion and exclusion criteria to enhance recruitment [49], a multicenter or multinational ( n = 319; [80]) study with an adequate sample size and stringent criteria may provide clinically valid results. As shown in Table 1, it is difficult to draw a firm conclusion from a failed study with a small sample size and several limitations and methodological issues.…”

“…Hence, a reversal of anomalous activity in one system, or any combinations thereof, may have beneficial effects on the entire system [49]. After all, at the end of the day, schizophrenia is dementia praecox, weakening of volition [165], and Bleuler’s 4 As.…”

“…A perception remains in the field that galantamine and memantine were found to be ineffective in schizophrenia, yet there are many reasons why this combination is worth trying if the studies are well designed. This article sheds light on the possibility that these RCTs failed to detect a clinically meaningful efficacy signal due to limitations, methodological issues, and possible medication nonadherence [49]. This objective coincides with the new National Institutes of Health policy on how to address scientific premise to enhance reproducibility through rigor and transparency [50, 51].…”

Iloperidone in the treatment of schizophrenia: an evidence-based review of its place in therapy

“…Iloperidone has been accepted on the market after 12 years of premarketing evaluation and was approved by the US Food and Drug Administration (FDA) in May 2009, becoming available for use in early 2010. Recently (2013), the European Medicines Agency (EMA) has accepted evaluation of this drug application 30,37,39…”

Neurobiological Role of Hypocretin in Regulation of Psychiatric Disorders

“…This disease has been managed by using pharmacological means including compounds that interact with monoaminergic transmission [47][48][49][50]. Recent data have suggested the putative role of hypocretin in modulation of schizophrenia [36].…”