The pipeline and future of drug development in schizophrenia

Abstract

While the current antipsychotic medications have profoundly impacted the treatment of schizophrenia over the past 50 years, the newer atypical antipsychotics have not fulfilled initial expectations, and enormous challenges remain in long-term treatment of this debilitating disease. In particular, improved treatment of the negative symptoms and cognitive dysfunction in schizophrenia which greatly impact overall morbidity is needed. In this review we will briefly discuss the current pipeline of drugs for schizophrenia, outlining many of the strategies and targets currently under investigation for the development of new schizophrenia drugs. Many of these compounds have great potential as augmenting agents in the treatment of negative symptoms and cognition. In addition, we will highlight the importance of developing new paradigms for drug discovery in schizophrenia and call for an increased role of academic scientists in discovering and validating novel drug targets. Indeed, recent breakthroughs in genetic studies of schizophrenia are allowing for the development of hypothesis-driven approaches for discovering possible disease-modifying drugs for schizophrenia. Thus, this is an exciting and pivotal time for the development of truly novel approaches to drug development and treatment of complex disorders like schizophrenia.

Building a Better Antipsychotic: Receptor Targets for the Treatment of Multiple Symptom Dimensions of Schizophrenia

“…21 Therefore, 5-HT 2C presents an intriguing but challenging target for therapeutics (i.e., agonism at 5-HT 2C in the mesolimbic dopamine pathway may reduce dopaminergic transmission and improve positive symptoms of schizophrenia). However, a concern is that dopaminergic suppression via 5-HT 2C agonism in the mesocortical pathway could potentially worsen cognition, 22 whereas, in the nigrostriatal pathway the same action might cause EPS. [23][24][25] On the other hand, 5-HT 2C antagonism at inhibitory gamma-aminobutyric acid (GABA) interneurons in the brain stem may be expected to reduce depression and improve cognition by disinhibiting dopamine and norepinephrine release in the prefrontal cortex.…”

“…54,55 As a result of these findings, N-desmethylclozapine (ACP-104) and other M 1 receptor agonists are in clinical trials as potential treatments of the cognitive dysfunction of schizophrenia. 22 …”

The Presynaptic Component of the Serotonergic System is Required for Clozapine's Efficacy

“…This hypothesis has led to a new crop of muscarinic subtype-selective allosteric potentiators currently being developed (Conn and Roth, 2008;Gray and Roth, 2007). Furthermore, it has also been shown that clozapine can potentiate NMDA activity by directly binding to glycine B site (Bressan et al, 2005;Javitt et al, 2005;Schwieler et al, 2008), thus contributing to its unique clinical efficacy.…”

“…Importantly, atypical antipsychotic drugs like clozapine are unique in their ability to normalize PCP-induced disruption of PPI (Bakshi Figure 1 Mining the druggable genome identifies molecular targets for clozapine action. (a) Results from hierarchical clustering analysis of affinities of approved typical and atypical antipsychotic drugs at molecular targets implicated in antipsychotic drug action (Gray and Roth, 2007;Roth et al, 2004). See Supplementary Table 2 for complete data set.…”

“…The targets interrogated included both validated antipsychotic drug targets (eg, D2, D3 dopamine; 5-HT 2A serotonin) as well as most of the currently investigated targets (eg, M1, M4 muscarinic; mGluR2/3 metabotropic glutamate; nicotinic acetylcholine) (Conn and Roth, 2008;Gray and Roth, 2007;Jensen et al, 2008). We then performed hierarchical clustering analysis to identify atypical antipsychotic drugs that were most similar to clozapine and typical antipsychotic drugs that were most dissimilar.…”