12:00 AM
Oct 24, 2013
 |  BC Innovations  |  Strategy

Synaptic synopsis

The early promise that neurotransmitter research would unlock the door for neurological diseases has devolved into sagging interest from several pharmas following repeated failures in clinical trials. Now, genetic findings are pointing to new targets in the synapse and reawakening commercial interest in fields such as autism spectrum disorders, schizophrenia and depression.

Although the behavioral features of those three conditions are quite dissimilar, new hypotheses about their origins suggest they all are diseases of connectivity. The common thread is synaptic dysfunction and disrupted communication between different brain regions.

The last decade has seen companies pursue compounds directed at new targets, in particular related to glutamate signaling because it contributes to the pathology of ASD, schizophrenia and depression.

In addition, data from recent academic-driven, large-scale genetic studies are pushing companies to pursue public-private partnerships (PPPs) as a way to explore new therapeutic real estate.

According to Atlas Venture partner Bruce Booth, academic research is injecting new life into the field.

"As industry has pulled back, academic research is advancing on the mechanistic basis of many of these diseases," he told SciBX.


There are more than 15 drugs approved for schizophrenia, at least 15 for depression and 2 for ASD. The majority are based on the early theory that the conditions are caused by an imbalance in monoamine neurotransmitters, most notably dopamine and serotonin.

The two ASD drugs, Risperdal risperidone and Abilify aripiprazole, are indicated for irritability associated with the disorder. Both drugs were first developed as antipsychotics and act on dopamine


Risperdal is marketed by Johnson & Johnson. Abilify is marketed by Otsuka Pharmaceutical Co. Ltd., a subsidiary of Otsuka Holdings Co. Ltd.

The dopamine hypothesis of schizophrenia dates back to the 1960s, when dopaminergic antagonists such as haloperidol were approved. Since then, the most significant improvements have been in reducing side effects, with the last big breakthrough being the approval of atypical antipsychotics such as clozapine in the 1970s.

Similarly, the monoamine hypothesis of depression emerged in the 1960s with the use of monoamine oxidase (MAO) inhibitors and tricyclic antidepressants that inhibit monoamine reuptake transporters. In the 1990s, selective serotonin reuptake inhibitors such as fluoxetine entered the market, alleviating many of the cholinergic side effects of the earlier generation.

Although the dopamine antagonists and monoamine reuptake inhibitors represented a major leap forward in psychiatry, the molecules have drawbacks that limit their use or result in their discontinuation.1

For example, depression drugs only work in about two-thirds of the patient population and carry black box warnings of an increased risk of suicide in children, adolescents and young adults.2

Nevertheless, there are at least 30 companies pursuing new compounds in all...

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