GlyT-1 Inhibitor Helps Negative Symptoms of Schizophrenia

Image: Flickr - Mark Cummins
Last week, Roche reported data from a 320 patient phase II proof-of-concept study with its first-in-class investigational glycine transporter-1 (GlyT-1) inhibitor, RG1678. Dysfunction of neurotransmission at the NMDA-type glutamate receptor has been implicated in the pathophysiology of schizophrenia, suggesting that enhancement of receptor function may be effective in treating schizophrenia; GlyT-1 inhibitors increase glycine levels and hence NMDA signalling.

Schizophrenia is a chronic, severe and disabling mental health problem that is found all over the world, affecting roughly one per cent of the population. Although men and women are equally affected, men tend to experience symptoms at a slightly earlier age than women, often in their late teens. The symptoms of schizophrenia can be broadly classified as positive, negative or cognitive. Positive symptoms are psychotic behaviours including hallucinations, particularly hearing voices; delusions, or false yet strongly held personal beliefs; and disorders of thinking. Negative symptoms, which are harder to recognise and can be mistaken for depression, include blunted emotions; lack of motivation; an inability to take an interest in, or enjoy, life; and poor social functioning. Cognitive symptoms include problems with working memory and trouble focusing or paying attention.

Antipsychotic medications, which have been available since the mid-1950s and work primarily by suppressing dopamine activity, are the current mainstay of treatment for schizophrenia. These are generally able to reduce hallucinations and delusions and allow patients to function more effectively and appropriately. They are, however, less helpful with negative symptoms such as reduced motivation and emotional expressiveness, which for many patients contribute more to poor quality of life and functional disability than do positive symptoms.

Possible structure of RG1678, taken from this patent.
Possible structure of RG1678, taken from this patent.
When given as an add-on treatment to patients who were stable on antipsychotic therapy and suffered mainly from negative or disorganised thought symptoms, RG1678 was well tolerated at all doses tested and was able to improve negative symptoms and patients’ personal and social performance, reaching statistical significance on primary and secondary endpoints. The company believes that RG1678, which is being co-developed globally with Chugai, has the potential to enable patients to better establish social relationships and participate in functional activities, reducing the burden for caregivers and patients alike.

New Antipsychotic Mechanism Discovered

PET scanIt has been estimated that as many as 50 million people worldwide suffer from schizophrenia and many of these will be treated with antipsychotic medicines. The so-called typical antipsychotics have been available since the mid-1950s and a number of newer agents, the atypical antipsychotics, have been introduced since 1990. Increased dopaminergic activity is thought to be a contributory factor in schizophrenia and all of the antipsychotic medicines interact with the dopamine D2 receptor although they have different affinities and modulate the receptor in different ways.

A new study has shown that, regardless of their effect on G-protein coupled signalling via the D2 receptor, antipsychotic drugs potently antagonize the dopamine-mediated interaction of the D2 receptor with β-arrestin-2.

Arrestins are proteins that were initially found to regulate signal transduction by silencing GPCRs, although they have recently been shown to directly activate signalling pathways. The new results suggest that selective targeting of the interaction of D2 with β-arrestin-2 may provide a new opportunity for the development of antipsychotic medicines. More generally, targeting β-arrestin signalling pathways may open opportunities in other therapeutic areas.

New Approach to Treatment of Schizophrenia

Schizophrenia is a complex disorder, generally believed to arise from dysregulation of dopamine and glutamate neurotransmission pathways. Current front-line treatment comprises the atypical antipsychotics, which provide symptomatic relief but are associated with significant side-effects. These agents are broad-spectrum GPCR antagonists that act primarily at the dopamine and serotonin receptors.

Muscarinic acetylcholine (mACh) receptors regulate dopamine levels in areas of the brain associated with psychosis, with the M4 subtype speculated to be a key regulator of dopaminergic hyperactivity. The absence of subtype-selective modulators has, however, hindered validation of this hypothesis. Now scientists at Lilly have reported (PNAS, 5th August 2008) a selective small molecule, LY2033298, that targets the M4 subtype.

LY2033298The compound has been shown to act at an allosteric site on the receptor, potentiating agonist binding while having little effect on antagonist binding. The authors have further demonstrated in vivo activity in preclinical models that are predictive of antipsychotic drug effects.