Activity at receptors other than D2 may modulate the efficacy of different antipsychotic agents against different kinds of schizophrenia symptoms, and exacerbate or lighten the burden of adverse events. Throughout, though, the D2 receptor has remained the primary player. Even the D1, D3 and D4 subtypes have had minimal share of the action. But must this always be the case? Professor Shitij Kapur (Institute of Psychiatry, King’s College, London, UK) asked during the final education session of the Amsterdam meeting. Is there life beyond dopamine?
The broad answer: new life forms have struggled to emerge from the neurochemical swamp -- but none so far has grown to full maturity.
This has not been for lack of effort. In recent years, of 110 or so agents in development for psychiatric disorders, thirty have been for schizophrenia. Half are still in phase I. But several have progressed to large, late-stage clinical trials and then fallen at the final hurdle. These include drugs that have tried to replicate the effect of D2 receptor blockade but through a different mechanism. One approach has been via inhibition of phosphodiesterase 10 (the PDE10 inhibitors). Another attempt has been to exploit the alpha2 adrenoceptor.
A second strand of development has focused on the idea that the DA receptor can be bypassed altogether. This has led to the development of mGlutamate II/III agents to treat psychosis and – with the hope of targeting negative symptoms and cognitive deficits -- we have had Glycine transporter-1 inhibitors and the alpha7 nicotinic receptor agonists to modulate the nicotinic cholinergic system.
All of these ideas are logical and all showed promise in early studies. Targeting the second messenger PDE10, for example, makes perfect sense; and animal studies suggested an antipsychotic effect. As an add-on therapy for D2 agents, there is nothing more logical than an agent acting via glutamate. Yet – despite promising clinical evidence from phase II studies – the general picture has been one of failure in pivotal randomised studies. An exception to this is the 5HT2 blocker approach to psychosis associated specifically with Parkinson’s Disease. But whether this success will cross over to schizophrenia is unknown.
Despite these setbacks, 61% of the audience thought that there was life after dopamine. Asked when we can expect the next major breakthrough in the pharmacology of schizophrenia, only 10% said “Not in my lifetime”. Half thought it likely in 5-10 years. Professor Kapur agreed that this was a realistic hope.
Professor Kjell Fuxe (Karolinska Institute, Stockholm, Sweden), has made an unmatched contribution to half a century of advance in our understanding of neurons, where they project to, and the intricate networks that they form. Speaking earlier in this educational session, he described different kinds of D2 heteroreceptor complexes in the ventral striatum which modulate brain circuits to the prefrontal cortex and occur at important places along the pathway.
They offer interesting potential targets for treatment of schizophrenia, he suggested. Our understanding of these complexes is at an early stage, but it is likely that pharmacological tools will be developed that influence mood and behaviour by adjusting the balance between heteroreceptors and homoreceptors and receptor-receptor interactions in D2 heteroreceptors.
A potentially important insight is that hallucinogens increase D2 receptor signalling in the D2R-5HT2A heterodimer complexes. There is also interest in D2R-oxytocin receptor complexes. The social attachment hormone oxytocin may be a naturally occurring antipsychotic, with dysfunction or disruption of this complex implicated in the disturbed emotional and social aspects of schizophrenia.
If he had to choose one of the four types of D2 heteroreceptor complexes discussed (the others involved neurotensin and A2A) Professor Fuxe would put money into the development of agents that influenced oxytocin-D2 interactions. In creating molecules that are sufficiently specific for the different types of receptor complex, though, medicinal chemists can expect busy times ahead.
Occupancy of the dopamine (DA) D2 receptor subtype predicts the clinical efficacy of antipsychotic medications. This finding cemented the DA hypothesis.
Access to a small number of data packages for candidate agents has already been attained and interest in some of the 9 drugs so far collected is already apparent.
Over the past three years, The Medicine Chests Initiative has been taking shape, the purpose of which is to gain access to ‘failed’ compounds and facilitate their reinvestigation, ideally in clinical experimental studies. Indeed, should it be necessary, resynthesis of interesting compounds is being and could be considered (albeit via. research grants) should an agent no longer be physically available. As these agents have already been administered in patients, toxicological studies are unlikely to be needed, as toxicology reports are included in the Medicines Chest repository.
As Dr Ann Hayes, UK, explained, access to a small number of data packages for candidate agents has already been attained and interest in some of the 9 drugs so far collected is already apparent.
Dr Trevor Robbins, UK, outlined how he has applied for a research grant to investigate whether a D1 receptor antagonist previously developed in Alzheimer’s disease might be used both to further investigate the basic science underlying D1 receptor antagonism and also the effect of this drug on cognition – an area of research in which it has not previously been investigated in clinical patients but one now considered worth of pursuit.
To find out more about the Medicines Chest and the agents available go to https://www.ecnp.eu/projects-initiatives/ECNP-medicines-chest.aspx
What does a pharmaceutical company do with a psychotherapeutic drug once it fails in clinical trials? As often as not, it bins it.
Proper brain development requires coordinated glycosylation, and in particular correct glycosylation of neural cell adhesion molecule (NCAM). The polysialylated version of NCAM (PolySia-NCAM) is vital in neurogenesis, playing a role in axon and dendritic outgrowth, and important for synaptic plasticity and normal neural development.
These were some of the key points made during a preclinical research track symposium entitled “Merging mouse and human data on the role of PolySia-NCAM in neurodevelopment and schizophrenia”, jointly chaired by Professor Herbert Hildenbrandt, of the Institute of cellular Chemistry, Hannover University, Germany and Professor Jean Mariani, of the Pierre and Marie Curie University, Paris, France.
In presentations by Dr Juan Nacher, of the University of Valencia, Spain and Dr Marta Barabara Wisniewska of the University of Warsaw, Poland, delegates learned of some of the latest research involving cultured immature neurones, animal models of neurodevelopment, imaging studies and research involving transgenic mice that point to the importance of normal polysialyation of NCAM in neurodevelopment. Dr Wiseniewska showed histological evidence of the impact of abnormal, or poly-Sia-free-NCAM, seen as demyelination and abnormal on neuronal structure and morphology.
Professor Hildebrandt described preclinical studies which suggest that in knock-out mice lacking an enzyme (ST8SIA2) responsible for modifying NCAM to PolySia-NCAM, the resulting reduced polysialyation leads to pathological brain development and schizophrenia-like behaviour. According to Professor Hildebrandt, a genetic variation in ST8SIA2 is not associated per se with schizophrenia but has been associated with schizophrenia where cognitive function is particularly poor, and he suggested that lacking ST8SIA2 has the potential to confer a neurodevelopmental predisposition to schizophrenia. He then went on to describe research suggesting that having this genetic deficiency, coupled with juvenile exposure to cannabis was linked with synergistic, negative effects on cognition in adulthood.
There has been inconsistent data regarding whether NCAM levels are increased or decreased in schizophrenia.
The final speaker at the symposium, Professor Gianfranco Spalletta, of the IRCCS Santa Lucia Foundation and Laboratory of Clinical and Behavioural Neurology in Rome, Italy, presented research findings relating to NCAM and polysialic acid serum levels in patients with schizophrenia. He said that there has been inconsistent data regarding whether NCAM levels are increased or decreased in schizophrenia. He reported his own, as yet unpublished data suggesting that PolySia-NCAM serum levels are significantly raised in schizophrenia and appear to be modifiable – as shown by lower levels in patients receiving treatment for the condition. He also reported that levels of this marker appear higher in patients with disease characterized by predominantly negative symptoms. Professor Spalletta said that brain neuroimaging studies may help with further understanding of the role of this intriguing molecule in subtypes of schizophrenia.
One of the first symposia on Day One ECNP 2015 was a research-track-focus on the possible roles of polysialylated neural cell adhesion molecule (PolySia-NCAM) in neurodevelopment and schizophrenia.
