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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.
SD, unlike loneliness, is an objective term to describe social isolation, Junghee Lee, UCLA, Los Angeles, USA, explained. It is prevalent in schizophrenia and is important because it affects survival direly – and to a greater extent than smoking. Unlike loneliness, you can die from SD.
Both social cognition and affiliation are affected in psychosis. This makes its study difficult. After all, how to you recruit socially-reclusive people to a clinical study?
By advertising, it would appear! Two small adverts were posted requesting people with few friends and no real inclination to make friends to respond. And respond they did – 66 calls over 3 days. By a sifting process, the general population was enriched for 28 individuals who were engaged in the community (i.e. they worked) but were socially isolated.
Unlike patients with schizophrenia, however, such individuals showed no evidence of social cognition deficits. They did show low levels of social affiliation. It seems, in the community, there are people who naturally avoid social situations. Intriguingly, their curiosity as to why this might be was what induced them to answer the ads.
Melissa Selb, of the WHO ICF Research Branch, Germany,, explained how, as part of its drive for health for all, the WHO has changed tack. Now instead of compiling only mortality and morbidity (ICD) statistics, it is collating the associated functioning and disability (ICF) that accompanies a condition.
Functioning and disability refer to a person’s:
Participation – e.g supported work programme
Activities e.g ability to wash oneself
Body function e.g thought function
Body structure e.g brain function
Environmental interactions e.g medication, family
Aspects of each of these were taken into consideration when creating the ICD-11 report with specific reference to schizophrenia. In total, 1400 ICF categories were described. As these are cumbersome to use, ICF core sets and brief core sets have been developed, making the classification system more user-friendly.
The ICF core sets were developed in 3 phases: a preparatory phase, phase I and phase II. Currently, the guidelines are in Phase II of development but the other phases were outlined.
Georgina Guilera, University of Barcelona, Spain, described the initial preparatory phase of the WHO project. Here the functional and environmental factors associated with schizophrenia were considered from 4 perspectives – clinical, research, patient and health care professional.
To address the clinical perspective, an empiric, multicentre study was conducted. Five Spanish centres contributed to this study and data were collected by health care professionals using the extended WHO checklist. Their responses were extracted and translated into ICF categories. ICF categories described functional impairment in body function (32), activities and participation (45) and environment (18).
A systematic literature review was undertaken to address the research perspective. A total of 206 studies identified ICF categories. These described functional impairment in body function (30), body structure (2) activities and participation (34) and environment (4).
The mortality associated with social disconnectedness in schizophrenia is greater than for smoking
For the patients’ perspective, a qualitative study was undertaken comprising 11 focus groups (7 for patients and 4 for caregivers) in Spain and US. The outcomes yielded ICF categories for body function (45), body structure (6) activities and participation (60) and environment (38).
Overall, the preparatory phase identified 184 candidate categories – clearly far too many for daily use. Oscar Pino, University of Barcelona, described how these were whittled down to generate comprehensive ICF core sets and brief core sets.
International experts in schizophrenia from a variety of fields were invited to consider the candidate categories and to achieve consensus on the minimum that should be included. This minimum number should describe exhaustively the key functional disabilities of those with schizophrenia. If consensus was less than 40%, categories were excluded; if consensus was greater than 75%, they were kept. Those falling between these values were discussed in a second session to attain consensus.
Eventually, a comprehensive ICF core set was achieved containing 97 ICF categories: body function (17), body structure (0) activities and participation (48) and environment (32). Following further discussion and some serious ranking, a brief core set of 25 ICF categories was agreed.
Now that all this work has been completed, validation of the categories generated in phase I is being undertaken. Outcomes are awaited with interest.
Poor functioning is an acknowledged hallmark of schizophrenia.
Psychiatry is evolving as a profession. The number of patients with mental disorders in all life-cycle phases, from childhood to old age, is increasing all over the world and is responsible for enormous social and economic loss. The expectations for psychiatry as a profession are getting higher.
However, such complex and heterogeneous psychiatric disorders still cannot be classified and diagnosed precisely by diagnostic criteria such as DSM and ICD. Professor Yamawaki encourages us to establish objective diagnosis by utilizing findings of recent brain science research, and develop innovative treatments. If not, the expectation towards psychiatry may turn into disappointment.
The field of psychiatry is developing in a number of areas. Development of contemporary cognitive, affective and social neuroscience using neuroimaging are especially prominent. Molecular target data are being accumulated using genome and epigenome research and proteomics; however, issues such as reproducibility have arisen. In order to elucidate the pathophysiology of complex psychiatric disorders with variant, heterogeneous conditions, and to establish objective diagnosis, we need large cohort studies which have incorporated brain function and biomarker measurements, as well as clinical evaluation.
While there are many hurdles to achieving breakthroughs in our field, the theme of the 30th CINP congress is one to strive for - Innovation Integrated with Neuroscience for Mental Health.
The CINP have made active efforts to accelerate the development of biomarker and objective diagnosis by precompetitive collaboration of public and private institutions - a collaboration of basic and clinical academia, pharmaceutical companies and regulatory agencies.
By applying every brain science approach such as genomics, proteomics and neuroimaging and data analysis techniques, he is confident that we will see breakthroughs in the future.
The full video interview with Professor Yamawaki will be posted on www.progress.im soon. Also, look out for our interview with Professor John Krystal, CINP President Elect, in which we hear about future plans for the CINP as he takes the position of CINP president
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At the 30th international CINP congress in Seoul, Korea, we were privileged to speak with Professor Shigeto Yamawaki, President of the CINP, about changes and developments in the field and the valu