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.
Chairman Guy Goodwin introduced not only the speakers but also the audience to Pigeonhole live – the audience being enthusiastically encouraged to make use of their smart phones throughout this interactive meeting both to ask and answer questions via this medium. Traditional question cards were provided for the technologically-challenged!
Cognition needs to be treated differently from the other symptoms associated with MDD, Professor Raymond Lam, University of British Columbia, Canada, told the audience. Cognitive dysfunction in patients with MDD often persists into remission, and it is recognised that cognitive impairment drives functional impairment and, in particular, poor work functioning. This in turn means that patients who return to work are often working sub-optimally and this has associated costs – both financial costs for society but also costs in terms of the patient’s wellbeing. Work is important to patients, not just because of the money they earn – but as a source of accomplishment, intellectual stimulation, regular activity and social interaction.
As cognitive deficits affect a patient’s ability to functionally recover, new treatment options are needed to target cognitive dysfunction and better improve functional outcomes in patients with depression.
Which test is best in the assessment of cognitive dysfunction in MDD? This was the question posed by Dr John Harrison, VU University Medical Center, Amsterdam, The Netherlands and Metis Cognition Ltd.
An ideal test should be reliable, sensitive, valid, suitable for use in the long term, available in parallel forms and suitable for cross-cultural use. Dr Harrison cautioned the audience to do three things: choose the test to answer the question you want answered, remember that exploration informs confirmation and, most importantly, never be a slave to dogma. As he explained, tests to assess cognitive functioning in Alzheimer’s disease are insufficient and prone to a number of problems, yet they failed for 20 years because researchers were slaves to dogma!
In an assessment of the FOCUS study, cognition was successfully evaluated using the Digit Symbol Substitution Test (DSST) – suggesting that this would be a good candidate test for the assessment of cognitive dysfunction in MDD.
Interestingly, a Pigeonhole survey conducted during the meeting suggested that 70% of attendees already investigated cognitive deficits in their patients with MDD on a regular basis. However, 30% of attendees did not assess cognition regularly in their patients with MDD. Maybe those that don’t currently assess cognition in depression will find the THINC® Cognition Tool of interest.
Despite the increasing recognition of the importance of the assessment of cognition in MDD, as Professor Roger McIntyre, University of Toronto, Canada reported, no accepted and validated screening tool for the objective and subjective assessment of cognitive dysfunction in MDD suitable for use in daily clinical practice is currently available. Indeed, as he stated, what is needed is a tool to measure the extent of a deficit, not just aid in its identification.
This is the underlying rationale for the development of the THINC® Cognition Tool - a tool specifically developed to detect and measure cognitive dysfunction in MDD. The THINC® Cognition Tool incorporates several brief, easy to administer objective tests including the DSST, Choice Reaction Time (CRT), the Trail Making Test B (TMT-B), the One-Back Test (1BT) and the Pathfinder test as well as a subjective, patient reported assessment PDQ test. During the symposium a video demonstrating the objective tests was screened – showing the tests to be attractively designed and appealing to perform.
Currently, the THINC® Cognition Tool is being validated for the screening of cognitive dysfunction in adults with depression at the University of Toronto, Canada. It (along with many other useful materials concerned with cognitive deficiency in MDD) will be available to download from the THINC® website soon (THINCcognition.com). The tool will be free of charge and should be also be available in local languages.
‘Cognitive dysfunction in depression: are we THINC®ing about it enough?’ was the title of a well-attended satellite symposium sponsored by Lundbeck which took place on Sunday afternoon.
He believes it is important to detect alcohol-dependency and alcohol-related problems so that the illness can be treated as soon as possible. When making a diagnosis, he asks the patient to estimate their consumption of alcohol, administers the Munich Alcoholism Test (MALT) and the Alcohol Use Disorders Identification Test (AUDIT) and measures blood Gamma-GT and carbo deficient transferrin. DSM-V criteria are also followed. To complete the diagnosis, a family interview takes place for verification of the patient’s history as often patient’s estimates and accounts can be unreliable.
In order to diagnose depression correctly in patients with alcohol dependency, Dr Pascual feels it is important to reduce the patient’s alcohol intake because much of the depressive symptomatology is often guilt-associated. During this initial phase of treatment, pharmacological agents can help and after 1 month, and only once alcohol consumption levels are low, would Dr Pascual prescribe an antidepressant due to his having concerns about drug-alcohol interactions.
Motivational interventions – short, frequent interventions made by the whole mental health team - are excellent promotors of adherence as they continually reinforce the patient’s positive advances.
Motivational interventions – short, frequent interventions made by the whole mental health team - are excellent promotors of adherence as they continually reinforce the patient’s positive advances. Family intervention and mutual help groups are also very valuable in this respect. Having a family member as the ‘pill controller’, for example, can aid not only in adherence to a therapeutic programme but also in the avoidance of dependency on some of the therapeutic agents being given. Having the patient become involved in mutual help and other cultural activities also aid their recovery by simply making them feel better. After all, as Dr Pascual commented, “Patients need to feel they belong to society too.”
Dr Paco Pascual, UCA Alcoy, Alicante, Spain takes the same approach toward his treatment of the various dependencies he sees in his patients – a holistic one - the main aim of which is not only, id
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.
