British Association for Pyschopharmacology. To advance education and research in the science of psychopharmacology
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Guiding Principles for Behavioural Laboratory Animal Science has been published on the website.
Professor David Nutt has been awarded the international prize for courage in promoting science and evidence on a matter of public interest, despite facing difficulty and hostility in doing so. The judges awarded the prize to Professor Nutt in recognition of the impact his thinking and actions have had in influencing evidence-based classification of drugs, in the United Kingdom and elsewhere in the world, and his continued courage and commitment to rational debate, despite opposition and public criticism.
The Prize is a joint initiative of the science journal Nature, the Kohn Foundation, and the charity Sense About Science. The late Sir John Maddox, FRS, was editor of Nature for 22 years and a founding trustee of Sense About Science.
A new study has suggested that it may be possible to develop blood tests for suicide by identifying biomarkers in the blood.
A review of the 2013 BAP Summer Meeting by EUSARNAD (European and South African Research Network in Anxiety Disorders) member Carlotta Palazzo
Carmine Pariante is interviewed on BBC Radio 4 about depression in pregnancy.
Listen to the programme (01:51:18 - 01:57:26) - expires Mon 19th August 2013
Barbara Sahakian interviewed on BBC Radio 4 Today programme about the 50% increase in Ritalin prescriptions.
Listen to the interview (01:51:18 - 01:57:26) - expires Mon 19th August 2013
Wednesday was the final day of the conference, and following the conference dinner the night before, the organisers had scheduled a slightly later start for the final symposia (much appreciated!).
Again there was a choice of three, before the conference ended at lunchtime and the delegates made their way home.
Sessions about the impact of inflammatory challenges on mental function, and novel innovations in monitoring systems related to treatments for schizophrenia and bipolar disorders were on offer. However, I attended four talks discussing salience in schizophrenia, and whether psychological constructs such as this might make good drug treatment targets.
Salience refers to how much something, be it an object, a thought, or anything else, stands out, relative to the things around it, or around you. Paula Moran opened the session by describing the salience problems in schizophrenia, namely that there is a disrupted ‘associability’ of stimuli, or as she put it a ‘loosening of associations’. Things are given unusual significance, and people with schizophrenia also struggle to treat previously irrelevant stimuli as relevant if their status changes. She presented work in animal models, using latent inhibition to represent salience. This is a talk that alters the salience of a stimuli (in this case a tone) via repeated experience of it. Anti-psychotic drugs can reverse abnormal latent inhibition behaviours in rodents, but the mechanism by which they do this is not clear, though there is a suggestion that dopamine may be involved.
She showed data combining a genetic and pharmacological approach (dopamine knock-out mice, and amphetamine administration). These data suggested that dopamine DRD2 receptors are involved in how anti-psychotics exert an effect on latent inhibition, but that there is likely to be another mechanism involved too, as rodents given amphetamines showed changed in latent inhibition, even those without the dopamine gene. She concluded by pointing out that this combined model showed the possibility of two mechanisms, that either approach alone would not have revealed.
Her co-chair Colm O’Tuathaigh gave the next presentation, and began by discussing the difficulty with designing a mouse model of the positive symptoms of schizophrenia. He mentioned the value of endophenotypes – heritable biomarkers associated with illness – and suggested salience attribution could be one such marker. He posited two different alterations in salience, disruptive and persistent. Disruptive, the loss of ability to ignore irrelevant stimuli, could represent the positive symptoms of schizophrenia (hallucinations or delusions), and may be related to dopamine. Persistent, a failure to switch when a previously irrelevant stimulus becomes relevant, may model negative symptoms, and be influenced by glutamate.
He presented work on mice with various genes knocked-out, and concluded that there may be multiple routes to these abnormal behaviours, with genes interacting with each other, and the environment. Genetic and pharmacological animal models can be a useful way to identify new drug targets, and evaluate existing treatments.
After more caffeine, and a chance for people to take down their posters, Anton Loonen took us on a historical tour of salience and its likely location in the ‘emotional brain’, showing evidence for a role of the amygdala and basal ganglia. He suggested a consideration of cortical and sub-cortical pathways in salience modelling could aid our understanding of schizophrenia, and the pharmacology that may provide better treatment for it.
The final talk of BAP 2013 was by Peter Liddle. He presented a compelling suggestion that salience problems in schizophrenia may best be tackled by combining pharmacology with psychological interventions such as mindfulness meditation or cognitive training. To me, with my psychology background, this kind of combined treatment model really appeals.
So, that was my BAP. The issue that really stood out to me was the need to approach questions or problems from a variety of angles, in order to innovate. Well-designed animal models, which truly represent behaviours of interest, combined with a variety of imaging techniques, pharmacological models of disorders, and even lesion studies can together provide much more compelling evidence of mechanisms than any one could alone. This isn’t a new idea, of course, but it was great to see this translational approach in action across symposia, special sessions and posters.
See you next year!
Tuesday again began with a choice of sessions: dopamine imaging, Alzheimer's disease or computational psychopharmacology. I plumped for the latter. Quentin Huys introduced us to the concept of generative modelling, using a set of parameters to create a model which will output simulated data. He used decision making as an example to show how comparing different models can reveal what might be occurring at brain level. He showed data in rats which suggested that different types of decision making might be differentially associated with risk for addiction.
Tiago Maia opened his talk by pointing out a problem inherent in psychopharmacology; namely that the field tries to map from synaptic alterations (where drugs work) to behavioural changes, but that there is a large gap between these two, where we’re often unsure what is occurring. He proposed that computational models might be able to help us understand this gap, and presented an example from ADHD. Drugs currently used to treat ADHD all have some effect on norapinephrine, though this neurotransmitter's role is under-studied compared to dopamine.
What norapinephrine is actually doing is unclear though. A model can test various different abnormalities to see which results in the behaviour changes associated with ADHD. Conducting this research suggests that lower tonic and lower phasic norapinephrine best models ADHD. However, Maia points out that these data haven't measured or manipulated norapinephrine directly or specifically, so more work is needed. The findings look promising for considering it as a drug target, though, and the combined computational model, brain imaging and behavioural testing approach is a powerful way to assess neural substrates of psychiatric disorders.
Tim Behrens presented work on the prefrontal cortex and value judgement decision making. His findings again emphasised the importance of translational work between human brain imaging studies and animal models. He suggested that the ventral medial pre frontal cortex is capable of supporting multiple value codes simultaneously, which may compete to resolve goal directed choices when making decisions. The neurotransmitter GABA may play a role in this competition.
Douglas Steele ended the symposium by looking at modelling abnormal valuation seen in depression, schizophrenia and addiction. Anhedonia in depression, delusional beliefs in schizophrenia and increased perceived value of drugs in addiction all represent abnormal value estimation. He pointed out that assessing mechanisms of these abnormalities is difficult as we currently don't know why depression may be alleviated by SSRIs or dopamine D2 blockades may affect psychotic symptoms. Mechanistic models would allow us to better guide treatment developments, and help us understand why some people are treatment resistant.
In studying this, he has identified potential neural signals and brain mechanisms that may be involved in these abnormal valuation problems in these disorders, and could represent new approaches for treatments.
The annual post-doctoral symposium was next, which this year had an autism theme. As has been a theme across the conference, translation between animal and human models was often mentioned. Stephanie McTighe presented first; data investigating a mouse model of attentional deficits in autism. The model is an inbred mouse, rather than a genetic knock-out mouse, the mechanism by which the behaviours occur is not known.
McTighe assessed possible mechanisms for the behavioural abnormalities in these mice, and concluded that they may be an appropriate mouse to model attentional deficits in autism. However, she mentioned that more work on the motivational component and mechanisms is needed.
Michael Schmeisser presented translational work investigating the Shank knock-out mouse. The Shank gene is related to post-synaptic density, and has been linked to autism in patients with lesions. When mice are bred without the gene, they are hyperactive, show repetitive jumping and grooming behaviours, decreased social interaction and abnormal vocalisation behaviour. He also suggested neurotrophic factors as potential treatments here, as they are known to increase the number of dendritic spines, which are decreased in these mice. Insulin-like growth factor may be useful here, but deficits in dendritic spines are only seen in the hippocampus, meaning careful consideration of the effect of the growth factor on other, healthy areas, or a growth factor targeted specifically at the hippocampus, is needed.
Jamie Horder presented preliminary brain imaging data using both PET scanning and magnetic resonance spectroscopy to highlight the involvement of GABA and glutamate in autism. New neuroimaging designs support findings from animal and post-mortem models which again shows the value of approaching a problem from a number of different angles.
Hilgo Bruining closed the postdoctoral session with a description of creating a knockout mouse to model autism by starting with a behaviour of interest, and knocking out different genes until the desired behaviour is seen. His work identified Pcdh9 gene as a good model, behaviourally, and then assessed the brain changes seen in the mice. He found evidence to suggest that the brain changes seen do seem to account for the behavioural changes in the mice. His findings have been replicated in a different lab, suggesting this is a robust effect, and therefore these knockout mice are a good model for autism.
After lunch and another set of excellent posters, there were more parallel sessions. A session on reward and choice was very well received by colleagues of mine, as was ‘windows on the brain’, but I opted for the session with a pun in its title: ‘Special K: New horizons’, about ketamine research. Neil Dawson presented data on the DISC1 gene, known to be associated with schizophrenia and other mental illnesses. Mice with changes to this gene show different responses to ketamine, as well as different brain metabolism profiles, compared to wild type mice.
Niall Lally discussed ketamine as a treatment for depression, with particular reference to anhedonia. This particular symptom of depression is poorly treated by conventional anti-depressants, so a better treatment is required. Ketamine seems to improve symptoms of anhedonia independently of its effect on depression overall. Lally suggested some possible neural correlates for this effect as well.
Richard Joules spoke about the effects of ketamine on brain connectivity, concluding that it seemed likely that the connectivity effects of ketamine are not due to gluteminergic mechanisms, but more likely due to effects on NDMA receptors. He stated that further research is needed to confirm this.
Mitul Mehta concluded the session with a discussion of the psychosis-like effects of ketamine, and their relationship to brain activity, presenting the work of James Stone. Their findings suggested a role of the occipital-parietal cortex on perceptual disturbances seen while intoxicated on ketamine, but mania and cognitive disorganisation may arise via other mechanisms.
The final session of the day consisted of three presentations by BAP’s Psychopharmacology Award prize winners. Angela Attwood warned us all that she was presenting a null result: D-cycloserine (an NMDA partial receptor agonist) does not improve drug related cue exposure. However she used this null finding to discuss important issues about how we test drugs such as these. We need to have suitable behavioural models before we can adequately test a drug.
Jon Roiser gave a great talk about the importance of individual differences. Often overlooked, investigating sub populations can provide valuable insights in to underlying mechanisms. The same symptoms may have completely different causes in different groups of people.
Kuan-Pin Su finished the session with evidence that Omega-3 fatty acids, found in oily fish, may be effective as a treatment for depression. A fairly controversial idea, but if true, one that may help when other treatments are inappropriate. He suggested Omega-3 as a potential treatment for depression during pregnancy, when other drugs may not be suitable. Omega-3 has also been shown to have anti-inflammatory properties. so could be well used to treat depression in people with physical illness as well. Also, a neuroprotective effect has been suggested, meaning it could be a valid treatment for depression in the elderly or those with diseases such as Parkinson’s or Alzheimer’s.
After an excellent welcome reception and disco on Sunday night, Monday began with a choice of sessions. Social behaviour, brain-derived neurotrophic factor, and anxiety disorders were on offer. I picked anxiety. Nic Van der Wee from Leiden began by discussing the current state of drug treatments for anxiety disorders, and areas where improvement may be possible.
Drugs currently prescribed for anxiety include SSRIs (a common treatment for depression), SNRIs, benzodiazapines and others, but some people remain non-responsive to treatment, or find the side effects of some of these drugs too severe. Many people on these medications suffer problems with sexual function, drowsiness, or weight gain in particular.
Van der Wee suggests improvements can be made by looking at the course of recovery on different drug treatments, and by working out what can predict who will respond, relapse or show different outcomes by assessing trajectories. He also suggested looking at sub groups by gender, age and genotype, factors which are all known to affect likelihood to respond to a treatment.
He believes progress has to come from more basic insights. We need to better understand the onset and cause of anxiety, so we can improve development and evaluation of possible treatments for it.
Gerry Dawson from P1vital (a clinical research organisation) spoke next on experimental medicine. This uses healthy populations or small samples of patients to assess the function of new drugs while they are in development, by seeing if they alter behaviours in tasks which tap in to their proposed mechanism. These proof-of-concept studies can then inform larger scale clinical trials, potentially saving time and money.
Experimental medicine works well in disorders like anxiety which seem to exist on a continuum, where levels of anxiety vary in the general population, below levels where a person would be deemed ill. This means researchers can compare the effectiveness of a drug on anxious versus non anxious people before it is given to a group of people who have the disorder itself.
But, in order for experimental medicine to be effective, very well designed models are needed to test a drug’s effects. These models need to be robust, and replicable. Dawson described drug companies and academics working together ‘pre competitively’, as he put it, to develop well validated models, which will benefit drug development and testing.
After these two talks set the scene for possible treatments for anxiety disorders, and possible ways to test their effectiveness, the next two talks provided specific examples. Sally Adams presented fascinating work using cognitive bias modification tasks to reduce depression and aggression. I’ve written about the task, and the aggression work before here.
Not only does this task seem to induce lasting positive change, but there is a mobile app under development, which has the potential to make the task more generalisable than some other behavioural modification tasks, which work well in the clinic but don’t seem to translate to other settings.
Finally, Matt Garner discussed a method of inducing anxiety in a non-anxious population, using CO2 enriched air (this technique has been discussed here). This seems to work well to induce symptoms similar to generalised anxiety disorder, so could be a good way to test new drugs that might treat the disorder (such as duloxetine), or indeed behavioural treatments for anxiety (such as mindfulness).
Following a quick caffeine break, the annual guest lecture took place, this year given by Helen Mayberg from Emory in USA. Mayberg discussed a method for helping people with treatment resistant depression, using deep brain stimulation. An electrode is placed in the brain and stimulates a certain area, which can reduce negative feelings associated with depression.
She discussed reasons for locating the electrode at a point where various tracks in the brain converge, and showed evidence that if the electrode does not stimulate this intersection, the treatment will not be as effective. She described how even at the very initial switching on of the electrode, while the patient is still on the operating table, they spontaneously report an improvement.
However, she cautioned that recovery takes more than a stimulator, and that although treatment of this kind may be excellent at preventing some of the negative feelings which can cause debilitating problems, described by one patient as “immobilising”, a patient still has to work extremely hard to get back to full functioning ability once these feelings are stopped.
Lunch provided the opportunity to peruse the excellent array of posters that were being presented. There were poster sessions on mood disorders, sleep, dementia, anxiety, educational psychopharmacology and brain imaging. Food for thought, as well as for hungry conference delegates.
The plenary mental health session brought industry and academics together, to discuss approaches for developing new drugs to treat psychiatric disorders, in particular depression. Speakers from Janssen and Roche discussed new groups of drugs currently being investigated and developed.
Wayne Drevets discussed the development of rapidly acting antidepressants. Ketamine and scopolamine both seem to provide positive effects for people with depression, both in terms of their effects on the brain (increasing synaptic plasticity and certain types of brain activity), and in terms of behaviour (shifting emotional processing biases positively).
Joseph Wettstein from Roche discussed drugs related to glutamate which may variously have benefits for anxiety, depression, bipolar disorder or schizophrenia. In particular, one drug reversed fragile X syndrome (a cause of autism and mental retardation) in mice, suggesting there may be a therapeutic benefit to it. He described the work on glutamate as ongoing, but promising.
Trevor Robbins concluded the session by adding a word of caution about the use of mouse models. While mouse models are vitally important in developing new drug treatments, he mentioned the difficulties of accurately modelling high level concepts such as depression in a mouse. However, he suggested that with careful consideration this can be done, and gave examples where this is happening.
In order to improve our drug development, he said, we need very well defined descriptions of the effects of a disorder, and back-translation to animal models, with good equivalents for human tasks to test these animals on. He ended on a positive note, mentioning some excellent animal models for cognitive and affective biases, and encouraging people to continue to develop these.
Professor Naomi Fineberg, Professor David Nutt and Professor Barbara Sahakian discuss the cost of brain disorders in the UK.