Professor Ed Bullmore (Cambridge & GSK) opened the meeting and eloquently set up the challenge for psychiatry – that is, the therapeutic inertia in the field. The intertia was captured in a suggestion that a practicing psychiatrist today would perform reasonably well based on a text book from 1990! This is unlikely to be true in other fields. He proceeded to use a concrete example of an Experimental Medicine approach to drug development from his work at GSK in the development of an opioid antagonist for appetite control.
Through the example of GSK1521498 we were reminded of the power of positron emission tomography to determine how much of a drug gets into the brain (dose-occupancy relationships). The dose range from PET was applied to a study in obese patients, who were selected according to binge eating behaviour. Unfortunately these high binge eating participants showed no effect of the drug on body weight, fat mass or binge eating questionnaire. However, there was a dose-dependent reduction in hedonic response to dairy products and a significant reduction in calorific intake during a buffet meal after taking the drug. These are really important findings suggesting the drug is affecting the right functions in the right way. This emphasises the dangers of being over-focused on the primary outcome measures (things like weight and fat mass) and the need to systematically explore the mechanisms via which compounds may be operating. Brain imaging with fMRI was subsequently able to confirm modulation of the pallidum, a brain area known to be involved in hedonic responses.
Other important lessons were presented. Viagra was highlighted as a flagship example of repurposing – that is, the drug is being used for a purpose that differs from its original intention. It was a nimble response from Pfizer that led to its registration for sexual dysfunction.
Professor Bullmore proceeded to present an inspiring set of examples of potentially successful approaches that will likely underpin successful drug development, from cell culture assays and computational repurposing. Wonderful.
The meeting was subsequently split into four parallel workshops, on ‘Integrating Neuroimaging As Part of a Biomarker Matrix,’ ‘A Multidiscliplinary Approach for Identification of Biomarker in Mental Health,’ and a ‘Virtual Reality Workshop.’
I attended the workshop on ‘Developing Ketamine as a Rapid Acting Antidepressant,’ chaired by Dr. James Stone. We were fortunate to have Drs Wayne Drevets and Jaz Singh from Janssen as speakers. Wayne Drevets reminded us of the multiple classes of drugs that have rapid acting antidepressants effects; NMDA antagonists including AZ6765 and CP101106, scopolamine and ketamine. He proposed their shared mechanism as synaptic plasticity changes, specifically synaptogenesis. A brilliant and up-to-date overview of the importance of the subgenual cingulate constituted the core of the presentation, from the perspective of stress, synaptic loss, deep brain stimulation, metabolism and functional MRI.
Dr Singh from Janssen, San Diego presented the clinical effects of s-ketamine. S-ketamine is 3-4 times more potent than its mirror image, r-ketamine and less drug required than the racemic mixture which contains both s and r stereo-isomers. He promoted the intranasal administration route for clinical use because it is less invasive than injections and, potentially higher patient and prescriber access and rapid systemic absorption. Dr Singh tackled really important clinical questions for ketamine, such as frequency of dosing, dose range, how the antidepressant effect can be sustained and exposure of the body to the drug. We were able to see the unpublished results of a study by Janssen on the efficacy of s-ketamine in depression with clear reductions in depression ratings. This is an exciting development, with pharma taking on board these pragmatic clinical issues to determine the efficacy and best dosing regimen of a drug that is already widely available. In summary, the drug gets into the system, seems to work for many patients with 2-3 times per week seeming to be the most clearly efficacious frequency. The main side effect during infusion was dissociation, although side effects dissipated when the infusion stopped and appeared to reduce after multiple infusions. No psychosis symptoms were reported. Questions remain such as the long-term regimen.
Dr Rupert McShane talked of his experience running the red-kite project (http://www.red-kite.org.uk/) where ketamine is administered at 0.5mg/kg in the ECT clinic in Oxford. He presented the results of an open label trial. He highlighted the important small effects of saline and active placebo compared to ketamine. The response rate was 29% with ketamine and 7% for placebo. He also looked at cognitive and bladder functions as well as mood. Patients performed better in short story recall overall, with no effects on bladder function and an increase in mood. The 8/28 who responded had a mean duration of 79 days (range 35-175 days). The good news is that the Oxford Health NHS Foundation Trust has approved an NHS funded clinic.
The afternoon session was focussed on some exciting work at the Institute of Psychiatry. It was kicked off by Prof John Strang who showed us the important trials of buccal naloxone to reduce opiate abuse. The importance was sharply illustrated by data showing opiate abusers accounting for over 6000 drug abuse deaths, a rate way beyond what would be expected by its use (0.2%). He presented trials of buccal administration of naloxone as a more acceptable form of (self) administration compared to injection or other routes. Apart from the medical use, the important story here was how an academic can develop new treatments and the challenge involved.
Dr. Nina Mikita presented pilot data of mood induction combined with perfusion imaging (disclosure: I’m a collaborator on this). This is the first step in more objective assessments of mood which may be difficult in some groups such as those with autism. Using happy and sad films, clear mood induction was achieved paralleled by brain changes. Successful pattern recognition analysis is now being applied so that mood may be predicted using brain imaging data.
The final presentation was by Dr. Mitul Mehta (disclosure: I am Dr. Mitul Mehta), describing a programme of research to develop an assay to test the effects of existing and novel compounds in terms of their ability to modulate ketamine. This has relevance for (i) determining doses that can get into the brain and modulate function meaningfully and (ii) helping determine mechanisms of action. I was delighted that this work generated so many searching questions which continued on through the panel discussion that ended the day.
Overall, I got a sense that there is concern at the lack of major breakthroughs in psychiatry and a much reduced interest from pharmaceutical companies. This was countered by a renewed sense of what basic and clinical researchers need to be doing: working with the latest experimental methods to understand the biology of disorders and existing treatments, develop clever assessment methods and be prepared to collaborate widely. We might not discover new (pharmacological) treatments sitting in our laboratories that transform patient lives in our lifetime, but we might just discover a role for treatments outside of psychiatry within mental health or a biological marker that has prognostic value. These discoveries have the potential to be truly transformative and help avoid the current generation of researchers being – to quote Prof. Bullmore – ‘a lost generation.’