Clinical Psychopharmacology of Depression
Lead Research Organisation:
University of Oxford
Department Name: Psychiatry
Abstract
Clinical depression causes much personal suffering and disability and is a substantial economic burden to the UK through loss of employment. Many patients with depression can be effectively treated in primary care with psychological therapies and medication. However, those who are not helped by these standard treatments may have difficulties in making a good recovery and can be unwell for long periods of time. It has been hard for Industry to find new treatments for patients with resistant depression so the current proposal aims to use an 'experimental medicine' approach to see whether two novel pharmacological treatments might offer promise for depressed patients. The experimental medicine approach involves testing potential antidepressant therapies in depressed patients for a short period of time to see whether biological and psychological tests indicate that the treatment concerned may have true potential as a clinical antidepressant. If a positive result is obtained the treatment can then be studied in a formal clinical trial with a good expectation of success.
The first treatment we will test is called ebselen. In basic laboratory studies, ebselen has lithium-like properties, and also influences a neurotransmitter called glutamate which is thought to play an important role in the causation and treatment of depression. It is now possible to measure glutamate accurately in the brain using a technique called magnetic resonance spectroscopy (MRS). We will use a state-of-the-art MRS camera in Oxford to measure glutamate in depressed patients and examine the effect of one week of ebselen treatment on glutamate levels. In addition, to assess further whether ebselen may have potential as an antidepressant we will study its effects on the way the brain processes emotional information. Our previous work indicates that this can be a good way of finding out whether a drug is likely to be clinically effective in depressed patients.
The other drug we will test is an anti-inflammatory agent called tofacitinib. There is currently much interest in the role of inflammation in the causation of depression and patients with evidence of inflammation in the blood are often among those who do not respond well to standard antidepressant treatments. Tofacitinib is currently used as a treatment for patients with rheumatoid arthritis and is known to inhibit some of the inflammatory mechanisms that have been implicated in depression. We will therefore also carry out an experimental medicine study of tofacitinib to see whether one week of treatment produces changes in emotional processing that indicate a potential antidepressant effect in depressed patients with evidence of inflammation.
Positive results in either of these experimental medicine studies would prompt us to undertake collaborative studies with the NHS and Industry so that the effect of ebselen and/or tofacitinib can be assessed in formal clinical trials in depressed patients. The studies in this proposal will also provide an opportunity for us to characterise abnormalities in brain glutamate in patients with depression with greater precision than has been possible previously. This information will be of value in new treatment development.
The first treatment we will test is called ebselen. In basic laboratory studies, ebselen has lithium-like properties, and also influences a neurotransmitter called glutamate which is thought to play an important role in the causation and treatment of depression. It is now possible to measure glutamate accurately in the brain using a technique called magnetic resonance spectroscopy (MRS). We will use a state-of-the-art MRS camera in Oxford to measure glutamate in depressed patients and examine the effect of one week of ebselen treatment on glutamate levels. In addition, to assess further whether ebselen may have potential as an antidepressant we will study its effects on the way the brain processes emotional information. Our previous work indicates that this can be a good way of finding out whether a drug is likely to be clinically effective in depressed patients.
The other drug we will test is an anti-inflammatory agent called tofacitinib. There is currently much interest in the role of inflammation in the causation of depression and patients with evidence of inflammation in the blood are often among those who do not respond well to standard antidepressant treatments. Tofacitinib is currently used as a treatment for patients with rheumatoid arthritis and is known to inhibit some of the inflammatory mechanisms that have been implicated in depression. We will therefore also carry out an experimental medicine study of tofacitinib to see whether one week of treatment produces changes in emotional processing that indicate a potential antidepressant effect in depressed patients with evidence of inflammation.
Positive results in either of these experimental medicine studies would prompt us to undertake collaborative studies with the NHS and Industry so that the effect of ebselen and/or tofacitinib can be assessed in formal clinical trials in depressed patients. The studies in this proposal will also provide an opportunity for us to characterise abnormalities in brain glutamate in patients with depression with greater precision than has been possible previously. This information will be of value in new treatment development.
Technical Summary
The main aim of the study is to use experimental medicine methods to assess two novel pharmacological approaches to the management of treatment resistant depression (TRD), using change in emotional processing as a key biomarker for potential antidepressant efficacy. Ebselen is a putative lithium-mimetic which also inhibits the glutamate synthesising enzyme, glutaminase. We will use a placebo-controlled design to assess the effect of one week of ebselen treatment in TRD patients where we will use magnetic resonance spectroscopy (MRS), as well as neuropsychological and clinical measures, to determine changes in brain levels of inositol and glutamate, emotional processing and depressive symptomatology during ebselen treatment. We will use a similar design to test the effect of the JAK inhibitor, tofacitinib, a novel anti-inflammatory agent, in TRD patients with evidence of peripheral inflammation determined by elevated levels of C-reactive protein. Here we will use functional magnetic resonance imaging to measure the effect of tofacitinib on the neural response to emotional and rewarding stimuli in addition to neuropsychological and clinical measures. The recruitment of patients for the above studies will provide us with an opportunity to characterise glutamate and glutamine abnormalities in TRD in cortical-striatal regions with the outstanding precision permitted by MRS imaging at 7T using a case-control design. We will also use this 7T methodology to test the hypothesis that the decrease in glutamate level produced by ebselen is associated with diminished glutamate release in the living human brain in a functional MRS paradigm employing visual stimulation.
Planned Impact
Depression is a leading cause of disability worldwide, and a major contributor to the overall global burden of disease. Current treatments are limited in terms of efficacy, particularly in patients who fail to respond to first line approaches, so called 'treatment resistant depression' (TRD). The present study aims to develop two novel pharmacological approaches specifically for this group of patients. It will also clarify abnormalities in the neurotransmitter, glutamate in treatment resistant depression.
Therefore the main beneficiaries of this research, should it prove successful, are patients with depression and their families. In addition, because people with TRD are often unable to work, treatments which facilitate recovery will produce a substantial economic benefit to the UK as a whole.
Because of the lack of effective treatments, clinicians often find the management of TRD difficult; accordingly the availability of new treatments will be of great value to professionals striving to help their TRD patients.
The work will also be of importance to the field of psychiatry in general, emphasising that it is possible to continue to improve antidepressant drug treatments and that basic research and 'drug repurposing' are important in this effort. It will also provide a better understanding of the neurobiological basis of TRD.
Other beneficiaries could include the Pharmaceutical Industry who will benefit from the ability to have new targets to treat depression and associated disorders, as well as the demonstration that experimental medicine approaches can play a facilitatory role in psychotropic drug discovery.
Therefore the main beneficiaries of this research, should it prove successful, are patients with depression and their families. In addition, because people with TRD are often unable to work, treatments which facilitate recovery will produce a substantial economic benefit to the UK as a whole.
Because of the lack of effective treatments, clinicians often find the management of TRD difficult; accordingly the availability of new treatments will be of great value to professionals striving to help their TRD patients.
The work will also be of importance to the field of psychiatry in general, emphasising that it is possible to continue to improve antidepressant drug treatments and that basic research and 'drug repurposing' are important in this effort. It will also provide a better understanding of the neurobiological basis of TRD.
Other beneficiaries could include the Pharmaceutical Industry who will benefit from the ability to have new targets to treat depression and associated disorders, as well as the demonstration that experimental medicine approaches can play a facilitatory role in psychotropic drug discovery.
Publications
Chan SY
(2020)
A single administration of the antibiotic, minocycline, reduces fear processing and improves implicit learning in healthy volunteers: analysis of the serum metabolome.
in Translational psychiatry
Chen R
(2021)
Effect of the NMDA receptor partial agonist, d-cycloserine, on emotional processing and autobiographical memory.
in Psychological medicine
Colwell M
(2022)
Pharmacological targeting of cognitive impairment in depression: recent developments and challenges in human clinical research
in Translational Psychiatry
De Cates A
(2023)
5-HT4 Receptor Agonist Effects on Functional Connectivity in the Human Brain: Implications for Procognitive Action
in Biological Psychiatry: Cognitive Neuroscience and Neuroimaging
De Cates AN
(2021)
Déjà-vu? Neural and behavioural effects of the 5-HT4 receptor agonist, prucalopride, in a hippocampal-dependent memory task.
in Translational psychiatry
De Crescenzo F
(2022)
Comparative effects of pharmacological interventions for the acute and long-term management of insomnia disorder in adults: a systematic review and network meta-analysis.
in Lancet (London, England)
De Giorgi R
(2023)
Real-world outcomes of concomitant antidepressant and statin use in primary care patients with depression: a population-based cohort study
in BMC Medicine
De Giorgi R
(2022)
The effects of statin monotherapy on depressive symptoms: A systematic review and meta-analysis.
in Journal of affective disorders
De Giorgi R
(2021)
Effects of various statins on depressive symptoms: is there enough evidence?
in Journal of affective disorders
De Giorgi R
(2023)
The pharmacological bases for repurposing statins in depression: a review of mechanistic studies.
in Translational psychiatry
De Giorgi R
(2021)
Statins in Depression: An Evidence-Based Overview of Mechanisms and Clinical Studies.
in Frontiers in psychiatry
De Giorgi R
(2021)
Statins for major depressive disorder: A systematic review and meta-analysis of randomized controlled trials.
in PloS one
De Giorgi R
(2021)
The effects of atorvastatin on emotional processing, reward learning, verbal memory and inflammation in healthy volunteers: An experimental medicine study
in Journal of Psychopharmacology
Dean RL
(2021)
Ketamine and other glutamate receptor modulators for depression in adults with unipolar major depressive disorder.
in The Cochrane database of systematic reviews
Furukawa T
(2019)
Optimal dose of selective serotonin reuptake inhibitors, venlafaxine, and mirtazapine in major depression: a systematic review and dose-response meta-analysis
in The Lancet Psychiatry
Furukawa TA
(2020)
Optimal Dose of Selective Serotonin Reuptake Inhibitors, Venlafaxine, and Mirtazapine in Major Depression: A Systematic Review and Dose-Response Meta-Analysis.
in Focus (American Psychiatric Publishing)
Furukawa TA
(2019)
Optimal dosing of antidepressant drugs - Authors' reply.
in The lancet. Psychiatry
Furukawa TA
(2020)
No benefit from flexible titration above minimum licensed dose in prescribing antidepressants for major depression: systematic review.
in Acta psychiatrica Scandinavica
Godlewska B
(2021)
Brain glutamate concentration in men with early psychosis: a magnetic resonance spectroscopy case-control study at 7 T
in Translational Psychiatry
Jauhar S
(2023)
Are neurotransmitters passé? A view from the foothills in response to Rose.
in Psychological medicine
Jauhar S
(2023)
A leaky umbrella has little value: evidence clearly indicates the serotonin system is implicated in depression.
in Molecular psychiatry
Murphy SE
(2021)
The knowns and unknowns of SSRI treatment in young people with depression and anxiety: efficacy, predictors, and mechanisms of action.
in The lancet. Psychiatry
Murphy SE
(2021)
Translating the promise of 5HT4 receptor agonists for the treatment of depression.
in Psychological medicine
Murphy SE
(2020)
A role for 5-HT4 receptors in human learning and memory.
in Psychological medicine
Paton C
(2020)
Prescribing for moderate or severe unipolar depression in patients under the long-term care of UK adult mental health services.
in Therapeutic advances in psychopharmacology
Description | Membership of BAP Governance Committee |
Geographic Reach | National |
Policy Influence Type | Membership of a guideline committee |
Description | RCPsych committee auditing antidepressant treatment in mental health trusts |
Geographic Reach | National |
Policy Influence Type | Membership of a guideline committee |
URL | https://www.rcpsych.ac.uk/improving-care/ccqi/national-clinical-audits/pomh-uk/latest-news |
Description | MICA: An experimental medicine model for fast acting antidepressant drug treatment in treatment resistant depression |
Amount | £792,903 (GBP) |
Funding ID | MR/S035591/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 08/2019 |
End | 08/2024 |
Description | Botnar Collaboration |
Organisation | University of Oxford |
Department | Botnar Research Centre |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Theoretical framework which applies experimental medicine approaches to discover potential antidepressant effects of anti-inflammatory compounds |
Collaborator Contribution | Expertise in novel anti-inflammatory agents specifically Jacinibs which are being used for this study. |
Impact | Ethical approval for experimental medicine study of tofacitinib in patients with resistant depression. |
Start Year | 2019 |
Description | Oxford Health Biomedical Research Centre |
Organisation | Oxford Health NHS Foundation Trust |
Country | United Kingdom |
Sector | Public |
PI Contribution | Experimental medicine approaches to the study of novel compounds for the treatment of depression. Clinical expertise in the treatment of resistant depression |
Collaborator Contribution | Resources for the recruitment of patients and infra-structure for the conduct of experimental medicine studies and clinical trials |
Impact | Application to NIHR funded to study pramipexole in resistant depression (PAX-D) https://oxfordhealthbrc.nihr.ac.uk/wp-content/uploads/2019/05/PAX-D-Patient-Advisory-Group-Outline-FINAL.pdf |
Start Year | 2019 |
Description | Sound Pharmaceuticals |
Organisation | Sound Pharmaceuticals |
Country | United States |
Sector | Private |
PI Contribution | Study of lithium-mimetic in human models of emotional processing and brain neurochemistry |
Collaborator Contribution | Sourcing of ebselen suitable for human clinical trial use in study of treatment resistant depression |
Impact | Ethics submission of experiemntal medicine study |
Start Year | 2020 |
Description | Wellcome Trust Inflammation Collaboration |
Organisation | University of Cambridge |
Department | Department of Psychology |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Extension of collaboration into clinical trial of a P2X receptor blocker in patients with resistant depression |
Collaborator Contribution | Access to novel therapeutic compound, contribution to multiicentre study in patients with depression. |
Impact | Application for funding to Wellcome Trust- Funded approved in Sept 2014 |
Start Year | 2013 |
Title | Ebselen in depression |
Description | Ebselen is an anti-oxidant which produces lithium-like effects on the enzyme, IMPase. Ebselen also produces positive shifts in emotional processing suggesting an antidepressant action. Lithium is effective an as 'add-on' treatment in patients with resistant depression. We are therefore developing ebselen for this purpose via and experimental medicine model in depressed patients. Funding has been received from the MRC for an experimental medicine study examining ebselen in patients with treatment resistant depression. |
Type | Therapeutic Intervention - Drug |
Current Stage Of Development | Early clinical assessment |
Year Development Stage Completed | 2018 |
Development Status | Under active development/distribution |
Impact | Patent applied for the use of ebselen in patients with depression. |
Title | Tofacitinib in depression |
Description | Tofacitinib is a JAK inhibitor widely used in the treatment of auto-immune diseases such as rheumatoid arthritis. There are no data on these drugs in patients with depression, many of whom have an 'inflammatory' profile in blood tests. We have received MRC funding to allow an experimental medicine study of tofacitinib treatment in patients with ressatnt depression and evidence of mild peripheral inflammation. |
Type | Therapeutic Intervention - Drug |
Current Stage Of Development | Refinement. Clinical |
Year Development Stage Completed | 2019 |
Development Status | Under active development/distribution |
Impact | Collaboration between clinical immunologists and psychiatry |
URL | http://www.tidestudy.co.uk/ |
Title | prucalopride 5-HT4 receptor agonist |
Description | we found that the 5-HT4 receptor agonist, pruclaopriode had precognitive effects in Experimental Medicine studies. Studies are planned to a assess its precognitive effects in depression and psychosis. |
Type | Therapeutic Intervention - Drug |
Current Stage Of Development | Refinement. Clinical |
Year Development Stage Completed | 2022 |
Development Status | Actively seeking support |
Impact | Results from an emulated trial; suggested this agent might also be efficacious in the prevention of depression. |
Description | Interview for Science Centre on Pharmacology of hypnotic drugs |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Media (as a channel to the public) |
Results and Impact | Journalists attended for a briefing on a Lancet paper on which I was an author |
Year(s) Of Engagement Activity | 2022 |
Description | Radio interview about the role of serotonin in depression |
Form Of Engagement Activity | A broadcast e.g. TV/radio/film/podcast (other than news/press) |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | Radio interview about the controversy about the role of serotonin depression |
Year(s) Of Engagement Activity | 2023 |
Description | Radio interview on role of serotonin in the brain |
Form Of Engagement Activity | A broadcast e.g. TV/radio/film/podcast (other than news/press) |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | Prof Catherine harmer give a 20 minute talk on serotonin for a BBC radio science programme |
Year(s) Of Engagement Activity | 2020 |
Description | School Visit London |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | Dr Nisha Singh visited a sixth form in a LOndon School to discuss careers in science |
Year(s) Of Engagement Activity | 2020 |