Effect of amphetamine challenge on neuropsychological and neuroimaging parameters in lithium treated normal human males

Lead Research Organisation: Newcastle University
Department Name: Institute of Neuroscience

Abstract

Bipolar disorder (manic-depressive illness) is a common psychiatric disorder that is ranked in the top ten causes of disability worldwide. Although extremes of mood are characteristic, problems with concentration, motivation, and organisation commonly occur.

Dopamine is a chemical transmitter in the brain which controls various psychological and physical drives. It is a key candidate to explain some of the symptoms of mania. Manic symptoms can be briefly and safely reproduced in normal people by increasing dopamine levels using amphetamines. The effects can be detected by psychological testing and on scans assessing changes in brain activity (MRI).

Lithium both treats and prevents mania, though the relationship between brain concentration and response is unclear. The exact mechanism of its action is unknown, but it may decrease dopamine transmission by inhibiting cellular pathways within neurones. A protein called GSK-3 has been implicated.

We intend to investigate lithium‘s ability to block dopamine. MRI scans of lithium concentration and of brain function during psychological testing (with/without amphetamine) will be performed on normal males before and after lithium treatment. Correlations with GSK-3 measurements will be performed. Such research should increase our understanding of the treatment of bipolar disorder and will assist in the development future therapies.

Technical Summary

Background
Bipolar disorder is a severe psychiatric condition characterised by periods of mania and depression. Abnormalities of cognitive function (attention and central executive dysfunction) also occur and can persist into euthymia. These may arise from structural and functional abnormalities in the prefrontal cortex as demonstrated by cerebral imaging techniques. Attention and working memory are governed, in part, by dopaminergic neurotransmission, abnormalities of which have been implicated in bipolar disorder. Amphetamines increase dopaminergic neurotransmission and can reproduce symptoms of mania. Dopaminergic antagonists have antimanic effects. Lithium is an effective treatment and although the exact mechanism of action is unknown, it can reduce dopaminergic neurotransmission by pre- and postsynaptic effects. Inhibition of Glycogen Synthase Kinase-3 (GSK-3 ) may contribute to this. The cerebral distribution of lithium in humans is poorly understood, as is the relationship between serum levels, brain tissue concentrations and therapeutic effect.

Hypothesis
Lithium antagonises the neuropsychological and cerebral activation effects of amphetamines in normal human male subjects in a dose dependent manner.
Methods
Normal male volunteers, aged 18-45 years, will be recruited from local populations. Exclusion criteria (general medical and psychiatric conditions, psychiatric illness in first degree relatives and any previous substance abuse) will be applied by experienced clinicians, and informed consent obtained. Physical examination, blood tests and electrocardiogram will be performed on entry.
The study will follow a within-subject, single-blind sequential design. Following baseline neuropsychological testing in conjunction with fMRI, subjects will receive methamphetamine (0.15mg/kg iv) and the assessments will be repeated. Lithium carbonate will be administered at antimanic therapeutic levels (0.8mmol/L) for one week. Neuropsychological testing and fMRI will be repeated, followed by amphetamine challenge and repeat testing.
The primary neuropsychological outcome measure will be sustained attention assessed using Rapid Visual Information Processing task (block design) in conjunction with the n-back task (central executive function) and Sternberg paradigm (phonological loop). Neurobiological outcome measures assessing dopaminergic neurotransmission will include serial prolactin levels, a peripheral platelet assay of GSK-3 and Blood Oxygen Level Dependent fMRI signal change.
The study protocol will be repeated with antimanic and prophylactic (0.5mmol/L) lithium levels in conjunction with 7LiNMR, exploring the relationship between cerebral concentration, distribution and the antidopaminergic effects of lithium.
Implications of the research
Investigating the relationship between cognitive processes, brain activation and lithium dose distribution during stimulation of the dopaminergic system will provide valuable information about the mechanism of action of lithium, and will help to understand the pathophysiology of bipolar disorder.

Publications

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Cousins D. A. (2010) TRANSLATIONAL STUDIES ON THE EFFECTS OF LITHIUM in JOURNAL OF PSYCHOPHARMACOLOGY

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Cousins DA (2009) The role of dopamine in bipolar disorder. in Bipolar disorders

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Cousins DA (2012) Interpreting magnetic resonance imaging findings in bipolar disorder. in CNS neuroscience & therapeutics

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Cousins DA (2007) The armamentarium of treatments for bipolar disorder: a review of the literature. in The international journal of neuropsychopharmacology

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Cousins DA (2013) Lithium, gray matter, and magnetic resonance imaging signal. in Biological psychiatry

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Kenny ER (2010) Functional connectivity in late-life depression using resting-state functional magnetic resonance imaging. in The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry

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Palaniyappan L (2010) Brain networks: foundations and futures in bipolar disorder. in Journal of mental health (Abingdon, England)

 
Title Lithium imaging 
Description A, RF coil for a multinuclear MR scanner was developed, capable of detecting lithium. On the basis of this developement, scan algorithms are progressing to generate lithium images rather than FID spectroscopy outputs 
Type Of Material Physiological assessment or outcome measure 
Provided To Others? No  
Impact This is likely to greatly advance our understanding of the pharmacokinetics of lithium. 
 
Title Multinuclear imaging lithium 
Description Newly developed double coil for lithium imaging. Permits the generation of true magnetic resonance images encoding for location of lithium rather than spectral spread. 
Type Of Material Biological samples 
Provided To Others? No  
Impact Swift in vivo charting of the distribution of lithium in the human brain. 
 
Description ConLiGen 
Organisation ConLiGen
Country Germany 
Sector Charity/Non Profit 
PI Contribution Expertise in magnetic resonance imaging relating to the effects of lithium on the brain, with respect to response.
Collaborator Contribution Validated tool for rating of response, alignment of assessment techniques and agreed access to GWAS data.
Impact No outputs yet.
Start Year 2013
 
Description MDF group meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Participants in your research and patient groups
Results and Impact The nature and findings of the research undertaken was presented to the Manic Depression Fellowship monthly meeting. Patients were very positive about the direction of research and potential applications of brain lithium measurement and monitoring.

The MDF group agreed to review future submission to ethics committees for related research, providing service user input as is now deemed good practice.
Year(s) Of Engagement Activity 2008,2009
 
Description Mini Medical School 2012 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact "The art and science of psychiatry"
Evening session presenting latest research and views in science and psychiatry. Targeted at potential applicants to Newcastle Medical School.

Session fully booked with maximum attendance. Lecture ranked top in the series by audience feedback.
Year(s) Of Engagement Activity 2012
 
Description Research Feedback Forum 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Participants in your research and patient groups
Results and Impact Region-wide audience of patients, carers, research subjects and psychiatrists. We summarised the results of you research and fielded questions, Very positive feedback.

Stimulated recruitement drive.
Year(s) Of Engagement Activity 2011
 
Description School visit 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Sixth form college group with an interest in science and medicine responded positively to the presentation, finding it stimulating and challanging

A regualar annual session has been requested by that school
Year(s) Of Engagement Activity 2011
 
Description Target Lecture 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Health professionals
Results and Impact Invited lecture "Lithium and the NMR signal" International Review of Bipolar Disorder Copenhagen 2008

Invited be journal editor to submit the content of my presentation as a review article
Year(s) Of Engagement Activity 2008