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.
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.
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.