Steve Hodgkinson

One Tablet or Two? Towards the Development of Pharmacogenomically Informed Drug Dose Individualization

Over 50 years of pharmacogenetic research have produced many examples of how inherited variability in drug metabolism can influence individual responses to psychotropic drugs. However, this knowledge has largely failed to be translated into broadly applicable strategies for improvements in individual drug treatment in psychiatry. One important argument brought against the widespread adoption of pharmacogenetics as a clinical tool is the lack of available evidence showing its influence on contemporary clinical praxis and its potential role in improving the risk/benefit ratio for the patients. Individual drug-metabolizing capacity is assessed by genotyping drug-metabolizing enzymes. The information gained from genotyping patients may be used to adjust initial and maintenance drug doses according to genotype. However, even where the consequences of genotype on pharmacokinetics are significant and well-known, as in the case of many tricyclic antidepressants and several selective serotonin reuptake inhibitors, there is still considerable controversy as to whether the adjustment of dosage (based upon genetic information) to improve therapeutic efficacy and/or to reduce the occurrence of adverse events is of any practical importance in clinical practice. Pharmacogenetic studies can improve our understanding of the functional consequence of a genetic variant in the clinical setting, and the use of intermediate phenotypes instead of broad outcome parameters (such as drug response or remission) might improve our knowledge regarding the clinical response of an individual with a specific genotype to a specific drug. Here, we review the potential impact of adopting an integrated approach to patient treatment, which combines the use of intermediate phenotypes that arise from common genetic polymorphisms in drug metabolism enzymes, the monitoring of the therapy progress, and the possibility of pharmacogeneticbased response prediction in depression.

Electroencephalographic risk markers of suicidal behaviour

Since its inception nearly 100 years ago, EEG (electroencephalography) has offered a non-invasive approach to recording the intrinsic electrical activity of the brain. Despite its limitations and the

PATTERNS OF HYDROPHOBICITY FOUND IN THE FIRST AND SECOND TRANSMEMBRANE DOMAINS OF SOLUTE TRANSPORTERS SUGGEST A POSSIBLE ROLE IN NASCENT PROTEIN ANCHORING AND ORGANIZATION

Solute transporters (STs) are an important subgroup of integral membrane proteins that facilitate the translocation of a diverse range of solutes such as sugars, amino acids, and neurotransmitters across cell membranes. Sequence analysis indicates that STs possess multiple stretches of hydrophobic-rich amino acids that are organized into the transmembrane domains (TMDs) of the functional protein, but exactly how the correct spatial arrangement of these domains is achieved remains a challenging problem. We hypothesized that perhaps differences in interdomain hydrophobicity might play some role in this process. To test this hypothesis, we generated a heptadic model of the alpha helix and mapped the average hydrophobicities (coaxial) and hydrophobic moments (radial) of 108 TMDs found in 9 different human ST proteins. Our results, taken together with earlier work from other groups, suggest that spatial patterns of hydrophobicity found in TMDs 1 and 2 are consistent with a role for these domains in the initial anchoring of the nascent ST protein to the endoplasmic reticulum (ER), as it emerges from the ribosome complex and perhaps in the subsequent spatial organisation of STs.

P02-309 - Action-inhibition hierarchies: Using a simple gastropod model to investigate serotonergic and dopaminergic control of action selection and reinforcement learning

Introduction Basal ganglia (BG) activity plays an important role in action selection and reinforcement learning. Inputs from and to other areas of the brain are modulated by a number of neurotransmitter pathways in the BG. Disturbances in the normal function of the BG may play a role in the aetiology of psychiatric disorders such as schizophrenia and bipolar disorder. Aims Develop a simple animal model to evaluate interactions between glutamatergic, dopaminergic, serotonergic and GABAergic neurones in the modulation of action selection and reinforcement learning. Objectives To characterise the effects of changing dopaminergic and serotonergic activity on action selection and reinforcement learning in an animal model. Methods The food seeking / consummation (FSC) activity of the gastropod Planorbis corneus was suppressed by operant conditioning using a repeated unconditioned stimulus-punishment regime. The effects of elevated serotonin or dopamine levels (administration into cerebral, pedal and buccal ganglia), on operantly-conditioned FSC activity was assessed. Results Operantly-conditioned behaviour was reversed by elevated ganglia serotonin levels but snails showed no food consummation motor activity in the absence of food. In contrast, elevated ganglia dopamine levels in conditioned snails elicited food consummation motor movements in the absence of food but not orientation towards a food source. Conclusions The modulation of FSC activity elicited by reinforcement learning is subject to hierarchical control in gastropods. Serotoninergic activity is responsible establishing the general activity level whilst dopaminergic activity appears to play a more localised and subordinate ‘command’ role.