Clinical Psychopharmacology of 5-HT

Clinical depression is a common illness, often beginning in early adulthood, which can recur throughout a lifetime. The recurrent nature of clinical depression, together with the burden it places on patients and their families, makes this condition one of leading medical causes of suffering and disability. Understanding the biochemical changes in the brain in depression will help us devise better treatments and also improve efforts at prevention. A neurotransmitter called serotonin (5-HT) plays an important role in both the causation of depression and in current drug treatments. In this study we will use advances in brain imaging to study how 5-HT acts in the brain to alter mood. For example we will use magnetic resonance spectroscopy (MRS) to see how 5-HT interacts with special neurons in the brain that use a chemical messenger called glutamate. We believe that the interactions between 5 HT and glutamate may be very important in helping us understand the cause of depression and in developing more effective methods of treatment. A major problem in the treatment of depression is the unpredictability of response to current drug treatments; some patients do well, others are not helped very much. We believe that antidepressants which work through 5-HT such as the selective serotonin re-uptake inhibitors (SSRIs) may produce their therapeutic effects by acting on the way the brain analyses emotional information. The use of functional magnetic resonance imaging (fMRI) allows us to examine the brain networks involved in emotional experience. We will use therefore use fMRI to study how these brain networks are influenced by SSRIs in depressed patients and whether the changes we see enable us to predict those patients who will do well with treatment.

Abnormalities in brain serotonin (5-HT) function appear to play an important role in the pathophysiology of depression and the therapeutic effects of antidepressant treatment. The present proposal builds on our previous work with ligand positron emission tomography (PET) showing that people at high risk of depression have abnormal expression of 5-HT receptors on cortical and limbic neurones. We believe that the abnormal expression of 5-HT receptors on prefrontal glutamatergic neurones leads to excessive glutamatergic feedback on 5-HT cells in the dorsal raphe, an idea we shall test using ligand PET to measure 5-HT release in this brain region. Animal experimental studies suggest that the effects of ascending 5-HT pathways on mood in depressed patients are mediated via critical interactions with glutamatergic neurones, an idea we shall translate to human studies using developments in proton magnetic resonance spectroscopy (MRS) to measure glutamate concentrations in medial prefrontal cortex in response to 5-HT manipulation. We will also assess whether effects of the NMDA receptor antagonist, ketamine, on cortical glutamate are linked to its reported antidepressant action in patients unresponsive to conventional treatments. At a neuropsychological level we believe that the effects of 5-HT on mood are exerted via modulatory actions on the neural circuitry supporting emotional experience and regulation. We will therefore use functional magnetic resonance imaging (fMRI) to test the hypothesis that the therapeutic effects of selective serotonin re-uptake inhibitors (SSRIs) in depressed patients are mediated by early positive changes in the neural processing of emotional information.