The platelet as a peripheral marker of the (receptor regulated calcium) second messenger responses in psychiatric illness
This thesis examines the use of the platelet as a peripheral marker of receptor regulated calcium second messenger responses of neuronal cells in major depression, subsyndromal depression, panic disorder and schizophrenia. These psychiatric disorders have substantia] overlap in clinical symptomatology. Identification of a peripheral marker that might differentiate the disease conditions in terms of the underlying pathophysiology of the illness would greatly benefit the diagnosis and treatment o f the psychiatric illnesses.Platelet intracellular calcium in response to neurotransmitter stimulation was measured using the fluorescent dye fura-2. This study has shown that in major depression, treated with electro-convulsive therapy (to control for a drug effect), the augmented intracellular calcium response to serotonin stimulation changes with treatment. The response is correlated with clinical improvement and suggests the platelet response as a state marker in major depression. This platelet response is specific for major depression, since no abnormality in second messenger transduction to serotonin stimulation was seen in patients with subsyndromal depression. Furthermore, the platelet response demonstrates selectivity; in patients with panic disorder, no difference in the calcium response is seen between patients and controls, lending further proof that major depression and panic disorder may ha ve differences in terms of serotonergic dysregulation. The role calcium influx has in the augmented intracellular calcium response was measured by manganese influx and radiolabelled calcium uptake experiments. Calcium influx in response to serotonin stimulation is augmented in major depressive patients compared to normal controls. An interesting finding is that the uptake response is biphasic which may substantiate the two-pool model of calcium oscillations within cells that was proposed by Berridge, 1991. Although many peripheral markers for depression have been suggested,there is a paucity of information concerning peripheral markers of schizophrenia.Serotonin and dopamine have not shown encouraging results as agonists in this disorder.Glutamate is an excitatory amino acid that has been implicated in the pathogenesis of schizophrenia. On stimulation, the platelet glutamate receptoi activates divalent cation channels which cause intracellular calcium release, so in truth it is not a second messenger response. Schizophrenic patients show augmented intracellular calcium responses to glutamate stimulation in comparison to controls. This study supports the use o f the platelet as a peripheral marker in schizophrenia. The last analysis looked at the intracellular calcium response to thrombin in the various psychiatric illnesses. Panic disorder and major depression have the highest intracellular calcium responses to thrombin stimulation. Electroconvulsive therapy does not alter this response, suggesting that it is a trait of the illness. Schizophrenia and subsyndromal depression have no altered intracellular response to thrombin. These results support the growing evidence suggesting that major depression and panic disorder are associated with significant cardiovascular complications, yet whether this is a question of association or causality must still be investigated. I feel that the thesis supports the use of the platelet as a peripheral marker of the receptor regulated calcium second messenger response of the neuronal cell, and the findings may provide some utility in the diagnosis and treatment of the psychiatric disorders.