Chemical Biology: Approaches to Drug Discovery and Development to Targeting Disease

Chapter 14: Depression

Glen B. Baker

Nicholas D. Mitchell

University of Alberta, Neurochemical Research Unit, Department of Psychiatry, Edmonton, Alberta, Canada

Although the etiology of depression remains to be elucidated, our knowledge of the neurobiology and biochemistry of this mental disorder has been updated increasingly. Early research focused on the biogenic amines norepinephrine (NE; noradrenaline) and 5-hydroxytryptamine (5-HT; serotonin). The biogenic amine (monoamine) hypothesis of depression states that depression is the result of a functional deficiency of NE and/or 5-HT at central synapses. However, it soon became obvious that other factors were also important in the neurobiology of depression. Dopamine is thought to be involved in various aspects, which include reward and locomotion. The amino acids gamma-aminobutyric acid (GABA) and glutamate, their receptors, and various neuroactive steroids that act as allosteric modulators at GABA-A and/or NMDA glutamate receptors have been proposed to have an important role. Stress and the hypothalamic-pituitary-adrenal (HPA) axis play a central role, and it has been proposed that increased secretion of corticotropin releasing factor (CRF) may be critical in producing the symptoms of depression. Various other neurochemicals have also been implicated in depression, and in several cases they have links to the HPA axis. Abnormal levels of Substance P have been reported in depression, which led to development of potential antidepressants ...