| Summary: | Major depressive disorder (MDD) is a chronic, recurrent mood disorder (Kendler, Thornton, & Gardner, 2000; Kumar, Harmer, & Dourish, 2013) with an estimated lifetime prevalence of 16.2% (Kessler et al., 2003) which affects more than 350 million people globally (WHO, 2013). MDD has a complicated and multifarious neuropathology, a result of which is largely ineffective and out-dated pharmacological treatments (Skolnick, 1999). Typical antidepressants are either serotonin re-uptake inhibitors (SRI) or tri-cyclic antidepressants (TCA), both of which target the monoamine system (serotonin and/or dopamine). However, research has suggested a myriad of distinct hypotheses for depression through localisation of functionally distinct neuroanatomical structures, identification of neurotransmitter modulation and receptor subunit alterations as well as genetic, environmental and behavioural observations that could all be targets for antidepressant therapy. Alterations of the GABAergic and glutamatergic neurotransmitter systems have been reported in major depressive disorder (MDD), both post-mortem in-vitro and ante-mortem in-vivo. Evidence from magnetic resonance spectroscopy (MRS) studies reported lower bulk concentrations of GABA in currently depressed participants as compared with healthy controls, which may reflect a neurobiological pathology, serve as a biomarker, and guide development of new pharmacological therapies. If this area of research is to see translation to a clinical setting, the roles of GABA (and glutamate) in depression need to be fully elucidated. Some of the questions that arise are: Do alterations in GABA concentration reflect state or trait markers of depression? Does the GABA deficit observed in depression reflect ‘functional’ GABA? Does an existing pharmacological compound with antidepressant efficacy act on the GABA system? This thesis addresses these questions primarily utilizing multimodal neuroimaging techniques, along with computational neuronal modelling and pharmacological manipulation.
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