GABAb receptors are coupled to calcium channels. A role for GABA in the pathophysiology of depression has long been postulated, and several recent studies support this hypothesis.111,112 Preclinical studies have demonstrated decreased CNS GABA concentrations in animal models of depression.111 CSF and CI-1033 mouse plasma GABA concentrations have been reported to be decreased in depressed patients.111 Postmortem investigation of the hippocampus

in depressed patients suggested possible GABAergic Inhibitors,research,lifescience,medical dysfunction.113 GABAb receptors are found on most 5-HT-containing neurons in the dorsal raphe, and GABA release into the dorsal raphe decreases firing of 5-HT neurons.114 Modulating GABAb function has been shown to have important behavioral effects in animal models, with GABAb antagonists demonstrating certain antidepressantlike properties.112,114 Using magnetic resonance spectroscopy, Sanacora et al demonstrated decreased GABA concentrations in the

occipital cortex of depressed patients.100,115 Moreover, this group showed GABA concentrations increase in the occipital cortex Inhibitors,research,lifescience,medical after SSRI treatment and ECT,116,117 but not after Inhibitors,research,lifescience,medical CBT118 CNS GABA concentrations have also been shown to be normal in remitted depressed patients compared with controls.119 Neurokinins Neurokinins are neuropeptides widely distributed in the CNS and peripheral nervous system, and are believed to play a role in nociception. Substance P is the most abundant neurokinin in humans and is found in neurons in several brain regions implicated in the neurobiology of depression.120 Substance P is also colocalized in cells containing 5-HT and NE.121-124 Substance P binds to several receptor subtypes (NK-1, NK-2, NK-3, NKA, NKB), and appears to Inhibitors,research,lifescience,medical have an important role in modulating the mammalian stress response. In animal models, substance P results in behavioral and physiologic changes characteristics of a stress response.125,126 Inhibitors,research,lifescience,medical These changes can be attenuated by substance P antagonists.127,128 Supporting its role in depression, CSF substance P concentrations were reported to be elevated in depressed patients

compared with controls,129-131 and lower serum concentrations of substance P have been correlated with better antidepressant treatment response.130 Our group has reported elevations in CSF substance P concentrations in drug-free patients with major depression and PTSD.132 One placebo-controlled study using a neurokinin receptor (NK-1) antagonist (MK-869) suggested efficacy in treating depression,127 Tolmetin but several follow-up studies found no significant antidepressant effects for this agent.133 Two other selective NK-1 receptor antagonists (L-759274 and CP-122721) have shown potential efficacy in treating depression,134,135 although data are relatively limited. In general, these drugs appear to be well-tolerated. Neuroanatomical models Several lines of evidence support a neuroanatomical basis for depression.