Other neuromodulatory systems In addition to the monoamines and constituents of the neuroendocrine systems, there are a number of other neuromodulators that have been implicated in the neurobiology of depression. Increasing research efforts have focused on these systems, especially as potential targets for novel drug development. In general, future research studies will help clarify the role of these systems in the pathophysiology and treatment of depression. In particular, the relation between these

systems and other neurotransmitter systems will need to be better delineated. Also, given the general lack of anatomic specificity for some Inhibitors,research,lifescience,medical of these systems (such as glutamate and GABA), drug development will need to focus on agents that show potential antidepressant Inhibitors,research,lifescience,medical efficacy without additional unwanted adverse effects. A promising new direction in pharmacological research involves the system implicated in circadian rhythms. Agomelatine, which acts as an agonist at melatonin MT1/MT2 receptors and an antagonist at 5HT2c receptors, has proven its antidepressant efficacy in clinical trials,97 and has a favorable Inhibitors,research,lifescience,medical tolerability profile. Glutamate Glutamate is the primary

excitatory neurotransmitter in the brain. Glutamate receptors are divided into two types: ionotropic (including the N-methyl-D-aspartate [NMDA], α-amino-3-hydroxy-5-methyl-4-isoxazide propionic acid [AMPA], and kainite receptors) and metabotropic (including a family of G-protein Inhibitors,research,lifescience,medical coupled receptors associated with adenyl cyclase and phosphoinositide second messenger systems). Excitatory glutamatergic neurotransmission likely plays a role in depression.98,99 Indeed, stress may contribute to depression by increasing excitatory glutamatergic neurotoxicity

in brain areas involved in mood regulation. Sanacora et al reported that depressed patients had higher cortical glutamate levels compared with healthy controls, using magnetic resonance spectroscopy.100 Ionotropic glutamate receptor antagonists can decrease stress-induced loss of Inhibitors,research,lifescience,medical hippocampal neurons,101,102 and data suggest amantadine (a nonselective NMDA receptor antagonist) Resminostat may enhance antidepressant-like effects of typical antidepressants in animal models103,104 and depressed patients.105 Preclinical studies of selective NMDA receptor antagonists have revealed antidepressant-like effects in animal models.106,107 Additionally, agents that enhance AMPA receptor function may augment antidepressant effects of standard antidepressant medications.108 Riluzole, which inhibits glutamate release, has shown preliminary antidepressant effects in patients with bipolar depression,109,110 but no placebo-controlled data are available and effects in unipolar depression have not been studied. GABA GABA is the major inhibitory neurotransmitter in the CNS. There are two major types of GABA receptors: GABAa and GABAb.