Glutamate system as target for development of novel antidepressants.
Depression is a common psychiatric condition characterized by affective, cognitive, psychomotor, and neurovegetative symptoms that interfere with a person's ability to work, study, deal with interpersonal relationships, and enjoy once-pleasurable activities. After the serendipitous discovery of the first antidepressants, for years the only pharmacodynamic mechanisms explored in the search of novel antidepressants were those related to the 3 main monoamines: serotonin, norepinephrine, and dopamine. New-generation monoaminergic antidepressants, such as selective-serotonin and dual-acting serotonin/norepinephrine reuptake inhibitors, improved treatment and quality of life of depressed patients. Nevertheless, there are still important clinical limitations: the long latency of onset of the antidepressant action; side effects, which can lead to early discontinuation; low rate of response; and high rate of relapse/recurrence. Therefore, in the last several years, the focus of research has moved from monoamines toward other molecular mechanisms, including glutamatergic (Glu) neurotransmission. This review provides a comprehensive overview of the current knowledge on the Glu system and on its relationships with mood disorders. Up to now, N-methyl-D-aspartate (NMDA) receptor antagonists, in particular ketamine, provided the most promising results in preclinical studies and produced a consistent and rapid, although transient, antidepressant effect with a good tolerability profile in humans. Although data are encouraging, more double-blind, randomized, placebo-controlled trials are needed to clarify the real potentiality of ketamine, and of the other Glu modulators, in the treatment of unipolar and bipolar depression.
1 Department of Psychiatry, Neurobiology, Farmacology and Biotecnology, University of Pisa, Pisa, Italy.
Mario
M
Catena-Dell'Osso
Andrea
A
Fagiolini
Francesco
F
Rotella
Stefano
S
Baroni
Donatella
D
Marazziti
D000447:Aldehydes / Q000378:metabolism*; D000928:Antidepressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D003866:Depressive Disorder / Q000188:drug therapy* / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D017470:Receptors, Glutamate / Q000378:metabolism*
D000447:Aldehydes; D000928:Antidepressive Agents; D017470:Receptors, Glutamate; C007860:glutaconaldehyde