[Mechanism of action of antidepressants and therapeutic perspectives].
Depression is an incapacitating disease which needs appropriate treatment. This article reviews the pharmacology of antidepressant drugs and the future perspectives of treating mood disorders such as depression. The foremost theory for explaining the biological basis of depression has been the monoamine hypothesis. Depression is due to a deficiency in one or other biogenic monoamines (serotonin, 5-HT; noradrenaline, NA; dopamine, DA). Antidepressant drugs are therefore classified according to their ability to improve monoaminergic transmission. Since this first theory, other explanations based on abnormal function of monoamine receptors or associated with impaired signalling pathways have been suggested. Notable progress has been accomplished in the treatment of major depressive disorders with new compounds recently discovered (selective serotonin reuptake inhibitors: SSRI; serotonin noradrenaline reuptake inhibitors: SNRI). Behavioural, electrophysiological and microdialysis studies have shown that serotonin (5-HT) receptors, mainly 5-HT1A, 5-HT1B and 5-HT2C sub-types, exert a key role in modulating antidepressant activity. Indirect activation of neurotransmitter receptors by antidepressants may also lead, via increases in endogenous levels of serotonin in synapses in specific brain regions, to activation of various G proteins coupled to a receptor, signal of transduction, transcription factors and neurotrophic factors such as brain-derived neurotrophic factor (BDNF). Thus, depression may be considered as a transduction mechanism anomaly. This hypothesis needs to be clarified by molecular biology. Although antidepressants have improved the therapeutic potential compared to tricyclics (TCA) in terms of reduced side effects, a number of problems still occur with these drugs. Clinical effects are not always observed until after this time has elapsed (4-6 weeks) and a substantial proportion of depressed patients show only partial or no response to antidepressants. Knowledge of the existence of links between neurotransmitter systems and the discovery of the most specific target, 5-HT receptors, should lead to improvements in antidepressant therapy. Developing drugs using innovative mechanisms such as directly acting on 5-HT receptors (5-HT1A agonists or 5-HT2 antagonists), would appear to be useful in the treatment of depression. The use of antidepressants in anxiety disorders such as obsessional compulsive disorders and even generalised anxiety, highlights the distinction between antidepressants and classic anxiolytics such as benzodiazepines, or even buspirone.
Bourin
M
M
Laboratoire de Neuropharmacologie Upres EAD MENRT, Institut de signalisation et d'innovation thérapeutique (IFR75), Faculté de Pharmacie, Université Paris-Sud, Châtenay-Malabry, France. mbourin@sante.univ-nantes.fr
David
D J P
DJ
Jolliet
P
P
Gardier
A
A
D000928:Antidepressive Agents / Q000009:adverse effects / Q000145:classification / Q000494:pharmacology* / Q000627:therapeutic use*; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology / Q000627:therapeutic use; D003866:Depressive Disorder / Q000188:drug therapy* / Q000523:psychology; D006801:Humans; D011985:Receptors, Serotonin / Q000187:drug effects
D000928:Antidepressive Agents; D018687:Antidepressive Agents, Second-Generation; D011985:Receptors, Serotonin