Demontis, Francesca (2015) Effetto della memantina su modelli animali di disturbi dell'umore. Doctoral Thesis.
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AIM: Mood disorders are one of the leading causes of morbidity, disability and premature mortality contributing for about 50% of the non-fatal burden of mental disorders.
Bipolar disorder (BD) has a lifetime prevalence of approximately 1.0% for BD-I, 1.1% for BD-II and 2.4% for BD-NOS. Eighty-three percent of BD cases are classified as “seriously severe” and 17.1% as “moderately severe”.
Long-term prophylactic treatment of BD aimed at preventing recurrences of the various phases is a leading clinical and research challenge for contemporary psychiatry. Dopaminergic behavioural supersensitivity induced by chronic treatment with antidepressants might be involved both in the antidepressant action and in the mechanisms underlying antidepressant treatment-related mania (antidepressant-induced mood switch and possibly, rapid cycling bipolar disorder).
The stimulation of NMDA receptors is required for the development of dopamine receptor sensitization induced by antidepressants. Indeed, the administration of MK-801, a selective non-competitive NMDA receptor blocker, completely prevents the dopamine receptor sensitization induced by imipramine and by electroconvulsive shock.
These observations strongly suggest that the non-competitive blockade of NMDA receptors should result in an anti-manic and mood stabilizing action, and that it should also be effective in the treatment of the disorders resistant to currently used antimanic and mood stabilizers.
Memantine is a non-competitve NMDA receptor antagonist, she has been on the market in since 1982 for the treatment of Parkinsonism, before its approval in 2002 and 2004 by EMEA and FDA for the treatment of moderate to severe Alzheimer's Disease.
Although its actual efficacy on the AD patient's quality of life has proven to be moderate, several pre-marketing and post marketing studies have demonstrated the excellent safety and tolerability profile of the drug.
Moreover, the drug has been used off-label in a number of neurological and psychiatric conditions, including depression, with conflicting and inconclusive results.
To further clarify the farmacology of memantine, I studied hers effect in animal models of in mood disorders.
METHOD: Male and Female rats treated with memantine in animal model of:
• dopaminergic behavioural supersensitivity
• bipolard disorders by chronic antidepressant
• catatonia by haloperidol
• tardive dyskinesia by cronic haloperidol
RESULTS: The results show that memantine, at variance with antidepressant treatments (including drugs, electroconvulsive schock, REM-sleep deprivation), fails to induce dopaminergic behavioural supersensitivity. Therefore has not an antidepressant action.
Memantine prevents not only, as observed with MK-801, the sensitization of dopamine receptors induced by chronic imipramine (mania), but also the ensuing desensitization of those receptors and the associated depressive-like behavior. Thus stabilizes the course of the manic-depressive illness Furthermore, memantine prevents stress, catatonia and tardive dyskinesia.
This observation is consistent with the results of clinical studies suggesting that memantine has not an antidepressant action but an antimanic and mood-stabilizing effect.
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