*6.3. Anxiety, Compulsive, and Depressive Disorders*

Anxiety or closely related disorders are characterized by fear and anxiety related to behavioral disturbances, including panic disorder or obsessive-compulsive disorder (OCD). The search for new treatments for anxiety disorders has long led to an analysis of the effect of MI administration. It has been shown by 1H-MRS that frontal cortex MI levels are reduced in patients with depressive and sleep disorders, and MI levels are negatively correlated with depression severity [235,236]. Despite a mechanism of action that is partially unknown, many clinical trials in humans have probed MI at a dose ranging from 12–18 g/day, finding that the dosage is effective for the treatment of panic disorders, OCD, and depression, which are included in the broad spectrum of disorders mainly treated with selective serotonin reuptake inhibitors (SSRIs) [20–22].

Since serotonin receptors (5-HTs) are G-protein-coupled receptors, the net effect of MI was thought to be mediated by the replenishment of PI and PIP2 availability, avoiding receptor desensitization [237]. In a forced swim test in rats, MI administration reduced depressive behavior, which was abolished by the addition of the specific 5-HT2A/5-HT2C antagonist ritanserin, but not the 5-HT1A/5-HT1B/β adrenergic antagonist pindolol, which suggests that the MI anti-depressant mechanism specifically involves 5-HT2 subtype receptors [238]. Moreover, the administration of 1.2 g/kg MI for 12 weeks significantly increased type 2 dopamine (D2) and slightly increased 5-HT2 receptor density in the striatum of guinea pigs, a region involved in locomotor and stereotype behavior [239]. Although the

MI mechanism has not been fully elucidated, its use for anxiety and depressive disorders is still under evaluation. It should also be noted that MI has no additive effect with SSRI treatment, which suggests that somehow both families of compounds intersect regarding their mechanism of action [240,241].
