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The neuropsychiatry of multiple sclerosis: a review of recent developments. Curr Opin Psychiatry . 2007; 20:278Y285. 18. Kosmidis MH, Giannakou M, Messinis L, et al. Psychotic features associated with multiple sclerosis. Int Rev Psychiatry . 2010; 22:55Y66. N-Acetylcysteine Augmentation to Tranylcypromine in Treatment-Resistant Major Depression To the Editors: T he treatment of major depressive dis- order (MDD) has evolved in the past decades with the advent of selective se- rotonin reuptake inhibitors because of their tolerability and safety profile. Nev- ertheless, recent evidence indicates that only 33% of patients achieve remission with a single agent in real-world scenarios. 1,2 Some patients fail to remit even with com- plex combination regimens. 3 These group of difficult-to-treat patients represent a major challenge for clinical psychiatrists. 3 In these instances, the use of monoamine oxidase inhibitors (MAOIs) is often nec- essary. 4,5 However, the Sequenced Alter- natives to Relieve Depression (STAR*D) trial reported that only approximately 7% of these treatment-resistant patients remit with MAOIs. 6 Evidence to guide sub- sequent psychopharmacological strate- gies for patients with MDD who did not achieve remission after a MAOI trial derive from a few published case re- ports. 7,8 Here, we report for the first time the successful use of N-acetylcysteine (NAC) augmentation in patients who did not achieve response after a trial with the MAOI tranylcypromine. Several pharmacodynamic properties of NAC anticipate putative antidepressant properties. 9 For instance, NAC is a pre- cursor of glutathione, a main antioxidant of the brain. 9 Several other actions of NAC may be relevant to its possible antide- pressant activity: (1) its anti-inflammatory effects; (2) the indirect decrement of syn- aptic release of glutamate, and (3) the fa- cilitation of striatal dopamine release. 9 N-acetylcysteine has antidepressant prop- erties in the rat bulbectomy model of depression. 10 Moreover, preliminary evi- dence indicates that adjunctive NAC may be effective for the treatment of depres- sive episodes of bipolar disorder. 11,12 CASE 1 In January 2011, a 22-year-old male medical student presented with a se- vere, treatment-refractory, first episode of MDD without psychotic symptoms. He presented with atypical features (rejection sensitivity, increased appetite, hypersom- nia, and mood reactivity) along with sui- cidal thoughts, intention, and plans. He had never experienced manic symptoms. The patient did not have a personality disorder (as assessed with the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Axis II Disorders). The episode had been lasting for approximately 18 months. A comprehensive medical ex- amination that included laboratory exami- nations did not reveal abnormalities. His mother had a history of recurrent MDD. He was previously treated with 2 SSRIs (escitalopram, up to 30 mg/d for 12 weeks; and paroxetine, up to 80 mg/d for 8 weeks), venlafaxine (up to 375 mg/d for 12 weeks), and clomipramine (up to 300 mg/d for 12 weeks). The patient did not achieve a clear treatment response. Therefore, we augmented clomipramine (300 mg/d) with lithium (up to 1500 mg/d; serum levels, 1.1 mEq/L for 4 weeks) and quetiapine (up to 300 mg/d for 2 weeks). His score on the 17-item Hamilton De- pression Rating Scale (HDRS-17) was 19. Tranylcypromine was initiated at a daily dose of 10 mg and was then titrated to a maximum daily dose of 90 mg for 4 weeks. The patient was on tranylcy- promine, 90 mg/d, for 12 weeks and had a HDRS-17 score of 12 and a Clinical Global ImpressionVImprovement (CGI-I) score of 3 (minimally improved). Blood pressure was monitored throughout the treatment, and there was no alteration. No adverse effects were reported by the pa- tient. At this time, we had suggested bi- lateral electroconvulsive therapy (ECT), but the patient declined this treatment modality. N-acetylcysteine was started at a daily dose of 2 g/d 2 times a day orally (with a 12-hour interval between doses). After 8 weeks, the HDRS-17 score was 5, and the CGI-I score was 1 (very much improved). The patient has been followed up for 7 months since then and is still in symptomatic remission; he is now re- garded as a very good-acting intern in his medical school. CASE 2 In November 2010, a 43-year-old woman presented to our clinic with treatment-resistant MDD. She had a previ- ous episode 12 years ago triggered by ar- guments with her husband, which ultimately led to a divorce; that episode was suc- cessfully treated with fluoxetine (daily dose, 60 mg). Fluoxetine was discontinued 1 year after recovery. The patient was asymp- tomatic for 10 years. However, in the past 2 years, she had a second episode of MDD. She did not have psychotic symp- toms, but she presented with typical melancholic features. She had lost 7 kg (approximately 10% of her weight) and experienced excessive guilt, early morn- ing awakening, psychomotor retardation, and passive suicidal thoughts (‘‘I would be better off dead’’). Her mother had a history of recurrent MDD, and her oldest sister had chronic recurrent depression and eventually committed suicide. A compre- hensive medical evaluation did not reveal any abnormalities. She had been treated with several antidepressant drugs, includ- ing 2 SSRIs (fluoxetine, up to 50 mg/d for 12 weeks; and sertraline, up to 200 mg/d for 2 months), duloxetine (up to 120 mg/d for 8 weeks) and imipramine (up to 250 mg/d for 28 weeks). Lithium was added to impramine (1200 mg/d; serum levels, 1.2 mEq/L for 20 weeks). Because the patient did not achieve response, olanzapine (10 mg/d for 3 months) was added to imipramine (250 mg/d) plus lith- ium (1200 mg/d). Her HDRS-17 score was still 21. She had also been treated with a course of 14 bilateral ECT sessions over 5 weeks. Her HDRS-17 score reduced to 17 (CGI-I score, 3: minimally improved). After this unsuccessful intervention, we started tranylcypromine at a daily dosage of 10 mg, which was titrated up to 60 mg/d for 4 weeks. The patient could not tolerate Journal of Clinical Psychopharmacology & Volume 33, Number 5, October 2013 Letters to the Editors * 2013 Lippincott Williams & Wilkins www.psychopharmacology.com 719 Copyright © 2013 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Copyright © 2013 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.