Kaplan + Sadock's Synopsis of Psychiatry, 11e

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Chapter 29: Psychopharmacological Treatment

of agranulocytosis associated with mirtazapine use, persons should be attuned to signs of infection. Because of the sedat- ing effects of mirtazapine, persons should determine the degree to which they are affected before engaging in driving or other potentially dangerous activities. Drug Interactions Mirtazapine can potentiate the sedation of alcohol and benzodi- azepines. Mirtazapine should not be used within 14 days of use of an MAOI. Laboratory Interferences No laboratory interferences have yet been described for mir- tazapine. Dosage and Administration Mirtazapine is available in 15-, 30-, and 45-mg scored tablets. Mirtazapine is also available in 15-, 30-, and 45-mg orally dis- integrating tablets for persons who have difficulty swallowing pills. If persons fail to respond to the initial dose of 15 mg of mirtazapine before sleep, the dose may be increased in 15-mg increments every 5 days to a maximum of 45 mg before sleep. Lower dosages may be necessary in elderly persons or persons with renal or hepatic insufficiency. R eferences Banerjee S, Hellier J, Romeo R, et al. Study of the use of antidepressants for depression in dementia: the HTA-SADD trial—a multicentre, randomised, double-blind, placebo-controlled trial of the clinical effectiveness and cost- effectiveness of sertraline and mirtazapine. Health Technol Assess. 2013; 17(7):1–166. Cettomai D, McArthur JC. Mirtazapine use in human immunodeficiency virus- infected patients with progressive multifocal leukoencephalopathy. Arch Neu- rol. 2009;66(2):255. Clayton AH, Montejo AL. Major depressive disorder, antidepressants, and sexual dysfunction. J Clin Psychiatry. 2006;67(Suppl 6):33. Fava M, Rush AJ, Wisniewski SR, Nierenberg AA, Alpert JE. A comparison of mirtazapine and nortriptyline following two consecutive failed medication treatments for depressed outpatients: A STAR*D report. Am J Psychiatry. 2006;163(7):1161. Kim SW, Shin IS, Kim JM, Park KH, Youn T, Yoon JS. Factors potentiating the risk of mirtazapine-associated restless legs syndrome. Hum Psychopharmocol. 2008;(7):615. McGrath PJ, Stewart JW, Fava M, Trivedi MH, Wisniewski SR. Tranylcypromine versus venlafaxine plus mirtazapine following three failed antidepressant medication trials for depression: A STAR*D report. Am J Psychiatry. 2006; 163(9):1531. Papakostas GI, Homberger CH, Fava M. A meta-analysis of clinical trials compar- ing mirtazapine with selective serotonin reuptake inhibitors for the treatment of major depressive disorder. J Psychopharmacol. 2008;22(8):843. Papakostas GI, Thase ME, Fava M, Nelson JC, Shelton RC. Are antidepressant drugs that combine serotonergic and noradrenergic mechanisms of action more effective than the selective serotonin reuptake inhibitors in treating major depressive disorder?Ameta-analysis of studies of newer agents. Biol Psychiatry. 2007;62(11):1217. Schatzberg AF, Kremer C, Rodrigues HE, Murphy GM Jr. Double-blind, random- ized comparison of mirtazapine and paroxetine in elderly depressed patients. Am J Geriatr Psychiatry. 2002;10:541. Schittecatte M, Dumont F, Machowski R, Fontaine E, Cornil C. Mirtazapine, but not fluvoxamine, normalizes the blunted REM sleep response to clonidine in depressed patients: Implications for subsensitivity of alpha(2)-adrenergic receptors in depression. Psychiatry Res. 2002;109:1. Stenberg JH, Terevnikov V, Joffe M, et al. Predictors and mediators of add-on mirtazapine-induced cognitive enhancement in schizophrenia—a path model investigation. Neuropharmacology. 2013;64:248–253. ThaseME. Mirtazapine. In: Sadock BJ, SadockVA, Ruiz P, eds. Kaplan&Sadock’s Comprehensive Textbook of Psychiatry. 9th edition. Vol. 2. Philadelphia: Lippincott Williams & Wilkins: 2009:3152.

▲▲ 29.22 Monoamine

Oxidase Inhibitors Introduced in the late 1950s, MAOIs were the first class of approved antidepressant drugs. The first of these drugs, isonia- zid, was intended to be used as a treatment for tuberculosis, but its antidepressant properties were discovered by chance when some treated patients experienced elevation of mood during treatment. Despite their effectiveness, prescription of MAOIs as first-line agents has always been limited by concern about the development of potentially lethal hypertension and the conse- quent need for a restrictive diet. Use of MAOIs declined fur- ther after the introduction of the SSRIs and other new agents. They are now mainly relegated to use in treatment-resistant cases. Thus, the second-line status of MAOIs has less to do with considerations of efficacy than with concerns for safety. The currently available MAOIs include phenelzine (Nardil), isocarboxazid (Marplan), tranylcypromine (Parnate), rasagiline (Azilect), moclobemide (Manerix), and selegiline (Eldepryl). Two subsequent advances in the field of antidepressant MAOIs involve the introduction of a selective reversible inhibi- tor of MAO A (RIMA), moclobemide (Manerix), in the early 1990s into most countries except the United States, and in 2005, the introduction of a transdermal delivery form of selegiline (Emsam) in the United States that is used for the treatment of parkinsonism. Other RIMA agents, including brofaromine (Consonar) and befloxatone, have not been submitted for regis- tration despite favorable outcomes in clinical trials. Pharmacologic Actions Phenelzine, tranylcypromine, and isocarboxazid are readily absorbed after oral administration and reach peak plasma con- centrations within 2 hours. Whereas their plasma half-lives are in the range of 2 to 3 hours, their tissue half-lives are consid- erably longer. Because they irreversibly inactivate MAOs, the therapeutic effect of a single dose of irreversible MAOIs may persist for as long as 2 weeks. The RIMA moclobemide is rap- idly absorbed and has a half-life of 0.5 to 3.5 hours. Because it is a reversible inhibitor, moclobemide has a much briefer clinical effect after a single dose than do irreversible MAOIs. The MAO enzymes are found on the outer membranes of mitochondria, where they degrade cytoplasmic and extraneuronal monoamine neurotransmitters such as norepinephrine, serotonin, dopamine, epinephrine, and tyramine. MAOIs act in the CNS, the sympathetic nervous system, the liver, and the GI tract. There are two types of MAOs, MAO A and MAO B . MAO A primarily metabo- lizes norepinephrine, serotonin, and epinephrine; dopamine and tyramine are metabolized by both MAO A and MAO B . The structures of phenelzine and tranylcypromine are simi- lar to those of amphetamine and have similar pharmacologic effects in that they increase the release of dopamine and norepi- nephrine with attendant stimulant effects on the brain. Therapeutic Indications MAOIs are used for treatment of depression. Some research indicates that phenelzine is more effective than tricyclic