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29.33 Valproate

dosage of a TCA. Nortriptyline is unique in its association with a therapeutic window—that is, plasma concentrations below 50 ng/mL or above 150 ng/mL may reduce its efficacy. Plasma concentrations may be useful in confirming com- pliance, assessing reasons for drug failures, and documenting effective plasma concentrations for future treatment. Clinicians should always treat the person and not the plasma concentra- tion. Some persons have adequate clinical responses with seem- ingly subtherapeutic plasma concentrations, and other persons only respond at supratherapeutic plasma concentrations with- out experiencing adverse effects. The latter situation, however, should alert the clinician to monitor the person’s condition with, for example, serial EKG recordings. Overdose Attempts Overdose attempts with TCAs are serious and can often be fatal. Prescriptions for these drugs should be nonrefillable and for no longer than 1 week at a time for patients at risk for suicide. Amoxapine may be more likely than the other TCAs to result in death when taken in overdose. The newer antidepressants are safer in overdose. Symptoms of overdose include agitation, delirium, con- vulsions, hyperactive deep tendon reflexes, bowel and blad- der paralysis, dysregulation of BP and temperature, and mydriasis. The patient then progresses to coma and perhaps respiratory depression. Cardiac arrhythmias may not respond to treatment. Because of the long half-lives of TCAs, the patients are at risk of cardiac arrhythmias for 3 to 4 days after the overdose, so they should be monitored in an intensive care medical setting. R eferences Anderson I. Selective serotonin reuptake inhibitors versus tricyclics antidepres- sant: A meta-analysis of efficacy and tolerability. J Affect Disord. 2000;58:19. Anton RF, Burch EA. Amoxapine versus amitriptyline combined with perphen- azine in the treatment of psychotic depression. Am J Psychiatry. 1990;147:1203. Bech P, Allerup P, Larsen E, Csillag C, Licht R. Escitalopram versus nortriptyline: How to let the clinical GENDEP data tell us what they contained. Acta Psychi- atr Scand. 2013;127(4):328–329. Charney DS, Delgado PL, Price LH, Heninger GR. The receptor sensitivity hypothesis of antidepressant action: A review of antidepressant effects on sero- tonin function. In: Brown SL, van Praag HM, eds. The Role of Serotonin in Psychiatric Disorders. NewYork: Brunner/Mazel; 1991:29. Choung RS, Cremonini F, Thapa P, Zinsmeister AR, Talley NJ. The effect of short- term, low-dose tricyclic and tetracyclic antidepressant treatment on satiation, postnutrient load gastrointestinal symptoms and gastric emptying: A double- blind, randomized, placebo-controlled trial. Neurogastroenterology Motility. 2008;20:220. Danish University Antidepressant Group. Paroxetine: A selective serotonin reup- take inhibitor showing better tolerance, but weaker antidepressant effect than clomipramine in a controlled multicenter study. J Affect Dis. 1990;18:289. Duman RS, Heninger GR, Nestler EJ. A molecular and cellular theory of depres- sion. Arch Gen Psychiatry. 1997;54:597. Elkin I, Shea T, Watkins JT. NIMH treatment of depression collaborative research program: General effectiveness of treatments. Arch Gen Psychiatry. 1989; 46:971. Frank E, Kupfer DJ, Perel JM. Three-year outcomes for maintenance therapies in recurrent depression. Arch Gen Psychiatry. 1990;47:1093. Lai MW, Klein-Schwartz W, Rodgers GC, Abrams JY, Haber DA. 2005 Annual report of the American Association of Poison Control Centers’ national poison- ing and exposure database. Clin Toxicol. 2006;44:803. Lapierre YD. A review of trimipramine: 30 years of clinical use. Drugs. 1989; 38:17. Liebowitz MR, Quitkin FM, Stewart JW. Antidepressant specificity in atypical depression. Arch Gen Psychiatry. 1988;45:129. Nelson JC. Tricyclics and tetracyclics. In: Sadock BJ, Sadock VA, Ruiz P, eds. Kaplan & Sadock’s Comprehensive Textbook of Psychiatry. 9th edition. Vol. 2. Philadelphia: Lippincott Williams & Wilkins: 2009:3259.

Nelson JC, Mazure C, Jatlow PI. Antidepressant activity of 2-hydroxy-desipra- mine. Clin Pharmacol Ther. 1988;44:283. O’Malley PG, Jackson JL, Santoro J, Tomkins G, Balden E. Antidepressant ther- apy for unexplained symptoms and symptom syndromes. J Fam Pract. 1999; 48:980. Roose S, Laghrissi-Thode F, Kennedy JS, Nelson JC, Bigger JT. A comparison of paroxetine and nortriptyline in depressed patients with ischemic heart disease. JAMA. 1998;279:287. Shenouda R, Desan PH. Abuse of tricyclic antidepressant drugs: A case series. J Clin Psychopharmcol. 2013;33(3):440–442. Tremblay P, Blier P. Catecholaminergic strategies for the treatment of major depression. Curr Drug Targets. 2006;7:149. Yoshimura M, Furue H. Mechanisms for the anti-nociceptive actions of the descending noradrenergic and serotonergic systems in the spinal cord. J Phar- macol Sci. 2006;101:107. ▲▲ 29.33 Valproate Valproate (Depakene, Depakote), or valproic acid, is approved for the treatment of manic episodes associated with bipolar I disorder and is one of the most widely prescribed mood stabiliz- ers in psychiatry. It has a rapid onset of action and is well toler- ated, and numerous studies suggest that it reduces the frequency and intensity of recurrent manic episodes over extended periods of time. Chemistry Valproate is a simple-chain branch carboxylic acid. It is called valproic acid because it is rapidly converted to the acid form in the stomach. Multiple formulations of valproic acid are marketed. These include valproic acid (Depakene); divalproex sodium (Depakote), an enteric-coated delayed-release 1:1 mix- ture of valproic acid and sodium valproate available in tablet and sprinkle formulation (can be opened and spread on food); and sodium valproate injection (Depacon). An extended-release preparation is also available. Each of these is therapeutically equivalent because at physiologic pH, valproic acid dissociates into valproate ion. Pharmacologic Actions Regardless of how it is formulated, valproate is rapidly and completely absorbed 1 to 2 hours after oral administration, with peak concentrations occurring 4 to 5 hours after oral administration. The plasma half-life of valproate is 10 to 16 hours. Valproate is highly protein bound. Protein binding becomes saturated at higher dosages, and concentrations of therapeutically effective free valproate increase at serum con- centrations above 50 to 100 m g/mL. The unbound portion of valproate is considered to be pharmacologically active and can cross the blood–brain barrier. The extended-release preparation produces lower peak concentrations and higher minimum con- centrations and can be given once a day. Valproate is metabo- lized primarily by hepatic glucuronidation and mitochondrial b oxidation. The biochemical basis of valproate’s therapeutic effects remains poorly understood. Postulated mechanisms include enhancement of GABA activity, modulation of voltage-sensitive sodium channels, and action on extrahypothalamic

neuropeptides.