Comparison to Other AntidepressantsTreatment outcomes in major depressive disorder after therapy with sertraline have been compared to outcomes seen with amitriptyline, bupropion, citalopram, clomipramine, dothiepin (Prothiaden, Dosulepin, not available in the United States), fluoxetine, fluvoxamine, imipramine, moclobemide, nortriptyline, paroxetine, and others. In general, these studies have demonstrated equivalent efficacy (determined by response rates) between sertraline therapy and treatment with the comparator agent.Depression is a recurrent disorder for many patients. The efficacy of sertraline in preventing the recurrence of a major depressive episode has been studied in a comparative study with fluvoxamine. Sixty-four patients with a mean age of approximately 50 years of age and an average of seven lifetime episodes of depression were randomized to receive 100 mg per day of sertraline or 200 mg per day of fluvoxamine. If a patient's depression worsened (functional impairment and a HAMD scale score of ≥15), sertraline was increased to 200 mg per day, or fluvoxamine was increased to 300 mg per day. Both agents were equally effective in this population with only 7 of 32 sertraline-treated patients and 6 of 32 fluvoxamine-treated patients experiencing a recurrence during the 24 months of the study.There does appear, however, to be a gender difference between sertraline and imipramine. A study of patients with DSM-III-R diagnosed chronic major depression or dysthymia superimposed on major depressive disorder found that premenopausal women responded better to treatment with the SSRI sertraline than to the TCA imipramine after 12 weeks of treatment. In contrast, men were more likely to respond to the TCA, imipramine.DYSTHYMIASertraline has been demonstrated to be effective in the treatment of dysthymia. Four hundred and sixteen patients with DSM-III-R dysthymia (271 women and 145 men, 25 to 65 years of age) of at least 5 years' duration and without current major depression were randomized to 12 weeks of treatment with sertraline, imipramine, or placebo. The mean duration of illness for all groups was approximately 30 years, with an average age of onset of 12 years of age. The baseline HAMD Scale score (17 items) was 12.7 plus or minus 4.0, 13.4 plus or minus 3.8, and 12.7 plus or minus 3.9 for the sertraline, imipramine, and placebo groups, respectively. Sertraline and imipramine were superior to placebo in terms of improving depression severity ratings, psychosocial function, and quality of life. The mean final dose of sertraline was 139.6 mg per day plus or minus 58.5 mg per day, and the mean final dose of imipramine was 198.8 mg per day plus or minus 91.2 mg per day. Sertraline appeared to be better tolerated, with a discontinuation rate due to adverse events of 6 percent for sertraline compared to 18.4 percent for imipramine.CHRONIC DEPRESSIONChronic depression, defined as major depressive disorder for at least 2 years, and so-called double depression (an episode of major depressive disorder superimposed on dysthymia) produce significant psychosocial dysfunction. Sertraline has been studied in these conditions for as long as 18 months of placebo-controlled maintenance therapy after 28 weeks of short-term and continuation therapy. Gains in psychosocial functioning made during acute and continuation therapy tended to be sustained during continuation therapy with sertraline to a much greater extent than was seen in the group receiving placebo.OBSESSIVE-COMPULSIVE DISORDERSertraline is approved by the FDA for the treatment of OCD. A placebo-controlled, randomized trial with 50, 100, or 200 mg per day of sertraline in 324 patients with OCD, without comorbid depression, demonstrated efficacy of the 50- and 200-mg-per-day doses in a 12-week treatment

trial after 1 week of placebo lead in. Individuals who met entry criteria (National Institute of Mental Health Global Obsessive Compulsive Scale ≥7 and HAMD Scale, excluding item 21, obsessions, of ≥17 and a score of ≥1 for the depression item) after 1 week of placebo were randomized to 50, 100, or 200 mg per day of sertraline or placebo. Subjects in the two higher dose groups were titrated upward in dose such that 100 mg per day was achieved by day 5 and 200 mg per day was achieved by day 14. The 100-mg-per-day dose did not differ from the placebo group in efficacy measures, except for the National Institute of Mental Health Global Obsessive Compulsive Scale. There was a higher dropout rate in the 100-mg-per-day group (27 of 81) compared to the 50-mg-per-day (17 of 80), 200-mg-per-day (21 of 80), or placebo group (24 of 84), which may account for the lack of efficacy of the 100-mg-per-day group.OCD typically is a chronic condition, requiring sustained periods of treatment. A study of patients with OCD who had responded to single-blind treatment with sertraline at 16 and 52 weeks explored the efficacy of sertraline therapy in preventing relapse compared to a group that was randomized to placebo treatment. Sertraline treatment was associated with significantly fewer dropouts owing to relapse or insufficient clinical response (9 percent and 24 percent) and a lower incidence of acute symptom exacerbation (12 percent and 35 percent, respectively) compared to treatment with placebo.Sertraline has also been studied in the treatment of OCD in children and adolescents. A 12-week, multicenter, placebo-controlled trial examined the effectiveness of sertraline (50 to 200 mg per day) compared to that seen with placebo treatment in 187 pediatric patients with OCD. Treatment with sertraline (mean dose of study completers, 178 mg per day) was associated with a seven-point drop in the Children's Y-BOCS total score from a baseline of 22, compared to a three-point drop seen in the group receiving placebo. There was no differential effect on treatment based on gender or age in this study.PANIC DISORDERThe efficacy of sertraline in panic disorder with or without agoraphobia has been assessed in three double-blind, placebo-controlled trials. In two studies, sertraline at mean doses of 131 mg per day and 144 mg per day was superior to placebo in change from baseline for number of full panic attacks. Sertraline was more effective than placebo in increasing improvement and decreasing severity, as assessed by the CGI Scale. A third, fixed-dose study also demonstrated superiority over placebo in panic attack frequency. Continuation therapy with sertraline has been shown to produce less discontinuation due to insufficient clinical response or exacerbation of panic symptomatology compared to placebo treatment in a 28-week, double-blind, placebo-controlled discontinuation trial after 52 weeks of open-label treatment.SOCIAL ANXIETY DISORDERTreatment with sertraline (50 to 200 mg per day) was found to be superior to treatment with placebo in a 20-week, double-blind study comparing the two treatments. The group receiving sertraline (N = 134) experienced a significantly greater response rate (CGI-I) than did the group being treated with placebo (N = 69), with response rates of 53 percent and 29 percent, respectively. A second study, of 12 weeks in duration, also found sertraline therapy to be superior to treatment with placebo in social anxiety disorder, using decreases in the LSAS score and CGI-I as the outcome measures.Sertraline has also demonstrated efficacy in preventing relapse in social anxiety disorder. In a placebo-controlled, 24-week continuation study, subjects who had responded to 20 weeks of treatment (50 to 200 mg per day of sertraline or placebo) were randomized to continue on sertraline therapy or to switch to placebo. Patients who responded to placebo during the initial

20-week trial were continued on placebo. The relapse rates seen after 24 weeks of additional study participation were 4 percent and 36 percent for the sertraline- and placebo-treated groups, respectively. A small open-label study in children with social anxiety disorder found sertraline therapy for 8 weeks (mean dose of 123 mg per day) to result in 5 of 14 subjects being rated as P.2912

responders and 4 of 14 as partial responders, using the CGI-I Scale as the outcome measure.PREMENSTRUAL DYSPHORIC DISORDERSSRIs are generally believed to be effective in the treatment of premenstrual dysphoric disorder. Two multicenter, placebo-controlled trials were the basis for regulatory approval of sertraline in the treatment of premenstrual dysphoric disorder. In one, sertraline treatment was initiated at a dose of 50 mg per day and could be adjusted upward to a maximal dose of 150 mg per day in subsequent cycles. The mean dose of sertraline was 102 mg per day for study completers. Sertraline treatment was associated with a better response to treatment compared to that observed with placebo on a number of measures, including the Daily Record of Severity of Problems, the 17-item HAMD Scale, and the CGI of Severity of Illness and Improvement scores. The second study explored the usefulness of intermittent sertraline administration in the treatment of premenstrual dysphoric disorder. In this multicenter, placebo-controlled, double-blind study of 281 women with premenstrual dysphoric disorder (DSM-IV), participants were first screened with two prospective screening cycles and one single-blind placebo cycle. Treatment with sertraline (50 to 100 mg per day) was compared to that of treatment with placebo during the 2 weeks of the luteal phase only. Treatment with sertraline (mean dose of study completers, 74 mg per day) was superior to that observed with placebo in the CGI-I and Severity Scale scores and the Daily Record of Severity of Problems.POSTPARTUM DEPRESSIONSertraline has been reported to have efficacy in the treatment of postpartum depressive disorder. An 8-week, open-label trial of 21 women with postpartum depressive disorder found a response rate (≥50 percent decrease in 21-item HAMD Scale) of 95 percent (20 of 21 participants) and a remission rate (HAMD Scale score of <7; CGI-I = 1; and Global Assessment of Function ≥80) of 66 percent (14 of 21 participants). The mean dose of sertraline was 109 mg per day plus or minus 37 mg per day for study completers.POSTTRAUMATIC STRESS DISORDERTreatment with sertraline (50 to 200 mg per day) has been shown to be associated with significantly greater improvement in patients with DSM-III-R PTSD. A randomized, double-blind, placebo-controlled, 12-week trial found response rates of 60 and 38 percent for sertraline and placebo, respectively. Another 12-week, placebo-controlled, double-blind-trial in DSM-III-Rdiagnosed PTSD patients found a similar result, with response rates of 53 and 32 percent for sertraline and placebo treatment, respectively. The mean dose of sertraline for study completers in both studies ranged from 146 to 152 mg per day. A post hoc analysis by gender suggested that the efficacy of sertraline in PTSD was confined primarily to women. The gender distribution in the studies (152 and 139 women on sertraline and placebo versus 39 and 55 men on sertraline and placebo; both studies combined), however, was such that the studies would appear to be underpowered statistically to detect a difference in men. Ongoing treatment of PTSD (as long as 52 weeks) has been demonstrated to be a successful approach to treatment in not only maintaining gains seen with short-term treatment, but also producing ongoing improvements in quality-of-life and functional measurements.

PREMATURE EJACULATIONSexual dysfunction is a common side effect of all of the SSRIs and is characterized by delayed ejaculation in men and delayed orgasm or anorgasmia in women. Like the other SSRIs, sertraline has been studied as a possible treatment for premature ejaculation. In a double-blind, placebo-controlled trial, 52 men with self-reported premature ejaculation were randomized to placebo or sertraline (50 to 200 mg per day) for 8 weeks. Compared to placebo, sertraline was more effective in prolonging latency to ejaculation (self-report), number of successful attempts at intercourse, and overall self-rated improvement.OTHERSertraline was not found to be a useful addition to individual cessation counseling in smokers with a history of major depressive disorder. In a study involving 9 weeks of treatment in which subjects with a prior history of major depressive disorder were randomized to sertraline or placebo, sertraline treatment decreased withdrawal symptoms, irritability, anxiety, craving, and restlessness more than placebo treatment, but abstinence rates at the end of treatment and at 6 months did not differ between the two groups. Sertraline (50 to 200 mg per day) was found to be effective in the treatment of DSM-IV diagnosed binge-eating disorder in a small (N = 34), placebo-controlled, double-blind, 6-week study. Treatment with sertraline was associated with a significantly greater reduction in frequency of binges, body mass index, and an improvement in CGI.Effects on Specific Organs and SystemsSertraline appears to be quite well tolerated in general, with only 15 percent of more than 2,500 patients in premarketing trials discontinuing owing to adverse events. The higher doses had more dropouts than the lower doses, and this may be partly a reflection of forced titration schedules, which are often more aggressive than what is routinely done in clinical practice. Starting doses in clinical trials have ranged, in general, between 25 and 50 mg per day.Heart and Blood PressureSertraline has not been demonstrated to significantly alter cardiac rhythm or blood pressure. Individuals with existing cardiac disease were excluded from premarketing trials, but there were no changes on ECGs noted with treatment. Studies of individuals with major depressive disorder after myocardial infarction or unstable angina have shown that, compared to administration of placebo, treatment with sertraline has no significant effect on left ventricular ejection fraction, treatment-emergent increases in ventricular premature complex runs, QTc interval greater than 450 msec at end point, or other cardiac measures. Treatment with sertraline in premarketing trials was associated with a 3 percent increase in total cholesterol and a 5 percent increase in triglycerides.BloodThere have been reports of abnormal bleeding or bruising in patients taking SSRIs, including sertraline. This appears to be a relatively rare occurrence. Sertraline was found, in premarketing trials, to possess a weak uricosuric effect, with a mean decrease of uric acid by 7 percent. The clinical significance of this, if any, is unclear. Hyponatremia has been reported after treatment with sertraline and other SSRIs; this side effect is reversed on discontinuation of sertraline. This may be secondary to the SIADH. Groups at risk include elderly patients, patients concomitantly treated with diuretics, or patients who were volume depleted.Gastrointestinal SystemThe incidence of nausea in controlled clinical trials is higher for sertraline than for placebo. The percentage of study participants reporting nausea in clinical trials has ranged from 13 to 30

percent for sertraline treatment, compared to a range of 3 to 18 percent among study participants receiving placebo. In a pooled analysis of placebo-controlled trials, approximately 4 percent of patients taking sertraline experienced an increase or decrease of greater than or equal to 7 percent of body weight. This did not, however, differ to a statistically significant level than what was observed in the placebo groups. Treatment with sertraline also was associated with a higher (range from 13 to 21 percent) incidence of diarrhea than placebo (range from 3 to 15 percent) in premarketing trials of major depressive disorder, OCD, social anxiety disorder, PTSD, premenstrual dysphoric disorder, and panic disorder.SkinApproximately 3 percent of participants in premarketing trials experienced a rash compared to 2 percent in the placebo group. Excessive sweating has been reported with sertraline at a rate threefold (7 percent compared to 2 percent) that seen in the placebo treatment groups.Central Nervous SystemIn premarketing trials, sertraline produced no greater incidence of headache (25 vs. 23 percent) than placebo. Insomnia, somnolence, agitation, nervousness, anxiety, yawning, and P.2913

impaired concentration were all reported more often in the sertraline group than the placebo group. The incidence of dizziness, tremor, twitching, hypoesthesia, and hypertonia were also all greater in the sertraline-treated group, when compared to the placebo group.Sexual DysfunctionThe reported incidence of sexual dysfunction in sertraline-treated individuals was 14 percent for men (1 percent in placebo group) and 1.7 percent for women (0.5 percent in the placebo-treated group), although, in clinical practice, it is now clear that sertraline and all other SSRIs produce significantly higher rates of sexual dysfunction. Decreased libido was reported by 6 percent of men and women in clinical trials treated with sertraline compared to an incidence of 1 percent in the group receiving placebo treatment. This incidence also appears to be an underestimation compared to what is seen in clinical practice.Therapeutic IndicationsSertraline is currently approved by the FDA to be marketed for use in major depressive disorder, OCD, social anxiety disorder, PTSD, premenstrual dysphoric disorder, and panic disorder. Similar to other newer generation antidepressants, sertraline is also used in other affective and anxiety disorders, including dysthymia and generalized anxiety disorder.Precautions and Adverse ReactionsThe most commonly experienced CNS effects include headache (but not greater than placebo), insomnia, somnolence, dizziness, and tremor.Common GI system side effects include nausea, diarrhea, and dyspepsia. Nausea generally dissipates over time, and this can be minimized by administration after meals, even though this strategy increases maximal serum levels of sertraline.Sexual dysfunction in the premarketing trials is reported to occur at a low incidence. The actual incidence in clinical practice is much higher and consists of delayed orgasm or anorgasmia, as well as decreased libido. There have been a number of strategies suggested to deal with this important adverse effect, including decreased dose, drug holidays for shorter half-life SSRIs, or addition of buspirone, amantadine, yohimbine, cyproheptadine, stimulants, or bupropion. None of these approaches appears to be completely successful.Drug Interactions

Sertraline, like fluoxetine and paroxetine, is tightly bound to serum proteins, and the manufacturer warns about a potential interaction between sertraline and other tightly protein-bound drugs, such as warfarin and digitoxin. Good clinical practice would dictate checking serum levels or activity when an antidepressant with high protein binding is added to a tightly protein-bound drug with a low therapeutic index. Most assays do not differentiate between bound and free drug, so functional assays, such as prothrombin time with warfarin, are a better indicator.Sertraline should not be combined with a MAOI. At least 14 days after discontinuation of an MAOI should pass before sertraline is taken. Similarly, MAOIs should not be started in someone taking sertraline until the SSRI has been discontinued for at least 14 days.There have been occasional reports of weakness, hyperreflexia, and incoordination after the administration of SSRIs and triptans used in the treatment of migraine headaches.Sertraline inhibits the CYP 2D6 isoenzyme. Inhibition of the CYP 2C isoenzyme is potentially clinically significant when sertraline is coadministered with tolbutamide (Orinase), an oral hypoglycemic. It does not inhibit the CYP 1A2 or CYP 3A4 isoenzyme.Laboratory InterferencesSertraline does not interfere with any laboratory measures.Dosing and AdministrationSertraline is available in scored tablets of 25-, 50-, and 100-mg strengths. The oral concentrate is formulated at a concentration of 20 mg/mL with a 12 percent alcohol content and must be diluted before use. Owing to the alcohol content in the oral concentrate, it is contraindicated in conjunction with disulfiram (Antabuse). Initial dosing for major depressive disorder and OCD is typically at 50 mg per day, with escalation to 100 mg per day after 4 to 7 days of treatment. Initial treatment of panic disorder, social anxiety disorder, and PTSD is more typically initiated at 25 mg per day. Children in OCD studies were started at 25 mg per day, whereas adolescents in OCD studies were started at 50 mg per day. Treatment of premenstrual dysphoric disorder is usually started at 50 mg per day given daily or during the 2 weeks of the luteal phase. Individual patients may demonstrate improved tolerability starting at lower doses. Not uncommonly, patients require an upward titration of the dose. The mean dosages received by study completers in the acute treatment, flexible-dose studies are listed in Table 31.24-6.

Table 31.24-6 Mean Doses of Sertraline (Zoloft) (Mg per Day) Used in Phase III Clinical Trials

Indication Mean Dose Study Completers (mg/day)

Major depressive disorder 145Obsessive-compulsive disorder: adult 185186Obsessive-compulsive disorder: pediatric178Panic disorder 131144Posttraumatic stress disorder 146151Premenstrual dysphoric disorder 102 (daily treatment)

74 (luteal phase treatment)

The dose range in most patients with anxiety or affective disorders is typically 100 to 200 mg a day, although, certainly, some patients respond to 50 mg per day. Patients with OCD often require higher doses for full therapeutic effect.SUGGESTED CROSS-REFERENCES

Additional information regarding monoamines and their receptors appears in Section 1.4. The basic electrophysiology of neurons is discussed in Section 1.9. The neurobiology of mood disorders is discussed in Section 13.4, and biochemical aspects of anxiety disorders are covered in Section 14.4.The classification of mental disorders is discussed in Chapter 9, and mood disorders in geriatric patients are discussed in Section 51.3d. Lithium therapy is discussed in Section 31.17, and the biological treatment of mental illness in elderly adults is discussed in Sections 51.4a 51.4b 51.4c 51.4d 51.4e 51.4f 51.4g.Depression is discussed in Chapter 13, anxiety disorders are discussed in Chapter 14, and eating disorders are discussed in Chapter 19. Behavior therapy is discussed in Section 30.2, and tricyclic drugs are discussed in Section 31.29.REFERENCESAlfaro CL, Lam YW, Simpson J, Ereshefsky L: CYP2D6 status of extensive metabolizers after multiple-dose fluoxetine, fluvoxamine, paroxetine, or sertraline. J Clin Psychopharmacol. 1999;19:155.*Ballenger JC, Wheadon DE, Steiner M, Bushnell W, Gergel IP: Double-blind, fixed-dose, placebo-controlled study of paroxetine in the treatment of panic disorder. Am J Psychiatry. 1998;155:36.Bondareff W, Alpert M, Friedhoff AJ, Richter EM, Clary CM, Batzar E: Comparison of sertraline and nortriptyline in the treatment of major depressive disorder in late life. Am J Psychiatry. 2000;157:729.P.2914

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Glassman AH, O'Connor CM, Califf RM, Swedberg K, Schwartz P, Bigger JT Jr, Krishnan KR, van Zyl LT, Swenson JR, Finkel MS, Landau C, Shapiro PA, Pepine CJ, Mardekian J, Harrison WM, Barton D, Mclvor M: Sertraline Antidepressant Heart Attack Randomized Trial (SADHEART) Group. Sertraline treatment of major depression in patients with acute MI or unstable angina. JAMA. 2002;288:701.Greist JH, Chouinard G, DuBoff E, Halaris A, Kim SW, Koran L, Liebowitz M, Lydiard RB, Rasmussen S, White K: Double-blind parallel comparison of three dosages of sertraline and placebo in outpatients with obsessive-compulsive disorder. Arch Gen Psychiatry. 1995;52:289295.Hochstrasser B, Isaksen PM, Koponen H, Lauritzen L, Mahnert FA, Rouillon F, Wade AG, Andersen M, Pedersen SF, Swart JC, Nil R: Prophylactic effect of citalopram in unipolar, recurrent depression: Placebo-controlled study of maintenance therapy. Br J Psychiatry. 2001;178:304.Keller MB, Kocsis JH, Thase ME, Gelenberg AJ, Rush AJ, Koran L, Schatzberg A, Russell J, Hirschfeld R, Klein D, McCullough JP, Fawcett JA, Kornstein S, LaVange L, Harrison W: Maintenance phase efficacy of sertraline for chronic depression: A randomized controlled trial. JAMA. 1998;280:16651672.Koran LM, Hackett E, Rubin A, Wolkow R, Robinson D: Efficacy of sertraline in the long-term treatment of obsessive-compulsive disorder. Am J Psychiatry. 2002;159:88.*Kornstein SG, Schatzberg AF, Thase ME, Yonkers KA, McCullough JP, Keitner GI, Gelenberg AJ, Davis SM, Harrison WM, Keller MB: Gender differences in treatment response to sertraline versus imipramine in chronic depression. Am J Psychiatry. 2000;157:1445.Lauritzen L, Odgaard K, Clemmesen L, Lunde M, Ohrstrom J, Black C, Bech P: Relapse prevention by means of paroxetine in ECT-treated patients with major depression: A comparison with imipramine and placebo in medium-term continuation therapy. Acta Psychiatr Scand. 1996;94:241.*Leon AC, Keller MB, Warshaw MG, Mueller TI, Solomon DA, Coryell W, Endicott J: Prospective study of fluoxetine treatment and suicidal behavior in affectively ill subjects. Am J Psychiatry. 1999;156:195.Liebowitz MR, Stein MB, Tancer M, Carpenter D, Oakes R, Pitts CD: A randomized, double-blind, fixed-dose comparison of paroxetine and placebo in the treatment of generalized social anxiety disorder. J Clin Psychiatry. 2002;63:66.Liebowitz MR, Turner SM, Piacentini J, Beidel DC, Clarvit SR, Davies SO, Graae F, Jaffer M, Lin SH, Sallee FR, Schmidt AB, Simpson HB: Fluoxetine in children and adolescents with OCD: A placebo-controlled trial. J Am Acad Child Adolesc Psychiatry. 2002;41:1431.Loprinzi CL, Sloan JA, Perez EA: Phase III evaluation of fluoxetine for treatment of hot flashes. J Clin Oncol. 2002;20:1578.Marshall RD, Beebe KL, Oldham M, Zaninelli R: Efficacy and safety of paroxetine treatment for chronic PTSD: A fixed-dose, placebo-controlled study. Am J Psychiatry. 2001;158:1982.McElroy SL, Casuto LS, Nelson EB, Lake KA, Soutullo CA, Keck PE Jr, Hudson JI: Placebo-controlled trial of sertraline in the treatment of binge eating disorder. Am J Psychiatry. 2000;157:1004.Miner C, Brown E, McCray S, Gonzales J, Wohlreich M: Weekly luteal-phase dosing with enteric-coated fluoxetine 90 mg in premenstrual dysphoric disorder: A randomized, double-blind, placebo-controlled clinical trial. Clin Ther. 2002;24:417.

Montgomery SA, Kasper S, Stein DJ, Bang Hedegaard K, Lemming OM: Citalopram 20 mg, 40 mg and 60 mg are all effective and well tolerated compared with placebo in obsessive-compulsive disorder. Int Clin Psychopharmacol. 2001;16:75.Musselman DL, Lawson DH, Gumnick JF, Manatunga AK, Penna S, Goodkin RS, Greiner K, Nemeroff CB, Miller AH: Paroxetine for the prevention of depression induced by high-dose interferon alfa. N Engl J Med. 2001;344:961.Nierenberg AA, Farabaugh AH, Alpert JE: Timing of onset of antidepressant response with fluoxetine treatment. Am J Psychiatry. 2000;157:1423.Owens MJ, Knight DL, Nemeroff CB: Second-generation SSRIs: Human monoamine transporter binding profile of escitalopram and R-fluoxetine. Biol Psychiatry. 2001;50:345.Phillips KA, Albertini RS, Rasmussen SA: A randomized placebo-controlled trial of fluoxetine in body dysmorphic disorder. Arch Gen Psychiatry. 2002;59:381.Pohl RB, Wolkow RM, Clary CM: Sertraline in the treatment of panic disorder: A double-blind multicenter trial. Am J Psychiatry. 1998;155:1189.Riddle MA, Reeve EA, Yaryura-Tobias JA, Yang HM, Claghorn JL, Gaffney G, Greist JH, Holland D, McConville BJ, Pigott T, Walkup JT: Fluvoxamine for children and adolescents with obsessive-compulsive disorder: A randomized, controlled, multicenter trial. J Am Acad Child Adolesc Psychiatry. 2001;40:222.Roose SP, Glassman AH, Attia E, Woodring S, Giardina EG, Bigger JT Jr: Cardiovascular effects of fluoxetine in depressed patients with heart disease. Am J Psychiatry. 1998;155:660.*Stein MB, Liebowitz MR, Lydiard RB, Pitts CD, Bushnell W, Gergel I: Paroxetine treatment of generalized social phobia (social anxiety disorder): A randomized controlled trial. JAMA. 1998;280:708.Teicher MH, Glod C, Cole JO: Emergence of intense suicidal preoccupation during fluoxetine treatment. Am J Psychiatry. 1990;147:207.Thase ME, Fava M, Halbreich U, Kocsis JH, Koran L, Davidson J, Rosenbaum J, Harrison W: A placebo-controlled, randomized clinical trial comparing sertraline and imipramine for the treatment of dysthymia. Arch Gen Psychiatry. 1996;53:777.Van Ameringen MA, Lane RM, Walker JR, Bowen RC, Chokka PR, Goldner EM, Johnston DG, Lavallee YJ, Nandy S, Pecknold JC, Hadrava V, Swinson RP: Sertraline treatment of generalized social phobia: A 20-week, double-blind, placebo-controlled study. Am J Psychiatry. 2001;158:275.von Moltke LL, Greenblatt DJ, Giancarlo GM, Granda BW, Harmatz JS, Shader RI: Escitalopram (S-citalopram) and its metabolites in vitro: Cytochromes mediating biotransformation, inhibitory effects, and comparison to R-citalopram. Drug Metab Dispos. 2001;29:1102.Yonkers KA, Gullion C, Williams A, Novak K, Rush AJ: Paroxetine as a treatment for premenstrual dysphoric disorder. J Clin Psychopharmacol. 1996;16:3.Yonkers KA, Halbreich U, Freeman E, Brown C, Endicott J, Frank E, Parry B, Pearlstein T, Severino S, Stout A, Stone A, Harrison W: Symptomatic improvement of premenstrual dysphoric disorder with sertraline treatment. A randomized controlled trial. Sertraline Premenstrual Dysphoric Collaborative Study Group. JAMA. 1997;278:983.31.25: Serotonin-Dopamine Antagonists (Atypical or Second-Generation Antipsychotics)Daniel P. van Kammen M.D., Ph.D.Stephen R. Marder M.D.

Part of "31 - Biological Therapies"After more than 40 years of dopamine receptor antagonists with often unavoidable extrapyramidal side effects, a new generation of antipsychotic drugs has become available. These are, first and foremost, the serotonin-dopamine antagonists (SDAs), named after their alleged mechanism of action, now followed by newer dopamine type 2 (D2) receptor antagonists. SDAs are a group of antipsychotics that are comparable to dopamine receptor antagonists in terms of efficacy but differ in terms of structure, receptor affinities, and side effect profiles. At the same time, future successful agents will need to be effective in additional domains or primarily effective in such domains as cognition, primary negative symptoms, and social functioning. These agents now have a much wider use in psychiatry than do the traditional antipsychotics.Fifty percent of antipsychotics come from nonschizophrenia indications, such as bipolar disorder (mania, maintenance treatment), psychosis and other behavioral disturbances of dementia, depression (psychotic, bipolar, or treatment resistant), or psychosis in Parkinson's disease. Because of the better side effect profile, they are now used beyond the narrow indication of schizophrenia, in bipolar disorder, depression, autism, behavioral problems, and psychosis in patients with dementia. The decreased risk of extrapyramidal side effects and tardive dyskinesia has created usage beyond the labeled indicationsfor example, for posttraumatic stress disorder (PTSD), aggressive behavior, and adjunctive therapy in treatment resistant depression.P.2915

Clozapine (Clozaril) was the first antipsychotic agent with negligible extrapyramidal side effects and enhanced efficacy to be available in the United States. Introduced in the United States in 1990, clozapine heralded a new era in the treatment of schizophrenia, even though it had been available in Europe since the early 1970s. Fortunately for U.S. patients, the animal models for antipsychotic efficacy based on dopamine receptor blockade were not fully established at that time. If cataleptogenic, antiamphetamine, and antiapomorphine animal models had been used to test the agent for potential antipsychotic effects, the test results could have led to the rejection of clozapine for clinical trials.The success of clozapine has inspired the development of new and safer antipsychotic agents. The many unpleasant side effects, the weekly blood sampling, and the high cost of clozapine treatment made alternative drugs attractive. Several other drugs are now available, such as risperidone (Risperdal), olanzapine (Zyprexa), quetiapine (Seroquel), ziprasidone (Zeldox), and aripiprazole (Abilify), which are indicated for the treatment of schizophrenia and bipolar disorder. Sertindole (Serlect, Serdolect) never reached the U.S. market and was withdrawn in Europe due to QTc prolongation in 1998. However, a restricted reintroduction of this antipsychotic has recently been granted in Europe. Sertindole will initially only be given to patients enrolled in clinical studies, and all patients will be carefully selected and monitored. Amisulpride (Solian) is an antipsychotic agent with different mechanisms of action that has recently been approved for use in some countries, and other novel agents (e.g., iloperidone) are in development. The terms typical and atypical have lost their meaning as these new agents have become the treatment of choice. The terms traditional, conventional, and first-generation for the preclozapine dopamine antagonists and second-generation antipsychotic agents for SDAs may be preferable to typical and atypical agents.Compared with the traditional agents, all the second-generation agents have a higher ratio of serotonin (5-hydroxytryptamine [5-HT]) type 2 (5-HT2) to D2 receptor blockade and a greater

specificity for the mesolimbic compared to the striatal dopamine system. These new agents have shown selectivity for the limbic system in electrophysiological studies (percentage of silent dopamine neurons with chronic treatment) and in animal tests (low catalepsy in rodents and low extrapyramidal side effect liability in nonhuman primates). In contrast, traditional antipsychotic agents affect both the limbic and striatal dopamine neurons, which frequently results in extrapyramidal effects at therapeutic doses. Recently, low doses of haloperidol (Haldol) (≥6 mg) have been shown to be as effective as the SDAs.All of the new agents are now first-line drugs, except clozapine because of its side effects and the required weekly blood sampling. Preliminary data show that negative symptoms may respond better to the newer agents (e.g., risperidone, olanzapine, ziprasidone, quetiapine, and aripiprazole). Because negative symptoms are a critical determinant of the social and vocational outcome of schizophrenia, these newer agents should improve quality of life. However, whether the difference results from some intrinsic effects of the drug or can be accounted for by relatively decreased striatal D2 blockade is unclear.The SDAs are more expensive than the conventional agents, which has led to extensive campaigns to ensure that these agents are available for patients who need them. The relatively high costs of the new agents require justification for their usage, although clinicians do not seem to pay much attention to this. Pharmacoeconomic and quality-of-life studies of these agents suggest that increased efficacy and greater compliance (e.g., decreased rehospitalization rates and bed days of care) have offset the higher costs, particularly in the second year of treatment (e.g., with clozapine and risperidone). On the other hand, much remains to be improved, as indicated by the common use of antipsychotic drug polypharmacy. In spite of the claims for the present agents that they have a better cognitive profile and better outcomes than seen with typical agents, clinicians are looking forward to better third-generation antipsychotics that will have better negative symptom and procognitive effectiveness. In other words, drugs that finally are, indeed, antischizophrenia agents, not just antipsychotics. Short of that, the authors believe that agents that have procognitive or antinegative symptom effects, or even antidepressants with specific effectiveness in schizophrenia, will be developed either as cotreatments or for monotherapy.Other developments are that ziprasidone and olanzapine have short-acting injectable forms, whereas risperidone now can be given in a long-acting injectable form, Risperdal Consta, for maintenance and relapse prevention. At the same time, companies will bring newer long-acting agents, such as paliperidone, on the market within the next few years. Within a few years of each other, the oral forms of Risperdal, Zyprexa, Seroquel, Geodon, and Abilify will come off patent between 2007 and 2011, opening the door for generic versions. Newer oral antipsychotics will need a better efficacy and tolerability profile than the presently available agents to compete with the generic SDAs. The authors do not expect those third-generation agents to be on the market before 2006 or 2007.With the widespread use of these agents have come some intrinsic side effect problems. So far, weight gain and its metabolic consequences have been the major adverse events of the SDAs. All of the SDSa carry a risk of excessive weight gain (≥7 percent increase), increased risk of insulin insensitivity, diabetes mellitus, and hyperlipidemia. Clozapine and olanzapine carry the highest risk. Ziprasidone does not have the warning in the label and carries the lowest risk. Clinicians need to be aware of the consequences of diabetes and the cardiovascular risk of any of these metabolic disturbances, as well as diabetes management. Presumably, blockage of H1 and 5-HT2C

receptors are responsible for the increased weight. Some preliminary evidence exists that weight

gain and clinical improvement with these agents are related. All SDAs carry this risk on the label, in spite of some evidence that schizophrenia by itself is associated with an enhanced risk for diabetes mellitus. Risperidone and olanzapine have also been associated with a slightly higher risk of strokes in older patients with dementia. Whether this risk is shared with the other agents remains to be established. Although the risk of neuroleptic malignant syndrome is reduced with the SDAs (0.02 vs. 2.44 percent), neuroleptic malignant syndrome is associated with a similar incidence of extrapyramidal symptoms (90 percent) as conventional antipsychotics. This is observed with clozapine as well as with the other agents. Recently, 21 cases with clozapine, 23 with risperidone, 19 with olanzapine, and 5 with quetiapine were reported. These numbers are to be understood in the context of the best reporting for clozapine, as there is a clozapine registration, and the number of risperidone prescriptions is higher or approximately the same as for olanzapine, and quetiapine is still lagging behind in prescriptions compared to risperidone and olanzapine. Ziprasidone use was too short at the time of the data collection to be included. The mortality rate of neuroleptic malignant syndrome was lower than with typical agents, which may simply be a matter of great physician awareness and subsequent early treatment interventions. Some intriguing observations, such as lower suicidality (seen with clozapine), less smoking and lower water intoxication risks, continued improvement potential up to 2 years, and decreased or absent risk of tardive dyskinesia of all SDAs, require careful consideration. Additional benefits include the possibility of better long-term outcomes than with conventional P.2916

agents, improved adherence, diminished relapse risk, and improved quality of life. This section considers clozapine and five other SDAs in order of their historical appearance on the market, not their potential importance. Because clozapine, risperidone, and olanzapine have been on the market for the longest time, more is known about these drugs than the others.CLOZAPINEClozapine is the most effective antipsychotic agent for individuals who fail to demonstrate an adequate response to other agents. At the same time, it is also the antipsychotic with the worst side effect profile and is the most difficult to prescribe. However, it is important that the problems associated with clozapine do not limit its use. Patients should not be considered treatment-resistant or partially responsive until they have had an adequate trial with clozapine. It is estimated that, over 27 years, a total of 2.8 million patients have been treated with clozapine.HistoryClozapine was discovered in 1958 in Bern, Switzerland. It was first studied in animal experiments in May 1960. Soon after clinical trials with clozapine began, the drug appeared to be an effective antipsychotic agent that did not cause extrapyramidal side effects. The first studies showed that patients became calmer in the first 5 days, and psychotic excitement decreased from day 5 onward. Day 20 effects on psychosis were substantial, and negative symptoms improved at 40 days. However, early studies with clozapine in Europe were met with skepticism because this agent was inconsistent with the dogma that effective antipsychotic agents were associated with extrapyramidal effects. This dogma was challenged by a number of European authorities, including Hans Hippius, and, as a result, clozapine was eventually approved in several countries in Europe in 1972.The enthusiasm about clozapine was dampened when it was discovered that the drug was associated with significant hematological toxicity. In 1975, clozapine was introduced in Finland, where 16 of 1,600 treated patients developed granulocytopenia (≥1,600 cells per mm3). Eight of

the 13 patients in whom granulocytopenia progressed to agranulocytosis died of infectious diseases. After 50 patients around the world had died, clozapine was withdrawn from most European markets, and research with this drug came to a virtual halt. Some patients who were receiving clozapine before its withdrawal from the market continued on the drug because of its clear advantages over prior treatment. Regular monitoring of white blood cell (WBC) counts in these individuals showed that clozapine-induced agranulocytosis was reversible when drug use was stopped. In addition, controlled trials in Europe showed that clozapine was more effective than conventional agents for treating schizophrenic patients who were either severely ill or resistant to other antipsychotic agents.Discussions with the U.S. Food and Drug Administration (FDA) led to a U.S. multicenter trial to determine whether clozapine was effective for treatment-refractory patients. The effectiveness of clozapine was compared with that of chlorpromazine (Thorazine) in 268 schizophrenia patients with thoroughly documented failure to respond to conventional antipsychotic agents. The study, reported in 1988 by John Kane, Herbert Meltzer, and others, found that clozapine was more effective than chlorpromazine in terms of a number of important outcomes, including psychosis, mood, and anxiety. The results from this study and others led to the approval of clozapine in the United States in 1990 for schizophrenia patients who are resistant to treatment with other antipsychotic drugs or who are unable to tolerate conventional drugs because of extrapyramidal side effects or severe tardive dyskinesia.Treatment resistance in schizophrenia is a poorly defined concept that has evolved since clozapine's introduction. At that time, treatment resistance referred to a failure to respond to a conventional dopamine antagonist. Because of clozapine's side effect profile, it was hoped that other SDAs would replace it as the agent of choice for treatment-resistant patients, and, to some extent, this appears to have happened, as the introduction of other SDAs has led to a decrease in the use of clozapine. However, there is evidence that clozapine remains the most effective agent for severely ill treatment-resistant patients. The output from a consensus meeting held at Mount Sinai Hospital in New York in 1991 and the Texas Medication Algorithm both recommend that patients who have failed adequate trials with two antipsychotic agents (one of which is an SDA) should receive a trial with clozapine.ChemistryClozapine is a five-membered heterocyclic compound, 8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo-[b,e][1,4-] diazepine (Fig. 31.25-1). Its chemical formula is C18H19N4Cl with a molecular weight of 326.8. Substitutions for the A-ring have led to other clinically effective clozapine-like agents; however, loxapine (Loxitane), an antipsychotic with a clozapine-related molecular structure, has a clinical and side effect profile similar to other traditional antipsychotic drugs. Other clozapine-derived antipsychotic agents are olanzapine and quetiapine, but being a derivative does not translate to similar efficacy.

FIGURE 31.25-1 Molecular structures of serotonin-dopamine antagonists.Pharmacological ActionsPharmacokineticsThe pharmacokinetic profiles of clozapine and other SDAs in special populations are summarized in Table 31.25-1.

Table 31.25-1 Changes in Pharmacokinetics: Special Populations

Drug Elderly Renal Impairment Hepatic Impairment Ethnicity

Clozapine ↓↓ Dosage No Δ dosage ↓ Dosage ↓ Dosage womenRisperidone ↓↓ Dosage ↓ Dosage ↓ Dosage ↓ Dosage

Asians?CYP 2D6

Olanzapine ↓ Dosage (35%)

No Δ dosage No Δ dosage (preliminary)

↓ Dosage women

↓ Dosage Asians?

Quetiapine No PK Δa No Δ dosage Slight ↓ dosage No Δ dosage↓ Dosage 2 PD

Ziprasidone No Δ dosage No Δ dosage No Δ dosage ?Aripiprazole No Δ dosage No Δ dosage No Δ dosage No Δ dosage

CYP 2D6, cytochrome P450 system 2D6 polymorphism (These drugs may delay the therapeutic response in CYP 2D6 poor metabolizers. Poor metabolizers indicated by this genetic polymorphism include 4 to 10% of whites and smaller proportions of Asians and African Americans.); PD, pharmacodynamic; PK, pharmacokinetic; Δ, change in; ↓,↓↓, decrease;?, uncertain.aIncreased adverse reactions (α1-blockade).Adapted from Ereshefsky L: Pharmacokinetics and drug interactions: update for new antipsychotics. J Clin Psychiatry. 1996;57(Suppl):12.

ABSORPTIONClozapine is only available as an oral preparation. As with other antipsychotic agents, peak plasma levels are reached approximately 2 hours after oral administration (range, 1.1 0.5 to 3.0 1.5 hours). The elimination half-life is approximately 12 hours (between 10 and 16 hours; range, 6 to 33 hours). As a result, twice-daily dosing results in steady-state plasma concentrations in less than 1 week. Based on animal studies, coadministration of highly protein-bound drugs may increase free clozapine concentrations, although the total concentration (free plus bound) may be unchanged.DISTRIBUTIONClozapine has a large volume of distribution (mean of 2.0 to 5.1 L/kg [range, 1.0 to 10.2 L/kg]), although this is lower than other antipsychotic drugs.METABOLISM AND ELIMINATIONClozapine undergoes extensive first-pass metabolism in liver and gut. Absolute bioavailability (percentage of clozapine reaching the systemic circulation unchanged) after oral administration varies from 27 to 47 percent. Demethylation and oxidation of the terminal nitrogen of the piperazine side chain form the two main metabolites. These N-demethyl and N-oxide metabolites are cleared as fast as or faster than clozapine. Reportedly, 80 percent of administered clozapine appears in the urine or feces as metabolites. Less than 5 percent of the parent compound is found unchanged in the urine. The N-demethyl clozapine metabolite is a muscarinic type 1 (M1) receptor agonist, whereas clozapine itself has muscarinic antagonist effects. According to Herbert Meltzer, this metabolite is suspected to be the major contributor to clozapine's superior effects on cognition and negative symptoms compared to the other agents.Pharmacodynamics

MECHANISM OF ACTIONThe explanation for clozapine's unique clinical profile remains controversial. Preclinical studies in

FIGURE 31.25-1 Molecular structures of serotonin-dopamine antagonists.

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rats have shown that clozapine blocks the conditioned avoidance response, indicating that the drug has potential antipsychotic activity. On the other hand, it did not produce catalepsy in animals, suggesting that it is unlikely to produce extrapyramidal symptoms in humans. This made it different from conventional antipsychotic medications, which all cause extrapyramidal side effects as a direct result of their D2 receptor blockade in the forebrain. The relatively low affinity for D2 receptors (Fig. 31.25-2) may explain clozapine's lack of extrapyramidal side effects. In patients treated with conventional SDAs, positron emission tomography (PET) scan studies have shown that, with doses comparable to 10 mg of haloperidol, more than 80 percent of striatal D2 receptors are occupied. Higher doses do not increase receptor occupancy further. In clinically effective doses, clozapine only occupies 40 to 50 percent of D2 receptors. This weak effect at the D2 receptor site may be related to clozapine's unusual biological profile that combines a low D2 affinity with activity at a number of other receptor sites, including serotonergic (e.g., 5-HT2 and 5-HT1C), adrenergic, and cholinergic sites.

Several hypotheses address the mechanism of action of clozapine. Because its D2 receptor activity is lower than that of traditional antipsychotic agents and its 5-HT2 receptor blockade is stronger than that of haloperidol, Herbert Meltzer has proposed that the differential antipsychotic effect of clozapine is related to its low D2 to 5-HT2 ratio. Clozapine's affinity for the 5-HT2 receptor is among the highest for antipsychotic agents. An alternative hypothesis proposes that clozapine is effective because it has a selective preference for the mesolimbic dopamine system. D2 receptor blockade in the striatum caused by conventional agents may interfere with their antipsychotic effects and induce negative symptoms. Others have focused on clozapine's stronger

5-HT3 blockade and its stronger α1- and α2-adrenergic receptor blockade. Other differences include its stronger affinities for histamine type 1 (H1) receptors and acetylcholine muscarinic receptors but lower affinity for sigma receptors than haloperidol (Fig. 31.25-2). All values are expressed as nanomoles of the drug needed to replace 50 percent of the radiolabeled receptor ligand (i.e., the inhibitory constant [IC50]). IC50 values may vary between laboratories and are sometimes conflicting. Philip Seeman and Shatij Kapur have proposed that the lack of extrapyramidal symptoms with clozapine and other SDAs is related to their fast dissociation from the D2 receptor. Conventional dopamine receptor antagonists tend to bind more tightly to dopamine receptors than dopamine itself. Clozapine and nearly all of the other SDAs bind more loosely and tend to come off the receptor more readily in the presence of dopamine. As a result, these newer agents may block these receptors more transiently, coming off the receptor to permit more normal dopamine transmission. Clozapine also has a tenfold higher affinity for the D4 receptor than do other antipsychotics. The D4 receptor is present in the cortex and less so in the striatal areas. However, other agents with high affinity for D4 receptors have failed to demonstrate that they are effective antipsychotics.BLOOD CONCENTRATIONS AND RELATION TO ACTIONAs with most antipsychotic drugs, patients display considerable variability in their clozapine plasma concentrationsapproximately 45-fold among patients receiving the same daily dose. This probably results from differences in both absorption and metabolism. Variability is also observed within patients, which is presumably related to variable absorption rates rather than changes in hepatic metabolism and clearance. Some reports show that women have slightly higher and smokers slightly lower plasma levels (20 to 30 percent). The plasma levels of older adults may be twofold higher than those of young adults.Several investigators have studied the relationship between plasma concentrations of clozapine and clinical response. Their findings suggest that monitoring clozapine plasma concentrations may be useful under certain conditions. A wide range of clozapine concentrations appears to be associated with a clinically meaningful response. Plasma concentrations of clozapine average approximately 10 to 80 ng/mL/mg of drug given per kilogram of weight. Thus, a typical daily dosage of 300 to 400 mg (approximately 5 mg/kg) is associated with plasma concentrations ranging from 200 to 400 ng/mL. Studies indicate that patients are more likely to respond when their clozapine plasma concentrations are greater than 350 ng/mL. If patients with a plasma concentration of 250 ng/mL have not responded by 6 weeks, the clinician should adjust the dosage to raise the concentration to approximately 350 ng/mL. The likelihood of response with levels above 350 ng/mL is very small; therefore, patients with high concentrations who exhibit side effects may benefit from having their dosage reduced. The correlations between plasma concentration and clinical improvement or side effects are weak, as is observed with other antipsychotic agents.Design and Interpretation of Clinical Drug StudiesDesignOpen-label clinical trials conducted in the early 1970s suggested that clozapine was an effective antipsychotic drug that lacked extrapyramidal side effects. These findings were then reinforced with double-blind trials comparing clozapine with other agents, although, to date, no double-blind trials comparing clozapine with placebo have been reported. In 79 percent of the controlled trials that compared clozapine with another antipsychotic drug, clozapine was superior. In reviewing these studies, Ross Baldessarini cautions that the differences between clozapine and

the comparator drug were relatively small. Nevertheless, certain patterns emerge. One comparison with chlorpromazine found a small advantage favoring clozapine when a heterogeneous group of patients was studied, but differences favoring clozapine were clearer when the most severely ill subgroup was studied. Another study compared haloperidol with clozapine in more severely ill and treatment-refractory patients and found a clear advantage of clozapine over haloperidol. One study comparing clozapine with risperidone found no differences in clinical response at the end of 6 weeks. Response to risperidone came sooner, but some extrapyramidal effects were observed with risperidone. Few treatment-refractory patients were included. In summary, these studies suggest that clozapine may be particularly effective for a subgroup of patients with schizophrenia who are both severely ill and refractory to treatment with conventional drugs. Whether clozapine is more effective in acutely psychotic patients who are likely to respond to conventional antipsychotics is unclear, although a study from New York suggests that clozapine also P.2919

has advantages in these patients. In a U.S. multicenter study of patients who had tardive dyskinesia or were sensitive to extrapyramidal side effects, clozapine was superior to chlorpromazine.Efficacy in Treatment-Refractory PatientsEarly clinical experience with clozapine suggested that it was more effective than conventional drugs for patients who were unresponsive to conventional antipsychotic agents. Moreover, the studies cited in the previous section suggested that the differences between clozapine and other antipsychotics were greater in patients who were severely ill and refractory when treated with conventional dopamine receptor antagonists. Before marketing clozapine for these patients, the FDA and the manufacturer of clozapine developed a study comparing clozapine with chlorpromazine plus benztropine (Cogentin). The 268 patients who participated in this trial had previously responded poorly in at least three prior antipsychotic trials and a prospective single-blind trial of haloperidol. This study compared the effectiveness of chlorpromazine and clozapine in 248 patients who had thorough documentation of poor responsiveness to conventional antipsychotic agents. During this 6-week trial, the clozapine-treated patients did better on a range of measures of both positive and negative symptoms. Thirty percent of clozapine-treated patients met a priori criteria for significant improvement, in contrast to only 4 percent of chlorpromazine-treated patients. Other studies show that this 6-week trial may have significantly underestimated the proportion of patients who respond to clozapine and that up to 60 percent of patients may display substantial improvement after a 6-month trial. Clozapine in this trial was superior to chlorpromazine on 14 of 18 Brief Psychiatric Rating Scale (BPRS) items, as well as on the Clinical Global Impression (CGI) and such nursing ratings as social competence, social interest, personal neatness, irritability, manifest psychosis, and motor retardation. When patients were classified as having improved (by prospective criteria) to a clinically significant extent, 30 percent of clozapine patients improved within 6 weeks versus only 4 percent of those receiving chlorpromazine plus benztropine (P <.001). Based on this trial, the FDA approved clozapine for limited use in the United States.Long-Term EffectivenessLong-term studies have supported the concept of maintaining patients on clozapine. A 29-week study reported in 2001 found that 60 percent of moderately refractory outpatients with schizophrenia treated with clozapine met improvement criteria compared with 12 percent of

haloperidol-treated patients. In a study of patients with schizophrenia in Connecticut state hospitals, those who were discharged on clozapine treatment were more likely to remain out of the hospital when compared with individuals discharged on treatment with other agents. A Department of Veterans Affairs Cooperative Study comparing 1 year of treatment with clozapine to that of haloperidol also found that clozapine was associated with a decreased need for hospitalization. Moreover, patients treated with clozapine demonstrated a greater likelihood of participating in psychosocial treatments and rehabilitation programs.Therapeutic IndicationsBefore the arrival of other SDAs, the second author (Stephen Marder) and Ted Van Putten suggested that three populations of patients with schizophrenia were obvious candidates for clozapine: (1) patients with severe schizophrenic symptoms that respond poorly to conventional antipsychotic medications; (2) patients with severe tardive dyskinesias; and (3) patients who experience severe extrapyramidal side effects at doses of conventional antipsychotic drugs that are necessary for treating their symptoms. Because the concept of treatment resistance will change with the newer SDAs, the authors suggest that groups (1) and (2) be replaced by patients who have not responded to other SDAs.Treatment-Resistant PatientsPatients with severe positive symptoms despite treatment with adequate dosages of antipsychotic agents are probably the largest group of candidates for clozapine. These patients may be inpatients or outpatients experiencing continuous psychotic symptoms. The findings from the John Kane and coworkers' multicenter trial indicate that approximately one-third of these patients will show significant improvement at 6 weeks and 60 percent at 5 to 6 months. In the authors' experience, these patients show a range of improvements. Some will recover from all or nearly all of their positive symptoms. These patients will then be challenging candidates for psychosocial rehabilitation programs. Others will demonstrate substantial improvement in psychotic symptoms but will still experience lingering schizophrenic experiences that resist even clozapine treatment. For these patients too, clozapine is a better antipsychotic agent with fewer side effects. Others will fail to show substantial improvement with clozapine and may prefer the side effects of conventional drugs to those of clozapine and its required participation in the blood-monitoring system.As mentioned in an earlier section, there is evidence that patients who are unresponsive to treatment in adequate trials of conventional dopamine receptor antagonists may respond when treated with SDAs other than clozapine. As a result, patients who respond poorly to conventional dopamine receptor antagonists may benefit from a trial of at least one of these agents before receiving a clozapine trial. This recommendation is consistent with the consensus opinion of the Mount Sinai Consensus Conference of 2001, as well as the 2002 version of the Texas Medication Algorithm Project. However, the authors of this chapter emphasize that patients should not be considered treatment-resistant or only partially responsive to antipsychotics until they have received an adequate trial with clozapine. Clinicians should also consider that prolonged sequential trials with a number of antipsychotics may take months or even years, thus delaying treatment with an agent that may be effective.Severe Tardive DyskinesiaPatients with severe tardive dyskinesias should also be considered for a clozapine trial. Most clinical reports indicate that clozapine can suppress abnormal movements in tardive dyskinesia. This is not surprising, as conventional antipsychotic agents are effective for the short-term suppression of tardive dyskinesia. However, clozapine is probably less likely to cause the

disorder and, therefore, is promising for the long-term management of patients, particularly those who already have tardive dyskinesia. Although rare cases of tardive dyskinesia have been found in patients who receive clozapine, the risk of developing this disorder is substantially reduced. Studies using animal models indicate that clozapine does not result in the increased sensitivity of striatal D2 receptors that is associated with typical antipsychotic agents and has been theorized to result in tardive dyskinesia. It remains to be established whether a positive effect on tardive dyskinesia results from a direct effect of clozapine on certain transmitter systems or whether clozapine spares the striatal D2 receptors, which allows spontaneous remission of tardive dyskinesia. The former interpretation is supported by the reports of a return of tardive dyskinetic movements after clozapine withdrawal.Patients with a Low Extrapyramidal Side Effect ThresholdAnother group of patients with schizophrenia who may be reasonable candidates for clozapine are those who develop severe P.2920

extrapyramidal side effectsparticularly, severe akathisiawhen they receive relatively low doses of conventional antipsychotic drugs. The benefits of antipsychotic treatment are often only obtainable at the price of severe discomfort and dysphoria that is not adequately responsive to antiparkinson medications or propranolol (Inderal). The incidence of akathisia is considerably lower with all SDAs.Treatment-Resistant ManiaClozapine can be an effective treatment for manic symptoms that are not responsive to other agents. Early clinical case reports indicated that clozapine was effective both as monotherapy and as an adjunct to mood-stabilizing agents in this population. An open-label, randomized trial in acutely manic patients found that clozapine had a more rapid onset of effect than that of chlorpromazine. In another open-label trial involving patients with schizoaffective disorder or bipolar disorder who were randomized to either clozapine or treatment as usual, clozapine-treated patients demonstrated greater improvements. Although the available data support clozapine's effectiveness in mania, none of these trials has used a double-blind design.Severe Psychotic DepressionThe effectiveness of clozapine in the treatment of patients with major depression with psychotic features is supported by clinical case reports alone.Neurological IllnessesClozapine has also found uses in patients with neurological disorders. It has been used in idiopathic Parkinson's disease as a treatment for psychotic symptoms that are secondary to dopaminomimetic agents that are used to treat the disease. These patients may respond to relatively low dosages of clozapine (doses of 25 to 75 mg). Higher dosages (e.g., 100 to 250 mg a day) may exacerbate the parkinsonian symptoms. The effectiveness of clozapine in patients with idiopathic Parkinson's disease is supported by at least two double-blind studies. Patients with benign essential tremor or with Huntington's disease have also responded positively to clozapine.Polydipsia-Hyponatremia SyndromeCase reports suggest that clozapine may have advantages over other antipsychotic agents in patients who tend to intoxicate themselves with water. This syndromecalled polydipsia-hyponatremia syndromecan result in seizures.Suicidal Patients with Schizophrenia or Schizoaffective Disorder

Patients who are severely suicidal or agitated with schizophrenia or affective disorders are candidates for clozapine treatment. This indication is supported by evaluation of evidence from large databases, which found that patients who were treated with clozapine had lower-than-expected rates of suicide. A study reported by Herbert Meltzer found that patients who had their medications changed to clozapine demonstrated a reduction in the number of serious suicide attempts. The most convincing study supporting clozapine's advantage for patients with suicidal risk was a comparison of clozapine and olanzapine in 980 patients with schizophrenia who were considered at risk for suicideclozapine was found to be more effective in reducing suicidal ideation and suicide attempts. The FDA has approved clozapine in schizophrenia patients with emergent suicidal behaviors in December, 2002.Treatment Resistance in Other DisordersTreatment-resistant patients with a pervasive developmental disorder, autism of childhood, or obsessive-compulsive disorder (OCD) have responded well to clozapine, either by itself or in addition to their regular treatment.Precautions and Adverse ReactionsSide effects associated with the use of clozapine and the other SDAs are compared in Table 31.25-2. The only contraindications to the use of clozapine are a WBC count below 3,500 cells per mm3, a previous bone marrow disorder, a history of agranulocytosis during clozapine treatment, or the concomitant use of another bone marrow suppressant drug such as carbamazepine (Tegretol). Although the mechanism of action is unknown, a slight risk of respiratory depression or collapse may occur if treatment is initiated while patients are taking benzodiazepines.

Leukocytopenia and AgranulocytosisThe risk for clozapine-induced agranulocytosis is 0.73 percent during the first year of treatment and 0.07 percent in the second year. Review of the clozapine register indicates that the incidence may be as low as 0.038 percent. The risk for this adverse effect is greatest during the first 3 months of treatment, but a significant risk remains during the first year of treatment and, perhaps, indefinitely. For neutropenia, the risk is 2.32 percent in the first year and 0.69 percent in the second year. Increased familiarity of clinicians with agranulocytosis (absolute neutrophil count <500 cells per mm3 or WBC <1,000 cells per mm3) decreased the incidence of agranulocytosis by more than 50 percent from before 1995 to after 1997.Agranulocytosis due to clozapine is a potentially fatal condition that requires immediate medical attention. The risk of agranulocytosis increases with age and is higher in women. Therefore, before treating patients with clozapine, clinicians must register patients with a clozapine monitoring system. The United Kingdom and Australia require, in addition to the 3,500 WBC per mm3, that granulocyte count is 2,000 cells per mm3 or higher when clozapine is initiated. Patients who are treated with clozapine in the United States must receive weekly monitoring of their WBC count for the first 6 months of treatment. If the WBC count remains normal, the frequency of blood sampling is reduced to every 2 weeks. The requirement for WBC count monitoring is continued for as long as patients receive the drug and for at least 1 month after it is discontinued. Current guidelines specify that any fever or sign of infection (e.g., pharyngitis) is an immediate indication for a WBC count, particularly in the first 18 weeks of treatment. If the patient has a WBC count below 2,000 cells per mm3 or a granulocyte count below 1,000 cells per mm3, clozapine must be discontinued. Reports of clozapine reexposure after hematologic

recovery have shown that all such patients again experienced agranulocytosis, but sooner and at lower doses than during initial treatment. As a result, patients who develop agranulocytosis should not receive clozapine again. Although a WBC count below 3,500 cells per mm3 is not a proven risk factor, clozapine should be administered cautiously in patients with such low counts because of the difficulty in early identification of agranulocytosis. While the FDA allows U.S. patients to be rechallenged if the WBC count is between 2,000 and 3,000 cells per mm3 and the granulocyte count is between 1,000 and 1,500 cells per mm3 (moderate leukopenia), the regulatory agencies in the United Kingdom and Australia do not allow for rechallenge. Similarly, carbamazepine should not be given concomitantly with clozapine. Clozapine therapy should be discontinued whenever the total WBC count falls below 3,000 cells per mm3 or the granulocyte count falls below 1,500 cells per mm3.Other hematological changes have been reported with clozapine, including leukocytosis (0.6 percent), eosinophilia (1 percent), and leukopenia, neutropenia, decreased WBC count (3 percent), and, rarely, thrombocytopenia.SialorrheaSialorrhea is an uncomfortable adverse effect that develops early in treatment. Hypersalivation is most profound during sleep, and patients may complain that their pillow is wet in the morning.