Clozapine discontinuation

Vulnerability to relapse after clozapine discontinuation increased with the length of clozapine treatment. 

Shore D, Matthew S, Cotte J, et al. Clinical implications of clozapine discontinuation report of an NIMH workshop. Schizophr But 1995 21 333-338. 

Konakanchi R, Grace JJ, Szarowicz R, Pato MT. Olanzapine prolongation of granulocytopenia after clozapine discontinuation. J Clin Psychopharmacol 2000 20(6) 703 1. 

Moeller FG, Chen YW, Steinberg JL, et al Risk factors for clozapine discontinuation among 805 patients in the VA hospital system. Ann Clin Psychiatry 7 167-173,1995... 

Antipsychotics (especially FGAs and clozapine) should be tapered slowly before discontinuation to avoid rebound cholinergic withdrawal symptoms. 

Myocarditis Analyses of postmarketing safety databases suggest clozapine is associated with an increased risk of fatal myocarditis, especially during, but not limited to, the first month of therapy. In patients in whom myocarditis is suspected, discontinue clozapine treatment promptly. 

ECG changes - A minority of clozapine patients experience ECG repolarization changes similar to those seen with other antipsychotic drugs, including S-T segment depression and flattening or inversion of T waves, which all normalize after discontinuation of clozapine. 

Patients who are being treated with clozapine must have a baseline white blood cell (WBC) and differential count before initiation of treatment and regular WBC counts during treatment and for 4 weeks after the discontinuation of clozapine. 

Monitoring Patients must have a blood sample drawn for a WBC count before initiation of treatment with clozapine and must have subsequent WBC counts done at least weekly for the first 6 months of continuous treatment. If WBC counts remain acceptable (WBC at least 3,000/mm, absolute neutrophil count [ANC] at least 1,500/mm ) during this period, WBC counts may be monitored every other week thereafter. After the discontinuation of clozapine, continue weekly WBC counts for an additional 4 weeks. 

Discontinuation - In the event of planned termination of clozapine therapy, gradual reduction in dose is recommended over a 1- to 2-week period. However, should a patient s medical condition require abrupt discontinuation (eg, leukopenia), carefully observe for the recurrence of psychotic symptoms and symptoms related to cholinergic rebound (eg, headache, nausea, vomiting, diarrhea). After the discontinuation of clozapine, continue weekly WBC counts for an additional 4 weeks. 

Reinitiation of treatment - Nhen restarting patients who have had even a brief interval off clozapine (ie, 2 days or more since the last dose) treatment should be reinitiated with one half of a 25 mg tablet (12.5 mg) once or twice/day. If tolerated, patients may be titrated back to a therapeutic dose more quickly than is recommended for initial treatment. Any patient who has previously experienced respiratory or cardiac arrest with initial dosing but was then able to be successfully titrated to a therapeutic dose should be retitrated with extreme caution after even 24 hours of discontinuation. 

Agranulocytosis is a potentially catastrophic idiosyncratic reaction that usually appears within the first 3 months of therapy. Although the incidence is extremely low (except for clozapine), mortality is high. Thus, any fever, sore throat, or cellulitis is an indication for discontinuing the antipsychotic and immediately conducting white blood cell and differential counts. 

Patel J, Keith RA, Salama AI, et al Role of calcium in regulation of phosphoinositide signaling pathway. J Mol Neurosci 3 1-9, 1991 Patil VJ Development of transient obsessive-compulsive symptoms during treatment with clozapine. Am J Psychiatry 149 272, 1992 Pato MT, Zohar-Kadouch R, Zohar J, et al Return of symptoms after discontinuation of CMl in patients with OCD. Am J Psychiatry 145 1521-1522, 1988 Pato PT, Pigott TA, Hill JL, et al Controlled comparison of buspirone and CMl in OCD. Am J Psychiatry 148 127-129, 1991 Patterson JF Treatment of acute mania with verapamil (letter). J Clin Psycho-pharmacol 7 206-207, 1987... 

Weekly WBC count and ANC are required for the first 6 months of treatment and for 4 weeks after discontinuation of clozapine. After 6 months, monitoring is required every 2 weeks and after 12 months, monitoring is required every 4 weeks. 

If WBC count is less than 2,000/mm or ANC is less than 1,000/mm , discontinue clozapine and do not rechallenge. Perform WBC and differential counts daily until WBC count is greater than 3,000/mm and ANC is greater than 1,500/mm. Then monitor twice weekly until WBC count returns to more than 3,500/mm and ANC is greater than 2,000/mm . Then monitor weekly for 4 weeks. Treat any infection with antibiotics. Consider bone marrow aspiration to ascertain granulopoietic status. If granulopoiesis is deficient, consider protective isolation. 

As noted earlier, this switch should always be done by cross-tapering, thus overlapping risperidone with clozapine. We suggest starting with a low clozapine dose (12.5 or 25 mg/day), with gradual increments, paralleled by a gradual reduction of the risperidone until it is totally discontinued. 

Case Example Because of a patient s partial response to 5 months of clozapine therapy at 600 mg/day, risperidone was added for augmentation (started with 0.5 mg b.i.d. and increased to 1 mg b.i.d. after 1 week). Before this addition, the clozapine plasma level was 344 ng/mL, but after 2 weeks of risperidone augmentation, the level was elevated to 598 ng/mL with no adverse effects and substantial clinical benefit. In another report, there was an increase in the steady-state plasma levels of clozapine (675 mg/day) and its active metabolite norclozapine after the addition of risperidone 2 mg/day in a patient treated for 2 years. Before the addition of risperidone, her clozapine and norclozapine levels were 829 and 1,384 ng/mL, respectively. Two days after risperidone was added, these levels rose to 980 and 1,800 ng/mL. Clozapine dosage was reduced to 500 mg/day, and after 5 days of combined treatment with 4 mg/day of risperidone, the clozapine and norclozapine levels were 110 and 760 ng/mL, respectively. Aside from some mild oculogyric crises, she had no symptoms of clozapine toxicity or clinical changes during the period of cross-tapering. In another case, risperidone was added to clozapine because the patient had relapsed after discontinuation of fluphenazine and had not responded to clozapine. The addition of risperidone resulted in an acute remission of psychosis ( 100). 

Clozapine is principally metabolized to N -desmethylclozapine (norclozapine). It is also metabolized to and n-oxide, other hydroxyl metabolites, and a protein-reactive metabolite. The n-oxide can be converted back to clozapine. The enzyme responsible for the metabolism of clozapine to norclozapine is the cytochrome P450 1A2 enzyme (325). This is consistent with a study showing that caffeine, a marker for 1A2, is cleared in relationship to the conversion of clozapine to norclozapine ( 326). Discontinuation of coffee intake can decrease the clozapine plasma levels by more than 50%, and increasing caffeine intake can produce a reemergence of the side effects (e.g., drowsiness, excess salivation). Additionally, smoking, which induces 1A2, lowers clozapine plasma levels. Fluvoxamine, an inhibitor of 1A2, dramatically increases plasma levels, and on occasion, adverse effects are seen ( 327). This phenomenon can lead to clozapine intoxication in patients on high doses of fluvoxamine. 

Clozapine. Withdrawal symptoms after the abrupt discontinuation of clozapine differ from those noted with other antipsychotics ( 98, 477). Thus, rapid discontinuation may result in the following ... 

For example, withdrawal of haloperidol in one patient revealed little change in either mental status or involuntary movements 3 weeks after discontinuation ( 478). In contrast, there was a marked deterioration in mental status and involuntary movements in this same patient 1 week after clozapine withdrawal. This rebound psychosis was attributed to increased dopamine release, a mechanism suggested by earlier observations made after withdrawal studies in humans and animals. For example, a study of the effects of abrupt withdrawal in rats showed increased and decreased striatal basal dopamine release with discontinuation of clozapine and haloperidol, respectively ( 479). The exacerbation of dyskinesia after clozapine withdrawal suggests that human nigrostriatal dopamine receptors (putatively involved in the emergence of dyskinetic movements) may be altered pharmacologically by this drug. 

Clozapine also produces nonspecific inverted T waves, but again, this is not considered clinically relevant. As far as is known, abrupt discontinuation of antipsychotics, including clozapine, does not produce serious adverse cardiac effects, although common sense dictates a gradual reduction over several days ( 39). 

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