Clozapine drug withdrawal

Of 39 patients taking lithium, 18% had neutrophilia and 15% had raised activity of polymorphonuclear elas-tase (a marker of granulocyte activation) (345). In keeping with these observations, a chart review of 38 patients taking clozapine showed an increase in leukocyte count when lithium was added (42). A man with olanzapine-induced neutropenia (with a prior history of risperidone-induced neutropenia), which normalized with drug withdrawal, had no difficulty when the drug was reintroduced after the patient had been treated with lithium (43). 

Once TD has developed, spontaneous improvement occurs in 30-50% of cases within 2 years after discontinuation of the APD. The main goal in treating TD is to desensitize the hyperactive dopaminergic receptors or to counterbalance their activities. Because prolonged and complete drug withdrawal is often difficult, total or partial substitution with SCAs (especially clozapine) is proposed as the first-line strategy for patients who have to continue APDs. It is assumed that SCAs,... 

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. 

Meltzer HY, Lee MA, Ranjan R, et al. Relapse following clozapine withdrawal effect of neuroleptic drugs and cyproheptadine. Psychopharmacoiogy 1996 124 176-187. 

Seeman P, Tallerico T (1999) Rapid release of antipsychotic drugs from dopamine d2 receptors An explanation for low receptor occupancy and early clinical relapse upon withdrawal of clozapine or quetiapine. Am J Psychiatry 156(6) 876-884... 

There has been one comprehensive meta-analysis including over 80 studies and over 30 000 patients (489). A meta-analysis of trials of neuroleptic drugs showed the following mean weight gains in kg after 10 weeks of treatment clozapine, 4.5 olanzapine, 4.2 thioridazine, 3.2 sertindole, 2.9 chlorpromazine, 2.6 risperidone, 2.1 haloperidol, 1.1 fluphenazine, 0.43 ziprasidone 0.04 molindone, —0.39 placebo, —0.74 (490,491). In one study, excessive appetite was a more frequent adverse event in patients treated with olanzapine versus haloperidol (24 versus 12%) (185). Loss of weight has been observed after withdrawal of neuroleptic drugs (492). 

In a cohort study, based on a prospective drug exposure database, the effectiveness of centralized routine monitoring of blood counts was evaluated in 1500 patients taking clozapine between March 2001 and December 2001 (157). Seven patients developed severe neutropenia while taking clozapine (neutrophil counts below 1.5 x 109/ 1). The mean time to withdrawal of therapy was 1.6 days (maximum 6 days), and neutrophil counts recovered to normal in all cases after 6.4 days (maximum 13 days). Based on an estimate of 500 patient-years of exposure, the frequency of severe neutropenia was one case per 71 patient-years of therapy or 1.4% per annum. 

Rebound psychosis or delirium or both have been reported after withdrawal of clozapine (207-212). Clozapine withdrawal has also been associated with nausea, vomiting, diarrhea, headache, restlessness, agitation, and sweating (213,214), which occur as the result of cholinergic rebound and which may respond to anticholinergic drugs (215), and with dystonias and dyskinesias. Delirium and the return of dyskinetic movements can occur within days after clozapine withdrawal. 

A 28-year-old man complained of unbearable thirst 2 weeks after starting risperidone 8 mg/day, and would drink 4-5 liters of water within a variable period of a few minutes to 8 hours he did not develop hyponatremia (172). The condition lasted about 2 years and remitted after withdrawal of risperidone. After a drug-free interval of 2 weeks, clozapine was started and the condition had not recurred after 6 months. 

Antidepressants (especially venlafaxine), bromocriptine, buspirone, carbamazepine, clozapine, desfulrane, ketamine, metoclopramide Clonidine//J-blocker combination Pheochromocytoma /J-blocker without a-blocker first Street Drugs and Other Natural Products Cocaine and cocaine withdrawal ... 

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