Try clozapine.
Perhaps the best predictor of good outcome in schizophrenia with clozapine is presence of parkinsonian side effects during previous treatment with a standard, typical neuroleptic.¹ Another group that does better is patients with a diagnosis of paranoid-type schizophrenia.
Predictors of less robust outcome include early age of onset and female gender.
Clozapine is usually initiated at 12.5 mg once or twice daily and increased gradually by no more than 25-50 mg per day, if tolerated, until the target dose is reached, which is about 300 mg in the Europe and 450 mg in the U.S.A. The APA practice guidelines for the treatment of schizophrenia is a good reference for details on how to prescribe clozapine,² and a recent review by Lieberman on managing side effects is helpful to have available.³
Although plasma levels are not routinely used to titrate dose, they may be useful if the response is unsatisfactory or if side effects are significant and you want to know if the dose is too high (or too low and the patient is intolerant to an optimal plasma level). Adjust clozapine plasma level (NOT clozapine plus norclozapine) to above 350 ng/ml if side effects allow, going up to the Package Insert maximum dose of 900 mg per day if necessary. (4) [Note that the studies establishing this plasma level measured the parent compound (clozapine) only, and did not obtain metabolite (norclozapine) levels. Some labs give you both levels and suggest they should be added to determine therapeutic level, but this will not give you information to enable you to compare your patient's levels with the levels found in the best studies. Studies in the early 90s, cited in the papers in reference (4) established that there is no difference in the predictability of response with parent compound versus combined levels]
If you need to go over 600 mg per day the manufacturer currently recommends obtaining an EEG and if abnormal, using an anticonvulsant such as valproate for prophylaxis of seizures. Clozapine levels over 350 ng/ml are associated with an increased risk of seizures, drowsiness, and slowing on the EEG.(5) About 6% of patients in one study (5) did not achieve clozapine levels over 350 despite 900 mg of clozapine. Smoking may be a factor in this, due to nicotine's stimulation of cytochrome P450 1A2 metabolism of clozapine.
Some studies have indicated that certain SSRIs, especially fluvoxamine because of it's P450 1A2 inhibitory activity, can be added to clozapine to boost the blood level and reduce the dose of clozapine needed to produce levels over 350 ng/ml. (6) For example, a dose of 100 mg of clozapine plus 50 mg of fluvoxamine puts 2/3 of patients above 350 ng/ml. Heavy smokers were again found in the group that did not achieve therapeutic levels on this combination.(6) The impact of this combination on therapeutic outcome is not clear. Some studies showed improved efficacy and some showed apparently reduced effect of the clozapine.(6) Two patients were reported to develop extrapyramidal symptoms on the combination. Medication costs were reduced by using the combination, however.(6) With close monitoring of benefits and side effects, this approach seems worth further assessment.
¹Lieberman JA, Safferman AZ, Pollack S, et al. Clinical effects of clozapine in chronic schizophrenia: response to treatment and predictors of outcome. Am J Psychiatry 1994;151:1744-1752.
²American Psychiatric Association. Practice guidelines for the treatment of patients with schizophrenia. Am J Psychiatry 1997;154:4(Suppl):17-20.
³Lieberman JA. Maximizing clozapine therapy: managing side effects. J Clin Psychiatry 1998;59[suppl 3]:38-43.
(4)VanderZwaag C, McGee M, McEvoy, JP, et al. Response of patients with treatment-refractory schizophrenia to clozapine within three serum level ranges. Am J Psychiatry 1996;153:1579-1584. and Kronig MH, Munne RA, Szymanski S et al. Plasma clozapine levels and clinical response for treatment-refractory schizophrenic patients. Am J Psychiatry 1995;152(2):179-182.
(5)Freudenreich O, Weiner RD, McEvoy JP: Clozapine-induced electroencephalogram changes as a function of clozapine serum levels. Biol Psychiatry 1997;42:132-137.
(6)Lu M-L, Lane H-Y, Chen K-P, et al. Fluvoxamine reduces the clozapine dosage needed in refractory schizophrenic patients. J Clin Psychiatry 2000;61:594-599.
Recommendation #116
