ORIGINAL Clozapine plasma levels and dosing strategies in patients with treatment-refractory schizophrenia Peter Buckley, Philip Cola, Mitsuru Hasegawa, Christine Lys & Paul Thompson Ir J Psych Med 1997; 14(3): 85-88 Abstract Objective: To determine the effect on clinical response to clozapine of increasing the plasma levels of clozapine and its major metabolite N-desmethylclozapine in 19 patients with schizophrenia who had plasma clozapine levels < 370ng/ml, a level previously determined to identify patients who were unlikely to have an adequate response to clozapine. Method: The dosage of clozapine was increased by 20% in 11 patients and left unaltered in the other eight patients. Clozapine and N-desmethylclozapine plasma levels were measured after six weeks at the higher dose. Results: Nine of the 11 patients in whom clozapine dosage was increased subsequently achieved plasma clozapine levels > 370ng/ml. However, in this group of patients who already had partially responded to clozapine, increasing the dosage of clozapine did not produce additional clinical improvement. Conclusion: Clozapine plasma levels are useful in clinical practice to guide dosage strategies. However, these results suggest that increasing the dosage of clozapine to achieve plasma levels > 370ng/ml is unlikely to produce further improvement in patients who have already achieved a partial response to clozapine at plasma levels < 370ng/ml. Introduction There now exists compelling evidence that clozapine has superior efficacy compared to typical neuroleptic drugs for the treatment of neuroleptic-refractory schizophrenic patients. 13 This benefit is evident for the treatment of both positive, negative and disorganisation symptoms of schiz- ophrenia. 23 In addition, clozapine has been shown to produce clinically significant improvements in some aspects of cognitive function, 46 quality of life 7 and in global functioning. 3 Moreover, available evidence suggests that the time course of response to clozapine differs from that seen with standard conventional neuroleptic drugs. 1X7 Using conservative outcome criteria, some 30% of patients showed a substantial improvement in the first six weeks of treatment whereas approximately 60% of patients receiv- ing clozapine will show a substantial benefit if followed up to 12 months. 7 This observation has suggested that in *Peter F Buckley, MD, Department of Psychiatry, Case Western Reserve University, University Hospitals of Cleveland, Hanna Pavilion, 2040 Abington Road, Cleveland, Ohio 44106, USA. Philip Cola, MA, Mitsuru Hasegawa, MD, Christine Lys, BA, Paul Thompson, PhD, Department of Psychiatry, Case Western Reserve University, School of Medicine, Cleveland, Ohio 44106, USA. *Correspondence SUBMITTED: OCTOBER 30, 1996. ACCEPTED: JULY 29,1997. clinical practice, at least a six month trial of clozapine treatment should be given before considering clozapine to lack significant advantage. 8 A variety of approaches to enhance the response to clozapine have been suggested. 2 Increasing the dose up to the maximum clinically accepted level of clozapine (900mg/day) has been recommended. 2 The addition of a high potency neuroleptic drug such as haloperidol 9 and the selective serotonin reuptake inhibitor, fluvoxamine 10 have been found to be useful in some clozapine non-responders. Nevertheless, a substantial minority, perhaps some 30% of patients receiving clozapine, will fail to derive measurable benefit from this agent. Therapeutic monitoring of clozapine plasma levels has also been reported to be useful as a guide to dosage." ,12 In an earlier study of 59 treatment-resistant schizophrenic patients, 12 we observed that a clozapine concentration > 370ng/ml discriminated clozapine responders from non- responders. Sixty-seven per cent of responders and 72% of non-responders to clozapine were correctly classified using this cut off point. It was noted that some patients responded well despite plasma clozapine levels consider- ably less than 370ng/ml but poor responders had lower levels more frequently than good responders. These results replicated those of Perry and colleagues and are consistent with more recent findings. 13 ' 15 Two studies have demon- strated that increasing plasma levels of clozapine to at least 370ng/ml in patients who had responded poorly and who had clozapine levels less than this, produced further clini- cal improvement. 1415 However, other investigators have been unable to demonstrate a relationship between plasma levels of clozapine and clinical response. 16 " 18 Thus, the possibility that clozapine plasma levels may prove clini- cally useful requires further study. Moreover, the manner in which clozapine plasma level determination is best incorporated into clinical practice remains to be clarified. The present study sought to determine whether increas- ing the dose of clozapine in patients who had an adequate duration of treatment and substantial clinical response, despite plasma clozapine levels < 370ng/ml, but still had significant psychopathology, including positive symptoms, could produce additional clinical response. Method Subjects Nineteen patients (14 males, five females), all of whom had a DSM III-R" diagnosis of schizophrenia based upon a structured interview using the Schedule for Affective Disorders in Schizophrenia-Life and Change versions (SADS-C 20 ) were evaluated for participation in this study. The mean (sd) age of the patients was 32.5 (sd 8.2) years, the duration of illness was 13.9 (sd 7.1) years, and the age at onset of illness was 18.7 (sd 4.3) years. All patients had been on clozapine at least six months 85