Clozapine maintenance therapy in schizophrenia Abstract long-term pharmacotherapy with antipsychotic agents is an important aspect of management of schizophrenia.

In patients responsive to the chosen treatment, maintenance therapy is usually conducted by halving the drug dose that has proven effective during the acute phase. This strategy is suitable for maintaining remission, moreover, it can improve the patients quality of life. Records from over 1000 patients treated with clozapine during the past 22 years were examined; 782 of these patients were diagnosed with schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition-Text Revision (DSM-IV-TR) criteria (with the modification in early years). From this group, 181 patients were treated with clozapine for at least a year. The mean duration of long-term maintenance treatment with clozapine was 12.2 4.25 years (range: from 14.5 months to 18 years). Clozapine was administrated in a daily dose of 50-200 mg (mean: 71.5 14.12 mg). in 76 schizophrenics, treatment was initiated with clozapine, whereas 105 patients were switched over from other treatments after their failure. The control group comprised 152 patients on long-term maintenance therapy with haloperidol. Clozapine administrated for long-term maintenance therapy was effective both in paranoid and in catatonic schizophrenia, it also accomplished good results in patients with disorganized or residual schizophrenia, as well as in individuals with schizoaffective psychosis. Relapse rate was similar to that observed in the haloperidol group; however, patient compliance, side-effect profile, and therapeutic efficacy were all superior in the clozapine group. Long-term maintenance therapy with clozapine is successful. Compliance is good; schizophrenic patients are willing to take this atypical antipsychotic for years on end. Clozapine treatment is associated with a low relapse rate and a favorable safety profile. Introduction The earliest effective treatment for psychoses (and schizophrenia in particular) was based on clinical observation rather than on scientific knowledge of the neurobiological background of psychoses or the mechanism of action of effective antipsychotic agents. The first antipsychoticchlopromazine-was demonstrated to be an effective drug; its mechanism of action was elucidated by experimental studies. Clozapine is regarded as the prototype of atypical antipsychotic agents. It is the first drug with only a few-if any-extrapyramidal side effects, the use of which is not associated with the risk of tardive dyskinesia or hyperprolactinemia. Clozapine has been shown to exert antipsychotic effect, which proves particularly beneficial in cases where conventional (and/or other atypical) antipsychotic agents have failed. After the Intersept study (Meltzer et al., 2003), it can be the first choice. Treatment with this drug almost completely restores cognitive, interpersonal and vocational functions and substantially improves both the positive and the negative manifestations of psychosis.

Clozapine is an atypical antipsychotic agent of the dibenzoazepine family. Although its mechanism of action has not been elucidated completely, its antipsychotic efficacy and complete lack of extrapyramidal adverse effects are well documented (Helmchen, 1989; Meltzer et al., 1994; Bunney, 1992). The most devastating complications of clozapine therapy are granulocytopenia and agranulocytosis (Bunney, 1992). It is also the sole antipsychotic, the use of which is associated with the risk of a life-threatening and occasionally fatal complication occurring in 0.5-2.0% of patients (Stahl, 2000). Nevertheless, the risk of this adverse event is related to genetic factor, as other authors report 0.2% incidence and no life-threatening or fatal events (Makkos et al., 2000; Gaszner et al., 2002). Being a serotonin 2A (5-HT2A) and dopamine (D2) antagonist, clozapine is characterized by one of the most complex pharmacologic profiles known to psychopharmacologists. In particular, this compound also antagonizes D3-, D4-, 5-HT3,4,6,7, M1-, H1- and 1-2 receptors. Nevertheless, serotonin/dopamine antagonist properties do not explain certain side effects of clozapine including weight gain, sedation, seizures and agranulocytosis (Bunney, 1992). If the risk/benefit ratio considere, clozapine is not regarded as a first-line agent for the treatment of psychosis but a second option-to be chosen when the other agents have failed. It isa particularly effective remedy for violence and aggression in difficult patients; it is also presumed to reduce the suicide rate of schizophrenics (Meltzer, 2001; Gaszner and Makkos, 1999). Some evidence suggest clozapine as a first-line antipsychotic agent with a marked effect on the positive and negative symptoms of schizophrenia. Remarkably, this drug was found to dramatically reduce suicide rate in schizophrenia (Gaszner and Makkos, 1999). Long-term maintenance therapy with antipsychotic drugs is a mainstay of the management of schizophrenia (preventing additional relapses such a psychosis, negative symptoms, cognitive symptoms)-it prolongs the symptom-free period and improves the quality of life. Although there is no consensus on the optimum duration of maintenance therapy, its usefulness is generally accepted (Fitton and Benfield, 1993). This paper describes our experience with clozapine administrated as maintenance therapy and discusses the risk/benefit ratio of this treatment. Patients and methods During the period from 1980 to 2002, 1075 patients have undergone treatment with clozapine for psychotic symptoms at our department; 782 patients were diagnosed as having schizophrenia (according to the Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition-Text Revision (DSM-IV-TR) criteria adjusted for time) (DSM-IV-TR, 2000). Table 1 shows the distribution of the patient population by age, gender, and diagnosis. Mean age of patients at the start of clozapine therapy was 48.3 15.02 years (range: 15-82 years; the male to female ratio

was 327:455). The following disease forms have been identified. 451 patients had paranoid schizophrenia and 6 suffered from catatonic schizophrenia. Disorganized schizophrenia was recognized in 163 patients and residual schizophrenia was diagnosed in 47 patients. Furthermore, 115 patients were found to have schizoaffective psychosis. Table 1 Schizophrenic patients treated with clozapine (N = 782) Age: 15-82 years (mean: 48.3 15.02 years) Gender: 455 females, 327 males Subgroups by diagnosis: Paranoid schizophrenia 451 Catatonic schizophrenia 6 Disorganized schizophrenia 163 Residual schizophrenia 47 Schizoaffective psychosis 115 The duration of clozapine administration: 0.1-18 years (mean: 1.1 0.18 years) Table 2 Data of the schizophrenic patients undergoing long-term clozapine treatment (N = 181) Age: 16-59 years (mean: 42,4 7.44 years) Gender: 109 females, 72 males Subgroups by diagnosis: Paranoid schizophrenia 112 Catatonic schizophrenia 2 Disorganized schizophrenia 16 Residual schizophrenia 15 Schizoaffective psychosis 36 Duration of clozapine administration 1.2-18 years (mean: 12.2 4.25 years) Daily dose of clozapine 50-200 mg (mean: 71.5 14.12 mg) Serum clozapine level 24-78.5 ng/ml (mean: 32.5 10.87 ng/ml) One hundred and eighty-one schizophrenic had received clozapine as monotherapy for more than a year; all patients were symptom-free during this period. Table 2 summarizes the data from this subgroup. Mean age at the beginning of clozapine administration was 42.4 7.44 years (range: 16-59 years); M/F ratio was 72:109. Distribution by diagnosis was as follows: paranoid schizophrenia (112), catatonic schizophrenia (2), disorganized schizophrenia (16), residual schizophrenia (15), and schizoaffective psychosis (36) patients.