Clozapine combination therapy

In this context, there is anecdotal clinical data indicating that risperidone and clozapine can be overlapped or used concomitantly with beneficial results and no serious adverse reactions (99,100, 101 and 102). This strategy has been used successfully for residual positive symptoms during clozapine therapy and in patients who relapsed when a neuroleptic was withdrawn from combined therapy with clozapine. Indeed, up to 60% of clozapine-treated patients receive additional medication, including a second antipsychotic. 

Another area of continuing use of conventional antipsychotics is for the noncom-pliant patient who may require monthly injections of a depot antipsychotic. No atypical antipsychotic is yet available for depot administration, although such formulations are under development. Otherwise, most clinicians generally try several different atypical antipsychotics before resorting to a trial of clozapine (with its encumbrance of weekly or biweekly blood counts), conventional antipsychotics, or various combination therapies of atypical antipsychotics with other agents (Fig. 11 — 52 second- and third-line treatments). 

Reinstein MJ, Sirotovskaya LA, Jones LE, Mohan S, Chasanov MA. Effect of clozapine-quetiapine combination therapy on weight and glycaemic control. Clin Drug... 

In nine men who were given a single dose of clozapine 50 mg on two separate occasions with a 2-week interval, fluvoxamine increased clozapine plasma concentrations, and the total mean clozapine AUC was increased by a factor of 2.6 all the patients were sedated during combined therapy (38). 

Combined therapy with clozapine and fluvoxamine (n = 11) and clozapine monotherapy (n = 12) have been monitored before and during the first 6 weeks of medication (39). The co-administration of fluvoxamine attenuated and delayed the clozapine-induced increase in plasma concentrations of tumor necrosis factor-alpha, enhanced and accelerated the clozapine-induced increase in leptin plasma concentrations without a significant effect on clozapine-induced weight gain, and reduced granulocyte counts. 

Several controlled trials have shown that lithium is efficacious in the maintenance treatment of bipolar disorder, with higher serum levels (0.8 1 mol/1) being more indicative of successful prophylaxis (Keck and McElroy. 2002). Valproic acid also appears to have efficacy in maintenance therapy, specifically in bipolar patients with mixed mania and rapid cycling (Bowden et al., 1995). The results concerning carbamazepine s efficacy as a maintenance medication are controversial (Stuppaeck et al., 1994). Other potential agents with some evidence of good maintenance value include clozapine and olanzapine. A combination of lithium and carbamazepine or other anticonvulsants is recommended under certain conditions if an adequate preventive effect cannot be obtained with the substances individually (Bauer et al., 2002). 

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). 

Combined risperidone and electroconvulsive therapy (ECT) produced a remarkable improvement in one patient s refractory depression, but it also caused a return of prior TD symptoms (106). When clozapine was added to the ECT-risperidone regimen and risperidone was tapered gradually, the patient s TD signs and symptoms remitted, and she responded well to combined ECT and clozapine. 

Kupchik M, Spivak B, Master R, et al. Combined electroconvulsive-clozapine therapy. Clin Neuropharmaco, 2000 23 14-16. 

Frankenburg FR, Suppes T, McLean PE. Combined clozapine and electroconvulsive therapy. Convuls Ther 1993 9 176-180. 

Psychotic patients are most often treated with clozapine, haloperidol, lithium, olanzapine, or one of the phenothi-azines, or a combination of these drugs. Because response to these drugs is unpredictable and patients are difficult to control, monitoring serum concentration may aid in adjusting therapy. Numerous methods to measure the serum concentration of the various neuroleptic agents have been reported. ... 

In resistant patients, the combination of SCAs and lithium or carbamazepine seems a reasonable approach. Carbamazepine is contraindicated as augmentation therapy to clozapine, due to their synergistic effects on bone marrow suppression. Electroconvulsive therapy (ECT) may also be considered for patients with severe or treatment-resistant... 

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