Pharmacokinetics and Safety of Combination Therapy with Lithium and Risperidone

Several recent studies have demonstrated that the combination of antipsychotics, including risperidone, with a mood stabilizer, e.g. lithium, is effective and well tolerated in patients with bipolar disorders and mania [4] [13] [14] [15] [18] including some pediatric cases [11]. Since the first reports by Böszörményi [3] and Cohen and Cohen [7], a series of case reports and meta-analyses have been published describing neurotoxic effects during the course of treatment with lithium in combination with different antipsychotics. For risperidone, single case reports on neurotoxic interactions with lithium have also been published [6] [10]. Because the neurotoxic effects described have been attributed to a reciprocal pharmacokinetic influence, the pharmacokinetics of lithium combined with psychotropics [1] [2] [5] [12] [16] and non-psychotropics [17] have been studied. The pharmacokinetics of lithium in combination with risperidone has not been reported to date. We have now investigated the specific pharmacokinetics of a combined lithium and risperidone therapy in 13 psychiatric patients.

The subjects of this open-label 9-day trial were patients aged 22 to 62 years, with an ICD-10 diagnosis of bipolar disorder, schizoaffective disorder, or schizophrenia, who had been receiving long-term treatment with lithium and a conventional oral antipsychotic (e.g. pimozide, haloperidol, benperidol, perazine, flupentixol, fluphenacine, zuclopentixol).

Each subject received a combination of lithium and a conventional antipsychotic for at least 5 days prior to the beginning of the study. On days 1 and 2 of the study, subjects received lithium and the conventional antipsychotic, each twice daily. On day 3, subjects received lithium and 1 mg of risperidone twice daily. The therapeutic switch from the conventional antipsychotic to risperidone was made without overlapping the medications in order to minimize the influence of other antipsychotics on the pharmacokinetics of lithium and risperidone. The dose of risperidone was increased to 2 mg twice daily on day 4 and to 3 mg twice daily on days 5-9. Twice daily, patients received lithium tablets containing 400 mg of lithium carbonate (10.8 mmol of lithium), 450 mg of lithium carbonate (12.2 mmol of lithium), or 560 mg of lithium citrate (6 mmol of lithium). Plasma concentrations of lithium were measured by flame-photometry on study days 1, 2, 8, and 9. Plasma concentrations of risperidone and 9-hydroxyrisperidone were determined by radioimmunoassay on days 8 and 9.

Within each treatment phase (days 1 and 2, lithium plus conventional antipsychotic; days 8 and 9, lithium plus risperidone), the Kruskal-Wallis test was used to compare the steady state conditions of lithium after dose normalization to 12 mmol. Wilcoxon's signed rank test was used to compare lithium pharmacokinetic values on day 2 and day 9. An analysis of variance (general linear model procedure) was used to compare C_max and AUC12 h of lithium in subjects who had equal morning and evening doses. Least squares means were calculated allowing the construction of 90% confidence intervals on log-transformed C_max and AUC treatment ratio (F_rel).

Steady-state pharmacokinetic measures did not change significantly when treatment was switched from lithium plus conventional antipsychotics to lithium plus risperidone (Fig. [1]). The mean relative bioavailability (F_rel) of lithium, based on the lithium AUC12 h ratio (lithium plus risperidone/lithium plus conventional antipsychotic), was 112%. F_rel was calculated from the quotient of the AUC12 h (area under the concentration/time curve from 0 to 12 h, calculated by linear trapezoidal summation) values on day 9 (lithium plus risperidone) to the AUC12 h values on day 2 (lithium plus a conventional antipsychotic). In the nine patients who had identical morning and evening doses of lithium, mean F_rel based on the least squares means ratios of the dose-corrected log-transformed AUC12 h was 103%, with a 90% confidence interval of 92-116%.

Fig. 1 C_max and AUC_{0-12 h} values in 13 patients on day 2 (lithium+other AP) and day 9 (lithium+risperidone) (Lithium dose normalized to 12 mmol). AP=antipsychotic; RIS=risperidone.

In the present investigation, 13 patients were switched from a combination of lithium plus a conventional antipsychotic to a combination of lithium plus risperidone. After the switch, no statistically significant differences in the steady-state pharmacokinetics of lithium were noted. Plasma concentrations of risperidone, 9-hydroxyrisperidone, and the active moiety (risperidone plus 9-hydroxyrisperidone) were comparable to those reported previously [8]. The combination of lithium and risperidone was generally well tolerated. The present findings indicate that it is improbable that a combination of lithium plus risperidone would increase the risk of unwanted pharmacokinetic interactions. In one case report, there was no indication of a harmful interaction between risperidone and lithium taken in overdose [9]. However, limitations of our study, such as the small number of patients and relatively short period of observation, should be kept in mind and be considered in future investigations.

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