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unmetabolized, unbound drug.10,11 After N- is pharmacologi- Amisulpride Has No a one-time oral intake of amisulpride, cally active. About 50% of the orally Effect on Plasma only 24% to 47% of the oral dose was administered dose are eliminated in me- found in urine and, of this, 96% had tabolized form in the urine and about not been altered metabolically.12 There 30% in the feces. Concentrations are no active metabolites; after oral It is known that plasma concen- administration, only a minor portion of trations of clozapine are affected by a To the Editors: drug undergoes metabolism by hydroxy- variety of medications. It is also known, however, that clozapine affects the To date, only a few systematic lation, N-dealkylation, and oxidation of the tetrahydropyrrol core via the cy- plasma concentrations of other com- studies analyzing the use of combina- 15 tions of have been un- tochrome P-450 system. However, 2 in- pounds as well. We have demonstrated 1,2 active metabolites have been identified that clozapine increases the plasma con- dertaken. However, knowing how 13,16 clozapine and amisulpride interact could and found in urine; they correspond to centration of amisulpride. Based on be particularly important as patients with about 4% of the administered dose of the findings that plasma concentrations might well profit from amisulpride. A far greater percentage of amisulpride were higher in patients such a combination treatment; indeed, a of amisulpride is excreted unchanged: who were treated with both clozapine about 75% via the kidneys and about and amisulpride than in patients receiv- few case reports and studies support this 11 13 notion.3–5 Good efficacy and tolerabil- 20% via the feces. There is a linear ing amisulpride monotherapy, a longi- ity of this combination in treating posi- relationship between the dose and plas- tudinal study was conducted in 5 patients tive and negative symptoms have been ma concentration of amisulpride. As who received comedication with cloza- reported even when the disease has amisulpride is mainly eliminated via pine in addition to amisulpride; in all pa- previously been retractable to treatment. the kidneys, the dose of amisulpride has tients clozapine comedication increased The efficacy of the drug combination to be corrected if creatinine clearance is the plasma concentrations of amisul- can be attributed to the complementary restricted. Only little is known about pride, with an average increase of 62%. profiles of the two drugs. how the interaction with other medica- We assumed that amisulpride is actively tions affects the of The atypical drug 13 secreted via the renal transport system, in amisulpride is a derivative amisulpride. particular, via cation-proton-antipor- The dibenzodiazepine 17 that selectively blocks the D2 ters. The effect of clozapine on ami- clozapine is a strong D4 receptor antag- and D3 receptors with no affinity for any sulpride that we observed can most likely other known receptor. It preferentially onist. Furthermore, it has a slight antag- be attributed to competitive effects on blocks mesolimbic, rather than nigrostri- onistic effect on D1,D2,D3, and D5 this transport system. Presumably, both atal transmission, and the receptors and possesses , of the main metabolites, clozapine-N- antihistaminergic, antiserotonergic, and dopamine D2 autoreceptors, rather than oxide and N-desmethylclozapine, are the postsynaptic receptors; the dopamine anti-a-adrenergic properties. The phar- secreted via the renal tubules by cat- macokinetics of clozapine is subject to D3 receptors are antagonized preferen- ionic-proton-antiporters, whereby these tially in the limbic areas.6 The efficacy of numerous influencing variables. About metabolites are considerably better sub- amisulpride was confirmed in several 95% of orally administered clozapine strates than the parent compound.18 studies for both positive and negative is absorbed, that is, almost all of it. We thus assumed that the clozapine symptoms of schizophrenia.7 Amisul- After about 1 to 4 hours, the maximum metabolites in particular compete with pride is rapidly resorbed after oral intake plasma concentration is achieved. Clo- amisulpride for binding at the renal and the plasma concentrations reach a zapine has a low first-pass metabolism, transport system. Our assumption that maximum twice, once after 1 hour and with a of about 50% amisulpride is actively secreted and that again after 3 to 4 hours.8 The first-pass to 60%. About 95% of the substance other organic cations interfere with the metabolism of amisulpride is low; after bind to plasma proteins. The elimination transport process is supported by previ- oral intake the bioavailability is 48%. half-time is about 14 hours (6–26 hours) ous data of Kamizono et al,19 who Seventeen percent of amisulpride binds and steady state is not achieved until showed in rat studies that renal clear- to plasma proteins.9 Its elimination half- after about 6 to 10 days. Clozapine is ance of , a deaminated deriva- time is about 12 hours and steady state is almost completely metabolized in the tive of amisulpride, is significantly achieved after about 2 to 3 days.8 Ami- by the cytochrome P-450 isoen- decreased by procainamide. sulpride is mainly eliminated via the zymes CYP 1A2 and CYP 3A4 before it Because a combined clozapine- kidneys. After intravenous administra- is eliminated. To a minor degree, CYP amisulpride medication may offer thera- tion, 75% of the dose can be detected in 2D6 and CYP 2C19 are also involved peutic advantages, it would be very urine.10 Furthermore, about 90% of ami- in clozapine metabolism.14 Four me- interesting to learn whether the admin- sulpride in the urine was found to be tabolites are known; among these only istration of amisulpride, in addition to

494 Journal of Clinical Psychopharmacology Volume 25, Number 5, October 2005 n Psychopharmacology Clinical of Journal 05Lpict ilas&Wilkins & Williams Lippincott 2005

TABLE 1. Patient Characteristics, Overview of Clozapine and Amisulpride Plasma Concentrations at t0 and t1 as well as of Comedications Pat. 1 Pat. 2 Pat. 3 Pat. 4 Pat. 5 Pat. 6 Pat. 7 Pat. 8 Pat. 9 Pat. 10 Pat. 11 Pat. 12 Pat. 13 Summary* Age (years) 38 31 41 47 19 27 37 46 22 35 28 20 37 32.9 ± 8.9 [19–47] Sex female female female male male male female female female male male male male 6 women /7 men Smoker yes no yes no no yes no no no yes no yes no 5 yes/8 no Clozapine dose 600 250 400 500 125 700 400 250 600 600 350 400 450 433 ± 168 [125–700] (mg/d) at t0 Clozapine plasma 335 755 303 667 73 480 259 608 221 975 523 232 327 442 ± 250 [73–975] level (ng/mL) at t0 oue2,Nme ,Otbr2005 October 5, Number 25, Volume Dose-corrected 0.56 3.02 0.76 1.33 0.58 0.69 0.65 2.43 1.11 1.63 1.49 0.58 0.73 1.20 ± 0.74 [0.56–3.02] clozapine plasma level (ng/mL:mg) at t0 Days under 10 4 5 12 10 7 16 9 7 7 11 7 5 8.5 ± 3.1 [4–16] amisulpride until t1 Amisulpride dose 200 100 400 400 600 200 800 400 200 400 800 500 400 415 ± 199 [100–800] (mg/d) at t1 Clozapine dose 600 250 400 500 125 700 400 250 700 575 400 425 600 456 ± 175 [125–700] (mg/d) at t1 Clozapine plasma 296 709 348 549 84 423 264 541 193 979 543 210 479 432 ± 289 [84–979] level (ng/mL) at t1 Dose-corrected 0.49 2.84 0.87 1.10 0.67 0.60 0.66 2.16 1.10 1.70 1.36 0.49 0.80 1.14 ± 0.73 [0.49–2.84] clozapine plasma level (ng/mL:mg) at t1 Dose-corrected 88 94 115 82 115 88 102 89 100 105 91 85 110 97.2 ± 30.66 [82–115] clozapine plasma level at t1 [% of t0] Comedication Venlafaxine Venlafaxine Metixen — — — — Pirenzepine — — Pirenzepine Pirenzepine

*M ± SD = mean ± standard deviation [range]. Editors the to Letters 495 Letters to the Editors Journal of Clinical Psychopharmacology Volume 25, Number 5, October 2005 clozapine, leads to a change in plasma been receiving amisulpride for at least 4 Niels Bergemann, MD, PhD* concentrations of the latter. It is as- days and at most for 16 days (mean ± SD: Kai R. Kress, MD* sumed that this is not the case as, most 8.5 ± 3.1 days). At t1, the mean dose Alex Frick, MD* likely, only the metabolites but not the of amisulpride amounted to 415 mg Ju¨rgen Kopitz, PhDy parent compound are involved in the (SD = 199 mg, range: 100–800 mg). Departments of *Psychiatry and renal interaction. Nevertheless, product Blood specimens for determining yMolecular Pathology, University inhibition of clozapine-metabolizing en- plasma concentrations of clozapine were of Heidelberg, Germany zymes by accumulating clozapine me- taken between 8 and 9 AM (ie, 10–12 [email protected] tabolites could not be totally excluded hours after clozapine had last been taken). because such competitive product inhi- Clozapine concentrations were deter- bition of hepatic biotransformation was mined by high-performance liquid chro- REFERENCES already shown for desmethylated or hy- matography analysis with UV detection 1. Miller AL, Craig MC. Combination antipsy- droxylated metabolites of various other 23 chotics: pros, cons, and questions. Schizophr exactly as described previously. Bull. 2002;28:105–109. drugs, including aminopyrine and diaze- After administering amisulpride 2. Freudenreich O, Goff DC. Antipsychotic com- 20–22 pam. In the following section, we in addition to the existing clozapine bination therapy in schizophrenia. A review report on 13 patients treated with cloza- treatment, no significant changes were of efficacy and risks of current combinations. pine who received additional treatment Acta Psychiatr Scand. 2002;106:323–330. observed in the clozapine plasma con- 3. Munro JC, Matthiasson P, Osborne SA, et al. with amisulpride because the efficacy centrations. The average plasma con- Amisulpride augmentation of clozapine: an of the one drug was unsatisfactory in re- centration of clozapine at study point t0 open non-randomized study in patients with schizophrenia partially responsive to cloza- lieving negative symptoms. was 443 ng/mL, at t1 456 ng/mL; the Thirteen inpatients (6 women, 7 dose-corrected plasma concentration was pine. Acta Psychiatr Scand. 2004;110:292–298. 4. Zink M, Knopf U, Henn FA, et al. Combination men) between 17 and 47 years (mean ± 1.20 ng/mL:mg at t0 and 1.14 ng/mL:mg of clozapine and amisulpride in treatment- SD: 32.9 ± 8.9), who were being treated at t1. The difference between the two resistant schizophrenia—case reports and re- with clozapine at the Psychiatric Clinic points in time is not statistically signif- view of the literature. Pharmacopsychiatry. of the University of Heidelberg for icant (t test for dependent samples) and 2004;37:26–31. 5. Shiloh R, Zemishlany Z, Aizenberg D, et al. schizophrenia, received amisulpride as can be neglected. The individual daily augmentation in people with schizo- comedication. Doses of clozapine and doses of clozapine and amisulpride, the phrenia partially responsive to clozapine. A amisulpride were determined for each dose-corrected drug plasma concentra- double-blind, placebo-controlled study. Br J patient individually. A description of the tions in the 13 patients, and the mean Psychiatry. 1997;171:569–573. values for the patient group are pre- 6. Schoemaker H, Clausstre Y, Fage D, et al. patients, who were consecutively includ- Neurochemical characteristics of amisulpride, ed in the study, and the individual treat- sented in Table 1. an atypical dopamine D /D receptor antago- 13 2 3 ment regimens can be seen in Table 1. In a previous study, an elevated nist with both presynaptic and limbic selectiv- Six patients were taking other medica- amisulpride plasma concentration under ity. J Pharmacol Exp Ther. 1997;280:83–97. comedication with clozapine as com- 7. Davis JM, Chen N, Glick ID. A meta-analysis tions in addition to the antipsychotics. of the efficacy of second-generation anti- Plasma concentrations of cloza- pared with amisulpride monotherapy psychotics. Arch Gen Psychiatry. 2003;60: pine were determined before and after could be demonstrated. The effect was 553–564. the administration of amisulpride. Only attributed to a renal interaction. Al- 8. Dufuor A, Desanti C. Pharmacokinetics and though the clozapine metabolites cloza- metabolism of amisulpride. Ann Psychiatry. those patients were included in the study 1988;3:298–305. whose plasma concentrations of cloza- pine-N-oxide and N-desmethylclozapine 9. Rosenzweig P, Canal M, Patat A, et al. A pine had reached steady state and for compete with amisulpride for binding review of the pharmacokinetics, tolerability whom there was no doubt that the at the renal transport system, amisulpride and of amisulpride in comedication does not affect plasma healthy volunteers. Hum Psychopharmacol. medication was being taken regularly. 2002;17:1–13. If the patients were taking other drugs, concentrations of clozapine, as could be 10. Canal M, Epsie P, Thenot JP. Amisulpride: this was not changed during the study confirmed by the data presented here. metabolic and pharmacokinetic profile after Polypharmacy is a reality in con- [14C] intravenous administration. Eur Neuro- period. Before amisulpride (t0) was added to the treatment regimen, the temporary psychiatric practice, based psychopharmacol. 2002;12(3):311. upon experience rather than empirical 11. Coukell AJ, Spencer CM, Benfield P. Ami- patients had been receiving an average sulpride: a review of its pharmacodynamic daily dose of 433 mg clozapine (SD = evidence. Only a few data are available and pharmakodynamic properties and thera- 168 mg); after combining this with on the efficacy of the combination of peutic efficacy in management of schizophre- nia. CNS Drugs. 1996;6:237–256. amisulpride (t1), the average daily dose more than one antipsychotic in the treat- ment of schizophrenia. Antipsychotic 12. Noble S, Benfield P. Amisulpride: a review of of clozapine was 456 mg (SD = 175 mg). its clinical potential in dysthimia. CNS Drugs. The patients had received clozapine in polypharmacy thus clearly requires fur- 1999;12:471–483. the same dose between 11 and 61 days. ther trials before clinical recommenda- 13. Bergemann N, Kopitz J, Kress KR, et al. The average time span between tions can be made, not only to provide Plasma amisulprid levels in schizophrenia and evidence of its efficacy, but also to schizoaffective disorder. Eur Neuropsycho- the two measurements of clozapine plas- pharmacol. 2004;14:245–250. ma concentrations comprised 10.2 days enhance knowledge of drug-drug inter- 14. Linnet K, Olesen OV. Metabolism of cloza- (SD = 4.3). Before t1, the patients had actions. pine by cDNA-expressed human cytochrome

496 n 2005 Lippincott Williams & Wilkins Journal of Clinical Psychopharmacology Volume 25, Number 5, October 2005 Letters to the Editors

P450 . Drug Metab Dispos. 1997;25: to result in remission rates of approxi- other mood stabilizers, sedative antihist- 1379–1382. mately 40%.1 Similarly, low remission amines, or other antipsychotics; women 15. Stevens I, Glaenz D, Kraus F, et al. Bedeutung rates are observed for venlafaxine XR who are pregnant or breast-feeding; wom- des therapeutischen Drug-Monitoring im Rah- 2 3 men der Rezidivprophylaxe mit Clozapin [The (37%) and for (36%). The en of childbearing potential who are not relevance of therapeutic drug monitoring for low rates of remission and high rates of practicing a clinically accepted method the prophylactic use of clozapine]. In: Naber nonresponse reported with benzodiaze- of contraception; clinically significant D, Mu¨ller-Spahn F, eds. Leponex. Pharmako- abnormalities on electrocardiogram at logie und Klinik eines atypischen Neurolepti- pines and indicate treat- kums. Heidelberg: Springer; 1999:79–89. ment resistance for a significant number screening including, but not limited to, 16. Frick A, Kopitz J, Kress KR, et al. Clozapin of GAD patients treated with medica- a QTc greater than 480 milliseconds; erho¨ht den Amisulprid-Plasmaspiegel. [Clo- tion and warrant the investigation of comorbid psychiatric disorders such as zapine raises plasma levels of amisulpride] alternative or augmentation strategies to a major depressive episode during the Psychopharmakotherapie. 2003;10:28–31. reduce disability and suffering as a previous 6 months; substance depen- 17. Pritchard JB, Miller DS. Renal secretion of 4 organic cations: a multistep process. Adv result of this chronic disorder. dence or abuse during the previous 12 Drug Deliv Rev. 1997;25:231–242. In the past, Rickels et al5,6 have months; or lifetime bipolar and psy- 18. Schaber G, Stevens I, Gaertner HJ, et al. investigated the efficacy of earlier neu- chotic disorders. Pharmacokinetics of clozapine in psychiatric roleptics in anxiety with mixed results. An Axis I diagnosis other than patients: and renal clearance. Br J Pharmacol. 1998;46:453–459. Newer atypical neuroleptics with actions GAD, such as comorbid , pan- 19. Kamizono A, Inotsume N, Fukushima S, et al. on and dopaminergic path- ic attacks, or social phobia, was not Inhibitory effects of procainamide and pro- ways may prove to be more promising exclusionary, provided that GAD was benecid on renal of sultopride agents for the treatment of patients with the primary diagnosis. in rats. J Pharm Sci. 1993;82: The primary outcome measure was 1259–1261. GAD. These newer agents have also 20. Soda DM, Levy G. Inhibition of drug metabo- demonstrated an improved side effect the HAM-A, whereas secondary outcome lism by hydroxylated metabolites: cross-inhi- profile, with fewer extrapyramidal symp- measures were the CGI-S and the Clin- bition and specificity. J Pharm Sci. 1975; toms such as and parkinson- ical Global Improvement Scale (CGI-I), 64:1928–1931. ism, and a lower incidence of tardive the Hamilton Depression Scale (HAM- 21. Klotz U, Reimann I. Clearance of diazepam can be impaired by its major metabolite dyskinesia. Treatment with D), the Sheehan Disability Scale (SDS), desmethyldiazepam. Eur J Clin Pharmacol. does not appear to result in greater and the anxiety subscale of the Hospital 1981;21:161–163. changes in weight and levels Anxiety and Depression Scale (HAD-A). 22. Bast A, Scheefhals LW, Noordhoek J. Dose- than placebo in double-blind studies.7 The SDS, HAM-D, and HAD-A were dependent kinetics of aminopyrine metabo- Although ziprasidone’s efficacy administered at baseline, screen, and lism in the rat caused by product inhibition and determined by capillary GLC. Pharma- as an antipsychotic agent has been at- weeks 4 and 7, whereas the HAM-A, cology. 1982;25:130–137. tributed largely to its antagonism at the CGI-I, and CGI-S were assessed at all 23. Frick A, Kopitz J, Bergemann N. Omeprazole dopamine D2 receptor, its serotonergic visits. Side effects were monitored and reduces clozapine plasma concentrations. properties may make it a useful agent in recorded, and the Abnormal Involuntary Pharmacopsychiatry. 2003;36:121–123. the treatment of GAD. Movement Scale was performed at each The aim of this study is to provide visit. pilot data on the efficacy and safety of During this open-label flexible-dose Open-label Pilot Study ziprasidone in treatment-resistant GAD. study, subjects received ziprasidone as Thirteen adult subjects participated in monotherapy, for 7 weeks, followed by of Ziprasidone for this open-label study using ziprasidone a 3- to 7-day taper. Patients had the op- in a daily dose range of 20 to 80 mg. tion to continue ziprasidone treatment at Refractory Generalized The study protocol was approved by the the conclusion of the study. Anxiety Disorder institutional review board of the Uni- During the first week, all patients versity of Pennsylvania. received ziprasidone 20 mg daily. Then, To be eligible to participate in the depending on clinical response and To the Editors: study, subjects had to meet the following tolerability, the dose could be increased Although there are several classes inclusion criteria: a score of 4 or greater in 20 mg/wk increments to a maximum of medication indicated for the treat- on the Clinical Global Impression Sever- of 80 mg/wk. Although the relatively ment of adult generalized anxiety dis- ity of Illness Scale (CGI-S), a Hamilton short half-life of ziprasidone (approxi- order (GAD), less than half of treated Anxiety Rating Scale (HAM-A) score 16 mately 6–7 hours) would suggest the patients reach remission. For example, or greater after 8 weeks of treatment with necessity for bid dosing, the decision to benzodiazepine therapy has been shown at least 1 first-line antianxiety agent, use twice-a-day or once a day dosing male or female subjects, aged 18 years or was made by the subject and physician older, and a primary diagnosis of GAD based on degree of sedation. Study results were presented at poster ses- confirmed by the Mini-International Neu- Two-tailed paired t tests were per- sions at the annual meeting of the APA ropsychiatric Interview. formed to assess significance of change (May 1–6, 2004, New York, NY) and the Exclusion criteria included con- in primary and secondary outcome mea- NCDEU (June 1–4 2004, Phoenix, AZ). comitant use of anticonvulsants and sures between baseline and treatment n 2005 Lippincott Williams & Wilkins 497