Haloperidol Decanoate in Chronic Schizophrenia: a Study of 12 Months with Plasma Levels

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Haloperidol Decanoate in Chronic Schizophrenia: a Study of 12 Months with Plasma Levels Prop. Neuro-Psychophamvxxd. B Biol. Psychiot. 1990. Vol. 14, pp. 25-35 0276-5646/90 $0.00 + .50 Printed in Great Britain. All rights reserved @ 1990 Pergamon Press plc HALOPERIDOL DECANOATE IN CHRONIC SCHIZOPHRENIA: A STUDY OF 12 MONTHS WITH PLASMA LEVELS CARLO A. ALTAMURA, FULGENZIO COLACURCIO. MASSIMO C. MAURI, ANNA R. MORO and FEDELE DE NOVELLIS Department of Clinical Psychiatry, Laboratory of Clinical Neuropsychopharmacology, University of Milan, Milan, Italy (Final form, April 1989) Abstract Altamura, Carlo A., Fulgenzio Colacurcio, Massimo C. Mauri, Anna R. Moro and Fedele De Novellis: Haloperidol Decanoate in Chronic Schizophrenia: A Study of 12 Months with Plasma Levels. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1990, 14: 25-35 1. Clinical activity, extrapyramidal side-effects were evaluated in 22 schizophrenic out patients diagnosed according to DSM III and treated with haloperidol decanoate (50-300 mg i.m. monthly dose) for 12 months. 2. BPRS total scores did not show significant fluctuations showing a clinical stability of the patient population. 3. Patients with a duration of illness z- 10 yrs (Group 2) showed significant (p-zO.Ol! higher EPSE total scores compared to those with a duration of illness cl0 yrs (Group 1). 4. A positive correlation was found between the administered dose and haloperidol plasma levels. 5. Patients from Group 2 reached the steady-state more slowly and showed a lower total L/D ratio compared to those from Group 1. 6. The pharmacokinetic approach seems desirable in order to adjust the dose and avoid schizophrenic relapses. Keywords: haloperidol decanoate, pharmacokinetics, schizophrenia. Abbreviations: brief psychiatric rating scale (BPRS), catatonic (Cl, disorganized CD), diagnosis (DG), extrapyramidal side-effects rating scale (EPSE), haloperidol (HL), haloperidol decanoate (HL-D!, level/dose ratio (L/D), not performed (NP), paranoid (PI, plasma levels (PL),patient (PT!, standard deviation (SD!,undifferentiated (U!, years (yrs). Introduction Haloperidol (HL), a widely used antipsychotic drug, is now available in its depot preparation, haloperidol decanoate (HL-D). Several clinical studies have demonstrated the efficacy of this ester in reducing 25 26 C. A. Altamura et al. schizophrenic relapses, but fewer studies have considered pharmacokinetic patterns as well (Deberdt et al 1980, De Buck et al 1981, De Cuyper et al 1986, Reyntjens et al 1982, Viukari et al 1982). Concerning pharmacokinetics, the intramuscular injection of HL-D gives subtained high plasma concentrations with a half-life of about 3 weeks (Reyntjens et al 1982). The release from the injection site seems to be a rate limiting step for the duration of action (about 4 weeks) of the injection. The steady-state seems to be achieved within 2-4 months (see Beresford and Ward for review, 1987). Moreover, follow- up studies lasting more than 6 months including evaluations of the clinical efficacy, side-effects and plasma levels monitoring, are scanty for this drug. The aim of this study was to evaluate clinical activity, extrapyramidal side-effects of HL-D and HL plasma levels in relation to the duration of illness in chronic schizo- phrenic patients treated with HL-D during a follow-up period of 12 months. Methods The study has beenperfonmzdina"naturalistic" setting since the HL-D monthly dose and drug combinations were left up to the physicians who had patients in charge. Moreover they were not aware of the aim of the study and of HL plasma levels determination. i) Population 22 schizophrenic out-patients of both sexes (14 male and 8 female), with age ranging from 16 to 62 years (yrs)(mean age 40.27 ? 12.92 SD), diagnosed according to DSM III (8 disorganized, 9 undifferentiated, 3 paranoid, 2 catatonic), with mean duration of ill- ness of 13.45 yrs f. 8.90 SD, were followed up for 12 months (Table 1). The patients were divided into two groups according to the duration of illness: in Group 1 the duration of illness ranged from 1 to 10 yrs (mean 5.30 yrs + 3.71 SD) and in Group 2, from 12 to 31 yrs (mean 20.25 2 5.39 SD). Patients suffering from organic disorders, drug addiction or alcoholism or tardive dyskinesia were not included in the study. ii) Drug Administration Each patient received a monthly HL-D dose ranging from 50 to 300 mg i.m. (158.6 mg +- 5.73 SD; 2.25 mg/kg + 0.83 SD) for 12 months. Patients from Group 1 were given a mean dosage of 2.04 mg/kg 2 0.62 SD and patients from Group 2 a mean one of 2.42 mg/kg + 0.97 Table 1 The Characteristicsof population Under Survey, Drug Doses (mg/kg), HL Plasma Levels (PL)(ng/ml),Level/Dos@Ratio (L/D), the BPRS and EPSE Scores Recorded in the Course of the Study GROUP 1 ~ 2.451.11 3.84.71 2319 1.11.0 3.421.91 2; ?$ g k1 2.952.00 2.232.45 5.95.0 IICit IpLO T’t 2.77 4.9 1.76 2.n1.20 3.95.4 2423 1.41.3 3.251.94 1:20 do 10 1.0 3.30 0.10 3.1 10 0.9 3:O7 0.92 4.1 19 1.0 4.45 0.92 3.6 10 0.9 3.91 $ [; [ g ; 0.Y 1.6 18 1.1 1.06 1.351.29 3.63.4 2.662.63 2.022.58 3.95.7 2610 1.41.1 2.201.93 2.O21.72 4.T4.3 Ip18 Ip1.1 2.422.50 2.021.72 4.04.1 IFI IIP0.8 2.37 ; JD 36 I 09 P 2.92 4.9 35 2.68 1.19 4.3 3.61 2.39 5.5 22 1.1 2.31 !:a f!O ii & 51 2.r) Iv I@ Iv pa 1.19 3.2 28 1.1 I.1 1.64 2.98 4.2 1.44 2.61 5.2 22 1.6 1.99 2.98 5.3 la 1.4 1.77 3, I#. ::: 2.030.90 3.21.1 27.25.8 0.261.28 0.4111.71 2.04 4.2 2.36 2.16 4.9 22.5 1.2 2.41 1.07 5.1 19.4 1.1 2.28 1.13 4.b 18.1 1.0 2.87 8 0.96 0.7 0.74 0.69 LO 3.7 0.19 0.57 o.liJ 0.0 2.5 0.2 0.26 0.71 5.9 0.4 0.2 0.88 f g. GROUP 2 -L PLBPW EP3E LID IhgBlI Ii*: Y I.9 J.72 ” 3:L 61 :-: f% II 55 f 22 iI 1.26 r:, 2:n 15 62 I 31 D 0.29 D ;.i; :*: ii 1.7 3.00 16 49 I! 23 2:9 41 2.0 1.47 17 42 F 20 D I2 45 II 17 c 1kS 1-i ifI 19 55 II 24 II 2:4 44 20 4l F 20 D :% 2.7 23 2.45 7.4 21 4.2 31 3 ; ; g : 3:271.25 Id 18 1.25 2.3 Idi4 1.2S 2.9 18 ix. 3. 5 WfIlItern 49.5 7.07 20.25.3 2.161.02 0.62.6 37.713.1 0.21.U 1.40 2.K 3.7 1~59 2.S2 4.4 37.1 1.6 1.92 2.44 5.1 36.3 1.7 2.2S 2.44 3.I 37.S 1.4 2.16 0.53 0.93 1.0 0.49 0.93 1.3 13.7 0.2 0.55 1.03 1.7 13.7 0.3 0s 1.03 I.7 13.2 0.2 0.44 PT = Patients 3G = Diagnosis (D = Disorganized; C = Catatonic; P = Paranoid; 0 = Undifferentiated) DI = Duration of illness NP = Not Performed 2% C. A. Altamura et al. SD. No other drugs were associated except for anticholinergicsin case of dire necessity. All patients had been receiving conventional neuroleptics (mostly HL) for at least 3 months before starting treatment with HL-D. In Group 2. all patients had previously received neuroleptic associations. iiiI Clinical Assessment Psychopathologicalfeatures and extrapyramidal side-effects were evaluated at months 1, 3, 6, 12 using the Brief Psychiatric Rating Scale (BPRS)(Overall& Gorham 1962) and ExtrapyramidalSide Effects Rating Scale (EPSE)(Simpson& Angus 1970) respectively. iv) HL Determination HL plasma levels were monitored using a gaschromatographicmethod (Abernethy et al 1984) at months 1, 2, 3, 6, 12. From patient 21 and 6 HL plasma levels were obtained also during the first month of treatment, at times 1, 2, 3, 6, 12, 24, 28 days after the injection. v) Statistical Analysis The analysis of variance was performed using the ANOVA procedure of SAS package (1979) completed by the SNK test (Student-Newman-Keuls)for multiple comparisons. Regression analysis was performed on data from months 1, 6 and 12. Results i) Clinical Data In all patients, BPRS total scores did not show significant fluctuations over the lenght of the study (Fig 1). Drop-outs were 4 (patients 4, 7, 9 after 6 months and patient 2 after 8 months) all due to lack of compliance in coming to the scheduled check-up visits. Basal BPRS values did not differ significantly in the two Groups. Concerning positive (grandiosity,suspiciousness, hallucinations, unusual thought content) and negative (emotionalwithdrawal, depressive mood, motor retardation, blunted affect) symptoms, the former were more present in patients from Group 1 and the latter in patients from Group 2 (negative/positivetotal score ratio: 0.96 vs 1.23).
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