Psychopharmacology (1986) 90:412-416

Psychopharmacology
Springer-Verlag 1986

Serum concentrations and clinical effect of zuclopenthixol in acutely disturbed, psychotic patients treated with zuclopenthixol acetate in Viscoleo
A. Amdisen 1 and T. Aaes-Jorgensen 2, N.J. Thomsen 1, V.T. Madsen 1, and M.S. Nielsen 2 1 Psychiatric Hospital of ~rhus, DK 8240 Risskov, Denmark z H. Lundbeck A/S, Ottiliavej 7-9, DK 2500 Valby, Denmark

Abstract. Zuclopenthixol acetate, 5%, in Viscoleo was administered IM to 19 acutely disturbed, psychotic patients in doses of 50-150 mg. Fifteen patients received one injection, whereas four of the patients had two or three injections, usually with intervals of 3 days. The zuclopenthixol concentrations in serum were measured in series of samples taken from each patient during a 3-day period following the injection. In patients given identical doses serum concentrations of about the same order were obtained. Significant and good correlations were found between dose and maximal serum concentration and between dose and area under the serum concentration curve. The average serum concentration curve obtained when adjusting the data to a 100 mg dose has a maximum of 41 ng/ml after about 36 h, decreasing to 15 ng/ml after 72 h. A dose of 50-150 mg zuclopenthixol acetate in Viscoleo appeared to be sufficient for controlling the symptoms for most acutely disturbed, psychotic patients. The frequency of side effects, including extrapyramidal reactions, was low and the adverse reactions mostly mild, indicating that the risks for severe complications generally might be minimal. With a rapid onset of action, few and mild side effects, good tolerability at the injection site, and a duration of effect of 2-3 days, zuclopenthixol acetate in Viscoleo appears to offer advantages compared to conventional neuroleptic treatment in patients in whom an acute, calming effect is desired. Key words: Neuroleptic - Zuclopenthixol acetate - Intramuscular injection - Serum levels - Acutely psychotic patients - Antipsychotic effect

An injectable antipsychotic drug with both a rapid onset of action and a duration of effect longer than that of aqueous injections and oral preparations will probably offer obvious advantages in the initial treatment of acutely disturbed, psychotic patients. In order to achieve a preparation with such properties, zuclopenthixol acetate in Viscoleo (in the following CPT-A) has been developed. Zuclopenthixol is the active cis(Z)-isomer of clopenthixol which is a mixture of cis(Z)- and trans(E)-clopenthixol. Clopenthixol has been used for many years as a neuroleptic drug. The aim of the present study was to obtain pharmacokinetic knowledge of CPT-A and to evaluate the clinical effect in relation to the time after an IM injection. Materials and methods

Patients. Twenty-two male patients suffering from acute

psychoses, including mania or acute exacerbations of chronic psychotic states, were included in this open phase II study and observed during a 3-day period. Patients treated with short-acting neuroleptics within the last 24 h and patients treated with depot neuroleptics within the last 3 months were not included. Additional neuroleptic treatment was not allowed during the test period and concomitant medication was to be avoided as far as possible, but antiparkinsonian drugs and a benzodiazepine could be administered if necessary. The selection criteria required acute psychotic patients in whom calming effect by parenteral neuroleptic treatment was considered necessary. Patients with severe somatic disease, organic brain disease or pathological laboratory values were excluded from the study. The protocol had been approved by the local ethical committee, and the study was carried out in accordance with the Helsinki Declaration II. All patients gave informed verbal consent after the purpose of the study had been explained to them. Three of the patients were excluded from the evaluation of the study: Patient No 16 because it was the same individual as pt. No 13, and ptt. Nos 18 and 20 because they retrospectively did not meet the inclusion criteria as they had other neuroleptics during the study. Personal data for the remaining 19 patients are given in Table 1. Eight were chronic schizophrenics, three suffered from an acute mania, and eight patients were treated for a severe psychotic state not specifically classified at the time of the study. Six patients had not previously received any treatment with psychotropics. The remaining patients

In acutely severely disturbed, psychotic patients a rapid effect is often desired, but the patients are frequently not willing to receive medical treatmenL Difficulties may therefore arise in connection with the use of oral neuroleptics in these phases of the treatment and aqueous solutions of neuroleptics are, therefore, often administered parenterally. As the duration of effect of such preparations is relatively short, the injections often have to be given three or four times daily, which in many cases harms the necessary, positive relationship between patient and staff. Furthermore, aqueous solutions of neuroleptics often cause local muscle tissue damage and pain at the injection site.

Offprint requests to: T. Aaes-Jorgensen

413 Table 1. Patient data, diagnosis, dose, maximal concentration in serum (Cmax)at time tmax and additional medication given Ptt No 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 17 19 21 22 Age (years) 35 51 34 26 36 27 32 21 27 25 23 20 43 23 43 45 26 44 28 Weight (kg) 74 77 80 69 78 73 72 61 67 61 77 57 78 64 87 75 77 105 76 Height (cm) 184 180 179 176 176 186 184 180 177 178 181 178 178 180 177 171 178 178 185 Diagnosis Dose (mg) 50 50 50 50 100 100 150 150 100 100 100 100 150 100 tma. (h) 24 24+48 24 35 24 24 24 36 36 36 24 24 35 36 Cmax (ng.ml- 1) 17 18 13 23 15 68 43 68 48 42 38 50 54 49 26 25 41 16 Additional medication

Paranoid schizophrenia Paranoid schizophrenia Hebephrenic schizophrenia Unspecified psychosis Paranoid psychosis Acute schizophrenia Paranoid schizophrenia Acute paranoid psychosis Unspecified psychosis Acute paranoid psychosis Unspecified psychosis Hebephrenic schizophrenia Manic-depressive psychosis, manic type Abnormitas psychica nature incertae Reactive confused psychosis Manic-depressive psychosis, circular type Manic-depressive psychosis, manic type Paranoid schizophrenia Hebephrenic schizophrenia

Diazepam Diazepam Diazepam Diazepam Diazepam, biperiden Diazepam, biperiden Orphenadrine Diazepam, orphenadrine Diazepam, orphenadrine Diazepam, biperiden Diazepam -

50 50 (12 h) 50 48 50 (72 h) 100 (144 h) 50 24 100 50 (72 h) 50 25(72 h) 35 36

h a d been in p s y c h o p h a r m a c o l o g i c a l therapy for 7 months 10 years. The d u r a t i o n of mental illness varied from only 2 days-21 years (mean 7 years), whereas the d u r a t i o n o f the present hospitalization was 1-10 days (mean 2 days).

tions additional b l o o d samples were d r a w n during the period until 72 h after the last injection. In addition, b l o o d samples for l a b o r a t o r y tests were taken initially and after the study period.

Medication. C P T - A was given I M as a single injection to ptt. N o s 1-14 and N o 19. Patients N o s 15, 21, and 22 received two injections and pt. N o 17 three injections. The doses and dosage intervals are given in Table 1. Eight o f the patients were not given any additional medication during the study, ten o f the patients occasionally received diazepare, and six of the patients received antiparkinsonian drugs (Table 1). Ratings. Overall severity of illness (7-point scale), therapeutic effect (5-point scale), and side effects (4-point scale) were assessed according to the Clinical G l o b a l Impressions scale (CGI) ( G u y 1976). A 4-point sedation scale a n d a check list o f 18 items for u n w a n t e d effects were also filled in. Ratings were done by a psychiatrist at baseline and at 4, 24, 48, and 72 h after the injection. F o r practical reasons some of the assessments were omitted.

Drug estimation. The concentrations of zuclopenthixol were

determined in the serum samples by means o f a high performance liquid c h r o m a t o g r a p h i c m e t h o d (HPLC). The lower limit o f sensitivity was a b o u t 0.5 ng/ml using a 2-ml sample (Aaes-Jorgensen 1980). The administered ester, zuclopenthixol acetate, was not determined by this method.
Results

Pharmacokinetics. The concentration of zuclopenthixol in

serum samples was measured in 15 patients given a single dose and in four patients given two or three doses o f C P T - A IM. Examples of serum concentration curves are given in Fig. 1. The maximal serum levels (Cm,x) appeared over a period of 2 4 4 8 h after injection (tm,x) , the Cm, x and tm,x values are given in Table 1. After the m a x i m u m the curves declined slowly reaching a 72-h level o f a b o u t one third of Cmax. M o s t of the patients given identical doses had serum levels which were very similar. However, one patient (No 5) had rather low levels c o m p a r e d to the dose, and another patient (No 6) had relatively high serum levels. In the patients given two or three injection the serum concentrations were followed until 72 h after the last dose. In Fig. 2 is shown the serum concentration curve for pt. N o 17, who was dosed three times. The serum concentration curve obtained after the first 50-mg dose reached a m a x i m u m after 48 h. After the second (50 mg) and third (100 mg) dose the levels increased because of accumulation,

Blood pressure. The b l o o d pressure was measured initially

and after the study period.

Blood sampling. Blood samples for the pharmacokinetic studies were obtained from the patients during a 72-h period after the injection. Blood samples were d r a w n by venepuncture before and 2, 4, 7, 12, 16, 24, 36, 48, 60, and 7 2 h after the I M injection. In some o f the patients the samples were taken at slightly different times, and in some fewer samples were taken. In the patients given two or three injec-

414
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Fig. 4. Serum concentrations from 18 patients adjusted to a 100 mg dose of zuclopenthixol acetate in Viscoleo. The figure close to each point indicates number of patients having a sample taken at that point 0.80, P < 0 . 0 0 1 , and between dose and Cmax; r = 0 . 7 7 , P < 0.001. Since the d a t a correlate linearly to the dose, the serum concentration d a t a for the 18 patients given a single injection or having a 72-h interval to the second dose, have been adjusted to a 100 mg dose. The average serum levels corresponding to the 100 mg dose are given in Fig. 4. The average curve has a m a x i m u m o f 41 ng/ml at a b o u t 36 h, then the curve declines to 15 ng/ml at 72 h. The 18 patients m a y be d e r i d e d into three groups, one group of eight patients, who were not given additional medication during the study, a second group o f five patients whose only additional medication was diazepam and a third group of five patients given antiparkinsonian drugs. F o u r patients in the third group were also given diazepam. To directly compare the three groups the A U C d a t a were adjusted to a 1 0 0 m g dose, the mean +_sd was 1,870_+470, 1,850 _+ 880, and 2,030 _+290 ng-ml-h- 1 for the three groups, respectively, i.e. the d a t a from the three groups are not statistically significantly different.

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Fig. 1. Serum concentrations of zuclopenthixol in patients given

a single intramuscular dose of zuclopenthixol acetate in Viscoleo
NG/ML PT. No. i / 50MG + 50 MG + 100 MG I.M.

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Fig. 2. Serum concentrations in a patient given repeated doses of zuclopenthixol acetate in Viscoleo'IM

since the patient was not yet in steady state, and because the third dose was higher than the previous ones. The areas under the serum concentration curves ( A U C ) were calculated according to the trapezoidal rule in the period from zero to 72 h after the first injection. A U C for pt. N o 15 was not estimated because the second injection had already been given 12 h after the first injection (Table 1). The A U C s versus dose are given in Fig. 3. The highest variation in A U C between individuals given identical doses of C P T - A was a factor of 4. Highly significant and g o o d correlations were found between dose and A U C ; r =

Clinical effect. Initially, the mean score for severity o f illness was 3.8 and ranged from 2 = "mildly ill" to 6 = " a m o n g the most extremely ill patients". The severity Of illness h a d decreased significantly ( P < 0 . 0 1 , paired t-test) at 24 and 72 h, and the mean score was reduced by one fifth to 3.1. The assessment of therapeutic effect showed that already after 4 h 10 out o f 17 patients had improved and after 72 h two thirds of the patients had either m a r k e d l y or m o d erately improved (Table 2). The mean score for unspecific sedation, as defined by Lingjmrde (1976), had increased significantly at all assess-

415 Table 2. Therapeutic effect according to CGI Status 4h 24 h 48 h 72 h Marked 3 3 3 3 Moderate 4 6 11 7 Minimal 3 6 2 3 Unchanged N 7 3 3 3 17 18 19 16 tration curve which is far closer to that obtained after injection of aqueous solution of zuclopenthixol where maximum concentrations appear 0.25-2 h after injection, whereafter the concentration decreases quickly (Aaes-Jorgensen, to be published), than to that obtained after injection of the depot preparation, zuclopenthixol decanoate in Viscoleo, where maximum concentration appear after about I week, and the serum concentrations decrease slowly over some weeks (Jorgensen and Fredricson Overo 1980, Aaes-Jorgensen et al. 1983). When zuclopenthixol tablets were given to patients twice a day mean steady state serum levels of 12-16 ng/ml were obtained on doses of 10 mg x 2 daily (Aaes-Jorgensen et al. 1981). These levels are of thb same order as the level obtained 72 h after injection of 100 mg CPT-A. In patients given zuclopenthixol decanoate, 100 mg I M every 2 weeks, the mean serum level in a dosage interval was about 8 ng/ml (Aaes-Jorgensen et al. 1983). However, these examples are from patients in a stable phase of psychosis, who had been treated for some time, whereas the patients treated with CPT-A were acutely disturbed psychotic patients and patients with acute exacerbations who initially need higher serum levels in order to get a satisfactory clinical effect (Bjorndal and Aaes-Jorgensen 1982, 1984). Clinically, CPT-A was found to be an efficacious antipsychotic preparation. The results obtained suggest that C P T - A is a better preparation than the known short-acting injectable neuroleptics in initial treatment of severely disturbed psychotic patients. The drug appeared to have an early onset of action and a duration of effect of 2-3 days. A single dose of 50-150 mg CPT-A appears to be sufficient to control the symptoms for most acutely disturbed, psychotic patients. C G I showed improvement of the patients at the first rating which was made 4 h after the injection. As a supplement to the antipsychotic effect the unspecific sedation is a wanted effect in most severely disturbed psychotic patients. The unspecific, sedative effect of CPT-A was observed in most cases 1-3 h after the injection, and the scores for unspecific sedation were increased significantly already at the first assessment at 4 h after the injection. In general, the frequency of unwanted effects, including extrapyramidal side effects, was low after treatment with CPT-A. Despite the fact that zuclopenthixol is pharmacologically regarded as almost devoid of anticholinergic activity a mild degree of dryness of the m o u t h was the most frequent side effect. Mild dizziness and drowsiness were seen in some patients too, but generally side effects did only interfere slightly to moderately with the patient's functioning. Two cases of acute dystonia appeared after 48 and 60 h, respectively. The two patients responded rapidly to IM injection of an antiparkinsonian drug and no further such episodes appeared during the trial. The low frequency of extrapyramidal reactions is remarkable as administration of haloperidol I M as well as orally to acute psychotic patients has been found to give a high frequency of extrapyramidal reactions after both low and high doses (Neborsky et al. 1981). Likewise, other studies have shown high frequencies of extrapyramidal symptoms in the acute treatment of psychotic patients (Bollini et al. 1984; Donlon et al. 1980). Determination of serum creatine phosphokinase activity (Amdisen and Nielsen, to be published), did not show an increase during the test period. This indicates that CPT-A is well tolerated at the injection site.

Table 3. Unspecific sedative effect.

Status 0h 4h 24 h 48 h 72 h

Mean 0.2 1.0"* 1.5"** 0.9** 0.3*

SD 0.5 1.1 0.7 0.5 0.5

N 19 19 18 17 17

0 = no sign of sedation, 1 = mildly sedated, 2 = moderately sedated, 3 = fallen asleep * P<0.05, ** P<0.O1, *** P<0.001 vs 0 h (paired t-test) ments during the test period (Table 3). In most cases the unspecific sedation appeared 1 3 h after the injection, and two thirds of the maximum score was recorded already at 4 h. The maximum mean score, 1.5 was reached around 24 h after the injection and thereafter it began to vanish rather rapidly. Side effects were mostly mild. A total of 16 different adverse effects were recorded and the most frequent ones were (number of cases in parentheses): dryness of mouth (15), drowsiness (11), dizziness (7). The following extrapyramidal side effects were seen: parkinsonism (2), dystonia (2), and tremor (1). Overall side effects on C G I showed that two thirds of the patients were not at all or only slightly troubled by side effects. In one patient side effects, mainly because of drowsiness, were at 48 h assessed as 3 = "strong interference with patients functioning"; one patient had an increase in BP and one an increase in ESR, but apart from this no clinically relevant changes of BP, S-ALAT, S-creatinine, ESR, B-hemoglobin and fasting blood sugar were observed.
Discussion

In serum samples from dogs dosed 5 or 25 mg/kg CPT-A every 3rd day for 4 weeks in a toxicological study the possible presence of the ester, zuclopenthixol acetate, was investigated, but no ester was found (Aaes-Jorgensen, unpublished). Furthermore, in vitro studies of the decanoic ester of zuclopenthixol have shown the rate of hydrolysis to be high (Aaes-Jorgensen et al. 1977) and in patient studies with zuclopenthixol decanoate injected every 2nd or 4th week no ester was found in the serum samples (Fredricson Overo 1980; Jorgensen and Fredricson Over~ 1980). It is therefore very unlikely that the ester should have been present in the samples from the present study and we did not analyse for content of the acetate ester. The shape of the serum concentration curves seems to be suitable for acute treatment, as the absorption is relatively fast and the maximum is reached within 24-48 h followed by a slow decrease, reaching a serum level of about one third of the maximum after 72 h. Thus the preparation of zuclopenthixol acetate in Viscoleo gives a serum concen-

416 In the present study six of the patients were given antiparkinsonian drugs during the study, and ten were given diazepam. In a previous study on zuclopenthixol decanoate given to patients there was no indication for interaction between zuclopenthixol and the antiparkinson treatment, as strong and highly significant correlations ( r = 0.92-0.96, P < 0 . 0 0 1 ) were found between serum levels on separate days and dose for all patients, i.e. they were independent of additional medication (Aaes-Jorgensen et al. 1983). For perphenazine, another neuroleptic drug closely related to zuclopenthixol, no significant difference was found between plasma levels of perphenazine in groups of patients with and without treatment with anticholinergic drugs (Bolvig Hansen et al. 1979). It is therefore unlikely that the antiparkinsonian drugs given to some of the patients in the present study would have influenced the serum levels of zuclopenthixol. Diazepam, which was given to nine of the patients at least once, has not previously been investigated for a possible effect on the pharmacokinetics of zuclopenthixol. However, when separating the patients from the present study into three groups - o n e group not given additional medication, a second group given diazepam alone and a third group given antiparkinsonian drugs alone or together with diazepam - n o difference between the A U C values was found. The highly significant and good correlations between dose and A U C (r=0.80, P < 0 . 0 0 1 ) and between dose and Cmax(r = 0.77, P < 0.001) in the present study also support the hypothesis that the additional medication does not influence the serum levels of zuclopenthixol in h u m a n beings. Zuclopenthixol serum concentrations obtained after CPT-A injection indicate linear kinetics of zuclopenthixol in patients. Significant correlations were found for dose versus Cm,x and AUC. Significant correlations between dose and serum concentrations have previously been found for orally administered zuclopenthixol (Aaes-Jorgensen et al. 1981; Bjorndal and Aaes-Jorgensen 1982 and 1984) and for intramuscularly injected zuclopenthixol decanoate in Viscoleo (Jorgensen and Fredricson Overo 1980; AaesJorgensen et al. 1983). In conclusion, the shape of the serum concentration curves demonstrates the suitability of zuclopenthixol acetate in Viscoleo for acute treatment, as the absorption is relatively fast and the maximum is reached within 24-48 h. Clinically, the preparation in Viscoleo seems to offer advantages compared to conventional neuroleptic therapy in the initial treatment of acutely disturbed, psychotic patients. It has a surprisingly rapid onset of action and in spite of this a duration of effect of 2-3 days, it causes few and mostly mild side effects and is well tolerated at site of injection. chiatric Hospital for valuable assistance with the study. Our thanks are also due to Miss Karin Bogvad, H. Lundbeck A/S for technical assistance with the assay and to Mrs. Ruth Sparre Andersson, H. Lundbeck A/S for typing of the manuscript and drawing of the figures.

References

Aaes-Jorgensen T (1980) Specific high performance liquid chromatographic method for estimation of the cis(Z)- and trans(E)isomers of clopenthixol and a N-dealkyl metabolite. J Chromatogr 183:23%245 Aaes-Jorgensen T, Gravem A, Jorgensen A (1981) Serum levels of the isomers of clopenthixol in patients given cis(Z)-clopenthixol or cis(Z)/trans(E)-clopenthixol. Acta Psychiatr Scand 64, suppl. 294 : 70-77 Aaes-Jorgensen T, Fredricson Overo K, Bogeso KP, Jorgensen A (1977) Pharmacokinetic studies on clopenthixol decanoate; a comparison with clopenthixol in dogs and rats. Acta Pharmacol Toxicol 41 : 103-120 Aaes-Jorgensen T, Kirk L, Petersen E, Danneskiold-Samsoe P, Jorgensen A (1983) Serum concentrations of the isomers of clopenthixol and a metabolite in patients given cis(Z)-clopenthixol decanoate in Viscoleo. Psychopharmacology 81:68 72 Bjorndal F, Aaes-Jorgensen T (1982) Manibehandling med cis(Z)clopenthixol (Cisordinol, Clopixol). Nord Psykiatr Tidskr 36:321-324 Bjorndal F, Aaes-Jorgensen T (1984) Serum koncentrationer red akutte paranoide psykoser behandlet med cis(Z)-clopenthixol. Nord Psykiatr Tidsskr 38:229-233 Bollini P, Amdreani A, Colombo F, Bellantuono C, Beretta P, Arduini A, Galli T, Togni G (1984) High-dose neuroleptics: Uncontrolled clinical practice confirms controlled clinical trials. Br J Psychiatry 144:2%27 Bolvig Hansen L, Elley J, Rosted Christensen T, Larsen N-E, N~stoft J, Hvidberg EF (1979) Plasma levels of perphenazine and its major metabolites during simultaneous treatment with anticholinergic drugs. Br J Clin Pharmacol 7: 75-80 Donlon PT, Hopkin JT, Tupin JP, Wicks J J, Wahba M, Meadow A (1980) Haloperidol for acute schizophrenic patients. Arch Gen Psychiatry 37:691 695 Fredricson Over~ K (1980) A specific fiuorimetric method for assay of drug levels in serum of patients treated with clopenthixol decanoate injections. Acta Psychiatr Scand 61, suppl 279: 92-103 Guy W (1976) ECDEU assessment manual for psychopharmacology. DHEW publication No (ADM) 76-338. National Institute of Mental Health, Rockville, Maryland, USA Jorgensen A, Fredricson Overo K (1980) Clopenthixol and flupentixol depot preparations in outpatient schizophrenics. III. Serum levels. Acta Psychiatr Scand 61, suppl. 279:41-54 Lingj~erde O (1976) Psykofarmaka. Tanum-Norli A/S, Oslo Neborsky R, Janowsky D, Munson E, Depry D (1981) Rapid treatment of acute psychotic symptoms with high and low dose haloperidol. Arch Gen Psychiatry 38:19~199 Received December 2, 1985; final version June 16, 1986

Acknowledgement. The authors wish to thank laboratory assistent Vibeke Ghid and the staff of Department B, Ward i Risskov Psy-