ZUCLOPENTHIXOL - A REVIEW

Dr. Somanathan M.D., Consultant Psychiatrist, S.H. Hospital, Paynkulam, Thodupuzha

Introduction
 Neuroleptic drugs are the main stay in the clinical management of various psychiatric disorders like schizophrenia, acute psychosis, delusional disorder etc. They are widely used along with mood stabilizers in the management of various affective disorders. It has also become common for neuroleptic agents to be used as short-term sedatives, often co-administered with a benzodiazepine.
 In recent years, there has been growing interest in s0-called "atypical" neuroleptics, which have a lower incidence of extra pyramidal side effects and are effective in some previously refractory cases of schizophrenia. These atypical have greater affinity for the D4 receptor and for the 5 HT2 receptor
 Zuclopenthixol, a typical neuroleptic agent, is also receiving now particular clinical attention because of a number of unique properties, and most notably its availability in three distinct product formulations. this review will examine the pharmacological and clinical profiles of Zuclopenthixol, and its current role in psychiatric practice.
Clinical Pharmacology
 Zuclopenthixol is a thioxanthene derivative belonging to the same group of conversional anti psychotic drugs like flupenthixol. Zuclopenthixol is available in three distinct forms namely Zuclopenthixol dihydrochloride tablets, Zuclopenthixol acetate (acuphase) & Zuclopenthixol decanoate (depot)
 Zuclopenthixol dihydrochloride tablets when taken orally reaches a maximum serum concentration in approximately 4 hours (range : 2-12 hours), and has an elimination half-life of approximately 20 hours (range : 12-28 hours)
 The two injectable preparations Zuclopenthixol acetate and Zuclopenthixol decanoate are made more lipophilic by esterification with acetic acid decanoic acid. The acetate formulation, which is provided in a concentration of 50mg/ml, is of special interest due to its extended duration of action. Maximum serum concentrations are reached 24-48 hours after an intramuscular injection. This is then followed by a gradual decline in concentration, so that 72 hours after injection serum levels remain approximately one third the maximum.
Finally, the decanoate  depot form of Zuclopenthixol is available in dosages of 200 mg/ml and 500mg/ml. With these formulations, maximum serum concentrations are reached 3-7 days following intramuscular injection, and the half-life is 19 days.
Zuclopenthixol in small amounts crosses the placental barrier, Zuclopenthixol is excreted in small amounts with milk. The metabolites are devoid of psychopharmacological activity. The excretion proceeds mainly with faces but also to some degree with urine.
 The neuroleptic agent has high effinity for dopamine D1 and D2 receptors as well as for alpha 1-adrenergic and 5HT2 receptors: it has weak histamine H1 receptor blocking activity and even lower affinity for muscarinic and alpha 2-adnergic receptors.
 Zuclopenthixol may induce a transient dose dependent sedation. However such as initial sedation is advantageous in the acute/sub acute phase of psychosis. Tolerance to the unspecific sedative effects occurs rapidly. The anti-psychotic effect of neuroleptic is normally related to their dopamine receptor blocking effect, which seems to release a chain reaction as other transmitter system are influenced as well. The specific dampening effect of Zuclopenthixol makes it particularly useful in the treatment of psychotic patients, who are agitated, restless, hostile, or aggressive.
Indications
 Acute and chronic schizophrenic and other psychosis, especially with symptoms such as hallucinations, delusion, thought, disturbances, as well as agitation, restlessness, hostility and aggressiveness.
 Manic phase of manic-depressive illness.
 Mental retardation associated with psychomotor hyperactivity, agitation, violence, and other behavioural disturbances.
 Senile dementia with paranoid ideas, confusion and/or behavioural disturbances.
Adverse Effects & Contra indications
Neurological : Extra pyramidal symptoms may occur, especially during the early phase of treatment. Tremors, rigidity, bradykinesia, dystonia, akathisia, have all been reported. In most cases these side effects can be satisfactorily controlled by reduction of dosage and/or antiparkinonian medication is not recommended. Tardive dyskinesias may occur very occasionally  in patients of long-term therapy. Antiparkinsoniam drugs do not alleviate these symptoms. Reduction in dosage or, if possible, discontinuation of therapy is recommended.
 Psychic : Sedation initially. Depression and asthenia have been reported in certain clinical trails. (John Fernandes et al 1999)
Autonomic and Cardiovascular : Dry mouth, disturbances of accommodation, micturition disturbances, constipation, tachycardia, orthostatic hypotension, and dizziness occur in small percentage of patients.
Liver: Transient slight alternation in the liver function test may occur.
 A single case of priapism has been reported in a patient on Zuclopenthixol decanoate (Van Hemert et al 1995)
 The drug is contraindicated in cases of acute alcohol, barbiturate, and opiate intoxications, comatose states.
PRECAUTIONS
 Patients on long-term therapy should be monitored carefully. Zuclopenthixol should be used with caution in patients with convulsive disorders or advanced hepatic, or cardiovascular disease.
Zuclopenthixol should  preferably not be given during pregnancy and lactation
DRUG INTERACTIONS
 Zuclopenthixol enhance the response to alcohol and the effects of barbiturates and other CNS depressants. It should not be given concomitantly with guanathidine or similar acting compounds, since neuroleptics may block the antihypertensive effect of these compounds. Zuclopenthixol lowers the effect of levodopa and adrenergic drugs and concomitants use of metaclopramid and piperazine increases the risk of extra pyramidal symptoms.
Clinical Trials with Zuclopenthixol
 In a multicentre study of 148 patients, a Zuclopenthixol dihydrochloride tablet was compared with oral Haloperidol. In acutely psychotic patients who entered the study Zuclopenthixol dihydrochloride tablets was found to be superior to Haloperidol at 24 hour after the initiation of the treatment. This difference was mainly due to initial sedative effect of Zuclopenthixol as no difference was noticed between the two drugs at the end of 6 days (Baastrup et al 1993)
 In a recent trial in which oral Zuclopenthixol was compared with Risperidone. It was found that Risperidone produced lesser extra pyramidal side effects although no differences were noticed in the clinical efficacy. A mean dose of 8 mg. of Risperidone and 38 mg. of Zuclopenthixol was used in this trial which lasted for 6 weeks (Huttunen et al 1995)
 In an open trial comprising Zuclopenthixol acetate and Haloperidol in acutely psychotic patients Zuclopenthixol acetate was found to produce more sedation and less extra-pyramidal side effects. This initial sedative effect of Zuclopenthixol along with its lesser propensity to produce extra pyramidal side effects makes it a very useful preparation in acute settings. (Bobon D & DeBleeker E, 1989)
 The need for oral p.r.n. medications in acutely psychotic patients who were treated with Zuclopenthixol acetate was found to be significantly less as compared to those who were on other treatment. (Baastrup et al 1993)
 It is also of interest to note that Zuclopenthixol acetate 50mg has been compared with Holoperidol 5mg in an assessment of the relative degree of resulting muscle tissue damage. Single Zuclopenthixol acetate injection produced 26 items less muscle tissue damage compared to injection haloperidol. (Norteved Hand Hojelse F 1989)
 Although depot preparation of Zuclopenthixol has been in use in Europ since 1990 very few comparison trial with other depot preparation are available. Lower incidence of extra-pyramidal side effects with Zuclopenthixol decanoate as compared to fluphenazine has beenreported. (Walker C.A 1983)
 Comparison with Haloperidol decanoate has found both them to equally effective with few side effects (Wistedt et al 1991)
 Zuclopenthixol has also found to be useful in the management of elderly patients with dementia (Nygaard et al 1994) and in mentally handicapped children with behavioural problems (Singh I and Owens W.J. 1992)
 Indian Experience
 In a multicentre study (John Fernandes et al 1999) the efficacy of two Zuclopenthixol preparations were revaluated. It was found that injection Zuclopenthixol acetate in thin vegetable oil (Viscoleo) was effective in bringing down the severity of psychosis in acute psychotic conditions within 72 hours. This efficacy was evident using CGI-S, CGI-I, BPRS, -all three instruments. This was achieved with just one injection of acuphase.,. Only 13.5% patients needed another injection of acuphase within 72 hours. This findings is consistent with earlier reports of acuphase efficacy in acute psychosis.
 Acutely psychotic patients are often given acqueous parenteral neuroleptics (such as Haloperidol) during the initial days of treatment. As the effect of such preparation is short asting several injections are often given during 24 hour period. Apart from causing additional pain and attendant risk of developing injections-related complications, this system of giving multiple injections disrupts patient staff relationship. Therefore parentaral neuroleptic with rapid onset of action and longer duration of effect is likely to be a better alternative. Zuclopenthixol acetate as acuphase dose just that.
 Once the acutely ill patients were stabilized with acuphase they were shifted to injection Zuclopenthixol decanoate in vegetable oil (depot) At 72 hours intake, one injection of acuphase and a double dose depot injection were together in the same syringe. This made the treatment easier, acceptable and faccilated compliance with a monotheruptic regime (Hebenstreit, 1990). Over the period of next 8 weeks depot Zuclopenthixol was found to be effective in controlling the psychotic as indicated by periodic assesments.
 In an another multicentre trial conducted all over India by various clinicians (unpublished), each one had to try out Zuclopenthixol on 5 patients of which 2 were cases of first episode of psychosis and remaining were the cases of acute exacerbation of chronic psychosis (Relapse). 270 relapse cases & 152 cases of first episode of psychosis finished the trial, which lasted for 2 months.
 The result of this study clearly showed a rapid decrease in severity of symptoms within 72 hours with the use of injection Zuclopenthixol acetate. The study also demonstrated that these patients could be effectively maintained on Zuclopenthixol depot given at the interval of two weeks. Certain salient features of Zuclopenthixol acetate which were high lighted in this study were-
 Rapid onset of action
 Sedation and antipsychotic property
 Single injection has to 2-3 days of action
 Well tolerated.
 Recommended Dosage and treatment Regimen:
Zuclopenthixol Acetate
  The acetate formulation of Zuclopenthixol  is particularly useful in dealing with agitated and aggressive patients, rapidly and efficiently. The usual duration of a single intramuscular injection of Zuclopenthixol acetate is 2-3 days (compared with only 3-6 hours for other neuroleptic agents). The usual dosage in most cases is 50 mg. (1ml), although larger, more aggressive patients or those who achieve an insufficient responsse may require 100-150mg. For some patients, an additional injection one day after the first may be needed, but more typically the interval to the  next injection is approximately three days.
 Zuclopenthixol acetate is not intended for long-term use; The maximum duration of treatment should be two weeks, and the cumulative  dose should not exceed 400mg (with a maximum of four injection). Following treatment with Zuclopenthixol acetate , therapy can continue with oral Zuclopenthixol tablets or administration of the depot form.
 Zuclopenthixol tablets or administration of the depot form.
 Zuclopenthixol dihydrochloride tablets. The usual starting dose is 10 to 50 mg/day. Dosage increases may be made incrementally in 10 or 20 mg. steps every 2-3days, 100 mg daily if required. Once stabilized, patients can be maintained on approximately 20-40 mg daily.
Zuclopenthixol decanoate
 The usual dose recommended is 200mg. every two weeks although larger doses up to 500 mg. fortnightly have been used in certain centers. This preparation is only 1/5th as potent as flupenthixol, which already exists in our market.
 Following is a recommended treatment regimen
Day - 1 Inj;- Zuclopenthixol acuphase (50-150mg) given deep i.m.
(There is a provision to repeat the initial dose (50-150) 24 hours after the first dose only if the patient is still very disturbed)
Day 4 - Second dose of Zuclopenthixol acetate (10-150mg) l.m along with injection Zuclopenthixol decanoate (200-400mg)
Both these preparation can be mixed in the same syringe and can be given as a single injection. (Arne G&Tove A0J 1989)
Day 18 - Maintain them on injection Zuclopenthixol depot (200-400) mg every 2 to 4 weeks.
 If the patient needs to be maintained oral medicines Zuclopenthixol dihydrochloride tablets (25-50mg daily) from day 4 onwards after initially claming them down with Zuclopenthixol acetate injection.
Conclussion
 Atypical antipsychotics like respiridone, clozapine, olanzepine are rapidly emerging as the main stay in the treatment of various psychotic illnesses. In such a scenario many would question the relevance of a conventional drug like Zuclopenthixol in the current psychiatric practice. The advantage with this drug undoubtedly is its availability in its three distinct formulation, the oral tablets and the two inject able preparations. in Zuclopenthixol acetate, which is a rapid, and relatively long acting intramuscular preparation we have an effective agent to manage the acutely disturbed patients. Zuclopenthixol decanoate is an effective addition to the already existing array of long acting depot preparations. which have helped the clinicians to tackle the problem of drug complaints to a great extent. Thus these different drug preparations could turn out to be helpful tools in our crusade against the major psychiatric illnesses.
REFERENCES
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