Zuclopenthixol acetate (ZA) (Clopixol-Acuphase)is a novel antipsychotic formulation. It has a uniqueduration of action such that, when administered as anintramuscular injection, it has clinical effect for aperiod of several days. This property, along with itssubstantial sedative effects, has contributed to its useand promotion in the short-term management of agi-tated or aggressive psychotic patients. As such, ZAis

the only currently available example of a relativelylong-acting medication that is used in clinical prac-tice as a form of restraint. Its use has raised a numberof therapeutic, ethical and legal issues that will be thefocus of this paper. Although this paper will referspecifically to ZA throughout, the arguments raisedmay well apply to any medication with similar clini-cal properties that may become available in thefuture.

Clinical background

Zuclopenthixol is a thioxanthene derivative thatbinds primarily to dopamine D1, D2, 5HT2a and α1-adrenergic receptors. It is available in three formula-

Ordinary article OA 627 EN

Long-acting antipsychotic medication,restraint and treatment in the management of acute psychosis

Paul Fitzgerald

O b j e c t i v e : Zuclopenthixol acetate (ZA) is the first parenteral antipsychotic medica-tion introduced for clinical use in the treatment of aggression and agitation that hasa relatively prolonged duration of action. The aim of this paper is to explore a numberof important ethical and clinical issues that are raised by the use of this novel thera-peutic formulation.M e t h o d : Relevant literature is explored and several issues are identified from whicharguments for and against the use of medication of this type are raised. These issuesare considered in general and with the use of a number of stylised clinical scenarios.R e s u l t : The use of long-acting antipsychotic medication is complicated by its impactupon patient autonomy, by considerations of informed consent and by the need toprovide justice to all patients and staff in a psychiatric treatment setting. The use ofZ A in the emergency treatment of psychotic patients may only be justified under spe-cific clinical circumstances and its use is not appropriate as routine chemicalr e s t r a i n t .C o n c l u s i o n s : Zuclopenthixol acetate is a novel and potentially useful treatmentalternative in the acutely disturbed patient. Institutions in which ZA is used in emer-gency settings should develop protocols to guide clinicians in its appropriate use andprovide monitoring.Key words: emergency treatment, ethics, restraint, sedation, zuclopenthixola c e t a t e .

Australian and New Zealand Journal of Psychiatry 1999; 33:660–666

Paul Fitzgerald, Consultant Psychiatrist

Dandenong Psychiatry Research Centre and Dandenong AreaMental Health Service, David Street, Dandenong, Victoria 3199,Australia. Email: <pbfitz@ozemail.com.au>

Received 18 November 1998; revised 21 April 1999; accepted 22 June1999.

661P. FITZGERALD

tions: as a tablet, as a long-acting depot(zuclopenthixol decanoate) and as a shorter-actingdepot (zuclopenthixol acetate). The pharmacokinet-ics of ZA are such that it reaches peak serum con-centration 24–48 h following an intramuscularinjection. The levels gradually fall from this time andare at approximately one-third of the peak level at72 h [1]. In the one in vivo study of the mechanism ofaction of ZA, it was found that within this periodzuclopenthixol acts to block a high proportion ofdopamine D2 receptors in striatum [2]. This is con-sistent with the proportion of dopamine receptorblockade that is usually associated with antipsychoticefficacy in typical neuroleptics [3–5]. A number ofopen studies have demonstrated a reduction in BriefPsychiatric Rating Scale [6] scores during the 3-dayperiod of action, including scores on psychotic itemssuch as hallucinatory behaviour and unusual thoughtcontent [7,8]. This is not consistent with the gener-ally accepted time frame for onset of antipsychotice ffect and may reflect general sedation or themethodology of these open studies more than anactual amelioration of psychotic symptoms.

Zuclopenthixol acetate is used in the managementof acutely disturbed patients with psychotic disorderssuch as schizophrenia. The commonly used doseranges from 50 to 150 mg in a single injection thatmay be repeated after 24 h if insufficient responsehas been achieved. Current prescribing guidelinesrecommend that ZAshould not be used for more than2 weeks and no more than 400 mg (in a maximum offour injections) be administered. Sedation isachieved rapidly, usually within 15–30 min. Thepeak effect is at approximately 8 h post injection.This effect is dose-dependent and in most patientspersists for up to 3 days [9].

Several studies have been conducted that havecompared the use of ZAin acutely disturbed patientswith standard therapy [10,11], although concernshave recently been raised as to the depth of thisresearch [12]. A review recently published by theCochrane group failed to find any substantial evi-dence that ZA offers advantages over standard treat-ment [13]. The majority of published studies havetended to find a similar clinical response with ZAanda control medication (oral or intramuscular haloperi-dol). Patients receiving ZAreceived fewer injectionsand experienced greater sedation in several studies.Concerns raised about the possibility of a high inci-dence of extrapyramidal side effects associated withhigh dopamine D2 occupancy [3] were partiallyborne out with higher rates in patients treated with

ZAthan with comparison medication in some studies[11] but not all [14]. Whilst it is noticeable that thetrials of ZAare limited, it is important to consider thesubstantial difficulties in performing studies inacutely disturbed patients and to consider the resultsboth of these studies but also the open reports previ-ously mentioned.

Although not fully borne out by the aforemen-tioned studies, there appear to be a number of poten-tial therapeutic benefits to the administration of ZAthat relate to the reduction in the number of par-enteral injections required during a fixed period oftime. These include: (i) a reduction in traumaticmuscle injury; (ii) a reduction in psychologicaltrauma associated with physical restraint requiredduring the administration of parenteral medication;(iii) a reduction in the incidence of physical injury toboth patients and staff, including reduction in theincidence of needle stick injury; and (iv) a reductionin ‘breakthrough’ symptoms of agitation andepisodes of aggression. Alternative managementstrategies often will involve waiting until symptomsre-emerge prior to the subsequent re-administrationof a sedating medication. These symptoms are likelyto be distressing in themselves as well as place thepatient and others at risk of harm.

There has been little systematic evaluation of thesepotential advantages although one study indicatedthat ZAmay offer a cost savings by reducing nursingtime required for the management of agitatedpatients [15]. It appears reasonable to assume thatreducing the number of injections received bypatients will lower the number of staffing injuries asthe time of administration of parental medication isone of significant risk for nursing staff [16].

Inadequately treated aggressive symptoms willhave an impact upon the patients, other patients, vis-iting family and staff. The aggressive patient is at riskof physical injury, of harming others (and experienc-ing future legal sanctions) and a period of ‘out ofcontrol’behaviour which may have substantial nega-tive psychological impact upon the patient’s self-image and perception of his or her illness assomething he or she can manage and bring undercontrol. This may lead to denial or repression of theillness experience and affect future compliance.Additionally, the experience of receiving repeatedparenteral medication for sedation is likely to beexperienced as an assault and to invoke images ofpunishment and incarceration for the patient ratherthan those of therapy and relief. This may include thedevelopment of posttraumatic symptomatology [17].

662 MANAGEMENTOF ACUTE PSYCHOSIS

There are, however, clinical concerns with theadministration of a long-acting medication to anacutely disturbed patient. Any idiosyncratic or dose-related side effects will be experienced for a longerperiod of time than had a shorter-acting agent beenadministered and the patient may not experiencerelief from these until the medication effects havesubsided. The history available from a disturbedpatient may be unreliable and if this is not availablefrom another source, comorbid physical illnessesmay be overlooked. Performing a physical examina-tion on a patient prior to administration of the sedat-ing medication may also be impossible. In addition,it may not be possible to exclude the use of illicitsubstances either as the cause for the disturbedbehaviour or as a coexisting problem. Both the pres-ence of substance use or physical illness may raiseconcerns about the safety of administering a par-enteral neuroleptic and the prolonged half-lifeensures that any adverse consequences of doing sowill be relatively prolonged.

Ethical issues

A number of ethical concerns have been raisedabout the use of ZA [18]. These concerns have pre-sented in the context of the use of ZA to sedate orcontrol patients experiencing disturbed behaviourand the legal framework under which this practice iscontrolled. There are concerns in regards to the effectZA will have on patient autonomy, as well as con-cerns in regards to the balance between the rights ofan individual patient versus the rights of others (staffand other patients) around him/her. Several of theseissues arise due to a lack of clear distinction betweenthe use of ZA as a form of chemical restraint as dis-tinct from treatment.

Impact upon autonomy

One of the primary concerns with ZA relates to itscapacity to affect patient autonomy over a relativelyprolonged period of time. This argument states thatthe sedation and modulated mental state produced byZA will remove the patient’s free capacity to makedecisions, to refuse consent or to appeal a determina-tion of incapacity. The medication may temporarilyaffect cognitive functioning as well as consciousarousal and the patient will lose the opportunity toregain control of him or herself for up to 3 days. Thisduration of action appears not to be in keeping withthe use of the medication to control a discrete episode

of disturbed behaviour. The imposition of sedativeeffects for several days is also not the least restrictivemeans with which control of an episode of behaviourmay be achieved and is therefore problematic.

Opposing this stance is the argument that patientshave a right to receive the best available treatmentand that denying patients this treatment option mayresult in adverse clinical consequences. Additionally,it may be argued that the continuous action of ZAover several days is much more likely to return thepatient’s capacity and autonomy rather than fluctuat-ing treatment that may result in the periodic re-emer-gence of agitation and aggression. It may restorealready compromised autonomy rather than removeor impair it despite temporarily limiting the patients’freedom of behaviour. Finally, it may be argued thatwhile the duration of action is not consistent with atreatment being the least restrictive option, theadministration of fewer injections with ZA does insome way meet this standard.

A conflict of rights

A further ethical issue that may be considered rele-vant concerns the rights of other patients to be pro-vided with a safe and therapeutically beneficialenvironment. Additionally, the staff who care forpatients have the right to be provided with a safework environment. Both of these conditions are morelikely to be achieved if timely and effective sedationis provided to disturbed patients. It may be arguedthat in reducing the need for repeated injections, ZAwill reduce the injuries experienced by staff. Nomember of society, and no patient in hospital, is ableto exercise absolute freedom and limits may be seenas appropriate in the balance for ‘overall good’.Interestingly, where this has been addressed legally,the courts have recognised that there is a need for apatient’s right to liberty to be balanced with an insti-tution’s duty to protect the patient and others fromthe consequences of acts of violence [19].Unfortunately, one of the most influential of deci-sions in this area considered the use of seclusion andmechanical restraint but not the use of involuntarymedication [20].

Informed consent, restraint and treatment

As with any medication, issues associated with theprovision of informed consent are crucial in theappropriate use of ZA. If a patient is able to giveinformed consent, its use is unproblematic. However,

663P. FITZGERALD

the capacity of a patient to provide informed consentin an emergency or a state of agitation is likely to belimited. In some jurisdictions, such as that of theprovince of Ontario in Canada, provisions exist forconsent to be provided by a substitute decision-maker following a determination of incapacity. Thismay be possible in some circumstances but emer-gency sedation is usually required rapidly andcontact with a third party will frequently be imprac-tical. This poses the question of how best to protectthe rights of the patient while not hindering the pro-vision of acute care needed for the safety of theindividual and others. Legally this has beenaddressed in a variety of ways. One of these is to dis-tinguish between restraint (which may not requireconsent) and treatment (that does). By distinguishingbetween these two concepts, it is possible to definean argument that clearly states that the use of ZA,without informed consent, is problematic. In its sim-plest form this argument states:

(1) There is a significant and definable differencebetween restraint and treatment. Restraint (physicalor chemical) is an act performed in an emergency sit-uation to prevent harm to a patient or others and assuch may occur without informed consent. It shouldconstitute the minimal use of the force required.Treatment, however, is a process directed at theillness experienced by the patient and alwaysrequires consent from the patient or a defined substi-tute decision-maker.

(2) Parenteral medication used in an emergency isa legitimate form of chemical restraint.

(3) The duration of action of ZA is such that it actsbeyond the time appropriate for restraint and as suchis better conceptualised as a treatment.

(4) Zuclopenthixol acetate should not be prescribedor administered without informed consent and there-fore should not be used routinely as a chemicalrestraint.

The crucial issue here appears to be whether it islegitimate and useful to distinguish between restraintand treatment. Attempts to do so have appearedwithin the law and within mental health legislationalthough noticeably these distinctions are not com-monly represented in current Australian mentalhealth legislation. For example, in Ontario, theMental Health Care Act (1996) defines restraint as,‘to place under control when necessary to preventserious bodily harm to the patient or to anotherperson by the minimal use of such force, mechanicalmeans or chemicals as is reasonable having regard tothe physical and mental condition of the patient’.

Treatment (in the Health Care Consent Act) ‘meansanything that is done for a therapeutic, preventative,palliative, diagnostic, cosmetic or other healthrelated purpose’. The Victorian Mental Health Act(1986) defines treatment in relation to a mental dis-order as, ‘things done in the course of the exercise ofprofessional skills to—(a) remedy the mental dis-order; or (b) lessen its ill effects or the pain and suf-fering which it causes’. Restraint is not defined,although there is a specific section in the act on theuse of mechanical restraint. The use of medication aschemical restraint is not addressed. Likewise, theQueensland Mental Health Regulations (1985)define restraint in terms of ‘mechanical means’without reference to medication, although this defin-ition appears to separate restraint from what wouldbe considered standard treatment.

Clearly, mechanical restraint (and the use of seclu-sion with which it is usually considered) appears tobe different from treatment. The distinction ofrestraint from treatment has been legally explored:for example, in an important case in Massachusetts[21], psychiatrists in a university hospital werecharged with the use of seclusion in non-emergencysituations. The judge in the case found that the use ofseclusion in non-emergency circumstances was anadministrative sanction and not a treatment. Thisdecision has led to a reconsideration of the indica-tions for the use of seclusion and restraint, and prin-ciples under which these interventions may be usedhave been defined [22,23]. Criteria for the use ofthese interventions include the acute control of vio-lence, for the containment of destructive impulsesand to provide isolation from the demands of inter-personal relatedness and sensory stimulation.

Mechanical restraint appears to only be acceptablewhen it comprises the minimal use of force requiredto prevent harm coming to a person or persons. Inthese circumstances, the treating team are actingunder the principle of beneficence, to do good (byacting to prevent harm), while temporarily compro-mising the patient’s freedom. Mechanical restraintwould be applied only when a patient’s capacity toact autonomously is compromised by the effects ofmental illness. The use of restraint in this way mayalso be justified by considering the principle ofjustice, in particular the right of other patients toreceive equitable, safe and reasonable treatment. Theprovision of restraint is not undertaken with theintention of acting in accordance with what thepatient, when calm and competent, would be likely tochoose given the circumstances. The act of restraint

664 MANAGEMENTOF ACUTE PSYCHOSIS

does not alter the course of the illness and the illnessis not the direct target of the intervention.

Restraint appears to differ from what we wouldcommonly consider treatment but the distinction isless clear when we consider treatment undertaken inan emergency situation. Emergency treatment is notuncommonly provided without informed consent incertain circumstances in areas of medicine other thanpsychiatry. For example, emergency surgery may beundertaken to save the life of an unconscious patientwithout consent if there is no available relative toprovide substitute consent. A decision to undertaketreatment would be based predominately upon theprinciples of beneficence. In these circumstances, thetreatment is considered to be provided in what isregarded as the ‘best interests’ of the patient or insuch a way as to be consistent with what a ‘reason-able’ patient would be likely to choose. There aresimilarities in the circumstances of an unwilling andacutely disturbed psychotic patient. Usually, in thesecircumstances, treatment may be provided where thepatient has been deemed incapable to refuse (or give)consent to treatment. Consent provided by a substi-tute decision-maker is considered to be most ethi-cally appropriate if it is given as an expression ofwhat the patient would be likely to choose rather thanwhat is deemed by others to be in the patients’ bestinterests. It is not always possible to represent theseideas, however, and often decisions are made on thestandard of ‘best interests’. In both the circumstancesof the unwilling incapable patient and the uncon-scious patient, the provision of treatment directly hasan impact upon the course of the illness and it is theillness that is the focus of the intervention.

Is the use of medication to manage an acutely dis-turbed patient more closely analogous to the use ofmechanical restraint or to the example of emergencymedical care? In that the aggression or agitation maybe seen as secondary to the illness, we may considerthat the use of medication in this way is at least treat-ing a manifestation of the illness; this would be con-sistent with the Victorian Mental Health A c tdefinition of treatment; to ‘lessen its ill effects’.More specifically, however, there is no evidence thatthe use of parenteral antipsychotic medications in adisturbed patient will alter the long-term course ofthe illness, as these medications work over a timecourse of weeks rather than hours. Additionally, dis-turbed behaviour rather than the actual illness is thefocus of the intervention.

There does not appear to be a clear demarcationbetween the notions of restraint and treatment when

applied in these circumstances. To move forward, Ibelieve it is necessary to consider in more detail someof the clinical circumstances in which the dilemmamay be resolved. To do this, I will consider two clini-cal possibilities while acknowledging from the outsetthat there will be a difficult grey area between theseends of the spectrum of clinical presentation.

First, we will consider the majority of patients whopresent requiring the use of a sedative or restraint.These patients will clinically improve with theadministration of one or perhaps a few doses of stan-dard short-acting treatment (such as parenteralhaloperidol). They may continue to experience psy-chotic symptoms but the problematic behaviour willbe controlled or resolve. In these patients, it is rea-sonable to consider that restraint is the focus of theintervention and that this should be done in the leastrestrictive manner. The use of ZA would not beappropriate in these circumstances. The use of med-ication in these circumstances is closely analogouswith the use of mechanical restraint for the control ofviolence.

The second circumstance is one that appears tooccur uncommonly and in a minority of patients. Inthis circumstance, a patient presents with persistentagitation associated with the relapse of psychosis. Apatient may have presented repeatedly in this fashionover the course of a number of episodes of relapse andhave demonstrated persistent agitation despite the useof repeated doses of standard treatment in eachepisode. It is difficult to estimate the proportion ofdisturbed patients who fall into this category.H o w e v e r, we can get some indication from researchon the use of seclusion as a method of responding todisturbed behaviour. Anumber of studies of seclusionpractices have found that the average duration ofseclusion use tends to be low (e.g. a mean length of1 0 . 8 h and a median of 2.8 h in one study [24]). T h e s estudies indicate, however, that a small group ofpatients with persistent disturbed behaviour requireseclusion for extended periods of time (up to 120 h inthe study by Soloff and Turner [24], up to 72 h in astudy by Binder [25]) or may require repeated periodsof seclusion. Additional evidence is found in studiesof parenteral sedation such as that of Baastrup e t a l.[10]. In this study, patients treated with intramuscularhaloperidol or zuclopenthixol (not ZA) required up to12 injections over 6 days, although the mean numberof injections was quite low (1.1–4.0 for variouspatient subgroups). This indicates that there appearsto be a small group of patients in whom the use of al o n g e r-acting medication would be useful.

665P. FITZGERALD

The presentation of persistent disturbed behaviourin these circumstances often appears closely relatedto the psychotic disorder and as such does not presentas an isolated incident to which restraint may applyin isolation from treatment. Zuclopenthixol acetatewould appear to be appropriate in these circum-stances as it would be directed towards the treatmentof the episode of disturbed behaviour in conjunctionwith the underlying psychosis. There are severalgoals of treatment with ZAin these circumstances: torestore patient autonomy by ameliorating both psy-chosis and agitation; to act in the interest of thepatient to relieve distress and provide protection; andto provide justice to staff and co-patients by provid-ing a safe environment and timely treatment. The useof ZAas a treatment in these circumstances is analo-gous with the use of seclusion or restraint as ‘treat-ment’ as defined by some authors [22,23]. Thisdistinction refers to the use of restraint in certain cir-cumstances where the target of the intervention is theamelioration of ongoing aggression associated withpsychosis rather than the acute control of violence.

In the second scenario described, the use of ZAappears consistent with notions of treatment ratherthan just restraint. As a treatment, however, concernsabout the provision of informed consent (by a substi-tute) still exist and may be legally mandated in somejurisdictions. If this were the case, it would seemappropriate for a short-acting medication to be ini-tially administered to allow time for consent for ZAtreatment to be obtained from a third party. Thiswould also allow the patient opportunity to gain selfcontrol if the episode differs in nature from thoseseen previously, as well as allowing the initiation ofan appeal of incapacity or involuntary status.

Clinical suggestions

Ethical difficulties with the use of ZA wouldappear to be most satisfactorily resolved by the limi-tation of its use to specific clinical circumstances inwhich the following criteria are satisfied: (i) the priorestablishment of a diagnosis of a psychotic disorder,such as schizophrenia, that is not secondary to sub-stance intoxication/withdrawal or a general medicalcondition; (ii) a previous history of similar agitatedor violent behaviour that required treatment with par-enteral medication, seclusion or physical restraint fora period of at least 24 h; and (iii) some clinical indi-cation that the present disturbed behaviour is relatedto a relapse of the psychotic illness.

Attempts to obtain informed consent (from the

patient or substitute decision-maker) should alwaysbe made. Where this is not possible immediately, theuse of a short-acting medication to ‘buy time’ toallow a substitute to be contacted should be consid-ered. Where the use of a substitute decision-maker isnot local practice, a judgement should be made con-sidering: (i) any views previously expressed by thepatient or substitute decision-maker; (ii) the degreeof physical and emotional trauma involved with theadministration of parenteral medication to the parti-cular patient (the risks to the patient and staff); (iii) the acceptability of other alternatives to thepatient and the risks associated with these; and (iv) the likelihood that the targeted behaviour willrespond to alternative medication with a shorterduration of action.

In addition to these concerns, ZA should only beused where there is adequate monitoring for thedetection of extrapyramidal or other side effects. Therationale for its use, target symptoms and theresponse of target symptoms should be carefully doc-umented. It would seem appropriate that institutionsin which ZAis used develop protocols for the formalassessment of disturbed behaviour and the responseof patients to ZA. This may prevent the repeatedadministration of the medication to patients in whomclear benefit is not evident. Finally, as with all diffi-cult clinical decisions, obtaining a second opinion orconsultation should be considered.

Conclusion

Zuclopenthixol acetate is a novel and potentiallyuseful treatment alternative. Its use raises a numberof clinical and ethical issues. These issues revolvearound concerns for the autonomy of patients, therights of other individuals who deal with and are incontact with disturbed patients and the right ofpatients to be able to provide (or have others providein their interest) informed consent to treatment.Adequate resolution of these issues requires carefulanalysis of both the ethical arguments and specificclinical issues. The use of ZAis appropriate in certainclinical circumstances but should occur only follow-ing careful individual and institutional consideration.

Acknowledgements

I wish to thank Mary Seeman of the University ofToronto in Ontario, Canada, for her helpful com-ments on this paper and her support during myFellowship in Toronto during which this paper was

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completed. I also thank Peter Prendergast and themembers of the Pharmacy and T h e r a p e u t i c sCommittee of Whitby Mental Health Centre inWhitby, Ontario, whose discussions contributed tothe genesis of this paper.

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