2009 Management After First Episode Psychotic

8/7/2019 2009 Management After First Episode Psychotic

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Management of Patients Presenting withAcute Psychotic Episodes of SchizophreniaPierre Thomas,1 Koksal Alptekin,2Mihai Gheorghe,3-Mauro Mauri,4JoseManuel Olivares5 andMichael Riedel6

1 Department of Psychiatry, University of Lille Medical School, Lille, France

2 Department of Psychiatry, School of Medicine, Dokuz Eylul University, Izmir, Turkey

3 Department of Psychiatry, Clinical Central Military Hospital, Bucharest, Romania

4 Department of Clinical Psychiatry, University of Milan, Milan, Italy5 Department of Psychiatry, Vigo University Hospital, Pontevedra, Spain

6 Department of Psychiatry and Psychotherapy, Ludwig-Maximilian University, Munich, Germany

Contents

Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1931. Management of Acute Psychosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1942. Treatment Objectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1943. Management Strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1954. Standard Paradigm for Management of Typical Relapses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195

4.1 The First 4 Days . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1954.2 The First 4 Weeks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198

5. Highly Agitated Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1995.1 The First 4 Days . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1995.2 The First 4 Weeks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200

6. First-Episode Psychosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2006.1 The First 4 Days . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2006.2 The First 4 Weeks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201

7. Patients at High Risk of Suicide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2027.1 The First 4 Days . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2037.2 The First 4 Weeks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203

8. Patients Presenting with Drug Intoxication and Withdrawal. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203

8.1 The First 4 Days . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2038.2 The First 4 Weeks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2049. Elderly Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204

10. Special Issues Related to Gender . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20611. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206

Abstract The initial management of patients with schizophrenia presenting to psy-chiatric emergency departments with an acute psychotic episode requires rapiddecisions to be made by physicians concerning the treatment of individualswho are likely to be relatively uncooperative, agitated and lacking insight.

The treatment decision must be adapted to the individual characteristics and

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REVIEW ARTICLECNS Drugs 2009; 23 (3): 193-212

1172-7047/09/0003-0193/$49.95/0

2009 Adis Data Information BV. All rights reserved.


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needs of each patient. This article reviews the issues from the perspective ofthe initial management of acute psychosis as it is currently practised in Europe,and discusses the pragmatic implications for initial treatment decisions andthe elaboration of a long-term treatment plan. Initially, administration ofantipsychotics to control psychotic symptoms and benzodiazepines to con-trol agitation represents the cornerstone of treatment. Oral medication ispreferable to injectable forms wherever possible, and atypical antipsychoticsare to be preferred over conventional agents because of their lower risk ofextrapyramidal adverse effects, which are a major determinant of poor ad-herence to treatment. Whatever antipsychotic is chosen by the physicianduring the initial period, it is likely that it will need to be continued for manyyears, and it is thus important to take into account the long-term safetyprofile of the drug chosen, particularly in relation to extrapyramidal adverse

effects, metabolic complications and quality of life. Building a therapeuticalliance with the patient and his/her family or carers is an important elementthat should be included in the initial management of psychosis. The long-termgoal should be to minimize the risk of psychotic relapse through adequatetreatment adherence.

1. Management of Acute Psychosis

The initial management of patients with schizo-

phrenia presenting to psychiatric emergencydepartments with an acute psychotic episoderequires rapid decisions to be made by physiciansabout which treatments are most suitable fortreating a patient who is likely to be relativelyuncooperative, agitated and lacking insight. Thedecisions that are made in such a situation haveimportant consequences for the likelihood ofsuccess of maintenance therapy once the patientreturns to the community and thus on the pre-vention of future psychotic relapses. In a number

of countries, professional associations have de-veloped guidelines and treatment algorithms forthe initial management of acute psychosis[1-10]

with the aim of optimizing both the short-termtreatment response and the long-term outcome.The relative importance of the issues underlyingthese recommendations varies from patient topatient, depending on clinical presentation, psy-chiatric and treatment antecedents, the structureof care in the community, and the extent of familysupport and awareness. This article reviews

these issues from the perspective of the initialmanagement of acute psychosis as it is currently

ti d i E d di th ti

implications for initial treatment decisions andthe elaboration of a long-term treatment plan.

2. Treatment Objectives

Treatment objectives for the initial manage-ment of acute psychotic episodes are multiple. Inthe short term, these objectives consist of rapidcontrol of symptoms, particularly agitation andpsychotic symptoms, and prevention of harm tothe patient or others. Prevention of harm includesreducing suicide risk, self-harm, domestic andpublic accidents, hostility and assaults, and

the medical complications of any co-morbidity.Subsequent treatment goals include establishingand consolidating a therapeutic alliance with thepatient and family, ensuring a smooth transitionto maintenance treatment, and establishing aplan to optimize adherence to treatment.[11] Therelative priority given to these different goals maydiffer according to the specific characteristics ofeach patient. For example, harm prevention iscritical in patients with antecedents of suicideattempts or suicidal ideation. In first-episode

patients, informing the patient and family andestablishing a therapeutic alliance is a specific,

d ti l l i t t i

194 Thomas et al.


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3. Management Strategies

Initial management of acute psychosis needsto take into account the specific needs, ante-cedents and prognosis of each individual patient.In addition, interventions need to evolve overtime as symptoms of psychosis resolve withtreatment. In this article, we consider differentpatient profiles, starting with a general descrip-tion of issues for care in a patient presenting witha typical psychotic relapse and then describingthe specific issues associated with particular pa-tient groups (table I). We discuss strategies for theshort- and medium-term initial management ofacute psychosis. Short-term management refersto the first 4 days, which is the period duringwhich it should be possible to gain control oversymptoms and stabilize the patient. Medium-term management refers to the time from the endof the short-term period out to 4 weeks, duringwhich period the state of the patient still needs tobe followed closely and a maintenance treatmentplan conceived and put in place.

4. Standard Paradigm for Managementof Typical Relapses

This section discusses the management ofpreviously treated patients regardless of the seve-rity of the psychotic symptoms but without majoragitation (characterized by behavioural hyper-activity, anxiety, tenseness, verbal aggressivenessand risk of harm to self or others) and who do notpresent any special treatment considerations (e.g.

relevant somatic or psychiatric co-morbidities,addictions or old age). In general, such patientscan be treated on an open ward or as outpatients,since they are sufficiently lucid and cooperativeto participate in treatment decisions and do notrequire constant attention. Such patients re-present over half of all cases of relapse seen inpsychiatric practice.[10,12-14]

4.1 The First 4 Days

On admission, it is important to carefully as-certain the nature and severity of the relapse andt l d lt ti di h d

induced psychosis. The patients medical recordsshould be scrutinized and the patients entourageinterviewed about previous psychotic episodes,response to treatment, and compliance. The pa-tients should be examined to detect other poten-tial somatic and psychiatric co-morbidities,which will need to be taken into account in thetreatment choice.

In these patients, it is important to set upcommunication channels with the patient fromthe very beginning in order to construct solidfoundations for a future therapeutic alliance.

This involves informing the patient of the needfor immediate and long-term treatment andstressing the importance of adherence to a treat-ment plan. The patients attitudes and beliefswith respect to treatment should be carefully in-vestigated and taken into account in the choice oftreatment. The family should also be involved inbuilding the therapeutic alliance, as their supportwill be essential in maintaining treatment ad-herence and in identifying early warning signsof relapse once the patient returns to the home

environment.If anxiety or agitation is present, benzodiaze-

pines should be given immediately to calm the pa-tient.[15] The dose of benzodiazepine chosen shouldbe based on the degree of agitation. Lorazepamand alprazolam are the benzodiazepines of choicefor this purpose. Appropriate use of benzodiaze-pines in the immediate phase allows the agitationof the patient to be controlled satisfactorily beforethe introduction of antipsychotic treatment. Inpatients with sleep disturbances, use of non-

benzodiazepine hypnosedatives (zopiclone, zolpi-dem or zaleplon) can be considered.

Time should be taken over choosing the mostappropriate antipsychotic drug based on the pre-vious experience of the patient, the adverse effectprofile of the drugs and the planned transi-tion into maintenance therapy. The antipsychoticdrug chosen should be considered suitable forboth the acute and maintenance phase withoutthe need for a switch in treatment. It should berecognized firstly that every medication switch

prolongs the inpatient stay and, secondly, that itis by no means guaranteed that antipsychotics

ill b bl t i t i t t l d

Management of Acute Psychosis 195


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Table I. Specific features and issues associated with particular groups of patients with acute psychosis

Parameter Typical relapse Highly agitated First episode High suicide risk Dr

Proportion (%) 50 1015


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prevent relapse. Many patients have had previousunsatisfactory experiences with antipsychoticsthat produce extrapyramidal adverse effects, suchas dystonia, and will be unwilling to take thesame medication again. Use of an atypical anti-psychotic should be proposed to such patientswith the reassurance that these drugs producefewer extrapyramidal symptoms than typicalagents. However, it should be borne in mind thatthe risk of extrapyramidal symptoms is not zeroand will vary between atypical antipsychotics,and that it is higher with high doses of risperidone

(>

6 mg).[16,17]

It is also important to take intoaccount other adverse effects that will influencethe acceptability of treatment, such as weightgain, sexual dysfunction, metabolic problems andsymptomatic hyperprolactinaemia. Again, thepropensity of individual atypical antipsychoticsto produce such adverse effects varies. A suc-cessful experience with an atypical antipsychoticat this stage will help cement trust betweenthe patient and the physician and thus increasethe chances of establishing an effective ther-

apeutic alliance. If the patient has respondedsuccessfully to a specific antipsychotic during aprevious relapse, and found the treatment ac-ceptable, this drug should be considered for thecurrent episode.

A detailed medical history should be taken, anECG performed and a serum sample taken forhaematological and biochemical measurements,notably of blood glucose, transaminases and li-pids. Some atypical antipsychotics, notably clo-zapine, olanzapine and zotepine, also carry the

risk of hyperglycaemia and development of dia-betes mellitus.[18] In patients with metabolic riskfactors, an antipsychotic with a low propensityfor inducing weight gain, dyslipidaemia or dys-glycaemia should be preferred, such as amisul-pride, aripiprazole or ziprasidone,[19] since thesecan be continued safely into the maintenancephase. If drugs with a high metabolic impact areused in the short term, it may be necessary toswitch to another drug for the maintenancephase, with an associated risk of loss of symptom

control or of treatment adherence. Ziprasidoneand sertindole are contraindicated in patients

ith di h th di d [20 22] U f

sedative antipsychotic such as olanzapine orquetiapine may be useful in the early stages oftreatment, but sedation is not always desirablelater on in treatment.[23] The incidence, intensityor troublesomeness of somnolence producedby these medications typically declines overtime,[24,25] although it should be recognized thatsome patients may need a medication switchduring the maintenance phase because of seda-tion. In most cases, it should be possible to con-trol agitation and anxiety sufficiently with abenzodiazepine without the need for a sedative

antipsychotic. However, the risk of developingdependency on benzodiazepines if treatment isprolonged should be taken into account whenchoosing between this strategy and the use of asedative antipsychotic. In all cases, benzodiaze-pines should be given for the minimum periodnecessary. A comparison between the differentatypical antipsychotics is presented in table II.

Once the most suitable antipsychotic has beenidentified, treatment should be started using themost effective dose from the outset. For certain

atypical antipsychotics, such as risperidone[26]

and quetiapine,[27] incremental dose titration isrecommended, and this may not be appropriatewhen rapid symptom control is required. Datafrom positron emission tomography studies havedemonstrated that treatment regimens that re-quire incremental dose titration do not achievefull occupation of central dopamine receptorsduring the first days of treatment.[28] Since there isa critical threshold of dopamine receptor occu-pancy for achieving the desired antipsychotic ef-

fect,[29,30] maximal antipsychotic effect may thusbe delayed when using treatments that requiregradual dose titration. In such cases, atypicalantipsychotics that can be used from the firstday at their recommended maintenance dose,such as amisulpride or aripiprazole, may thus bepreferred. If treatment compliance is an issue,solutions or rapidly dissolving forms are availablefor certain antipsychotics. In general, oral admin-istration of antipsychotics is recommended overparenteral administration, since it requires co-

operation by the patient in taking medication andis thus a first step towards building a therapeutic

lli [2 31]



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4.2 The First 4 Weeks

The objectives in medium-term managementare to consolidate the therapeutic alliance andensure a smooth transition to the maintenancephase with a treatment regimen that providesoptimal symptom control and quality of life withminimal risk of adverse effects. Patients and fam-ilies need to be fully informed about the po-tential adverse effects of antipsychotic drugtreatment and provided with advice about howthese can be avoided or handled. Possible psy-chosocial interventions and social rehabilitation

during the maintenance phase can be consideredand discussed with the patient and family, andthe necessary arrangements made for outpatientfacilities or social services.

Adverse effects, particularly extrapyramidalsymptoms, are a major determinant of long-time treatment adherence and thus of the risk ofrelapse.[32] A number of long-term studies haveprovided evidence that atypical antipsychoticsprovide superior relapse control to haloper-idol.[33,34] For example, Csernansky et al.[35] repor-

ted a nearly 2-fold higher risk of relapse inpatients with schizophrenia treated with haloper-id l d ith th i i i id

Qualitatively similar findings were reported in asubsequent study in patients with first-episode

disease.[36]

However, the CATIE (Clinical Anti-psychotic Trials of Intervention Effectiveness)trial,[37] performed in naturalistic care conditions,did not provide any evidence for better treatmentretention in patients receiving a first-generationantipsychotic (perphenazine) rather than an aty-pical antipsychotic. In any case, treatment ac-ceptability should be monitored carefully.

Psychopathology needs to be monitored closelythroughout the 4-week period. In patients withpersistent psychotic symptoms, the appropriate-

ness of the dose and duration of treatment shouldfirst be assessed and adjusted if necessary to ensuresatisfactory treatment control. If the dose wasadequate, then it is important to evaluate theadherence of the patient to medication. In casesof non-response, blood concentrations of anti-psychotics can sometimes be monitored to de-termine whether adequate plasma concentrationsof drug are present.[38] This may be most usefulwith amisulpride, olanzapine and quetiapine, forwhich there is some evidence for a relationship

between plasma concentrations and antipsychoticeffects.[39-41] In contrast, no such relationship ex-i t f b f ti l ti h ti

Table II. Properties of atypical antipsychotics influencing choice of treatment in the initial phase. Data were taken from the relevant

European or US summaries of product characteristics

Drug Need for

titration

Drug

interaction

potential

Metabolic

impact

Sedative

effect

Other tolerability issues Short acting

IM form

Solution

form

Amisulpride No Low Low Low Elevated prolactin levels No Yes

Aripiprazole No Low Low Low Agitation Yes Yes

Clozapine Yes High High High Agranulocytosis, prolonged QTc

interval, orthostatic hypotension,

weight gain

No No

Olanzapine In at-risk

patients

High High High Weight gain Yes Yes

Quetiapine Yes Moderate Moderate High Weight gain No No

Risperidone Yes Moderate Moderate Low Elevated prolactin levels, weight gain No Yes

Sertindole Yes Lowa Low Low Prolonged QTc interval No Yes

Ziprasidone In at-risk

patients

Low Low Low Prolonged QTc interval Yes No

Zotepine Yes High High Moderate Orthostatic hypotension, weight gain No Yes

a A specific issue is aggravation of cardiovascular risk (QT prolongation) when sertindole is used in combination with drugs that inhibit

its metabolism.

IM = intramuscular; QTc= corrected QT.

198 Thomas et al.


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and in the case of risperidone the relationship isparadoxical.[42,43] Monitoring may be helpful foridentifying ultrarapid metabolizers and detectingpotential drug-drug interactions leading to induc-tion of hepatic enzymes. In cases of emergence ofother psychiatric symptoms, for example, depres-sion, these should be treated. Certain atypical anti-psychotics have been demonstrated to be effectiveagainst depressive symptoms in schizophrenia,including amisulpride,[44,45] aripiprazole[46] olan-zapine,[47] quetiapine[48] and risperidone.[49] Duringthis period, benzodiazepines should be discon-

tinued, or the dose reduced as much as possibleif discontinuation is not possible without re-emergence of agitation. Any hypnosedative medi-cation should also be stopped.

As well as control over psychotic symptoms, itis important to ensure that the treatment is welltolerated. An ECG should be performed. Weight,body mass index and waist circumference shouldbe monitored and blood samples taken forhaematology and measurement of transaminases,blood lipids and glycaemia. If significant anom-

alies are detected, the patient should be switchedto another antipsychotic drug.

5. Highly Agitated Patients

Around 1015% of patients are admitted in ahighly agitated state or with significant psychoticanxiety and are considered to be at risk of harmto self or others.[50-56] These patients requirehospitalization, in a closed ward if necessary. In

such patients, it is important to assess the natureof the agitation. In particular, physicians shouldconsider delirium as a potential differentialdiagnosis in psychotic patients who are agitated.If agitation appears to be primarily delusional,it should be recognized that it may be secondaryto psychotic symptoms and unlikely to resolvebefore these symptoms are successfully treated.Undirected agitation may indicate a deliriumresulting from drug intoxication or withdrawal,brain damage or other co-morbid medical con-

ditions. This needs to be assessed, identified andpromptly managed, if necessary, once the state ofth ti t it


In highly agitated patients, cooperation of thepatient in the treatment plan is not feasible andrapid control of agitation is the immediate treat-ment goal. This is important both for the psy-chiatric well-being of the patient and to preventharm to the patient or others. Since these patientsare unlikely to be cooperative, physicians shouldmake every effort to obtain as much collateralinformation as possible on the patients historyand clinical state from the family or hospital re-

cords. An antipsychotic should be chosen andadministered by a route and at a dose to ensurerapid symptom relief and safety. The physicianwill generally not have the time or the informa-tion to make an informed choice on the mostsuitable antipsychotic for a given patient and willhave to make a decision based on the overall ef-ficacy and safety of the drug, as well as on thepsychopathological profile of the patient. Anantipsychotic with sedative properties such asolanzapine or quetiapine may often be suitable in

such patients. Although oral treatment is thepreferred route of administration, as it requiressome degree of patient adherence and is lesscoercive, in many cases this may be rejected bythe patient. In such cases, intramuscular admin-istration should be considered. Intramuscularinjectable forms are available for several con-ventional antipsychotics and for the atypicalantipsychotics olanzapine, ziprasidone and ari-piprazole. These formulations offer the ad-vantages of guaranteeing effective control over

psychotic symptoms, thus calming and reassuringthe patient and, from the physicians perspective,facilitating overall management of the patient.On the other hand, injectable formulations pre-sent certain disadvantages. For example, use ofintramuscular olanzapine[57] has been associatedwith transient hypotension and bradycardia. Useof intramuscular forms of certain conventionalantipsychotics is associated with significant neu-rological adverse effects, which may make thepatient distrustful of treatment in general and

thus compromise adherence during the sub-sequent consolidation and maintenance phases ofth t t t t t [58]



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Benzodiazepines, in particular lorazepam, canalso be administered orally or intramuscularly.Higher doses may be required compared with thestandard care paradigm (table III). In patients

who are particularly aggressive or violent, asedative antipsychotic such as pipamperone orcyamemazine, or intramuscular olanzapine orzuclopenthixol, may be preferred.


A therapeutic alliance can only be establishedonce the patient is no longer agitated and is re-ceptive and cooperative. Establishing the ther-apeutic alliance is the major goal for this period,

with the same objectives as in the standardtreatment paradigm. Selection of the most ap-propriate antipsychotic for use in the main-tenance phase needs to be made on the basis ofsafety and previous patient experience. Thetreatment chosen should be tailored to the needsof the individual patient with respect to thespecific efficacy and tolerability profiles of indi-vidual atypical antipsychotics, their potentiallybeneficial effects on negative, cognitive and af-fective symptoms, and their potential for adverse

effects such as hyperprolactinaemia, weight gain,metabolic problems or sexual dysfunction. Thismay well involve a change in medication fromthat used at admission; the new treatment alsoneeds to be initiated, its tolerability assessed andthe dose adjusted adequately before the patient isdischarged. In patients with antecedents of poorcompliance to maintenance therapy or whoare at risk of being violent, use of a depot anti-psychotic preparation may be considered. Theonly atypical antipsychotic available in a depot

preparation currently is risperidone, althoughsuch formulations are available for several

l i l ti h ti I ti t i h

aggressiveness is poorly controlled by the initialantipsychotic treatment, adjunctive treatmentwith mood stabilizers such as valproate may beconsidered.[59]

6. First-Episode Psychosis

Patients presenting with their first psychoticepisode need to be investigated with particularcare so that the most appropriate long-termtreatment that will have the greatest success inpreventing future relapses can be instigated. Withappropriate initial treatment, a minority ofpatients may never have another episode of acutepsychosis, although most (>80%) will have arelapsing course.[60]


A comprehensive diagnostic work-up shouldevaluate somatic and psychiatric co-morbidity,as well as antecedents of drug abuse. The differ-ential diagnoses of secondary psychosis, drug-induced psychosis, delusional disorders anddepression with psychotic symptoms, or psycho-tic mania need to be carefully ruled out.

Wherever possible, an atypical antipsychoticshould be used. Conventional antipsychoticsshould be avoided because their adverse effects,especially extrapyramidal symptoms, are an im-portant determinant of long-term adherence totreatment.[61] For example, Schooler et al.[36] re-ported that the rate of relapse was significantlylower and the time to first relapse significantlylonger in first-episode patients treated with ris-peridone compared with those treated withhaloperidol. There is also some evidence from

randomized comparative studies that atypicalantipsychotics may have beneficial effects on

iti t i fi t i d ti t

Table III. Recommended dose ranges for benzodiazepines for the treatment of agitation in patients with schizophrenia. Data were taken from

the relevant European or US summaries of product characteristics (SPC)

Drug Standard treatment (mg) Highly agitated patients (mg) Elderly patients (mg)

Alprazolam 4 Not indicated in SPC Initially 0.125, may be increased gradually

Diazepam 1520 2040 Not indicated in SPC

Lorazepam 26 Not indicated in SPC 0.53

200 Thomas et al.


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and that these effects are superior to those ob-served with first-generation antipsychotics.[62-67]

There is now a sufficiently large range of atypicalantipsychotics available to mean it should bepossible to find an effective treatment for all pa-tients. Several meta-analyses of randomizedclinical trials have concluded that the overallantipsychotic efficacy of these drugs is broadlysimilar.[68-72] Several studies comparing first-generation with atypical antipsychotics havefailed to demonstrate relevant efficacy differencesbetween medications, but have confirmed the

high susceptibility of first-episode patients to ad-verse effects with first-generation drugs.[62,73-77]

The CAFE (Comparison of Atypicals for First-Episode Psychosis) study directly comparedolanzapine, quetiapine and risperidone in first-episode patients and found all drugs to be essen-tially similar in terms of long-term (1-year)adherence, control of psychotic symptoms,response rates and tolerability, although weightgain and other metabolic disturbances weregreatest for olanzapine and least for risper-

idone.[78]

The EUFEST (European First EpisodeSchizophrenia Trial) observational study, whichcompared the effectiveness and tolerability offour atypical antipsychotics (amisulpride, que-tiapine, risperidone and ziprasidone) in first-episode schizophrenia, has recently beenreported.[79] This study found that all atypicalantipsychotics evaluated in this study were asso-ciated with significantly lower rates of any-causediscontinuation (between 33% for olanzapineand 53% for quetiapine) than haloperidol (72%).

However, the extent of symptom control in pa-tients remaining on treatment was comparablefor all antipsychotic drugs tested.

Nevertheless, it should be recognized thatindividual patients may respond better to oneatypical antipsychotic than another, although thedeterminants of individual patient responsesremain poorly characterized. Patients presentingwith their first psychotic episode appear to bemore sensitive both to the antipsychotic effects oftreatment and also to its adverse effects.[80] For

this reason, a lower initial dose of antipsychoticthan that used in psychotic relapse is generally

ff ti i fi t i d h i (t bl IV)

although results from the CAFE study indicatethat quetiapine may be an exception to this gen-eral rule.[78] Clozapine has a limited role in first-episode schizophrenia because its potentiallyserious haematological adverse effects restrict itsuse to treatment-resistant schizophrenia or to pa-tients in whom the risk of suicide is high. Sertin-dole is also not indicated as first-line treatmentfor first-episode patients because of its cardiacadverse effects (prolongation of the corrected QTinterval).[22]

The antipsychotic medication initiated at the

first episode should be considered as a potentiallylifelong treatment for individuals who are gen-erally very young adults. For this reason, long-term safety issues are important to consider,particularly the metabolic adverse effects asso-ciated with certain atypical antipsychotics andthe risk of early development of diabetes. Atypi-cal antipsychotics also differ widely in cost, andthis may be an issue in certain countries.

Communication with the patient and family orentourage, and provision of appropriate in-

formation and education need to be initiatedas soon as possible. This episode is likely to bethe familys first close experience with schizo-phrenia, and family members need to under-stand the implications of the diagnosis as wellas being reassured as to the possibility of suc-cessful treatment. A clear awareness by familymembers of the issues and their involvement inthe treatment plan will help reduce subsequentstigmatization when the patient returns to thecommunity.


During this period, treatment needs to be op-timized and a long-term care plan elaborated. Asindicated above, individual patients may respondmore or less well to individual drugs. In cases ofsuboptimal response to the drug initially used oremergence of troublesome adverse effects, timeneeds to be taken to change the treatment ifnecessary until a drug and dose are identified that

provide effective symptom control and accept-able tolerability. It is essential to ensure that pa-ti t d f il d t d th i t f



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treatment adherence, that potential issues relatedto adherence are investigated and that familiesare prepared for dealing with relapses. Monitor-ing for potential treatment adverse effects needsto be initiated. As some atypical antipsychoticscarry a high risk of metabolic adverse effects,monitoring and management guidelines havebeen developed, for example by the AmericanDiabetes Association[18] and Wetterling,[82] to

reduce the risk of developing diabetes. In addi-tion, patients should be informed about lifestylemeasures that may help prevent the emergence ofmetabolic adverse effects.

As well as medication, the long-term careplan needs to take into consideration psychoso-cial interventions that will help the patient copewith psychotic symptoms, measures to main-tain or improve social integration, and accessto self-help groups to avoid stigmatization. It isalso important to discuss lifestyle issues with

patients and their families, emphasizing the ben-efits of exercise, a healthy diet and good sleeph giene

7. Patients at High Risk of Suicide

Patients with schizophrenia have a muchhigher rate of suicide than individuals in thegeneral community, with psychosis being a majorcause of suicide in young adults. In a recent meta-analysis, the lifetime risk of suicide followingonset of schizophrenia was estimated as 5.6%.[83]

In patients with antecedents of suicide attempts

or strong suicidal ideation, physicians should beparticularly vigilant as to the risk of suicide orself-harm during the acute psychotic phase.These patients should always be hospitalized,either in a closed ward or in an open ward ifround-the-clock observation is possible.

In addition, several factors have been identi-fied that are associated with a high suicide risk inpatients with schizophrenia. These include co-morbid or previous depression, aggressiveness oragitation, substance abuse, fear of mental dis-

integration, previous suicide attempts, social iso-lation, recent bereavement and poor adherence totreatment [84-87] In patients presenting ith s ch

Table IV. Recommended dose ranges for atypical antipsychotics for initial treatment of acute psychotic episodes in patients with schizo-

phrenia. Data were taken from the relevant European or US summaries of product characteristics (SPC), except for the first-episode data

which were obtained from relevant clinical trials

Drug Standard treatment (mg) First episode psychosis (mg) Elderly patients (mg)

Amisulpride 800 600800a 200400

Aripiprazole 1015 15[81] No dose adjustment required

Clozapine Initial ly 25, adjusted to

300450

NA Caution

Olanzapine Initial: 510

Target dose: 10

510[81] Initial: 5

Quetiapine Initial: 50

Target dose: 300400

Efficacy dose: 150750

From 50 at day 1 to 400 at day 5 [81] Lower doses

Risperidone Initial: 2

Target dose: 6

Efficacy dose: 48

24[81] Initial: 1

Sertindole Initial: 4

Target dose: 1220

NA No data, slower titration suggested

Ziprasidone Initial: 40

Adjust to a maximum of 160

Efficacy dose: 20100

40[81] Lower dose, slower titration

Zotepine Initial: 75

Target dose: 75300

Median of 250[81] 50150

a Product SPC.

NA=not applicable, as only recommended as second-line therapy.

202 Thomas et al.


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features, suicide risk and suicidal ideation shouldbe carefully evaluated, and the patients mon-itored closely.[86]


While psychotic symptoms are still manifest, itis useful to try and evaluate the contribution ofhallucinations to suicidal ideation. If this is sig-nificant, then it would be useful to consider be-havioural or psychosocial interventions duringthe maintenance treatment phase that would helpthe patient cope better with hallucinations during

future relapses. Personal and familial antecedentsof suicidality should be investigated and takeninto account when assessing suicide risk andplanning follow-up in the community. Carefuldiagnostic evaluation may reveal the presence ofbipolar disorder, which should be treated withmood stabilizers. During the first few days fol-lowing admission, these patients should be keptunder close observation at all times.

With respect to the choice of antipsychotictreatment, clozapine has been shown to reducesuicidal ideation and suicide attempts in severalstudies[88] and is superior to some other atypicalantipsychotics in this respect.[89] However, thebenefits of clozapine in terms of suicide risk needto be carefully balanced against the risk ofpotentially serious haematological or cardio-vascular adverse effects. Otherwise, use of anantipsychotic with strong acute sedative effects,such as high dose olanzapine or quetiapine, orshort-term combination with a low-potencysedative antipsychotic, could be considered.


The responsiveness of affective symptoms andsuicidal ideation to antipsychotic treatmentshould be carefully monitored. Suicidal ideationmay be driven either by depressive symptoms orby psychotic symptoms. Distress in reaction tohallucinations and delusions is a key factor asso-ciated with suicidal ideation in individuals withpsychotic relapse.[90] In susceptible individuals,

suicidal behaviour may also occur in response toauditory hallucinations instructing the patienth t t [85 91 92] If d i t

predominate or persist, adjunctive therapy withantidepressant drugs may be useful. An anti-depressant with a low potential for clinically re-levant drug interactions with antipsychotics andbenzodiazepines and with an optimal adverseeffect profile should be chosen; in particular,selective serotonin reuptake inhibitors shouldbe considered in preference to tricyclic anti-depressants. A switch to an antipsychotic witheffects on depressive symptoms, such as amisul-pride or olanzapine, may also be considered.It should be recognized that the risk of suicide

is high not only during the acute episode andhospitalization but also during the first weeksfollowing discharge. This necessitates carefulevaluation of patients before they are dischargedinto the community. If suicidal ideation persists,a switch to clozapine could be made. Psychoso-cial interventions following discharge from hos-pital may be considered in order to reduce thesuicide risk over the long term.[86]

8. Patients Presenting with Drug

Intoxication and Withdrawal

Use of alcohol, tobacco and illicit drugs is highin patients with schizophrenia, as is the degree ofco-morbid drug and alcohol dependence.[93-95]

Patients experiencing an acute psychotic epi-sode may well be consuming large quantitiesof psychoactive drugs, and drug intoxication orwithdrawal is a common primary cause ofpresentation of acutely psychotic patients topsychiatric services. These patients present spe-

cific challenges, as they are more likely to respondless well to antipsychotic medication,[96] to re-quire longer hospitalization,[97] to present anelevated suicide risk[87] and to be poorly adherentto treatment.[98] Such patients are best managedon an inpatient basis.


At presentation, symptoms of drug intoxica-tion or withdrawal are likely to be confounded by

psychotic symptoms, and the two need to becarefully distinguished and treated appropriately.Th t ti h i t ll



12/22

substance use has stopped and wait for the drug-related symptoms to disappear whilst controllingpsychotic agitation with a benzodiazepine. Benzo-diazepines will also be beneficial in attenuatingsymptoms of withdrawal from alcohol or otherdrugs. Blood pressure and heart rate should bemonitored regularly because these may becomelabile during withdrawal from psychostimulantsor alcohol. Any form of agitation is consideredto be a risk factor for neuroleptic malignantsyndrome.[99] In particular, this is a risk to beconsidered with all antipsychotics in patients

experiencing drug withdrawal,[100]

and anti-psychotic treatment is best initiated once with-drawal symptoms have abated.

When antipsychotic treatment is initiated, thedrug chosen should have a low risk of interactionwith drugs of abuse or alcohol. From a pharma-codynamic point of view, this means choosing adrug with a selective pharmacological profile thathas a restricted range of neurotransmitter andreceptor interactions, such as amisulpride orziprasidone. From a pharmacokinetic point of

view, drugs that are extensively metabolized bythe hepatic cytochrome P450 system, such asolanzapine, or drugs that induce or inhibit theseenzymes, such as clozapine, should be avoidedwherever possible.


Before the patient returns to the community,both the patient and his/her entourage need tobe educated on the risks associated with drug

dependence. A drug rehabilitation programmeshould be initiated and effective treatment ofboth addiction and schizophrenia integrated intothe long-term treatment plan.[101] The family orentourage should be encouraged to be vigilantwith respect to adherence to this plan once thepatient leaves hospital. Treatment should involveantipsychotic maintenance therapy, pharmaco-therapy for the substance abuse if available andappropriate, and motivational interviewing or psy-chosocial interventions such as cognitive-beha-

vioural therapy.[101] Some atypical antipsychoticsmay have a positive influence on substance use as

ll h ti t [102] Alth h

prospective, randomized, controlled studies havebeen performed, some evidence has been ob-tained of a reduction in substance use in patientswith a dual diagnosis of schizophrenia and sub-stance abuse treated with quetiapine,[103] risper-idone,[104] ziprasidone,[104] amisulpride[105] and,in particular, clozapine.[106-113]

9. Elderly Patients

Although the frequency and intensity of acutepsychotic episodes declines with age, the physi-

cian is nevertheless confronted with elderly pa-tients presenting with acute psychosis in anemergency psychiatric setting. In this context, it iscritical to distinguish accurately between schizo-phrenia in the elderly and dementia with psy-chosis. This has important consequences for theprescription of antipsychotic medication in thesepatients, as the risk-benefit ratio for these drugsmay not be favourable in patients with dementia.In the CATIE-Alzheimers Disease (CATIE-AD)study comparing three atypical antipsychotics ver-

sus placebo in patients with Alzheimers disease,no better effectiveness for these drugs comparedwith placebo was demonstrated.[114] In addition,an increase in mortality due to cerebrovasculardisease in elderly patients with dementia-relatedpsychosis treated with antipsychotics has beenreported, leading to the US FDA mandatingan explicit warning about this risk in the pre-scribing information.[115] This warning was issuedfollowing an analysis of the results of 17 placebo-controlled trials conducted with aripiprazole,

olanzapine, quetiapine or risperidone in elderlydemented patients with behavioural disorders.These studies demonstrated a 1.6- to 1.7-fold in-crease in mortality compared with patients receiv-ing placebo, mostly due to cardiovascular eventsor infections. At present, such risks have not beenidentified in patients with schizophrenia, but itshould be noted that the large majority of ran-domized clinical trials in schizophrenia havespecifically excluded older patients.

In addition, elderly patients with schizo-

phrenia present particular issues for management,especially with respect to safety. Co-morbidity isf t i thi d di l

204 Thomas et al.


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and gastrointestinal function may be particularlyimpaired in elderly patients with schizophreniaas a result of many decades of intensive alcoholand tobacco use. In addition, elderly patientsare likely to be taking other medications, in-creasing the potential for drug interactions withthe antipsychotic prescribed.

Many elderly patients are likely to have beentreated with conventional antipsychotics for dec-ades, and the treating physician may be reluctantto change a treatment with which the patient hasgrown familiar. Nonetheless, these patients show

an increased sensitivity to the extrapyramidal effectsof these drugs,[116,117] especially tardive dyskinesia,and may thus benefit from a switch to an atypicalantipsychotic with fewer or less severe extra-pyramidal adverse effects. The atypical anti-psychotic for which there is most experience inthe elderly is risperidone, which has been shownto be a useful treatment option for switching fromconventional antipsychotics in this patient group.[118]

Randomized risperidone-controlled studies per-formed in the elderly have also demonstrated

comparable efficacy to risperidone in this patientgroup for both amisulpride[119] and olanza-pine.[120] There is also more limited evidence forthe utility of quetiapine in elderly patients.[121]

Although treatment adherence might be expectedto be higher with atypical antipsychotics becauseof their superior neurological adverse effect pro-files, adherence may be compromised by distrustarising from the switching of a long-standingtreatment or as a result of cognitive impairment.The physician needs to weigh up these factors for

each individual patient before deciding to switch.In addition, many elderly patients may presentco-morbidities that may be aggravated by theadverse effects of individual antipsychotic drugs,such as congestive heart failure, cardiac rhythmdisorders or diabetes, and these need to be takeninto account carefully in the treatment choice.[122]

Whatever the choice of antipsychotic rescuemedication, the dose should be lower than inyoung adults because of the increased risk of ex-trapyramidal adverse effects with conventional

agents and the cardiovascular adverse effects ofall drugs (table IV). In addition, the volume ofdi t ib ti f li hili d i i d

and their rate of elimination decreased as a resultof age-related changes in hepatic and renal func-tion, and in body fat and fluid distribution. Thesepharmacokinetic changes also render necessarythe use of a lower dose. In elderly patients withimpaired hepatic function, a drug eliminated prin-cipally by the kidney, such as amisulpride or ris-peridone, should be used in preference to a drugprincipally eliminated by hepatic metabolism,such as olanzapine. Amisulpride is of particularinterest in the elderly since it is not metabolized toany great extent[123] and thus can be used safely in

patients with impaired hepatic function and thosetaking other medications that induce or inhibitdrug-metabolizing enzymes. In addition, amisul-pride does not interfere with the metabolism ofother drugs.[124] In patients with impaired renalfunction, on the other hand, olanzapine is moresuitable than amisulpride or risperidone.

Antipsychotic drugs with prominent anti-muscarinic properties, such as clozapine andolanzapine, should be used with caution in pa-tients with prostate disease or glaucoma, as these

conditions can be aggravated by anticholinergicdrugs. In addition, antipsychotics with strongsedative properties may increase the risk of fallsand mental confusion, and the doses of suchdrugs should be minimized.[23] Similarly, drugsthat may cause orthostatic hypotension should beused sparingly. As discussed above, treatmentwith atypical antipsychotics is associated with anincreased risk of stroke in elderly patients withdementia, although such an association has notbeen identified to date in elderly patients with

schizophrenia. A hypothetical risk cannot, how-ever, be excluded and patients with other riskfactors for stroke should be treated with caution;in particular, hypertension should be controlledand blood pressure monitored regularly in elderlypatients receiving antipsychotic medication.

Practice guidelines for the treatment ofschizophrenia in the elderly published by theAmerican Psychiatric Association recommendthe use of an atypical antipsychotic administeredat a dose one-half or lower than that used in

younger patients.[1] Similar recommendationshave since been put forward by the World Fed-

ti f S i ti f Bi l i l P hi t [8]



14/22

Benzodiazepines must also be used with cau-tion in the elderly, as sensitivity to these drugsincreases with age. The sedative effects of ben-zodiazepines increase the risk of falls,[125] andthus the risk of fracture, particularly in subjectswith osteoporosis. These sedative effects, as wellas effects of benzodiazepines on memory, maycause confusion if the drugs are used at too high adose. This will also compromise the task ofgaining the patients confidence and adherence toa treatment plan. It is important that the patientremains a lucid partner in the therapeutic alli-

ance. Finally, high doses of benzodiazepinescan cause paradoxical disinhibition, which mayaggravate, rather than relieve, anxiety and agita-tion. The dose of benzodiazepines should there-fore be reduced in elderly patients compared withthat proposed for younger patients (table III).

10. Special Issues Related to Gender

There are a number of gender-specific issuesrelating to the choice of antipsychotic for the

maintenance phase. Since the choice of main-tenance antipsychotic treatment is made early,and influences the choice of treatment in theinitial treatment phase, these issues should beborne in mind during the initial treatment phase.

These issues relate to adverse effects of anti-psychotics that may have different repercussionsin men and in women. For example, the signif-icant weight gain associated with some atypicalantipsychotics may have a higher impact on self-image and thus on quality of life in women than

in men. In men, certain antipsychotics have de-leterious effects on sexual function,[126] witharound half of men treated with antipsychoticsreporting sexual adverse effects.[127,128] These areconsidered among the most distressing adverseeffects of antipsychotics,[129] interfere stronglywith quality of life,[127] and are an importantreason for non-adherence to maintenance anti-psychotic treatment.[128-136] Several atypicalantipsychotics can cause elevations of serumprolactin level, notably risperidone and amisulpride,

although this is generally asymptomatic.[137,138]

Comparative randomized trials have indicatedth t th i k f h l ti i i hi h

with risperidone than with amisulpride.[139] In-creases in prolactin levels are generally reversibleafter drug discontinuation. Hyperprolactinaemiacan sometimes lead to clinical manifestationsthat are distressing to the patient.[140] Elevatedprolactin levels can cause dysmenorrhoea, ame-norrhoea or anovulation as well as tender breastsin women. In addition, hyperprolactinaemiais a well characterized risk factor for osteopo-rosis[140-144] and some, but not all, studies suggestthat hyperprolactinaemia may also be asso-ciated with a higher risk of breast cancer.[145-148]

In men, rare cases of galactorrhoea have beendescribed in patients taking these drugs, althoughmale hyperprolactinaemia is associated withgynaecomastia, decreased libido, erectile dys-function and reduced sperm count.[149]

The second-generation antipsychotic drugsare contraindicated in pregnancy. However,discontinuation of antipsychotic drugs for a9-month period during pregnancy carries an ele-vated risk of psychotic relapse. Experience hasaccrued over the years on the use of anti-

psychotics during pregnancy and the associatedrisks. If women are to take antipsychotic medi-cation during pregnancy, caution would adviseselection of a drug for which there is more ex-perience compared with recently introduced treat-ments. The metabolism of oral contraceptivesmay be influenced by antipsychotic drugs thatinhibit or induce hepatic cytochrome P450 drug-metabolizing enzymes, with a potential loss ofcontraceptive control. It should be noted that thishas not been observed clinically, but remains a

hypothetical possibility. It is also inappropriatefor women taking highly sedative antipsychoticdrugs, or drugs with marked extrapyramidal ad-verse effects, to breast feed. Most antipsychoticsare highly lipophilic and pass readily into breastmilk, and insufficient information is currentlyavailable about the safety of antipsychotic drugsand their impact on child development.

11. Conclusion

The initial management of patients presentingith t h i d t b d t d t th

206 Thomas et al.


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individual characteristics and needs of each pa-tient. The core treatment consists of administra-tion of benzodiazepines to control agitation andof antipsychotics to control psychotic symptoms.Oral medication is preferable to injectable formswherever possible, and atypical antipsychoticsare to be preferred over conventional agents. Theantipsychotic chosen during the initial periodis likely to have to be continued for many years,and the long-term safety profile of the drugshould be taken into account when making thischoice, particularly in relation to extrapyramidal

adverse effects, metabolic complications andquality of life. In addition to drug treatment, theinitial management of psychosis should aim tobuild a therapeutic alliance with the patient andto elaborate a long-term treatment plan in con-cert with the patient and family. The long-termgoal should be to minimize the risk of psychoticrelapse through adequate treatment adherence.The importance of tailored psychosocial inter-ventions in maintaining social integration and inreinforcing treatment adherence should not be

neglected.

Acknowledgements

No sources of funding were used to assist in the prepara-tion of this review. Dr Thomas has received honoraria andeducational/research grants from Lilly, Janssen-Cilag, Bristol-Myers Squibb and sanofi-aventis. Dr Alptekin has acted as aconsultant to Lundbeck, Janssen, Pfizer, Lilly, Sanovel,sanofi-aventis, Eczacibasi-Zentiva, EGIS and Bristol-MyersSquibb, and has received educational/research grants fromLundbeck, Pfizer and Wyeth. Dr Gheorghe has received hon-oraria from sanofi-aventis. Dr Olivares has acted as a consul-tant to and/or received honoraria from Janssen-Cilag, Lilly,AstraZeneca, sanofi-aventis, Lundbeck, Bristol-Myers Squibband GlaxoSmithKline. Dr Riedel has acted as a consultant toand received honoraria from Otsuka Pharmaceuticals, Astra-Zeneca, Pfizer and Janssen-Cilag; has received honorariafrom Lilly, Sanofi-Synthelabo and GlaxoSmithKline; and hasreceived educational/research grants from Otsuka Pharma-ceuticals, Bristol-Myers Squibb, AstraZeneca, Pfizer, Lillyand Sanofi-Synthelabo. Dr Mauri has no conflicts of interestthat are directly relevant to the content of this review.

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Correspondence: Prof. Pierre Thomas, Pole de Psychiatrie,Hopital M. Fontan, CHRU de Lille, Rue Veraeghe, 59037Lille, Cedex, France.E-mail: [email protected]

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