cpa guidelines- schizophrenia

8/11/2019 CPA Guidelines- Schizophrenia

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T HE CAN ADIAN JOUR N AL OF

L A R EV UE C AN A D IE N N E D EPSYCHIATRY PSYCHIATRIE

November 2005 novembreVol 50, No 13, Supplement 1

CLINICAL PRACTICE GUITreatment of Schizophrenia


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Can J Psychiatry, Vol 50, Suppl 1, November 2005 1S

The Canadian Journal of Psychiatry

La Revue canadienne de psychiatrie

The Official Journal of the Canadian Psychiatric AssociationLa Revue officielle de lAssociation des psychiatres du Canada

Editor-in-Chief Joel Paris

Deputy EditorRoger Bland

Associate EditorsDavid GoldbloomPaul Grof (Book Review Section) Alain Lesage (French Submissions)David Streiner (Statistical Consultant)

Editorial BoardDonald AddingtonJulio Arboleda-FlrezChawki BenkelfatMichael BondGary Chaimowitz

Murray W EnnsLaurence Katz Ashok MallaMichael MyersScott PattenGilbert PinardBruce Pollock Arun RavindranRob van ReekumRonald A RemickMarc-Andr RoyDerryck H SmithPhil TibboBlake Woodside Ari Zartsky

Former Editors-in-Chief Quentin Rae-Grant, 19952004Edward Kingstone, 19771995Frederick H Lowy, 19721977F Rhodes Chalke, 1955 1971

Managing EditorVirginia St-Denis

Editorial CoordinatorCaroline Kay

Senior Copy EditorMelinda Hodgins

Copy EditorEryn Kirkwood

Advertising and Production ManagerSmita Hamzeh

Desktop PublisherLeah Chambers

Chief Executive Officer, CPA Alex Saunders

November 2005 (Vol 50, Supplement 1)

CLINICAL PRACTICE GUIDELINETreatment of Schizophrenia

Canadian Psychiatric AssociationWorking Group Members:

Donald Addington (Chair), MB, BS, MRCPsy, FRCPC Roch-Hugo Bouchard, MD

Joel Goldberg, PhD, CPsych Bill Honer, MD, FRCPC

Ashok Malla, MB, BS, DPM, MRCPsy, FRCPC Ross Norman, PhD, CPsych

Raymond Tempier, MD, MSc, FRCPC Sandy Berzins (Coordinator, Editor, and Science Writer), MSc

--------------------------These guidelines will be available in French.

Ces lignes directrices seront disponibles en franais.


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2SCan J Psychiatry, Vol 50, Suppl 1, November 2005

Please direct feedback, correspondence, and requests for reprints to thefollowing: Canadian Psychiatric Association 141 Laurier Avenue

West, Suite 701, Ottawa, ON K1P 5J3 Tel: 613-234-2815Fax: 613-234-9857 e-mail: [email protected]

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Disclaimer: These guidelines are not intended to be interpreted or to beused as a standard of medical practice. The recommendations may notrepresent the only correct approach to every clinical situation and may be subject to change as scientific knowledge and technology advance.Clinicians must determine the appropriate clinical care for eachindividual patient on the basis of all the clinical data available for theindividual case.

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Note:It is the policy of the Canadian Psychiatric Association to revieweach position paper, policy statement and clinical practice guidelineevery five years after publication or last review. Any such documentthat has been published more than five years ago and does not

explicitly state it has been reviewed and retained as an officialdocument of the CPA, either with revisions or as originally published,should be considered as a historical reference document only.


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Contents

I. INTRODUCTION 7S Rationale

8S Guideline Development Process

8S Table 1 Criteria for rating quality of published evidencein individual articles reviewed

9S Literature Search9S Screening Process

9S Table 2 Evidence level summary for rating evidence

10S Quality-Rating Process

II. ASSESSMENTS 11S General Principles

11S Acute Phase

12S Table 3 Assessments for patients with schizophrenia

13S Stabilization Phase

13S Stable Phase

14S Relapse and Adherence to Treatment

14S Table 4 Recommendation

15S Specific Clinical Situations and Assessments

15S First Episode

15S Neuropsychological Assessment

15S Genetic Assessment

16S Neuroimaging

16S Poorly Responsive or Refractory Illness

16S Comorbid Conditions

16S Physical Health Monitoring

17S Dual Diagnosis (Mental Retardation)


CLINICAL PRACTICE GUIDELINESTreatment of Schizophrenia

ISSN 0706-7437Vol 50, Supplement 1, 2005The Canadian Journal of PsychiatryLa Revue canadienne de psychiatrie


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III. PHARMACOTHERAPY 19S Medications

19S General Principles

19S Second-Generation Antipsychotics

20S Pharmacologic Strategies for Phase-Specific Treatment

20S Acute Phase

21S Table 5 Second-generation antipsychotic dosages and titrati

22S Stabilization Phase

22S Stable Phase

25S Management of Side Effects

25S Weight Gain and Abdominal Obesity

25S Impairment in Glucose Regulation and Diabetes

25S Dyslipidemia

25S QT Prolongation

25S Endocrine and Sexual Side Effects

26S Cognitive Side Effects and Sedation

26S Extrapyramidal Side Effects

26S Neuroleptic Dysphoria

26S Neuroleptic Malignant Syndrome

27S Clozapine Side Effect Profile27S Table 6 Recommendations

28S DrugDrug Interactions

IV. PSYCHOSOCIAL INTERVENTIONS 29S General Principles

29S Medication Adherence and Psychoeducation

30S Vocational Interventions

30S Skills Training

30S Cognitive-Behavioural Interventions

31S Family Interventions

32S Cognitive Remediation

32S Peer Support, Self-Help, and Recovery

33S Stigma

33S Associated Features and Special Situations

4S Can J Psychiatry, Vol 50, Suppl 1, November 2005


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33S Treatment of Comorbid Symptoms

33S Substance Use

33S Prenatal Planning

34S Psychosocial Interventions Across Illness Phases

34S Acute Phase34S Stabilization Phase

34S Stable Phase

35S Table 7 Recommendations

V. SERVICE DELIVERY 37S Service Delivery and the Treatment System

37S General Principles

37S Access

38S Availability

38S Coordination and Continuity of Care

38S Service Delivery Components

38S Early Psychosis Treatment Services

38S Acute Inpatient Care

38S Day Hospitals

39S Home-Based Acute Care

39S Mobile Crisis Service

39S Outpatient and Community Mental Health Services

39S Case Management

40S Residential Care


VI. SPECIAL ISSUES 43S The Prodromal Phase of Schizophrenia


LIST OF ABBREVIATIONS 45S

REFERENCES 47S



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I. Introduction

Clinical practice guidelines (CPGs) have been defined assystematically developed statements of recommenda-tion for patient management to assist practitioner and patientdecisions about appropriate health care for specificsituations (1).

The aim of these guidelines is to improve the assessment andtreatmentof patients with schizophrenia at allstages of theill-ness. These guidelines are written primarily for physicians;however they may be of value to other clinicians involved inthe treatment of patients (aged 16 years or over) who haveschizophrenia. Theguidelines mayalso beusefulas a guide to provider organizationsdeveloping services, to senior studentsin alliedhealth disciplines,and to those accrediting services.

The guidelines specify 4 main topics, each of which a physi-cian must consider when seeing a patient: assessment, pharmacotherapy,psychosocial interventions,and delivery of services. Within each of the first 3 topics, 3 phases of theillness are distinguished:

the acute phase, wherein signs and symptoms worsen,usually bringing the patient to medical attention

the stabilization phase, wherein the illness is subsidingafter an acute episode

the stable or chronic phase, wherein acute symptomsmay have subsided but functioning is often persistentlyimpaired

The guidelines highlight for particular attention the treatment possibilities for 2 groups of patients: 1) those in the demo-graphic majority, who have been ill for many years and mayhave a poor level of functioning and poor quality of life andwho deserve a review that takes new information into

account; and 2) first-episode patients, in whom the chanceimprove long-term outcome may be greatest. The guidelinalso address special issues such as the prodromal phase, sustance use or abuse, coexisting medical illnesses, pregnanccoexisting depression, and aging patients.

RationaleSchizophrenia is a serious but treatable mental illness wisignificant morbidity and mortality, affecting approximate

0.6% of the general population at somepoint in their lives (2Illness onset is most common in young adults, relapses acute episodes can occur throughout the lifespan, and funtioning is often significantly affected. The direct health caand nonhealth care costs in Canada were estimated to $1.12 billion in 1996 (3). Patients with schizophrenia are significantly increased risk for suicide, violence, substanuse or abuse, homelessness, unemployment, medical ilnesses, and victimization. Life expectancy for persons wischizophrenia is also significantly reduced (4).

The guidelines assert that symptoms and functioning aimproved and the risks for suicide and social dysfunctioreduced when patients with schizophrenia are given contin-ous treatment, long-term care from qualified service proviers, and access to appropriate housing and services. Netreatments and service delivery options reinforce this ther peutic optimism. Guidelines based on this new informatishould enable physiciansto helppatientsachievean improvelevelof functioning whileminimizing the potentially harmfeffects of theillnessor thetreatments.The guidelines describ practical clinical assessment and management strategies talored to the individual. Further, the guidelines emphasize t


The Canadian Journal of Psychiatry Volume 50 Ottawa, Canada, November 2005 Supplement 1


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benefits of combining physical or medical treatments with behavioural or lifestyle intervent ions. They ref lect a biopsychosocial approach that includes both types of inter-vention as important aspects of a full treatment plan. Theguidelinesfocusoninterventionsthataremostlikelytoleadtothe greatest benefit and least disruption for the individual patient and his or her caregivers. The medications mentionedinclude only those available in Canada at the time of writing.Theguidelines do notaddress forensic issuessuch as criminalresponsibility and provincial mentalhealth acts that pertain ina general way to all mental disorders.

Guideline Development ProcessThe development of these guidelines was sponsored by theCanadian Psychiatric Association (CPA). The Associationhas a Special Committee on Clinical Practice Guidelines thatoversees the development of clinical practice guidelines. TheCommittee has written guidelines for CPG development thatspecify the process and standards that must be followed. TheCommittee reviews all CPGs before they are given finalapproval by the CPA Board. The Committee establishesworking groups that produce the guidelines. The CPA raisesand administers funds for guideline development. There is nocontact between thefundersandthe working group that devel-ops the guidelines. The working group circulates the guide-lines to a wide range of stakeholders for review and comment before sending a final version to the Committee. A draft of

theseguidelines wasalso circulated to industry forreviewancomment regardingerrors of fact.Allsponsorshipisacknowedged when the guidelines are published, and any conflictsinterests of the individual working group members are indcated in the usual Canadian Journal of Psychiatry format.

For these guidelines, 2 evidence-based literature reviewwere conducted, and their results were combined. One wrelatedtospecifictreatments,andonewasrelatedtomodelsoservice delivery. These are described below in more detaRecommendationswere rated on levels ofevidenceaccordinto an algorithm, also listed below. We also reviewed othschizophrenia clinical practice guidelines, using the AGREinstrument (5), which is designed to provide a framework fassessing thequality of CPGs. This frameworkand theresulof a needs assessment surveywere used to develop theoutlinof the current guidelines.A systematicneeds assessment was conducted with the targaudience of psychiatrists. Two processes were used: a focugroup at theannualCPA meeting and an on-line surveybaseon the AGREE framework. The on-line survey was sent torandomsampleof50%of theCPA members,and theresponsrate was 12%. Ninety percent of respondents were aware the1998 CPGs (6). Themost frequently referenced section othis guideline was the section on management of refractosymptoms. The top 3 most frequent suggestions were to prvide up-to-date information, clear recommendations, andcomprehensive biopsychosocial approach. Finally, the dra


The Canadian Journal of PsychiatryClinical Practice Guidelines

Table 1 Criteria for rating quality of published evidence in individual articles reviewed

Ratings Cri teria

I Evidence from at least one properly randomized controlled trial (RCT)

II-1 Evidence from well-designed controlled trials without randomization (pretestposttest control group design)

II-2 Evidence from well-designed cohort or casecontrol analytic studies, preferably from more than one centre or researchgroup

II-3 Evidence from repeated measures studies with no control group (one group pretestposttest design)

III Evidence from hypothesis-generating or exploratory studies (modelling, path-analytic or factor-analytic studies) or studiesinvolving subanalyses

IV Evidence from descriptive, observational, or qualitative studies (case reports, correlational studies, or secondaryanalyses); opinions of respected authorities, based on clinical experience; reports of expert committees

V-1 Evidence from a metaanalysis, with all studies included in the metaanalysis classified as RCTs

V-2 Evidence from formal review (reviews with detailed description of search strategies, such as Cochrane reviews)

V-3 Evidence from informal reviews that summarize others research, or publication that does not provide review details


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guidelines were sent to a national advisory group for reviewand comment.

Literature SearchThe search strategy covered publications issued between Jan-uary 1992 and April 2004. In Medline, PubMed, Psycinfo,and CINAHL the following key words were used:

conventional antipsychotic medications and tranquilizingagents, neuroleptic drugs, effective drug therapy,tranquilizing agents, adjunctive treatments, clozapine andefficacy and side effect profile, ECT, individual psychotherapy, group psychotherapy, familyinterventions, vocational rehabilitation, psychosocialskills, schizophrenia and social skills training, assertivecommunity treatment, training in community living,family psychoeducation, behavioural family therapy, behavioural family management, cognitive therapy,cognitive-behavioural therapy, token economy

schizophrenia treatment and group therapy, group homes,

psychiatric department hospitals, day care, ambulatorycare, outpatients

costutility or costbenefit analysis, cost effectiveness,health resources, quality of life, case management,outcome assessment, process assessment, patientsatisfaction, performance monitoring, performancemeasures, performance indicators, access to treatment or health services, accessibility, quality indicators, qualitymeasures, health care costs or cost of treatment, mentalhealth delivery system, mental health services, models of care, community care, community mental health services,

hospital care, patient retention or physicianpatientrelations, patient engagement

In the Cochrane database and Cochrane DARE (Database Abstracts of Reviews of Effectiveness) the search terms uswere CochraneSchizophrenia Group,as well as thekey wordschizophrenia and treatment.

Screening Process

Several steps were taken in the review process. First as metioned, we conducted computerized searches of relevant liteature. These searches were limited to English-languag publications with study subjects aged 18 to 65 years. Secowe undertook a preliminary screening of the title and abstrafor each reference to determine eligibility for inclusion in tdatabase. Third, the appropriate references were importeinto a ReferenceManager, Version 10 database (7)specific tthe CPG systematic review. As a result of these searches athe initial review of abstracts, 7707 references were importinto the database. A detailed assessment of each abstract a(or) article resulted in the removal of 5009 references. Resons for exclusion were that the reference was an inappropate publication type (that is, dissertation or letter) and thsubject matter was irrelevant to the CPG update. During tCPG writing, members of the working group identified addtional references. Some were papers of historical intereswhereas others were papers published before the dateencompassed in the evidence-based review. We ranked thein the same way as the references in the evidence-base

I. Introduction


Table 2 Evidence level summary for rating evidence

Evidence level Description

A Strong research-based evidence, for example, for interventions, consistent evidence fromwell-designed randomized controlled trials (RCTs); or a metaanalysis, with all the studies includedin the statistical pooling classified as RCTs; or consistent evidence from well-designed cohort and

case studies (categories I, V-1, II-2 from Table 1); for evidence relating to prevalence, consistentfindings from appropriately designed studies

B Moderate research-based evidence, for example, from well-designed controlled trials withoutrandomization, cohort studies, casecontrol analytic studies, comparative studies with historicalcontrol, and repeatedmeasures studies with no control group; this rating is also used when thereare well-designed RCTs favouring effectiveness, but the evidence from such trials is not consistent(II-1, II-2, II-3)

C Weak or reasonable evidence from descriptive, observational, or qualitative studies (case reports,correlational studies, or secondary analyses); formal reviews; expert opinions or consensus in thefield; hypothesis-generating or exploratory studies, such as modelling, path-analytic or factor-analytic studies, or subanalyses (III, IV, V-2)

D No evidence of benefit or harm of treatment


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review and added them to the database. The final databasecontains 2864 references, with quality ratings assigned.

Quality-Rating ProcessEach reference was given a quality rating by the researchcoordinator or research assistant, based on theguidelines pro-vided in Table 1. Interrater reliability was established at thestart, with at least 85% agreement on a random selection of 40 references. Each case of disagreement was reviewed withthe working group chair, and consensus was reached. Theseguidelines were originally adapted from the Canadian Task Force Methodology (www.ctfphc.org/methods.htm), withfurther development based on study design detail obtained in Fo un da tion s of Cl in ic al Re se ar ch : Ap pl ic at io ns to Practice (8). Raters blinded to the author name and journal

gave clinical trials a second ranking system according to tJadad Scale (see Appendix 1).

The final CPG recommendations were also ranked accordito the strength of evidence supporting them. These rankinwere determined by a consensus process involving the me bers of the Clinical Practice Guideline Working GrouTable2 outlines thesystemfor ranking therecommendations

All the citations will be posted on-line with the CPGs. Tscore foreach article will also be included.Ratherthan cite a possible references in theGPG, we cited references to be illutrativerather thancomprehensive.Several systematic revieware cited, particularly those that summarize the curren balance of opinions.




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II. Assessments

General Principles1. Symptoms (mental and physical), signs, activities of

daily living (ADLs), level of functioning, and sideeffects are key areas to assess at all phases of theillness.

2. Collateral information (for example, from familymembers, caregivers, and health care professionals) isusually essential for a more complete understanding of symptoms, signs, and functioning.

3. Longitudinal follow-up by the same clinician(s) tomonitor improvements or worsening is optimal.

4. Patients will often not spontaneously bring complaintsand information to clinicians, and therefore, active,specific questioning and informed examination andinvestigation are usually necessary.

5. The patients competency to accept or refuse treatmentmust be periodically assessed and recorded.

Acute PhaseThe physicians goals are to make an initial diagnosis and to plan and initiate treatment. Investigation of the symptoms of psychosis begins with a history, a physical examination, andother appropriate investigations. The clinical history shouldinclude all aspects of a general psychiatric evaluation as wellas a focus on specific issues related to schizophrenia. Thepri-mary goal of the assessments described in this section is to provide a guide for clinicians caring for patients with schizophrenia, not for all forms of psychosis. Although notdescribed in detail here, the differential diagnosis of schizophrenia from schizoaffective disorder, bipolar disorder,depression with psychosis, and other forms of psychotic ill-ness has implications for outcome (911). Collateral informa-tion should be sought, with the knowledge and consent of the patient, fromothers who knew thepatientbefore theacuteepi-sode. Semistructured interviews may increase the reliabilityof application of diagnostic criteria and may elicit featuresthat might be otherwiseoverlooked. Clinical ratingscalescan

help quantify symptom severity and permit longitudinassessment. Most of these instruments require training ensure reliableadministration. Most important, taking timet build rapport with patients and caregivers will help maximiunderstanding of the longitudinal course and phenomenolog

of the illness.The initial assessment should include inquiries specificaldirected to the following (Table 3):

positive symptoms such as hallucinations and delusions negative symptoms such as flat or blunted affect, povertof thought or thought content, and avolition

disorganization such as thought disorder, inappropriateaffect, and disorganized behaviour

affective symptoms such as anxiety or depression, particularly in relation to the psychotic symptoms

suicidal or aggressive thinking and behaviour,impulsivity, because any risk for suicide or violence hasimplications for where the patient should be assessed antreated

the time of onset or exacerbation of symptoms and thecontext and possible precipitating factors

substance use and abuse in relation to the onset and persistence of psychotic and associated symptoms the current living situation, including housing, finances,social supports, ADLs, social activity, school, and work

a mental status examination, including office or bedside

assessment of cognitive function, based on data from allsources of information, in which positive and negativefindings should be documented, since they may changeover time

a physical examination, including neurologicexamination, and laboratory tests, including screeningtoxicology

a general medical history and review of symptoms

Repeated relapses necessitate special attention to assessmeof the patients insight (including patients and family



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Table 3 Assessments for patients with schizophrenia

Areas First episode Acute phase Stable

Psychopathology PositiveNegativeDisorganizationMoodSuicide, aggression, or impulsivity

Baselineassessment

Baseline and at least weeklythereafter, more frequentlydepending on clinical context

At least every 3 months for medication adherent, morefrequent for medicationnonadherent

Level of function SocialLiving situationOccupational or vocational

Baselineassessment

Baseline assessment Every 3 months

Substance use or abuse

InquiryToxicology screen

Baselineassessment

Baseline assessment As indicated clinically

Cognitive function Neuropsychological testing Baselineassessment

As indicated clinically As indicated clinically

Genetic Family history of psychosis Baselineassessment

Clinical screening for chromosome22q11 deletion syndrome (withtesting as indicated clinically)

Baselineassessment


Structural brainabnormalities

CT or MRI Baselineassessment


Hematology CBC Baselineassessment


Blood chemistries ElectrolytesRenal function testsLiver function testsThyroid function tests

Baselineassessment


Infectiousdiseases

Syphilis testHepatitis or HIV tests if indicated

Baselineassessment


Cataracts InquiryOcular exam

Baselineassessment

Basel ine assessment Every 2 years up to age 40

Yearly for age 40 and older

Cardiovascular Vital signs Baselineassessment

As clinically indicated withchanges in medications

As indicated clinically

ECG QTc indicated when affected bymultiple medications

continued


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attribution of the patients behaviour), awareness of the sig-nificance of illness, attitude toward treatment and restoringhealth, medication adherence, substance use or abuse, treat-ment response, and side effects, as well as attention to theavailability and use of psychosocial interventions designed toreduce symptom recurrence. The setting selected for treat-ment will depend primarily on safety issues and on the abilityof the patient to care for him- or herself and adhere totreatment.

Stabilization PhaseThe aim of assessment in the stabilization phase is to monitor for symptomatic and functional recovery after an acuteepisode. Treatment may not completely eliminate symptoms, but it is important to document changes, including diminishedfrequency or intensity of symptoms or behavioural responsesto treatment (12). The extent to which positive and negativesymptoms and cognitive impairment persist followingoptimal treatment of an index episode may be predictive of

more severe residual symptoms and a poorer functionrecovery (1316).

Stable PhaseAssessmentsin thestablephaseof theillnesssupport thetrea-ment goals of this phase. These goals are to optimize funtional recovery, to promote insight and understanding, learn to detect early signs of relapse, and to monitor for sieffects and comorbid conditions. Patients in the stable phawho have good functional recovery and are in a stable livisituation should be assessed by a physician at least eve3 months. More frequent assessments are often required b patients who, for example, have poor functional recovery associated conditions such as substance use or abuse, halimited social support, are changing medications, are initia-ing a new psychosocial intervention, or are experiencinstressful life events. Persistent symptoms (positive, negativand comorbid) are not always associated with overt patiedistress but often limit functional recovery (17).

II. Assessments


Table 3 continued

Areas First episode Acute phase Stable

Extrapyramidalsymptoms andsigns

Parkinsonism (bradykinesia, rigidity,tremor), Dystonia, Dyskinesia, Akathisia

Baselineassessment

Before initiating a newantipsychotic or when dosage ischanged, then weekly for 2 to 4

weeks

Every 6 months, or more oftenfor patients at higher risk

Body mass BMI Waist circumference Baselineassessment

Before initiating a newantipsychotic, then monthly for 6months

Every 3 months on a stableantipsychotic dosage

Blood sugar Fasting plasma glucose Baselineassessment

Baseline assessment,4 months after initiating a newantipsychotic

Yearly, or more frequently if symptomatic or gaining weight

Hyperlipidemia Lipid panel (total cholesterol, low-and high-density lipoprotein,cholesterol, triglycerides)

Baselineassessment

Baseline assessment At least every 2 years, or every6 months if LDL levels above thenormal range

Endocrine andsexual function

Functional inquiry:Women: menstruation, libido,galactorrheaMen: libido, erectile and ejaculatoryfunctionWhere clinically indicated: prolactinlevel

Baselineassessment

Baseline assessmentMonthly for 3 months after initiating a new antipsychotic

Yearly

Risk behaviours for STDs and HIV Baselineassessment



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Assessments of functional recovery focus on the severity of persisting or residual symptoms, on the ability to perform basic self-care functions and ADLs, on the extent of socialrelationships, on the ability to learn and work, and on the fre-quency of hospitalization due to relapses. Thorough assess-ment may be particularly important to inform decisionsconcerning level of care and housing support needed in thecommunity. Collateralinformation fromcaregivers and (or) ahome visitmaybe very helpful in this assessment.Poor recov-ery of ADLs and social function is often related to persistingcognitive dysfunction. In addition to objectively assessingfunctional recovery, seek the patients own account of satis-faction or quality of life. Setting realistic goals and expecta-tions for functional recovery requires knowledge of the patients longitudinalhistory, includinghis or her best levelof functioning, educational history, culture, interests, andsupports.

Relapse and Adherence to TreatmentThecourseof schizophrenia isoften characterized by relapseof acute psychosis (18). Signs and symptoms associated wrelapse are often observed by relatives or caregivers and usally appearmore than 1 week prior to relapse. Initial signs ansymptoms are likely to be nonpsychotic (such as anxiety, tesion, depression, decreased insight, trouble sleeping, ansocialwithdrawal). A relapse mayalsocoincidewith sensitiv-ity to minor stresses or hassles at home or work. Relap prevention is closely related to effective antipsychotic medcation and to adherence to treatment. Adherence to treatmeis promoted by a good relationship with the clinician, b patient and family knowledge about the illness, by unde-standing the risk of nonadherence to medication (up to 90chance of relapse within 1 year), and by low medication sieffects.Nonadherence isassociated with denialof illness,di-tressing side effects, complicated dosage schedules



Table 4 Recommendations

Recommendation Evidence Evidence level

Symptoms and signs of illness and functionalimpairment should be carefully evaluated anddifferential diagnosis made.

Among illnesses with psychosis as a clinical feature, thediagnosis of schizophrenia has significant implications for prognosis.

A

Suicidal and aggressive thinking and behaviour should be regularly assessed.

Patients with schizophrenia have increased risk of suicideand aggression.

A

Regular assessment of substance use and abuse isnecessary.

Substance abuse is common in patients withschizophrenia.

A

Neuropsychological testing is suggested in patientswith first-episode psychosis and those with poor response to treatment.

Schizophrenia is associated with mild but significantcognitive impairment, which is associated with poor functional recovery.

B

Symptoms, level of function, and factors associatedwith poor treatment adherence and relapse shouldbe regularly assessed.

Schizophrenia is frequently characterized byexacerbations of symptoms and periods of acute relapse.

A

Clinical features suggestive of chromosome 22q11syndrome should be evaluated in patients withschizophrenia and laboratory testing obtained whenindicated.

Chromosome 22q11 deletion is associated withschizophrenia.

B

Computed tomography or magnetic resonanceimaging at illness onset and in patients withrefractory illness should be done.

Patients with schizophrenia have an increased prevalenceof structural brain abnormalities.

B

Regular clinical and laboratory monitoring for movement disorders, obesity, diabetes,hyperlipidemia and sexual dysfunction indicated inpatients with schizophrenia.(see Table 3)

Patients with schizophrenia have reduced life expectancy;the combination of illness and the effects of antipsychotictreatment place patients at risk of movement disorders,obesity, diabetes, hyperlipidemia, and sexual dysfunction.

A


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substance abuse, problems with access to treatment, financialobstacles to receiving medication, and stigma.

Specific Clinical Situations and Assessments First EpisodeThe assessment for a first episode of psychosis is similar to an

acute phase assessment.Particular attention should be paid tothe longitudinal assessment of the onset of changes in behav-iour and to the timing and course of onset of the first symp-toms of psychosis. Developmental history, including socialand academic functioning in childhood and adolescence, mayhelp indicate the onset of decline in function and may be of prognostic value regarding degree of symptomatic and func-tional recovery. The duration of untreated psychosis (DUP)may have similar prognostic value (1921).For individuals referred with a suspicion of psychosis, vari-ables that maybe associated with increasedrisk ofconversionto psychosis include poor level of functioning (particularlywith recent decline), long duration of symptoms, depression,impaired attention, family history of psychosis, and recentsubclinical symptoms of psychosis (22).

Neuropsychological Assessment A consensus on cognitive testing for clinical trials in schizophrenia is developing through a US National Instituteof Men-tal Health initiative (23). Preliminary reports from this groupand additional studies suggest that cognitive testing infirst-episode illness maybe of prognostic value for functionalrecovery. As well, cognitive decline to frank dementia canoccurover thecourse of illness inschizophrenia, although it isuncommon (24). Baseline assessments are particularly valu-ableshould reassessmentbe indicatedclinically later in theill-ness course. Cognitive testing should include an estimate of premorbid IQ, current IQ, and specific tests related to workingmemory, attention, verbal learning and memory,visual learn-ing and memory, reasoning and problem solving, speed of processing, and social cognition. Adequate assessment of these domains of function is more important than the specifictests administered.Cognitive testing in the stable phase of illness may also be of significant value in addressing different issues related to theheterogeneity of schizophrenia and variability in functionalrecovery. Strengths and weaknesses in specific domains of cognitive function may help guide the design of individualstrategies for rehabilitation. Documentation of capacity tolearn may be particularly important.Thetimingof neuropsychologicalassessment also needs tobeindividualized. Psychometrists and psychologists experi-enced in testing patientswith psychosiscan obtainvalidinfor-mation in the presence of positive symptoms; however,testing in the stable rather than the acute phase of illness is

generally preferred. For patients experiencing a first episoof illness, testing within the first 3 months at a time whesymptoms do not directly disrupt the assessment process suggested. Finally, for any specialized assessmen(neuropsychological or the following genetic and imaginstudies),sufficient information shouldbeprovided to thecon-

sulting clinician to help inform the tests to be carried ouRequesting information on the previously described domaiof cognitive function is preferable to a referral question suas rule out organicity.

Genetic Assessment Schizophrenia is a complex disorder with significant intactivecomponents of genes and environment as etiologic fators. There are no screening genetic tests available th provide useful information in regard to most patientHowever, genetic assessment is indicated in patients whhave dysmorphic or other features suggesting the presence

chromosomal syndromes. Chromosome 22q11 deletion sydrome is associated with significantly increased risk for pschosis, predominantly schizophrenia (25). This syndrome present in approximately 1/4000 births and increases the rifor schizophrenia approximately 25-fold. Chromosom22q11 deletion syndrome is also known as velocardiofacisyndrome, DiGeorge syndrome, and Shprintzen syndromTesting samples of patients with schizophrenia for 22q1deletion yields widely variable prevalence estimates, likeinfluenced significantly by the ascertainment criteria useOverall, 1% to 2% of individuals with schizophrenia ha22q11 deletion syndrome (26). This is medically significan

as a range of associated conditions exists, including cardidefects, immune system dysfunction, platelet abnormalitieand hypocalcemia. Clinical features of 22q11 deletion sydrome in individuals with schizophrenia or first-episode pschosis include the following:

childhood learning difficulties, such as special educationdevelopmental delay, or articulation disorder

palatal features, such as hypernasal speech, high arched palate, or history of cleft palate

cardiac features, that is, a history of congenital cardiacabnormalities

craniofacial abnormalities, such as dysmorphic facies(typically, long, narrow face, flat cheeks, prominent nosewith bulbous tip, minor ear anomalies, may also includenarrow or slanted palpebral fissures and retrognathia)

other physical congenital abnormalities, including slendor tapered fingers, high arches or talipes, and scoliosis

a history of recurrent ear infections or hearing loss mayalso be relevant. Clinical screening of patients for the presence of features from 2 or more of the above areasmay indicate the need for fluorescent in situ hybridizatio

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(the FISH test) testing for diagnosis and (or) referral to amedical geneticist (27,28). Presence of 22q11 deletionsyndrome is also an indication for genetic counselling.

Neuroimaging Other brain diseases can mimic the presentation of schizophrenia. Rarely, patients with first-episode psychosis and noneurologic findings will have an unsuspected brain diseaserevealed by brain imaging with computed tomography (CT)or magnetic resonance imaging (MRI). The most commonfinding with CT imaging in first-episode psychosis is nonspe-cific ventricular and cortical sulcal enlargement, which may be present in 30% to 40% of patients (29). More severe atro- phy is related to poorer outcome. Focal findings, usuallydevelopmentalanomaliesthatdo not influencetreatment, willoccur in 2% to 6% of patients imaged with CT. Over 20% of MRI scans at the onset of psychosis may be read as abnormal by radiologists; this increases to as high as 50% in chronic ill-ness(30). Excludingpatientswithheadinjury,neurologic dis-ease, seizures, or substance abuse, 7.9% of MRI scansobtained in first-episode patients were of clinical impor-tance, affecting prognosis, diagnosis, or management (30, p 334) and led to referral for additional evaluation. The com- parable frequency in patients with chronic illness was 20%. Inthis study and in other studies of volunteers, incidental find-ings led to referral in 3% to 5% (30,31). Imaging data mayhelp patients and families to accept that neurologic causes of illness have been excluded.

Poorly Responsive or Refractory IllnessDiagnostic reassessment is a first step in developing a treat-mentplanfor individuals withincomplete treatmentresponse.Very few patients with apparently treatment-resistant schizophrenia actually have schizoaffective disorder, a mood dis-order with psychosis, or undetected physical conditions thatmayhavedifferenttreatment implications(32,33).Diagnosticcriteriamustbe applied systematically.Factors thatcontributeto misdiagnosis in severely ill patients include failure to con-sider lifetimehistory of illness; an assumption that all severe,chronic psychosis with functional impairment is schizophre-nia; failure to appreciate irritability, which may indicatemania; and confusion between negative symptoms and

depression. Access to collateral sources of information for assessment isparticularly importantin thisgroupofpatients.

Comorbid ConditionsComorbid conditions include suicidal behaviour, anxiety anddepressive symptoms, and substance abuse. Completed sui-cide and suicide attempts aredistressingly commonin schizophrenia patients (34). The following specific factors further increase the risk for suicide in those with schizophrenia:depression, being within 6 years of first hospitalization,young age, high IQ, high premorbid achievement and

aspirations, and awareness of loss of functioning. As wecommand auditory hallucinations,recent dischargefromho pital, treatmentnonadherence, and akathisiamay be related tsuicide risk.Depressive symptomsarecommonin schizophrenia andmu be differentiated from negative symptoms such as blunting

emotional expression, decreased spontaneous speech, anlackof motivation (35). Depressivesymptomsmay precedeo be coincident with psychotic symptoms, particularly in tearly course of illness, or may be more prominent followinresolution of psychotic symptoms.Anxiety symptomsmaybe comorbid in schizophrenia, part oa relapse, or secondary to caffeine, other drugs, or alcohabuse.Agitationand(or) violencemayaccompany an exace bation of symptoms but must be distinguished from akathior delirium (such as may occur secondary to substance abuor excessive water drinking).

Substance abuse is common in schizophrenia, with up to 80% lifetime prevalence and 25% cross-sectional prevlence (36). Multiple substances are often abused, and thisassociated with poor functional recovery. Substance use abuse may represent self-treatment of residual symptoms distressing sideeffects. Common substances include tobaccalcohol, cannabis, and amphetamines. Nonprescription anhistamines and analgesics may also be used. Knowledge the patients substance use history will aid inquiries about tuseof specificsubstances. Collateral information and specifurine drug screens mayhelp assess theextentof substanceusor abuse. Up to 80% of patients with schizophrenia smoke;for any patient, smoking cessation strategies should b pursued (37).Polydipsia and resulting hyponatremia may manifest as laafternoon restlessness, irritability, nausea, diarrhea, salivtion, ataxia, and eventually stupor. The clinician should spcifically enquire whether fluid intake exceeds about 3 L fluid (any) daily. Weight gain of more than 2 kg during thday, excessive bathroom use, or daytime wetting may alsindicate compulsive water drinking.

Physical Health Monitoring Pat ients wi th schizophrenia are at h igh r isk founderrecognition and undertreatment of physical illnesseSpecific questioning to uncover physical illnesses is monecessary than with other patients. As well as having a hisuicide rate,patientswith schizophrenia have a highermorta-ity rate from other causes, compared with the general popution (38,39).Additional risksmaybe present that arerelatedtantipsychotic medications, high prevalence of smoking, cafeine ingestion, comorbid alcohol or other substance abusand self-neglect.Common comorbid illnesses include cardio-vascular disease, obesity, type II (adult onset) diabete




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mellitus, hyperlipidemia, and sexual dysfunction. Table 2indicatesa suggestedapproach to screeningforthese illnessesand pathophysiological states.Monitoring for obesity can be carried out with assessment of body mass index (BMI)and waist circumference.Informationconcerning these measures can be found on-line at Health

Canada (www.hc-sc.gc.ca/hpfb-dgpsa/onpp-bppn/weight_book_tc_e.html). A BMI of 25.0 to 29.9 indicatesoverweight andan increasedrisk related tomorbidity andpos-sible mortality, and a BMI of 30.0 or greater is classified asobesity and is associated with a sharp rise in risk. Waistcircumference of 102 cm (40 inches) or greater in men, and88 cm (35 inches) or greater in women is associated withincreased risks to health. In addition to these absolute values,an increaseof1 BMI unitduring treatment should lead tocon-sidering an intervention (40) such as prescribing a weight-loss program, as would a 10% increase in total body weight.Canadian Diabetes Association CPGs identify schizophreniaas a risk factor for type II diabetes (41). An algorithm for screening is available on-line (www.diabetes.ca/cpg2003/chapters.aspx). Health care providers, patients, and familymembers should be able to recognize the signs and symptomsof diabetes, including weight loss, polyuria, polydipsia anddiabetic ketoacidosis, nausea, vomiting, dehydration, rapidrespiration, and clouding of the sensorium.Particular attention should be paid to patients who meet crite-ria for the metabolic syndrome, characterized by abdominalobesity,dyslipidemia,hypertension,dysglycemia,and insulinresistance. Although complete consensus on the definition of

this syndrome is lacking, a working definition is as followthe presence of 3 or more of fasting plasma glucose 6.1 mmol/L,blood pressure = 130/85 mmHg, triglycerides1.7 mmol/L, HDL-C < 1.0 mmol/L (men) or < 1.3 mmol/(women), and abdominal obesity indicated by waist circumference >102 cm (men) or 88 cm (women) (35).

Assessment of sexual functioning should be part of a systeaticreview of sideeffects in patientsreceivingantipsychoticIn women, menstrual calendars may be helpful. Questioninmasturbatoryactivities and, in men, thepresence of spontaneous morning erections may help differentiate deleteriou pharmacologic impacts of medication from relational difculties related to schizophrenia itself. Prolactin levels shou be routinely assessed in the presence of menstrual changeswomenandsexualdysfunctionsorgalacthorreain both sexeIf isolated hyperprolactinemia is detected without clinicsymptoms, treatment providers should remember that homonal perturbations and consequences are still possible duing the long-term course of treatment.

Dual Diagnosis (Mental Retardation)Patients with mental retardation, especially those who anonverbal, may be more challenging to assess; collaterinformation fromcaregivers is important.Cognitive andfuntional testing to delineate the patients developmental levand relative strengths andweaknesses arealso essential. Consultationwitha medical geneticist is recommendedif therearany dysmorphic features or congenital anomalies. Chromsomal studies using modern techniques mayrevealdetectabanomalies of diagnostic significance.

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III. Pharmacotherapy

MedicationsThese guidelines only refer to medications available inCanada at the time of writing. They refer to clozapine,olanzapine, quetiapine, and risperidone as second-generationantipsychotics (SGAs) or atypical antipsychotics; all other antipsychotic medications are referred to as first-generationantipsychotics (FGAs).

General Principles1. Pharmacotherapy with antipsychotic medications is an

essential component of a treatment plan for most patients with schizophrenia.

2. Psychosocial interventions work synergistically withmedication to optimize treatment adherence andsuccessful community living.

3. Medications must be individualized because the

individual response is highly variable. Considerationshould be given to the immediate presenting problemand the patients prior response to pharmacotherapy,including efficacy and side effects. Patients with a firstepisode of psychosis usually require a lower dosage, asdo the elderly.

4. Patients must be involved in decisions and choices for pharmacotherapy. This includes being provided withinformation on the risks and benefits of both taking andnot taking medications. However, because a high levelof benefit is achieved with medication, it should berecommended assertively, and patients agreement intaking mediation should be sought actively.

5. Side effect profiles vary according to the duration of drug exposure, the evolution of the disorder, and the patients general health.

6. Simple medication regimens, such as once-daily dosing, promote adherence to treatment.

7. Dosages should be maintained within the recommendedrange, and reasons for going outside the range should be clearly documented and justified.

8. Using more than one antipsychotic simultaneously isnot supported by available evidence.

9. Regular and ongoing evaluations are equally necessarywhen patients respond to medications, when they fail trespond, and when they develop side effects.Standardized scales are useful tools for baseline andlater assessments.

Second-Generation AntipsychoticsSGAs are increasingly replacing FGAs as first-line treaments. Reviews have not found clear and consistent diffeences between FGAs and SGAs in regard to treatmeresponse forpositive symptoms,withthenotable exceptionoclozapine for treatment-resistant patients (42). Secondgeneration drugs have a broader spectrum of therapeuteffects, with a small but significant effect size superiority the treatment of negative symptoms and cognitive impaiment (43,44). It has also been suggested that they are moeffective in the treatment of depressive symptoms (45).

The management of the metabolic side effects of SGAs discussed under assessment issues and, later in this sectiounder side effects. For clinicians, the challenge in managinthese side effects is that they must shift their thinking frothe earlier focus on managing extrapyramidal side effec(EPSEs). The focus on managing weight, glucose, and lipi brings psychiatrists back into the realm of general mediciand away from purely pharmacologic considerations. Stratgies fordealing with EPSEs,such as dosageadjustment,med

ication switches, or the addition of adjunctive medicationarenot strategies that have an immediateimpact on metabol parameters. Psychiatrists should not hesitate to consult witheirinternalmedicinecolleagues on these issues.Shared carwith family physicians is also helpful. Difficulty in accessisuch resources should not lead to postponing primarinterventions.

There aresignificant differences in side effectprofiles amonfirst- and second-generation drugs. In general, SGAs indufewer neurologic side effects (that is, EPSEs or tardiv



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dyskinesia [TD]) (46) and may have a greater propensity for metabolic side effects (that is, weight gain, diabetes mellitus,dyslipidemia,or metabolic syndrome), although the evidenceis mainly based on clinical experience and nonrandomized published reports (40,47). Depot preparations were limited tofirst-generation drugs, with the exception of risperidone,

which is now available in an intramuscular (IM), long-actingformulation (48). Other new formulations, such as rapid-dissolving tablets (olanzapine and risperidone) (49), concen-trate liquid (risperidone), and parenteral short-acting form(olanzapine), offer advantages in several situations wheredrug administration canbecomean issue (for example, emer-gency or geriatrics).

Pharmacologic Strategies for Phase-SpecificTreatmentSchizophrenia is a chronic disease that can be arbitrarily

divided into 3 phases: theacute, the stabilizing,and the stable phase of the disorder. In the acute phase, the patient experi-ences an escalating level of positive psychotic symptomsassociated with varying degrees of distress and disorganiza-tion that often lead to treatment seeking. The earlier in this phase of escalation that treatment can be initiated, the less thedisruption to the patients and their environments. If interven-tion does not occur earlier in the escalation, emergency inter-vention is required, with several different emergencytreatment options being available. In the recovering stage of the illness, the levels of symptoms and disorganization areusually decliningas a resultof treatment, andthe patient needs

less care. In the stable phase, symptoms and disorganizationhave been reduced as much as possible, and longer-term psych osocial and rehab il ita tio n str ate gie s can beimplemented.

Acute Phase

The general principles are as follows:

1. The assessment in the acute phase should be ascomprehensive as possible under the circumstances.

2. Particular attention needs to be paid to the potential for

danger to self or others.3. Engagement with the patient in the acute phase is

facilitated by acknowledging his or her experiences, providing clear simple communication, and includingfamily and supports where possible. Explaining the patients rights and any legal process is essential.

4. Pharmacologic treatment should be initiated as soon as possible, and the risks and benefits of pharmacotherapyshould always be explained.

5. All these principles apply in emergency situations, butemergency medication strategies are available tocontain the patient and maintain staff safety.

Emergency Treatment . Emergencies are defined as situationsor conditions having a high probability of disabling or immdiately life-threatening consequences or requiring first aid

other immediate interventions (Medical Subject HeadingsIndividuals with schizophrenia frequently present to eme-gency rooms, requiring immediate treatment. The CanadiaEmergency Department Triage and Acuity Scale (50) classfies acute psychosis as either a Level 2 or Level 3 emergenaccording to the degree of agitation. Where the patient aggressive or agitated and uncooperative, several pharmac-logic interventions are available, often in combination wi psychosocial interventions.Verbally engaging an agitated patient should always be triin the setting of an appropriately safe emergency room env

ronment with available security personnel. Oral medicatioshould be offered and, if accepted, can be as effective as Imedications (51). The rapid-dissolving forms of SGAs mhave benefits for treatment in emergencysituations becauseiseasierto confirm compliance.However, thereareno studiecomparing similar medications in different oral preparatioin emergency situations. When necessary to preserve patieand staff safety, restraint measures should be taken by trained team following an approved protocol.Historically, IM haloperidol has been the most widely ustreatment for agitated patients with psychosis. The combintion ofhaloperidol 5 mgIMwith lorazepam 2 mgIM has beeshown tobemore effectivethan haloperidol alone(52).Treament of schizophrenia is not an approved indication folorazepam in the current Compendium of Pharmaceuticalsand Specialties (53) product monograph. Olanzapine is thefirst SGA in Canada to become available in an IM form facutetreatment.IMolanzapine2.5mgto10mghasbeendemonstrated to be as effectiveas haloperidol alone(54,55) whishowing fewer EPSEs. In practice, 10 mg is the most frquently prescribed single dosage, except in special popultions. Combining parenteral olanzapine with benzodiazepishould be avoided because cardiac and respiratory difficuties, including fatalities, have been associated with this com bination in postmarketing reports. Several studies havreported thatoral solution or rapid-dissolving tablets of eithrisperidone or olanzapine are as effective as haloperidIM(56). In Canada, zuclopenthixol acetate hasbeen availabfor the treatment of acute agitation. Following injection, reaches a peak serum level in 24 to 48 hours and declinesone-third of peak concentrations at 72 hours. Thes pharmacokinetic properties support a potential reduction the number of injections required to stabilize agitation anaggression, but the agent should be avoided in drug-nai




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become the treatments of choice for the reasons mentionedabove. Although they do differ in terms of their side effect profiles, there is no clear evidence that, apart from clozapine,there are consistent group differences in efficacy among theSGAs (62). The general principle is to titrate up to an initialtarget dosage (in 1 to 2 weeks in most cases) and monitor for

side effects while awaiting an initial response. An adequatetrial of 4 to 8 weeks duration on the maximumtolerated dos-agewithintherecommendedrangeisgenerallyaccepted(63).Akathisia can be misinterpreted as psychotic agitation; if the patient is not responding to acute treatment with anantipsychotic, rule out akathisia before administering moreantipsychotic medication.

Dosing and Titration . Differentapproaches arepossiblewhena new medication is introduced. A first approach is the pre-scriptionofa targeted dosagestarted on Day1 andmaintainedat that level. Olanzapine can often be prescribed according tothis approach but can also be introduced according to a grad-ual titration over a few weeks to minimize early side effectsand ease medication acceptance. A second approach is totitrate the medication according to the patients response andtolerance. A third approach is fast titration over a few days to promotea rapid developmentof tolerance to sideeffects.Withquetiapine, this is particularly useful to diminish the durationof sedation andhypotension frequently observed at thebegin-ning of treatment. When medications are being started or changed, follow-up visits for outpatients need to be frequent(weekly intervals), but they may be much less frequent whenthemedicationisestablished in termsofdosage, response,and

side effects and when the patient is stable. SGAs can be takenonce or twice daily. A single daily dosage has advantages for patient treatment adherence (64). Rapid-dissolving tablets or liquid formulation may promote adherence to treatment.

Stabilization PhaseThe general principles are as follows:

1. The goals of pharmacotherapy in this phase are toreduce the intensity and duration of active psychoticsymptoms as fully as possible, to minimize side effects,and to promote adherence.

2. Medications selected for short-term control of agitated behaviour during the acute psychotic phase may not beoptimal for efficacy and tolerability.

3. Adjust the dosage to the individual within the givenrange for each medication. Seek the patientsmedication cooperation to enhance compliance.

4. Significant and sustained reduction in acute psychoticsymptoms often takes 4 to 8 weeks. Improvements inother symptoms and functioning may take much longer.

Improvement may continue over 1 year or more of uninterrupted treatment.

5. Premature discontinuation or reduction of antipsychotmedication during this phase places the patient at highrisk for relapse.

First Episode of Psychosis, No Previous Antipsychotic Treat-ment . In recent years, there has been an increasing interest the clinical care of the patient with a first episode of psychsis (65,66). Many of the challenges for the treatment of th patient with a first episode of psychosis arise in the stabilition phase of a first episode. The initial treatment respontends to be better in first-episode than in multiple-episoschizophrenia (66,67), but adherence tends to be poor (68)is important to maintain an active treatment relationship wfrequent contact and easyaccess. In the face of nonadherento pharmacologic recommendations, other components treatment, including family education, become even moimportant . A supportive educational approach irecommended.

Depression is a more common problem in the stabilizati phase of the first episode (69). Whereas depression tendsabate with the remission of psychosis in the multiple-episo patient, it tends to increase for the first 3 months following thfirst episode (70). The specific management of depressioncovered below. The diagnosis of first-episode psychosneeds to be kept under review, and pharmacotherapy maneed to be adjusted should the criteria change.

Multiple-Episode Patient . Medication management in thesta- bilization phase should focus on continuity of care and fituning the medication to adjust to developing side effects changes in the patients living situation. The stabilizatio phase provides the opportunity to review the causes relapse.Thesemayincludepoor treatmentadherence.The usof long-acting injectable formulations is an evidence-bas pharmacologic recommendation for reducingnonadherence (71). The strength of the evidence is limitedthe methodological difficulties of enrolling nonadheren patients in randomized controlled studies. More recently, tfirst long-acting atypical antipsychotic has becomeavailablThe evidence suggests that long-acting risperidone shouhave the same benefits as the first-generation depot medictions from an adherence perspective, but with feweEPSEs (72).

Stable Phase

The general principles are as follows:

1. Relapse prevention is an important but not exclusivegoal of pharmacotherapy in the stable phase.




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2. Over the longer term, other goals include minimizingnegative and comorbid symptoms and promotingmaximal functional ability.

3. There is a high level of individual variability in theantipsychotic dosage required to achieve functionalrecovery with minimal side effects.

4. To maintain treatment adherence in this phase, it iscrucial to have the patient participate in pharmacotherapy and to address individual barriers andresistance to ongoing therapy.

5. Assessments should take place at least every 3 monthsto achieve optimal dosages and choice of antipsychoticmedications and to monitor for drug-induced sideeffects.

6. There are no predictive factors indicating which patients can safely and permanently discontinueantipsychotic medication.

First Episode of Psychosis . An important issue that arises for the patient with a first episode of psychosis is the duration of prophylaxis for relapse prevention. The difficulties of con-ducting randomized controlled studies of medication with-drawal make it difficult to provide precise, evidence-basedrecommendations. In one of the larger early randomized placebo-controlled studies of maintenance antipsychotics,62%of thoseon placebo relapsed over 2 years,comparedwith46% of those on maintenance pharmacotherapy (73). How-ever, a reviewof longitudinalcohortstudies of patients in nat-ural treatment settings showed relapse rates of 60% at

2 years (74). A pragmatic recommendation to patients andtheir families is that patients who have made a functionalrecovery andhave been in remissionon medication forat least1 to2 years may beconsideredcandidatesfora trial ofno med-ication. Withdrawal of antipsychotic medication should bedone slowly over 6 to 12 months. The patients symptoms,functioning, insight, andattitude toward adhering to the treat-ment plan must bemonitoredclosely.Patients whowere illfor an extended period before initial treatment, who met criteriafor the diagnosis of schizophrenia at first contact, and (or)who have a history of violent or suicidal behaviour mayrequire more extended antipsychotic medication treatment.Eighty percent of patients with first-episode psychosis are atrisk for a second episode within the first 3 to 5 years, andrecovery from a second episode is slower and often lesscomplete.

Multiple-Episode Patient . There are no guidelines for identi-fying those patients who may remain relapse-free. A mini-mumof 5 years of stability, without relapse andwith adequatefunctioning, should be observed before a slow withdrawal of antipsychotic medication over 6 to 24 months is considered.Being medication-free is an unrealistic objective for many

patients, especially those with a history of suicidality, vilence, family history of schizophrenia, or the inability to cafor themselves.

Strategies for Inadequate Response . If response is inade-quate, the diagnosis must be reviewed, adherence must bexplored, and substance use or abuse must be ruled out. T

4 main pharmacologic strategies for initial nonrespondeinclude optimization, substitution, augmentation, and comb-nation. If there isa partial response,the best strategy isoptimzation.Inoptimization,thetrialoftheoriginalantipsychoticicontinuedwith thedosage increasedor decreasedasapproprate. In the case of no response, substitution can be tried. Tantipsychotic is gradually stopped, and another one is intr-duced with a short period where the 2 antipsychotics overlaAlthough there areothermedication-switchingstrategies, thmethod may be the safest way to switch from one agent another (75). The second trial is also likely to be an SGA. Thsame rules apply to the second drug trial, with optimizatiand substitution being instituted as needed. Persistent Positive Symptoms . Research definitions of treat-ment resistance have tended to focus on persistent positisymptoms (76). Despite adequate pharmacotherapy, at lea20% of multiple-episode patients have no positive-symptoresponse to antipsychotics. A further 30% respond only patially. Failed trials of 2 antipsychotics are accepted as evdence of treatment refractoriness. There is no consensus ohow manyor in which order the SGAs should be tried prior tclassifying thepatient as treatment-resistant. If poor treatmenadherence is a factor, an IM long-acting medication can b

considered. Given the options now available, physicianshould actively evaluate treatment responsiveness and detemine whether patients who have a poor functional recoveshould be offered trials of clozapine. Clozapine remains thtreatment of choice for partial (77) or total nonresponse treatment (76,78). Clozapine should be considered as soon treatment nonresponse has been demonstrated, even in thfirst or second year of the disorder. The duration of an adquate trial with clozapine is considered to be 4 to 6 monthIf a trial of clozapine is not effective, the next steps are aumentation, followed by combination strategies. A useful geeral principle is monotherapy before polytherapy (79). Tcommonly used augmentation strategies include addition lithium, anticonvulsants (that is, valproate, carbamazepintopiramate, and lamotr ig ine) , ant idepressants benzodiazepines, and electroconvulsive therapy (ECT) (80These combination strategies have been proposed essentiaon the basis of case reports (79), but a randomized controlltrial (RCT) has yielded some evidence for the efficacy lamotrigine (81). The last strategy is a combination treatmewith a second antipsychotic. The efficacy of combineantipsychotic treatment has not been adequately tested, b




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there is ample evidence of the likelihood of additional sideeffects. There is a lack of research evidence to support thisstrategy. The clinician should document the reasons for employingthis,closelymonitor sideeffectsand response,andstop the combination in case of no clear benefit.

ECT continues to be a strategy to consider for treatment-resistant schizophrenia. A recent Cochrane review identified24 trialsand concluded that therewaslimited evidence to support its use as adjunctive treatment with antipsychotics for those who show limited response to medication alone (82).

Persistent Negative Symptoms . Negative symptoms have been defined as the reduction or absence of several normalcapacities, such as the ability to experience pleasure(anhedonia), thefree flow of thoughts (alogia) and thenormalexpression of emotions (affective flattening). However, thisdefinition isproblematicin that several factors cancausethese

reductions. This has ledto theconcept of primary andsecond-arynegativesymptomsor deficit syndrome(83).This conceptcan be applied in clinical practice; clinicians should firstassess and treat any causes of secondary negative symptomssuch as residual paranoid delusions, anxiety, oversedation,depression, or EPSEs. When the secondary negative symp-toms have been dealt with, those remaining symptoms can beconsidered primary negative symptoms. This distinction can be useful for the clinician at the level of the single patient. Itmakes it more difficult, however, to address the issue of whether SGAsaremore effectiveagainst negative symptoms,compared with first-generation compounds. Most studies are based on general measures of negative symptoms, which donotmake thedistinction. Itcouldbearguedthat thedistinctionis not important from the patients perspective, whereas it isimportant to the clinical scientist. A recent and comprehen-sive metaanalysis comparing SGAs and FGAs supports thesuperior efficacy of several of the SGAs, compared withFGAs (62). It reaches this conclusion primarily by analyzingthe global outcome of positive, negative, and generalsymptoms. Smaller analyses of risperidone and olanzapineundertaken by the same authors support the conclusion that both were slightlysuperior to FGAs on positivesymptomsbutmodera te ly super ior on negat ive and genera lsymptoms (84,85).

Depression . In a longitudinal cohort study of 3 clinicalgroups, the presence of a major depressive episode (MDE)was as frequent in the schizophrenia sample as it was in theschizoaffectivegroup and the depression group (86). Depres-sion in schizophrenia is associated with reduced subjectivequality of life and with both attempted and completed suicideand, as a result, should be an important focus of clinicalattention.

In the acute stage, symptoms of depression remit along withepositive symptoms.There is some evidence that SGAsarmore effective than FGAs in thetreatmentof these depressivsymptoms (62). There is no evidence to support the additiof an antidepressant at this stage of the disorder.

In the stabilization phase, individuals with a first episode schizophrenia are more likely to experiencea depression thaare those with multiple-episode schizophrenia (70). ThDSM-IV recognized postpsychotic depressive disorder schizophrenia as a criteria set for further study(87). A revieof several clinical trialsthathave evaluatedthe treatmentof aMDE with antidepressant medications in the stabilization stable phase of the disorder provided cautious support (87Psychosocial interventions such as cognitive-behaviourtherapy (CBT)can also be useful (see Psychosocial Intervetions below for more information).

Suicide and AttemptedSuicide . Suicide andattemptedsuicide

are common problems in schizophrenia, with a lifetimexpectancy of about 10% and 30%, respectively (89). Thcritical nature of suicide sets it apart as an issue of concerAttention to all facets of the care of the patient is seen as critcal to theprevention of attemptedand completedsuicide (90In particular, attention should be paid to the assessment suicidality at moments of risk, such as during transitions fromhospital to the community. The critical nature of suicide alargues for the routine assessment of suicidality. From th pharmacologic perspective, 3 related symptom clusters m be the focus of attention: psychosis, depression, ansuicidality. Optimal pharmacotherapy for these target symtoms requires optimal dosing, duration of treatment, anadherence. There is some evidence, discussed above, thSGAs are more effective than FGAs in the treatment of thesymptoms. In the face of persisting suicidal ideationclozapine has been shown to be more effective than othantipsychotics (91).

Violence . Most patients with schizophrenia are not violenhowever, violence is a problem in a subgroup of the popu-tion. As in dealing with other clinical issues, pharmacologinterventions for violence need to be integrated with othinterventions, particularly with interventions for substan

abuse. The care of acutely agitated patients is discusseabove.

In the stabilization and stable phases, persistent aggressiocan be associated with residual psychotic features, whicshould be one focus of clinical attention. In general, moeffective treatment will generally the lower the associatio between a specific disorder such as schizophrenia and t probability of violence (92). There is some anecdotal evdence that clozapinemay have some specificbenefit in thesiuation of persistent aggression (93).




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Sex Differences . Sex differences are recognized in multipleaspects of schizophreniasuchas pathophysiology, symptoms,response to treatment, and sideeffects (94,95). Women expe-rience later age of onset, more comorbid problems, and polypharmacy. They show higher plasma concentration atequivalent dosage and more side effects (94). Although it has

been reported that women usually respond to lower antipsychotic dosages before menopause (95), this has nottranslated into evidence-based recommendations regardingdifferent dosage ranges for men and women.

Physiological changes that occur during pregnancy modifyantipsychotic elimination (that is, increased plasma volume,increased glomerular filtration rate, and increased hepaticenzyme activity). All psychotropic drugs pass though thepla-centa, as do the fat-soluble drugs in the breast milk. Sparsedata are available on the use of antipsychotics during preg-nancy. It is of primary importance to discuss fertility issuesand contraception with antipsychotic-exposed women.Although empirical data preclude strong recommendations,experts generally agree that the safest option is to avoid theuse of antipsychotics during the first trimester. In manysitua-tions, minimal time of antipsychotic exposure at the lowesteffective dosage may be inevitable (94,96).

Management of Side Effects

Weight Gain and Abdominal ObesityAll antipsychotics may increase body weight, but a differen-tial liability is well known among agents. Clozapine and

olanzapinehavebeenassociated withsignificant weight gain;risperidone and quetiapine have been associated with moder-ate weight gain (40,47,97). Detailed mechanisms underlying body fat, particularlyvisceral fat, accumulationare unknown.Lean persons as well as young patients seem to beparticularlyvulnerable to dramatic weight gain, but no clinical tool is yetavailableto predict such an effect (98,99). Combinationswithsome psychotropicdrugs such as lithium,valproate, andsomeantidepressants may significantly worsen the weight-gain profile (100).

Preventive lifestylestrategies shouldbeencouraged, even if itis well known that such strategies are difficult to implement,not only in patients with schizophrenia but also in the general population. Benefits of physical activities and good nutritionhabits should be emphasized both to the patient and to his or her family (101). If prevention is insufficient to limit weightgain, a change to an antipsychotic with a lower weight-gainliabilitycouldbeconsidered (102,103). In such cases,modifi-cation of lifestyle habits should still be a goal. (The CanadianTask Force on Preventive Health Care recommendations onthe detection, prevention, and treatment of obesity are avail-able on-line at www.ctfphc.org/Tables/Obesity_tab.htm.)

Impairment in Glucose Regulation and DiabetesMany glucose abnormalities have been reported with atypicantipsychotic treatment: insulin resistance, hyperglycaemiexacerbation of type 1 diabetes, new onset of type 2 diabetmellitus, and diabetic ketoacidosis (104,105). Additional stuiesarerequired to determinethedifferential liabilityof glucosimpairment among agentsand thedifferences in liabilityposs bly owing to genetic factors. It is possible that there are diffential responses between atypical agents; however, this issubjectof active debate (104,105). In Canada, all SGAs carrywarning for potential glucose abnormalities (53).

If diabetes is diagnosed, the Canadian Diabetes AssociatioGuidelines should be followed. (Clinicalguidelines on diabtes are available on line at www.diabetes.ca/cpg2003default.aspx.) A switch of antipsychotic could be considerin some cases,although fewstudies have directly assessed thimpact of a switch on metabolic parameters.

DyslipidemiaSecond-generation antipsychoticsmay elevate lipids.Clinicexperience and published reports indicate that clozapine anolanzapine can be associated with hyperlipidemia. A fecaseshave also been reported with theuse ofquetiapine,whirisperidone appears to be more neutral (40,104,106,107).

The 2003 update of Canadian recommendations for the maagement of dyslipidemia should be followed when lipidabnormalitiesare detected.A switch of antipsychoticcouldbconsidered in somecases, but advantages still need to be cofirmed. (Clinical guidelines on dyslipidemia are availab

on-line at www.cmaj.ca/cgi/data/169/9/921/DC1/1 anwww.nhlbi.nih.gov/guidelines/cholesterol/index.htm.) Psychiatrists should participate in the implementation anfollow-up of both nonpharmacologic and pharmacologtreatment in such cases (103,107).

QT ProlongationProlongation of the QT interval is an ECG abnormality thcanleadtotorsadesdepointes,arrhythmia,syncope,ventricular fibrillation, and sudden death. Risk seems to be greatwith QTc values over 500 ms (108). Thioridazine has fsome time not been permitted as a first-line antipsychoti

owing to concerns about QT prolongation(53), andis nowothe market. FGAs such as mesoridazine and pimozide shou be avoided in patients with heart disease, familial history deathatanearlyage(aged40 yearsandunder),andcongenitalong QT syndrome (40,108).

Endocrine and Sexual Side EffectsIn women, changes in libido, delayed or absent orgasm, mestrualchanges, or galactorrheaand, in men, changes in libiderectileor ejaculatory troubles,or galactorrheaareamongfrequentlyexperienced sideeffects(109), especiallywith FGAs




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Hyperprolactinemia may lead to decreased production of gonadal hormones in both men and women and may in partexplain sexual side effects, along with modulation of neurotransmitters (110). Prolonged hyperprolactinemia anddecreased hormonal levels may increase risk of osteopenia,osteoporosis (111), and impaired reproductive function in

women (102).SGAs show a lesser degree of elevation of prolactin levels,with the exception of risperidone, which is frequently associ-ated with marked and sustained hyperprolactinemia, particu-larly if higher dosages are used (112). Transient prolactinelevation is possible with olanzapine. Quetiapine andclozapineareconsidered prolactin-sparing agents (113). Still,sexual dysfunctions may be seen with all availableantipsychotics, regardless of their propensity to induce prolactin elevation (114).In the presence of signs and symptoms of endocrine distur- bance or impaired sexual functioning, a dosage reduction of the antipsychotic may be attempted. If unsuccessful, a switchto a prolactin-sparing agent should be tried (112). If adjunc-tive medication, particularly a selective serotonin reuptakeinhibitor, is also being prescribed, the need for these medica-tions shouldbe reassessed. Careful attentionshouldbepaid toissues of birth control for women changing from an FGA or risperidone to a prolactin-sparing agent, since fertility levelmay be unexpectedly restored (102,115).

Cognitive Side Effects and SedationFGAs induce sedation, and many patients complain of a sub- jective dulling effect. Cognitive testing has shown no benefitin cognitive functioning with FGAs. SGAs appear to showstatistically significant improvements in cognitive perfor-mance (43,116). Significant sedation may still occur, at leasttransiently, mainly with clozapine but also to a lesser extentwith olanzapine andquetiapine. It isworseduringthetitration phase and may remitover time,but in somepatients, increasedsleeptimeand excessivediurnal sedation persist.Risperidonemay be associated with both mild sedation or insomnia insome cases (117). High risperidone dosages (and to a lesser extent, high olanzapine dosages) increase EPSEs, which inturn may impair cognitive performance (114). Concomitant

agents such as anticholinergics or anticonvulsants mayincrease cognitive problems (78,118). The therapeutic goalshould be to at least prevent any cognitive harm and, ideally,to promote cognitive performance. In case of persistentcognitive dulling or sedation, dosage reduction should betried. If insufficient, a switch to another agent should beconsidered (117).

Extrapyramidal Side EffectsEPSEs are particularly associated with FGA medications.Acute reactions occurring in the first days or weeks of

treatment include dystonia, parkinsonism (akinesia o bradykinesia, tremor, and rigidity), and akathisia. Chronside effects, some irreversible and appearing months or yeaafter treatment, include TD and tardive dystonia. Neurologside effects are the major burden of FGAs and a limitationtheiruse(44,79,114). When used in therecommendeddosag

range, risks of neurologic side effects from SGAs are minmal, but subtlesigns of tremor, rigidity,andakathisiastill ca be detected and could be easily mistaken for anxiety, agittion, or negative symptoms. Higher dosages of risperidon(and to a lesserextent olanzapine)areassociated with a higherisk of EPSEs (44,79,114).

If neurologic symptoms are detected, a dosage reduction theantipsychotic shouldbe tried,or switchto another SGA. A benzodiazepineor betablockercan be prescribedfor akathisif a dosage reduction is insufficient. Anticholinergic mediction

cpa guidelines- schizophrenia

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