Treatment of psychotic disorders

Lucie Bankovská Motlová

7.10.2010

What is Psychosis?• Generic term• “Break with Reality”• Symptom or syndrome, not an illness• Caused by a variety of conditions that

affect the functioning of the brain.• Includes hallucinations, delusions and

thought disorder

Psychotic Disorders:

DSM-IV and ICD-10 Differences DSM-IV

• Schizophrenia• Schizophreniform disorder• Schizoaffective disorder• Delusional disorder• Brief psychotic disorder• Shared psychotic disorder• Psychotic disorder due to a

general medical condition• Substance-induced

psychotic disorder

ICD-10• Schizophrenia• Schizotypal disorder• Persistent delusional

disorders• Acute and transient

psychotic disorders• Induced delusional disorder• Schizoaffective disorders

Treatment of psychotic disorders

other

Psychosocial treatment

Pharmacotherapy

•Antipsychotics•Anxiolytics•Antidepressants•Anticholinergics

•Psychoeducation•Social skills training•Psychotherapy •Rehabilitation of cognitive function•Family intervention•Wellness programme

•Elektroconvulsive therapy•Transcranial magnetic stimulation

Treatment of psychotic symptoms

Antipsychotic medication

(„neuroleptics“)

Schizoaffectivedisorders

Schizophrenia

Acute psychotic disorders

Schizophreniphormdisorders

Toxic psychoses

PSYCHÓZYDOPAMINE

DOPAMIN

• Endogenous dopaminergic sensitization: PET

• Amphetamines intake = ↑↑↑ endogenous dopamin in schizophrenia patients in the acute phase, in comparison with healthy persons

• Relapse of schizophrenia = recurrence of hyperdopaminergic state in subcortical structures

• IMPLICATIONS FOR TREATMENT Chronic blockade of D2 receptors: blocking of sensitization processes

Laurelle 1999

Neurochemical sensitization in mesolimbic dopaminergic system

(studies in schizophrenia)

=

First and Second generation antipsychotics receptor profile

podle Stahla, 1999

Haloperidole and D2 receptor blockade

11C-Raclopride PET Scan

Coregistered MRI Scan

BeforeTreatment

Haloperidol2 mg/d (74% Occ.)

11C-Raclopride PET Scan

(Farde 1995)

5-HT2 and D2 receptor blockade

First generation antipsychotics

Generic name Product name Daily dose

chlorpromazine Plegomazin 200-600 (800)

levomepromazine Tisercin 50-400

thioridazine Thioridazin 100-600

periciazine Neuleptil 10-40

chlorprothixene Chlorprothixen 100-600

zuclopenthixol Cisordinol 20-60

perfenazine Perfenazin 16-64

prochlorperazine Prochlorperazin 20-80

tifluoperazine Stelazin 10-50

flupentixol Fluanxol 6-18

haloperidol Haloperidol 2,5-10

melperone Buronil 50-300

pimozid Orap 2-10

fluspiriliene Imap 2-10

penfluridol Semap 20-60

oxyprotepine Meclopin 5-20

First generation antipsychotics: Depot

Generic name Product name dose frequency

oxyprotepin decanoat Meclopin 12,5-75 3-4 weeks

haloperidol decanoat Haloperidol decanoate 12,5-75 4 weeks

fluspirilen Imap 2-10 5-7 days

flufenazin decanoat Moditen Depot 12,5-50 2-4 weeks

cis(Z)-flupentixol decanoat

Fluanxol Depot 20-60 2-4 weeks

zuclopenthixol decanoat Cisordinol Depot 100-400 2-4 weeks

zuclopenthixol acetat Cisordinol Acutard 50-150 2-3 days

Second generation antipsychotics

Generic name Product name Dosage (mg/day)

clozapine Leponex 200-600

olanzapine Zyprexa 10-20

quetiapine Seroquel 300-700

zotepine Zoleptil 100-300

risperidon Risperdal, Rispen 4-8

ziprasidon Zeldox 80-160

sulpirid Dogmatil, Prosulpin 400-1200

amisulprid Solian 400-1200

aripiprazole Abilify 10-30

paliperidone Invega 6-12

Second generation antipsychotics for

parenteral use Generic name Product name indication dosage

olanzapine Zyprexa Acute agitation 10 mg i.m.

ziprasidone Zeldox Acute agitation 10-20 mg i.m. (max. 40mg i.m./24 hodin).

risperidone Risperdal Consta Depot medication-long-term

Every 2 weeks

Advantages of Atypical Neuroleptics• Broader therapeutic spectrum

– therapeutic efficacy on • positive symptoms• refractory — residual

– reduction, prevention:• negative (deficit) syndrome• depressive symptoms• cognitive deficits

• No (fewer) side effects – objective: acute EPS, TD– subjective: dysphoric response

Side Effects of Antipsychotics

1. Effects of dopaminergic blockade

2. Effects of other receptors´blockade

Dopaminergic tracts

nigrostriatal

mesocortical

mesolimbic

tuberoinfundibular

Effects of dopaminergic blockade

Wanted effects:• blockade in mesolimbic

pathway:• - reduction of

psychotic symptoms• - relapse prevention

Unwanted effects:• blockade in

mesocortical pathway: apathy, lack of motivation

• blockade in tuberoinfundibular pathway: ↑ prolactin

• blockade in nigro-striatal pathway: extrapyramidal symptoms

Antipsychotics: nigrostriatal dopaminergic blockade effects

(Seem

an 1996)

Extrapyramidal side effects of antipsychotics

• Parkinsonism• Acute dystonia • Akathisia• Tardive dyskinesia

Video:Extrapyramidal syndromes

First and Second generation antipsychotics receptor profile

podle Stahla, 1999

Other side effects of antipsychotics

sleepeness low blood pressure dry mouth constipation

Sexual problems Weight gain Life threatening:Malignant

neuroleptic syndrome

Antipsychotics: Side EffectsAntipsychotics: Side Effects

• Neurological (Extrapyramidal) DA-blockNeurological (Extrapyramidal) DA-block

• Non-NeurologicalNon-Neurological • Histaminergic: Sedation, Wt gainHistaminergic: Sedation, Wt gain

• Anticholinergic: PerAnticholinergic: Periipheral & Centralpheral & Central• Alpha-Adrenergic: Orthostasis, EKGAlpha-Adrenergic: Orthostasis, EKG• Endocrine-Sexual: PRL, 5-HTEndocrine-Sexual: PRL, 5-HT• HHaaematologic: Agranulocytosisematologic: Agranulocytosis• Eye & Skin: retinopathy, photosensitivityEye & Skin: retinopathy, photosensitivity• Seizure threshold: loweredSeizure threshold: lowered• Liver: cholestatic jaundice Liver: cholestatic jaundice (chlorpromazine)(chlorpromazine)

tuberoinfundibulardopaminergic

blockade

nigrostriataldopaminergic

blockade

clozapine

Duration of antipsychotic treatment

• After first episode of psychosis: 1-2 years

• After second episode of psychosis: 5 years

• After 3 episodes: > 5 years

Schizophrenia: Acute phase, remission, relapse

20 30 40 50 60 70roky

M E D I K A C E

Symptoms in relapse

Pathophysiological processses

– asymptomatic during remision

Medication knowledge in the context of the disease

Medication

Medication

Antipsychotics: Summary

• Regulate dopamine

• Reduce hallucinations, delusions, improve cognitive functions, etc

• Prevent relapse

75 %one year relapse rate without medication

15 % one year relapse rate on medication

Howevher….Treatment noncompliance!!!!

10 days 6 months 12 months 24 months

25%

33%

40%

76%

69%

discharge

noncompliance(%)

Perkins, 2002; Kamali et al., 2006, Lam et al, 2002; Weiden et al., 1997

+

C

6 months

Reasons for non-compliance

Relapse prevention

Vulnerability factorsInformation processing deficitsAutonomic reaction anomalies

Social competence and coping limitations

Social Environmental Stress:Critical comments, overinvolvement

Chaotic family environmentStigma

Relapse

Enhance coping skillsMedication

Cognitive rehabilitationSupportive psychotherapy

PsychoeducationSocial skills training

Remove stressorsFamily interventionDestigmatization

Integrated therapy of schizophrenia

Phases of the illnessThe goal of the intervention

Pharmacotherapy Psychosocial inteventions

services

Prodroms Early diagnostics Only as an experiment

Keep in contact Outpatient services

Acute phase(First episode or relapse)

Treat psychotic symptoms Therapeutic relationship

Pharmacotherapy

Antipsychotics+Anxiolytics+hypnotics

Start therapeutic relationship

Structured communication

Avoid stress

hospitalization

Stabilization phase Remission Pharmacoherapy with special attention to side effects

Supportive psychotherapyPsychoeducation(patient +family)

Day care clinic, outpatient department

Stable phase (remission)

Relapse prevention Pharmacotherapy Social skills trainingCognitive rehabilitation

Community care, day care clinic, outpatient department

Lack of information about disease

Basic psychoeducation

Basic psychoeducation

Lifestyle improvement

Lifestyle improvement

Family psychoeducation

Family psychoeducation

Psychoeducation: What is it?

• Systematic, structured, didactic information on the illness and its treatment, which includes integrating emotional aspects in order to enable the participants to cope with the illness

Bauml et al.,2003

Extrapyramidal Sx. (EPS)Extrapyramidal Sx. (EPS)

• Acute DystoniasAcute Dystonias

• Antipsychotic-induced Parkinsonism Antipsychotic-induced Parkinsonism

• AkathisiaAkathisia

• Tardive Dyskinesia (TD)Tardive Dyskinesia (TD)

• Neuroleptic Malignat Syndrome (NMS)Neuroleptic Malignat Syndrome (NMS)

Acute DystoniasAcute Dystonias

• Muscle spasm face-neck-trunk-eye-larinxMuscle spasm face-neck-trunk-eye-larinx• Early in Tx., young malesEarly in Tx., young males• Dose Related, Tolerance, incidence 50%Dose Related, Tolerance, incidence 50%• Treatment:Treatment: biperiden 2,5-5 mg IM or IV (slowly); biperiden 2,5-5 mg IM or IV (slowly);

Benadryl 50 mg IM (IV 25-50 for laryngospasm), Benadryl 50 mg IM (IV 25-50 for laryngospasm), Cogentin 1-4 mg IM Cogentin 1-4 mg IM

• Prevention reduces incidence to 5% Prevention reduces incidence to 5% – Low dose, Low dose, – Benztropine 1 mg / every Haldol 5 mgBenztropine 1 mg / every Haldol 5 mg

Antipsychotic-induced Antipsychotic-induced ParkinsonismParkinsonism

• Incidence 50-75% with high pot.Incidence 50-75% with high pot.• RigidityRigidity• Bradikinesia: mask face-gait problemsBradikinesia: mask face-gait problems• Resting TremorResting Tremor• Flexed PostureFlexed Posture• Dif Dx. with flat affectDif Dx. with flat affect• Tx: Cogentin, Artane 2 mg bid-tid (elder)Tx: Cogentin, Artane 2 mg bid-tid (elder)

– Reduces incidence to 5-10%Reduces incidence to 5-10%

AkathisiaAkathisia

• Subjective feeling of restlesnessSubjective feeling of restlesness• Unable to sit still, pacingUnable to sit still, pacing• Incidence 20-30%, lower with low doseIncidence 20-30%, lower with low dose• Dif Dx.: psychosis, agitation, anxietyDif Dx.: psychosis, agitation, anxiety• Tx: Tx: lower the antipsychotic dose if possible, lower the antipsychotic dose if possible,

Propranolol 30-90 mg/d (not in asthma or Propranolol 30-90 mg/d (not in asthma or diabetes), Klonopin 1 mg biddiabetes), Klonopin 1 mg bid

• SSRI Antidepressants cause akathisia tooSSRI Antidepressants cause akathisia too

Tardive Dyskinesia (TD)Tardive Dyskinesia (TD)

• Slow choreo-athetotic movementsSlow choreo-athetotic movements

• Oro-facial musclesOro-facial muscles

• Risk 4% per year of exposureRisk 4% per year of exposure– Risk factors elderly women, mood DO, Risk factors elderly women, mood DO,

diab.diab.

• Risk managementRisk management– document informed consent, AIMS Testsdocument informed consent, AIMS Tests

• Tx?: Vit E 1600 U/d, Clozapine low riskTx?: Vit E 1600 U/d, Clozapine low risk

Neuroleptic Malignant Neuroleptic Malignant Syndrome (NMS)Syndrome (NMS)

• Medical Emerg, mort. 20% (now 4%)Medical Emerg, mort. 20% (now 4%)• 1. Fever1. Fever >100.4F / 37.5C >100.4F / 37.5C• 2. Severe EPS2. Severe EPS: lead-pipe/cogwheel : lead-pipe/cogwheel

rigidity, sialorrhea, oculogyric crisisrigidity, sialorrhea, oculogyric crisis• 3. Autonomic DysFx3. Autonomic DysFx: BP fluctuations, : BP fluctuations,

tachycardia, tachypnea, diaphoresistachycardia, tachypnea, diaphoresis• Also: Alt. conciousness, delirium, Also: Alt. conciousness, delirium,

leukocytosis (>15.000 WBC), CPK > 300, leukocytosis (>15.000 WBC), CPK > 300, seizures, arrseizures, arryythmias, mthmias, myyoglobinuria, ARFoglobinuria, ARF

NMSNMS

• Incidence 0.1-1%, (60% of it in 1st 2 Incidence 0.1-1%, (60% of it in 1st 2 wks)wks)

• Risk factors: multiple IM injections, Risk factors: multiple IM injections, high dose, rapid increase of dose high dose, rapid increase of dose agitation, dehydration, heat, lithium useagitation, dehydration, heat, lithium use

• Tx: STOP ALL antipsychotics, also Tx: STOP ALL antipsychotics, also antiemetic Reglan (Metoclopramide), antiemetic Reglan (Metoclopramide), antidepr. Amoxapineantidepr. Amoxapine

NMS TreatmentNMS Treatment

• Stop ALL AntipsychoticsStop ALL Antipsychotics• Dif. Dx: fever & deliriumDif. Dx: fever & delirium• Dantrolene (muscle relax) 1-3 mg/kg/day Dantrolene (muscle relax) 1-3 mg/kg/day

NTE 10 mg/kg/dNTE 10 mg/kg/d• Bromocriptine (DA Agonist) 5 mg tid-qidBromocriptine (DA Agonist) 5 mg tid-qid• Supportive Tx:Supportive Tx:

– IV fluids, antipyretics, cooling blankets, IV fluids, antipyretics, cooling blankets, close cardiac & renal monitoringclose cardiac & renal monitoring

Clozapine [Clozaril]Clozapine [Clozaril]

• Weak D1=D2 block, high 5-HT2 blockWeak D1=D2 block, high 5-HT2 block– (5-HT2/D2 = 20/1)(5-HT2/D2 = 20/1)

• alpha1, alpha2, H1, M1alpha1, alpha2, H1, M1

• Tx Res. Schizophrenia, mood stabilizerTx Res. Schizophrenia, mood stabilizer

• Effective in Negative and Positive Sx, Effective in Negative and Positive Sx, low EPS, low TDlow EPS, low TD

Clozapine: Side EffectsClozapine: Side Effects

• Agranulocytosis (1%), 80% in 1st 4.5 Agranulocytosis (1%), 80% in 1st 4.5 mo.mo.

• If WBC<3,000 and ANC<1,500 stop, wait If WBC<3,000 and ANC<1,500 stop, wait until it returns to 3,500 CBC bi-wkuntil it returns to 3,500 CBC bi-wk

• If WBC<2,000 and ANC<1,000 stop & do If WBC<2,000 and ANC<1,000 stop & do not re-startnot re-start

• Do not use with Carbamazepine or Do not use with Carbamazepine or other bone marrow suppressorsother bone marrow suppressors