Psychotic Disorders

Kheradmand Ali M.D.Assistant Professor of Shahid Beheshti Medical University

PSYCHOSIS

Mood disorders

Schizophrenia “spectrum”

disorders

“organic” mental disorders

Substanceinduced

DeliriumDementia

Amnestic d/o

“Functional”disorders

Differential Diagnosis• Medical/surgical/

substance-inducedPsychotic d/o due to GMCDementiasDelirium MedicationsSubstance induced

AmphetaminesCocaineWithdrawal statesHallucinogensAlcohol

• Mood disordersBipolar disorderMajor depression with psychotic

features

Differential Diagnoses: (Cont)

• Personality disordersSchizoidSchizotypalParanoidBorderlineAntisocial

• Miscellaneous PTSDDissociative disordersMalingeringCulturally specific phenomena:

Religious experiencesMeditative statesBelief in UFO’s, etc

Talking Points• Schizophrenia is not an excess of dopamine.• The differentiation between “functional” and

“organic” is artificial.• Schizophrenia and other psychiatric illnesses are syndromes.

• Schizophrenia is a diagnosis of exclusion.

Clinical features:Formal Thought Disorders

• Neologisms• Tangentiality• Derailment• Loosening of associations (word salad)• Private word usage• Perseveration• Non sequiturs

Clinical features:Delusions

• Paranoid/persecutory• Ideas of reference• External locus of control• Thought broadcasting• Thought insertion,

withdrawal• Jealousy• Guilt• Grandiosity

• Religious delusions• Somatic delusions

Clinical features:Hallucinations

• Auditory• Visual• Olfactory• Somatic/tactile• Gustatory

Clinical features:Behavior

• Bizarre dress, appearance• Catatonia• Poor impulse control• Anger, agitation• Stereotypies , mannerism

Clinical features:Mood and Affect

• Inappropriate affect• Blunting of affect/mood• Flat affect• Incongruent affect

Dopamine systems

Nigro-striatal

SubstantiaNigra

Caudate and putamen

Move-ment

Extrapyramidal symptoms, dystonias, Tardive dyskinesia

Meso-limbic

Ventral tegmental area, subst. nigra

Accumbens amygdalaOlfactory tubercle

Emotions,affect, memory

Positive symptoms

Meso-cortical

Ventral tegmental area

PrefrontalCortex

Thought, volition, memory

Blockade here can worsen negative symptoms.

Cell bodies Projections FunctionsClinical

implications

Anatomical abnormalities• Enlargement of lateral ventricles• Smaller than normal total brain volume• Cortical atrophy• Widening of third ventricle• Smaller hippocampus

Physiologic studies:PET and SPECT

• Generally normal global cerebral flow• Hypofrontality• Failure to activate dorsolateral prefrontal

cortex (problem-solving, adaptation, coping with changes)

Copyright © 2004 Allyn and Bacon

Copyright 2009 John Wiley & Sons, NY

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Etiology of Schizophrenia: Brain Structure and

Function

Congenital Factors» Damage during gestation or birth

– Obstetrical complications rates high in patients with schizophrenia

Reduced supply of oxygen during delivery may result in loss of cortical matter

» Viral damage to fetal brain– In Finnish study, schizophrenia rates higher

when mother had flu in second trimester of pregnancy (Mednick et al., 1988)

– Maternal exposure to parasite associated with higher rates of schizophrenia in their offspring

Copyright 2009 John Wiley & Sons, NY

27

Etiology of Schizophrenia: Brain Structure and

Function

Developmental Factors» Prefrontal cortex matures in adolescence or

early adulthood» Dopamine activity also peaks in

adolescence» Stress activates HPA system which triggers

cortisol secretion– Cortisol increases dopamine activity

May explain why symptoms appear in late adolescence but brain damage occurs early in life

Copyright 2009 John Wiley & Sons, NY

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Etiology of Schizophrenia: Psychological Stress

Reaction to stress» Individuals with schizophrenia and their first-

degree relatives more reactive to stress– Greater decreases in positive mood and increases in

negative mood

Socioeconomic status» Highest rates of schizophrenia among urban

poor. – Sociogenic hypothesis

Stress of poverty causes disorder– Social selection theory

Downward drift in socioeconomic status

» Research supports social selection

Copyright 2009 John Wiley & Sons, NY

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Etiology of Schizophrenia: Family Factors

Schizophrenogenic mother » Cold, domineering, conflict inducing» No support for this theory

Communication deviance (CD)» Hostility and poor communication

– Family CD predicted onset in one longitudinal study (Norton, 1982)

– CD not specific to families of schizophrenic patients

Paranoid Type Disorganized Type Catatonic Type Undifferentiated Type Residual Type

Paranoid Type Disorganized Type Catatonic Type Undifferentiated Type Residual Type

Paranoid Type Disorganized Type Catatonic Type Undifferentiated Type Residual Type

Paranoid Type Disorganized Type Catatonic Type Undifferentiated Type Residual Type

Disorganized Speech Disorganized Behavior Flat or Inappropriate Affect Hallucinations and Delusions

– Fragmented or Lacking a Theme Often Chronic

Disorganized Speech Disorganized Behavior Flat or Inappropriate Affect Hallucinations and Delusions

– Fragmented or Lacking a Theme Often Chronic

Disorganized Speech Disorganized Behavior

Waxy flexibility, rigidity, odd mannerisms, mimicry

Flat or Inappropriate Affect Hallucinations and Delusions

– Fragmented or Lacking a Theme Often Chronic

Disorganized Speech Disorganized Behavior

Waxy flexibility, rigidity, odd mannerisms, mimicry

Flat or Inappropriate Affect Hallucinations and Delusions

– Fragmented or Lacking a Theme Often Chronic

Beginnings of Breakdown Major Sx of Schizophrenia DO NOT Meet Other Criteria “Wastebasket” Category

Beginnings of Breakdown Major Sx of Schizophrenia DO NOT Meet Other Criteria “Wastebasket” Category

Have Had One Episode Now Mostly Symptom Free

Have Had One Episode Now Mostly Symptom Free

Once a Schizophrenic ,Always a Schizophrenic?

Once a Schizophrenic ,Always a Schizophrenic?

Psychotic Disorders

Schizo-phrenia

Usually insidious

Many Chronic >6 months

Delusional disorder

Varies (usually insidious)

Delusions only

Chronic >1 mo.

Brief psychotic disorder

Sudden Varies Limited <1 mo.

Onset Symptoms Course Duration

Workup of New-Onset Psychosis:“Round up the usual suspects”

• Good clinical history• Physical exam, ROS• Labs/Diagnostic tests:

Metabolic panelCBC with diffB12, FolateRPR, VDRLSerum AlcoholUrinalysisThyroid profile

URINE DRUG SCREEN!!!

CSF/LPHIV serologyCT or MRIEEG

Typical Neuroleptics• Low potency:

– Chlorpromazine– Thioridazine– Mesoridazine

• High potency:– Haloperidol– Fluphenazine– Thiothixene– Loxapine (mid)

Neuroleptic (typicals):side effects

• Acute dystonia• Parkinsonian side effects (EPS)• Akathisia• Tardive dyskinesia• Sedation, orthostasis, QTC prolongation,

anticholinergic, lower seizure threshold, increased prolactin

Extrapyramidal Sx. (EPS)

• Acute Dystonias• Antipsychotic-induced Parkinsonism • Akathisia• Tardive Dyskinesia (TD)

• Neuroleptic Malignat Syndrome (NMS)

Acute Dystonias

• Muscle spasm face-neck-trunk-eye-larinx• Early in Tx., young males• Dose Related, Tolerance, incidence 50%• Treatment: Benadryl 50 mg IM (IV 25-50

for laryngospasm), Cogentin 1-4 mg IM • Prevention reduces incidence to 5%

– Low dose, – Benztropine 1 mg / every Haldol 5 mg

Antipsychotic-induced Parkinsonism

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

– Reduces incidence to 5-10%

Akathisia

• Subjective feeling of restlesness• Unable to sit still, pacing• Incidence 20-30%, lower with low dose• Dif Dx.: psychosis, agitation, anxiety• Tx: Propranolol 30-90 mg/d (not in

asthma or diabetes), Klonopin 1 mg bid• SSRI Antidepressants cause akathisia too

Tardive Dyskinesia (TD)

• Slow choreo-athetotic movements• Oro-facial muscles• Risk 4% per year of exposure

– Risk factors elderly women, mood DO, diab.

• Risk management– document informed consent, AIMS Tests

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

Neuroleptic Malignant Syndrome (NMS)

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

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

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

leukocytosis (>15.000 WBC), CPK > 300, seizures, arrithmias, mioglobinuria, ARF

NMS

• Incidence 0.1-1%, (60% of it in 1st 2 wks)• Risk factors: multiple IM injections, high

dose, rapid increase of dose agitation, dehydration, heat, lithium use

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

NMS Treatment

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

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

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

Atypical Antipsychotics:• Risperidone• Olanzapine• Quetiapine• Clozapine• Ziprasidone• Aripiprazole (new-partial DA agonist)

Serotonergic Pathways and Innervation

Hypo = hypothalamus SN = substantia nigra

Thal = thalamus

Atypical antipsychotics

MARTA (multi acting receptor targeted agents)• clozapine, olanzapine, quetiapine

SDA (serotonin-dopamine antagonists)• risperidone, ziprasidone, sertindole

Selective D2/D3 antagonists• sulpiride, amisulpiride

Atypical Antipsychotics: Side Effects

• Sedation• Hyperglycemia, new-onset diabetes• Anticholinergic effects• Less prolactin elevation• QTC prolongation• Some EPS• Increased lipids

ESTIMATED MEAN WEIGHT GAIN AT 10 WEEKS

Allison DB , Mentore JL , Heo M, et al: Weight gain associated with conventional and newer antipsychotics :a meta - Analysis. AJP, 1999.

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•A comprehensive literature search identified 78 studies that included data on weight change in patients treated with a specific antipsychotic.

•For each agent a meta-analysis and random effects regression estimated the change in weight at 10 weeks of treatment.

HaloperidolHaloperidol ClozapineClozapine RisperidoneRisperidone OlanzapineOlanzapine

QuetiapineQuetiapine ZiprasidoneZiprasidone

5HT2A D2 D1 Alpha 1 Musc H1 5HT1A (agonist)

Casey 1994Casey 1994

Atypical Antipsychotics In Vivo Binding Affinities

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