psych 181: dr. anagnostaras lec 7: schizophrenia and parkinson's disease john nash

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Psych 181: Dr. Anagnostara Lec 7: Schizophrenia and Parkinson's Disease John Nash

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Page 1: Psych 181: Dr. Anagnostaras Lec 7: Schizophrenia and Parkinson's Disease John Nash

Psych 181: Dr. AnagnostarasLec 7: Schizophrenia and

Parkinson's DiseaseJohn Nash

Page 2: Psych 181: Dr. Anagnostaras Lec 7: Schizophrenia and Parkinson's Disease John Nash

Incidence about 1 in 100

Page 3: Psych 181: Dr. Anagnostaras Lec 7: Schizophrenia and Parkinson's Disease John Nash

SchizophreniaPositive Symptoms

Excesses, exaggerations, or distortions (+)

Disorganized speechindicating a thought disorder (loose association to word

salad)Hallucinationssensory experiences without external stimulationcommonly auditoryDelusionsbeliefs that are contrary to realitycommonly persecutory in naturesometimes delusions of grandeur

Page 4: Psych 181: Dr. Anagnostaras Lec 7: Schizophrenia and Parkinson's Disease John Nash

SchizophreniaNegative Symptoms

Characterized by behavioral deficits (–)

Avolitionlack of energy & inability to persist in routine activities

Alogia (poverty of speech)reduction in the amount or content of speech

Anhedoniainability to experience pleasure

Asocialitysevere impairment in social relationships

Flat Affect or Incongruent Affectlack of or inappropriate emotional expression

Page 5: Psych 181: Dr. Anagnostaras Lec 7: Schizophrenia and Parkinson's Disease John Nash

At least 2 of the following for 1 month:delusionshallucinationsdisorganized speechdisorganized or catatonic behaviornegative symptoms

Marked functional impairmentContinuous signs for 6 monthsNot due to drugs (e.g., amphetamine psychosis)

DSM-IV Criteria

Page 6: Psych 181: Dr. Anagnostaras Lec 7: Schizophrenia and Parkinson's Disease John Nash

Type I versus Type II

Page 7: Psych 181: Dr. Anagnostaras Lec 7: Schizophrenia and Parkinson's Disease John Nash
Page 8: Psych 181: Dr. Anagnostaras Lec 7: Schizophrenia and Parkinson's Disease John Nash

An Array of Related Psychotic Disorders

Page 9: Psych 181: Dr. Anagnostaras Lec 7: Schizophrenia and Parkinson's Disease John Nash

Three Subtypes of Schizophrenia (DSM-IV)

Paranoid Typepreoccupation with delusions and hallucinations

no disorganized speech catatonia or flat affect

Disorganized TypeDisorganized speech, behavior, often inappropriate

does not meet criteria for Catatonic Type

Catatonic TypeClinical picture with at least two:

motoric immobility, catalepsy, stupor (waxy inflexibility)

excessive motor activity that is apparently purposeless

extreme negativism or mutism

peculiarities of movement (e.g., voluntary assumption of bizarre postures), stereotypies, odd mannerisms, or grimacing

echolalia or echopraxia

Page 10: Psych 181: Dr. Anagnostaras Lec 7: Schizophrenia and Parkinson's Disease John Nash
Page 11: Psych 181: Dr. Anagnostaras Lec 7: Schizophrenia and Parkinson's Disease John Nash
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Ho

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Year

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Page 18: Psych 181: Dr. Anagnostaras Lec 7: Schizophrenia and Parkinson's Disease John Nash
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Page 22: Psych 181: Dr. Anagnostaras Lec 7: Schizophrenia and Parkinson's Disease John Nash

Increase in DA transmission exacerbates SchizophreniaDecrease in DA neurotransmission is therapeutic

Page 23: Psych 181: Dr. Anagnostaras Lec 7: Schizophrenia and Parkinson's Disease John Nash
Page 24: Psych 181: Dr. Anagnostaras Lec 7: Schizophrenia and Parkinson's Disease John Nash

Neuroleptic or Antipsychotic

• Literally means thins neural transmission

• In practice both terms refer to drugs used to treat schizophrenia only

• Wide variety of off-label applications

• Incorrectly known as "major tranquilizers"

Page 25: Psych 181: Dr. Anagnostaras Lec 7: Schizophrenia and Parkinson's Disease John Nash

Dopamine

Schizophrenia is thought to be caused by an overactive dopamine system in the brain.

Just block the dopamine Only helps positive symptoms

Not the whole picture (i.e. glutamate, 5-HT)

Page 26: Psych 181: Dr. Anagnostaras Lec 7: Schizophrenia and Parkinson's Disease John Nash

Dopamine Antagonist Drugs chlorpromazine SmithKlineFrench in 1950

ThorazineDerivative of phenothiazine (anti-emetic)

Very sedating at first but tolerance builds

Some anti cholinergic activity

Actively metabolized (Half life of 30hrs)

Tardive Dyskinesia

Page 27: Psych 181: Dr. Anagnostaras Lec 7: Schizophrenia and Parkinson's Disease John Nash

Side effects of neurolepticsParkinsonism Dystonia - abnormal face and body movements Akathisia (restlessness) Tardive dyskinesia (long term) Exacerbated by drug holiday regime More common in females Worsened in response to reducing drug Irreversible (denervation supersensitivity)Many undesirable side effects (e.g., constipation, metabolic syndrome, lactation, and retrograde ejaculation)

Page 28: Psych 181: Dr. Anagnostaras Lec 7: Schizophrenia and Parkinson's Disease John Nash
Page 29: Psych 181: Dr. Anagnostaras Lec 7: Schizophrenia and Parkinson's Disease John Nash

More DA Antagonists

haloperidol (Haldol)• Long time in the body. Only 60%

excreted in the first week.• Depressent fluphenazine (Permitil & Prolixin)• less sedating

Tardive Dyskinesia

Page 30: Psych 181: Dr. Anagnostaras Lec 7: Schizophrenia and Parkinson's Disease John Nash
Page 31: Psych 181: Dr. Anagnostaras Lec 7: Schizophrenia and Parkinson's Disease John Nash

Newer Drugs Dibenzodiazapine derivatives Treat positive and negative symptoms Some have less or less severe side

effects Some have more potential for liver

damage Expensive

Page 32: Psych 181: Dr. Anagnostaras Lec 7: Schizophrenia and Parkinson's Disease John Nash

Newer drugs clozapine (Clozaril)

Treats positive and negative symptoms

Half Life of 12 hrs

Limited to treatment resistant patients

Strong risk of seizures

Anticholinergic, adrenolytic, antihistaminic and antiserotonergic activity.

Page 33: Psych 181: Dr. Anagnostaras Lec 7: Schizophrenia and Parkinson's Disease John Nash

Newer drugs risperidone (Risperdal)

Blocks DA and 5-HT receptors.

Dose related mild Parkinsonian side effects

Some cases of cardiac hypotension

Approved for autism to quell violence, and used widely in children with “Emotional disturbance”

olanzapine (Zyprexa)

Binds to lots of DA and 5-HT receptors

Lower Tardative Diskinesia risk

Lower seizure riskCan be given once every 2 weeks as a depot

Page 34: Psych 181: Dr. Anagnostaras Lec 7: Schizophrenia and Parkinson's Disease John Nash

Newer drugs quetiapine (Seroquel)

Blocks DA, 5-HT, and NE receptors

High sedation

Low tardive dyskinesia risk

Lower seizure risk ziprasidone(Geodon)

Blocks DA, 5-HT, NE, and Histamine receptorsHigh metabolic syndrome riskBlack box warning for QTc interval increase

Apriprazole (Abilify) – marketed for bipolar mania Paliperidone (INVEGA) – active metabolite of risperidone

Page 35: Psych 181: Dr. Anagnostaras Lec 7: Schizophrenia and Parkinson's Disease John Nash

Olanzepine = 5-HT2, M1

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Page 38: Psych 181: Dr. Anagnostaras Lec 7: Schizophrenia and Parkinson's Disease John Nash

For Thu Pre-pulse inhibition of startle

Page 39: Psych 181: Dr. Anagnostaras Lec 7: Schizophrenia and Parkinson's Disease John Nash

DA Model of Schizophrenic Dysfunction

Page 40: Psych 181: Dr. Anagnostaras Lec 7: Schizophrenia and Parkinson's Disease John Nash

What do these people have in common?

Page 41: Psych 181: Dr. Anagnostaras Lec 7: Schizophrenia and Parkinson's Disease John Nash
Page 42: Psych 181: Dr. Anagnostaras Lec 7: Schizophrenia and Parkinson's Disease John Nash

James Parkinson, 1817“ ...involuntary tremulous motion, with lessened muscular power, in parts not in action and even when supported; with a propensity to bend the trunk forwards, and to pass from a walking to a funning pace, the senses and the intellects uninjured.”• rhythmic tremor at rest• rigidity with “cog-wheel characteristic”• akinesia• Also causes depression

Clinical Characteristics

Page 43: Psych 181: Dr. Anagnostaras Lec 7: Schizophrenia and Parkinson's Disease John Nash

Pathology of Parkinson's

• Death of Dopamine neurons in the Substantia Nigra

• Loss of Dopamine in the Caudate

• Loss of Inhibition in the Caudate

• Overactive output (globus pallidus) to the thalamus

• Thalamus overinhibits the motor cortex

• Complex basal ganglia-cortical loops

Page 44: Psych 181: Dr. Anagnostaras Lec 7: Schizophrenia and Parkinson's Disease John Nash

EPIDEMIOLOGY

• fifth or sixth decade of life

• 85% idiopathic

• prevalence: 3 per 1000

• cumulative life-time risk: 1 in 40

• approximately 1 million patients

• no cure

Page 45: Psych 181: Dr. Anagnostaras Lec 7: Schizophrenia and Parkinson's Disease John Nash

ETIOLOGY

Genetic Factors

1999 - examined 17,000 twins > 50 years old: no genetic effect < 50 years old: 10 % genetic defect

(13 known genes)

Diet↓ vitamins, antioxidants ⇒ ↑

incidence

Smoking ⇒ ↓ incidence

Environment↑ incidence in rural areas

dopamine neuron toxins

Page 46: Psych 181: Dr. Anagnostaras Lec 7: Schizophrenia and Parkinson's Disease John Nash

Rotenone

[Cyperquat]

Page 47: Psych 181: Dr. Anagnostaras Lec 7: Schizophrenia and Parkinson's Disease John Nash

XXXX--> for after exam

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Mona Thiruchelvam, Eric K. Richfield, Raymond B. Baggs, Arnold W. Tank, and Deborah A. Cory-SlechtaThe Nigrostriatal Dopaminergic System as a Preferential Target of Repeated Exposures to Combined Paraquat and Maneb: Implications for Parkinson's Disease J. Neurosci. 2000 20: 9207-9214.

Paraquat + Maneb impairs movement

Page 51: Psych 181: Dr. Anagnostaras Lec 7: Schizophrenia and Parkinson's Disease John Nash

Paraquat + Maneb depletes Dopamine

Mona Thiruchelvam, Eric K. Richfield, Raymond B. Baggs, Arnold W. Tank, and Deborah A. Cory-SlechtaThe Nigrostriatal Dopaminergic System as a Preferential Target of Repeated Exposures to Combined Paraquat and Maneb: Implications for Parkinson's Disease J. Neurosci. 2000 20: 9207-9214.

Page 52: Psych 181: Dr. Anagnostaras Lec 7: Schizophrenia and Parkinson's Disease John Nash

Normal

Page 53: Psych 181: Dr. Anagnostaras Lec 7: Schizophrenia and Parkinson's Disease John Nash

STAGES OF PARKINSON'S DISEASE

DOPAMINE(% control)

ADAPTIVECAPACITY

0

20

40

60

80

100

DECOMPENSATION

COMPENSATION-no symptoms

MILD SYMPTOMS

MARKED SYMPTOMS

Page 54: Psych 181: Dr. Anagnostaras Lec 7: Schizophrenia and Parkinson's Disease John Nash
Page 55: Psych 181: Dr. Anagnostaras Lec 7: Schizophrenia and Parkinson's Disease John Nash
Page 56: Psych 181: Dr. Anagnostaras Lec 7: Schizophrenia and Parkinson's Disease John Nash

• Main treatment is with L-DOPAPrecursor for dopamine

• Sinemet is L-DOPA + carbidopa carbidopa is a peripheral decarboxylase inhibitor

- prevents L-DOPA catabolism• Main problems:

- on/off fluctuations- dyskinesias- eventually doesn’t work- peripheral side effects (NE and E)

• Anticholinergics help as well• On-off fluctuations too great with DA agonists

Levodopa therapy

Page 57: Psych 181: Dr. Anagnostaras Lec 7: Schizophrenia and Parkinson's Disease John Nash

Drugs used to treat Parkinson’s Disease

Page 58: Psych 181: Dr. Anagnostaras Lec 7: Schizophrenia and Parkinson's Disease John Nash
Page 59: Psych 181: Dr. Anagnostaras Lec 7: Schizophrenia and Parkinson's Disease John Nash

Parkinson’s: Outlook

• Chronic dopamine treatment can also result in Schizophrenic symptoms

• Several surgical treatments for Parkinson’s- used after therapeutic window closes- stem cell transplantation- pallidotomy and thalamotomy- stimulators