Schizophrenia

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Schizophrenia

• Features, Diagnosis, Epidemiology, Etiology,
  Treatment, Neurochemistry
• Andrew P Mallon PhD MRPS

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Features of Schizophrenia - Positive Symptoms

• Hallucinations
• Disorganized speech/thinking/behavior
• Delusions

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(from The Hour of the Wolf, directed by Ingmar
Bergman)
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Features of Schizophrenia - Negative Symptoms

• Affective flattening
• Alogia
• Avolition
• Anhedonia
• Social Withdrawal

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Features of Schizophrenia - Cognitive Deficits

• Attention
• Memory
• Executive functions (organization, planning)

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Schizophrenia - DSM Diagnostic Criterion A

• Characteristic Sxs (2 for 1 month)
• delusions
• hallucinations
• disorganized speech
• grossly disorganized or catatonic behavior
• negative Sxs (flat affect, alogia, avolition)
• (Only one element required if delusions bizarre,
• or hallucinations commentary 2 voices conversing
  )

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Schizophrenia - DSM Diagnostic Criteria B - F

• Social/occupational dysfunction (decline)
• Duration - 6 months total, 1 month A Sxs
• Exclusion - SAFD, mood d/o
• Exclusion - sub abuse, gen med condition
• PDD/Autism - at least 1 month delusions or
  hallucinations

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Schizophrenia - Comorbid Conditions

• Depression
• Anxiety
• Aggression
• Substance use disorder

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Schizophrenia Who is at Risk?

• Lifetime prevalence
• Epidemiologic Catchment Area Study 1.3
• National Comorbidity Survey 0.7
• Demographic characteristics
• Age - typical onset late teens/early twenties
• Gender - earlier age of onset among men
• Marital status - less likely to be married

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Schizophrenia Who is at Risk?

• Predisposing factors
• Season of birth
• Pregnancy and birth complications
• Genetic background
• Precipitating factors
• Stress
• Substance Abuse

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In addition to interfering with normal brain
development, heavy marijuana use in adolescents
may also lead to an earlier onset of
schizophrenia in individuals who are genetically
predisposed Dr Sanjiv Kumra, Albert Einstein
College of Medicine
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Carriers of the COMT valine158 allele were most
likely to exhibit psychotic symptoms and to
develop schizophreniform disorder if they used
cannabis. Cannabis use had no such adverse
influence on individuals with two copies of the
methionine allele. Caspi A, et al. Biological
Psychiatry.2005 571117-1127.
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Genetic Risk Factors

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Etiology Neurodevelopmental Hypothesis

• Possible insult during gestation, environmental
  influences
• Disturbance in normal brain maturation
• Reduced size medial temporal lobe structures -
  amygdala, hippocampus
• Disturbed cytoarchitecture in hippocampus,
  entorhinal cortex

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Treatment Psychosocial Interventions

• Supportive therapy
• Behavioral family therapy
• Family education
• Social skills training
• Community support
• Lower relapse improved functioning, compliance
  and social adjustment

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Treatment Antipsychotics

• Used to treat psychotic disorders, such as
  schizophrenia, mania, psychotic depression
• Include both typicals (Haldol) and atypicals
  (Clozaril, Risperdal)

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Typical Antipsychotics

• Chlopromazine (Thorazine) - prototype
• Thioridazine (Mellaril)
• Fluphenazine (Prolixin)
• Haloperidol (Haldol)

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Typical Antipsychotics Drug/Receptor Effects

• Antidopaminergic (D2)
• Anticholinergic
• Antihistaminic
• Anti-alpha 1

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Effects of Typical Antipsychotics

• Four dopamine pathways
• Mesocortical (negative symptoms)
• Mesolimbic (positive symptoms)
• Nigrostriatal (EPS, TD)
• Tuberoinfundibular (hyperprolactinemia)

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Guillin O and Laruelle M. Cellscience Reviews.
2005 279-107
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DA Receptor Distribution

• D1- prefrontal cortex, striatum
• D5 - hippocampus and entorhinal cortex
• D2 striatum, low concentration in medial
  temporal structures (hippocampus, entorhinal
  cortex, amygdala), thalamus, prefrontal cortex
• D3 striatum and ventral striatum
• D4 - prefrontal cortex and hippocampus (have not
  been detected in the striatum)

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Guillin O and Laruelle M. Cellscience Reviews.
2005 279-107
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Side Effects of Typical Neuroleptics

• Extra-pyramidal syndrome (EPS)
• Tardive dyskinesia (TD)
• Neuroleptic malignant syndrome (NMS)
• Prolactin elevation

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Extra-Pyramidal Syndrome (EPS)

• Acute dystonia
• Akathesia
• Muscle rigidity
• Bradykinesia
• Treatment typically treated with
  anticholinergic compounds (Cogentin, Benadryl,
  Artane), Beta-blockers

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Tardive Dyskinesia (TD)

• 25-year continuous exposure risk 68 in Yale
  Incidence Study
• Annual incidence ?5
• Risk factors
• Increased age
• African-American race
• Dose and duration of drug exposure
• Early and severe EPS

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Neuroleptic Malignant Syndrome (NMS)

• Potentially fatal complication of neuroleptic Tx
• Temperature dysregulation T gt104F/40C
• Muscle rigidity
• Elevated CPK
• Elevated WBC
• Associated with TaqI A polymorphism in DRD2
• Tx withdraw neuroleptics, cooling, dantrolene,
  bromocriptine (DA agonist)

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Summary Limitations of Typical Antipsychotics

• Limited efficacy against negative symptoms
• A substantial portion of patients (25 to 40)
  respond poorly to treatment
• EPS occurs at clinically effective doses
• Side effects other than EPS (such as NMS)
• Liable to cause tardive dyskinesia
• Serum prolactin elevation

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Advantages of Typical Antipsychotics

• No blood monitoring
• Efficacious for positive symptoms
• Parenteral and depot preparations available
• Low-cost

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Antipsychotics Atypical

• Clozapine (Clozaril) - prototype
• Risperidone (Risperdal)
• Olanzepine (Zyprexa)
• Quetiapine (Seroquel)
• Ziprasidone (Geodon)
• Aripiprazole (Abilify)

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Atypical Antipsychotics Clinical and
Drug/Receptor Characteristics

• Clinically display less EPS, more effective
  against negative symptoms, some improvement in
  cognition
• Balanced D2/D1 antagonism
• Strong 5HT2 antagonists

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Serotonin-Dopamine Antagonists and TD
Hypothesized Site-Specific Neuromechanisms

Psychosis
EPS and TD
Limbic
Cortical
Caudate/Putamen
A10
A9
Ventral Tegmental Area
Substantia Nigra
Dopamine/5HT Antagonist Conventional
Antipsychotic Agents
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Atypical Antipsychotics
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Antipsychotic Receptor Affinities

• Haloperidol (Haldol)

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Antipsychotic Receptor Affinities

• Clozapine (Clozaril)

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Antipsychotic Receptor Affinities

• Risperidone (Risperdal)

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Antipsychotic Receptor Affinities

• Olanzepine (Zyprexa)

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Antipsychotic Receptor Affinities

• Quetiapine (Seroquel)

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Ziprasidone (Geodon)

• High affinity (antagonist) for D2, D3, 5HT2a,
  5HT2c, 5HT1d
• High affinity (agonist) for 5HT1a
• Inhibits re-uptake of 5HT and NE
• Moderate affinity for H1, a1
• Low affinity for D1, a2
• Negligible affinity for M1

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Ziprasidone (Geodon), cont.

• Positive symptoms improved (PANSS)
• Negative symptoms improved (PANSS)
• Depressive symptoms improved (MADRS)
• Low EPS (5HT2a/D2, 5HT1a)
• Low weight gain (H1)
• Low sexual dysfunction
• Minimal CYP450, CBC, LFT or CV effects (some
  QTc prolongation)

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Neurotransmitter Systems Implicated in
Schizophrenia

Dopamine
Acetylcholine
Serotonin
Norepinephrine

GABA
Neuropeptides
Glutamate
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Dopamine Hypothesis

• Induction or worsening of psychotic symptoms with
  dopamine agonists
• Amelioration of psychotic symptoms with
  antipsychotic drugs that are D2-receptor
  antagonists

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Serotonin (5HT) Hypothesis

• M-CPP (m-chlorophenylpiperazine) selective 5HT
  receptor agonist worsens psychotic symptoms
• Pretreatment with ritanserin (5HT antagonist)
  attenuates psychotic symptoms

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Glutamate Hypothesis

• Psychotomimetic effects of phencyclidine (PCP), a
  potent N-methyl-D-aspartate (NMDA) type
  glutamate receptor antagonist - mimics negative,
  positive and disorganization symptoms
• Possible beneficial effects of cycloserine,
  glutamate receptor agonist

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Glutamate, Dopamine, Ketamine

• Subanesthetic doses of ketamine, a
  noncompetitive NMDA receptor antagonist, impair
  prefrontal cortex (PFC) function in the rat and
  produce symptoms in humans similar to those
  observed in schizophrenia.
• These findings suggest that ketamine may disrupt
  dopaminergic neurotransmission in the PFC as well
  as cognitive functions associated with this
  region, in part, by increasing the release of
  glutamate, thereby stimulating postsynaptic
  non-NMDA glutamate receptors.

Moghaddam B et al. J Neurosci 1997 17 2921-2927.
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Aghajanian GK, Marek GJ. Brain Res Brain Res Rev
2000 31302-312.
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Neuronal Circuits in Schizophrenia

• Thalamic nuclei relay sensory information to
  pyramidal neurons in limbic cortex and neocortex
  through glutaminergic excitatory afferents
• Excessive response of pyramidal neurons is
  putative mechanism of psychosis (overstimulation)

Freedman R. Schizophrenia. NEJM. 2003
3491738-1749.
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Neuronal Circuits in Schizophrenia

• DA from VT nucleus increases Glu response
• 5HT from dorsal raphe nucleus facilitates release
  of Glu
• Antipsychotic drugs block DA and 5HT effects
• GABA interneurons regulate Glu release
• Clozapine increases Ach (excitatory) and blocks
  LC nucleus NE (inhibitory) which leads to
  increased GABA interneuron activity

Freedman R. Schizophrenia. NEJM. 2003
3491738-1749.
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Freedman R. Schizophrenia. NEJM. 2003
3491738-1749
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