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Overview of Psychosis and Antipsychotics in Psychiatry. Fred Michel, MD June 9, 2003. Review of Terminology. Hallucinations – Sensory perceptions in absence of external stimuli Delusions – Firmly held false beliefs

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review of terminology
Review of Terminology
  • Hallucinations – Sensory perceptions in absence of external stimuli
  • Delusions – Firmly held false beliefs
  • Thought Disorder – Disruption in form or organization of thinking – inchoerence, difficulty communicating, loose associations, thought blocking, clanging, echolalia,
hx of diagnostic classification of schizophrenia
Hx of Diagnostic Classification of Schizophrenia
  • Kraeplin – 1896:
    • “Dementia Praecox” distinguished from “Manic Depressive Psychosis”.
    • Emphasized Chronic Deteriorating Course
  • Bleuler – 1911:
    • Schizophrenia as a splitting of psychic functions
    • Four A’s: Autism, Ambivalence, Loose Associations, Inappropriate Affect
    • Emphasis on NEGATIVE SYMPTOMS
hx of diagnostic classification of schizophrenia1
Hx of Diagnostic Classification of Schizophrenia
  • Schneider – 1970’s
    • First Rank Symptoms
      • Hallucinations, delusions, thought withdrawal, thought insertion, imposed feelings…
      • Emphasized POSITIVE SYMPTOMS
dsm iv dx of schizophrenia
DSM IV Dx of Schizophrenia
  • Essential Features
    • Psychotic Symptoms for at least 1 month (less if treated)
    • Functioning below the highest expected level
    • Duration of illness for at least 6 months ( including prodromal, residual phases)
slide6
Active Phase
    • Requires bizarre delusions or
    • Hallucinations where
      • Two or more voices converse w/ eachother
      • Voice keeps a running commentary on a person’s thoughts or behaviors, or
      • Two or more of the following
        • Delusions, Hallucinations, Disorganized Speech, Grossly Disorganized or Catatonic Behavior or Negative Symptoms
slide7
Prodromal or Residual Phase
    • Social Isolation, Withdrawal
    • Impairment of Functioning
    • Peculiar Behavior
    • Impaired Personal Hygiene
    • Blunted or Inappropriate Affect
    • Abnormal Speech
    • Odd Beliefs
    • Unusual Perceptual Experiences
    • Apathy
ddx of schizophrenia
DDX of Schizophrenia
  • Mood Disorders
    • Schizoaffective Disorder: Mood issues > Thought Issues when euthymic
    • Bipolar Disorder
      • Psychosis is present only during manic or depressive episodes
    • Psychotic Depression
  • Schizophreniform Disorder – Scz w < 6mo duration
  • Brief Reactive Psychosis- Psychotic sx ,1month
  • Schizotypal Personality Disorder – Fails to meet active phase of schizophrenia criteria
  • Delusional Disorder – persistent, non-bizarre delusions
  • Organic Etiologies
organic etiologies
Drugs of Abuse

Neurological Disorders

Alzheimer’s Disease

Complex Partial Seizures

Huntington’s Disease

Hydrocephalus

Lupus

Parkinson’s

Infectious Diseases

Brain abscess

Encephalitis

Infectious Mononucleosis

Meningitis

Syphilis

Endocrine Disorders

Addison’s & Cushings

Hypo/hyper Thyroidism

Hypo/hyper Parathyroidism

Organic Etiologies
organic etiologies cont
Nutritional Deficiencies

Niacine (pellagra)

Thiamine Deficiency

Korsakoff’s psychosis

Beriberi

Vitamin B12 (pernicious anemia)

Organic Etiologies (cont)
evaluation of psychosis
Evaluation of Psychosis
  • Complete Physical and Neurological Exam
  • History – Subst Use, Past Psychosis, FHx, Medical Hx, Medications.
  • Mental Status Exam
  • Laboratory Screens:
    • Electrolytes, BUN, Cr, CA, Glucose, CBC, Thyroid Pannel, Liver enzymes, VDRL, B12, Folate, HIV when indicated
  • Tox Screen
  • Brain Imaging when indicated, or w/ neurological findings
  • EEG when suspicious of absence or partial seizures
theories of etiology
Theories of Etiology
  • Dopamine Hyperactivity
    • Schizophrenia and Acute Psycosis are associated with Increased Mesolimbic Dopamine Activity
  • Serotonin Dysfunction
    • LSD – 5HT agonist
    • Clozapine & other atypical antisycotics
      • Active at 5HT2 and 5HT1C receptors
  • Two Hit Model
    • 1st Hit: Genetic Predisposition
    • 2nd Hit: Environmental Stress or Injury - hippocampus
antipsychotic medications
Antipsychotic Medications
  • Classification
    • Conventional
      • Low Potency – Chlorpromazine (Thorazine), Thioridizine (Mellaril)
      • High Potency – Haloperidol (Haldol), Fluphenazine (Prolixin), Trifluoperazine (Stelazine), Pimozide (Orap)
      • Long Acting / Depot – Oil Based Injection
        • Prolixin or Haldol Decanoate
antipsychotic medications1
Antipsychotic Medications
  • Novel or Atypical –
    • 5HT/DA Antagonists
      • Clozapine (Clozaril)
      • Risperidone (Risperdal)
      • Olanzapine (Zyprexa)
      • Quetiapine (Seroquel)
      • Ziprasidione (Geodon)
    • Dopamine Partial Agonist/Antagonist
      • Aripiprazole (Abilify)
  • D2 Receptor Blockade
    • Essential for antipsychotic efficacy
  • 5HT2 Blockade
side effects key differentiator for antipsychotics
Side Effects: Key Differentiator for Antipsychotics
  • Extrapyramidal Side Effects (EPS)
    • Common with Conventional Agents
      • High Potency >> Low Potency
    • Stiffness, shuffling gait, loss of automatic associated movements. PARKINSONIAN SX
    • Occur when > 80% of D2 Receptors are occupied
    • Therapeutic Antipsychotic Effects: 65-70% Blocked
    • “Minimal Effective Dosing” - Dose to block for tx of psychosis but avoid excessive blockaid to minimize EPS
side effects key differentiator for antipsychotics1
Side Effects: Key Differentiator for Antipsychotics
  • Acetyl choline neurons also exert INHIBITING effect on Striatal Dopamine Neurons
    • Minimizing effect of Cholinergic Neurons on Dopamine Neurons can alleviate Drug Induced EPS
    • Anticholinergic medications
      • Cogentin
      • Artane
side effects key differentiator for antipsychotics2
Side Effects: Key Differentiator for Antipsychotics
  • Serotonin (5HT) Neurons also exert INHIBITING effect on Striatal Dopamine Neurons
    • This may be why Serotonin-Dopamine Antagonists (Atypical Agents) cause less EPS than Conventional Antipsychotics
side effects key differentiator for antipsychotics3
Side Effects: Key Differentiator for Antipsychotics
  • Postural Hypotension – Low Potency Agents
  • Somnolence – Low Potency Agents
  • Akathisia – Sense of restlessness
    • “ants in pants”
    • Tx with decreased dose, beta blockers, BZD’s
    • Some try Cogentin, Artane, Benadryl
side effects key differentiator for antipsychotics4
Side Effects: Key Differentiator for Antipsychotics
  • Tardive Dyskinesia
    • Etiology:Supersensitivity of DA Receptors from chronic blockade
    • Frequency:
      • Conventionals – 4 %/yr
      • Atypical/Novel Agents – 0.5%/yr
    • Increased risk with:
      • higher potency
      • longer exposure
      • conventional, typical agents
    • Tx with:
      • decr dose
      • switch to novel agents, esp Clozapine
side effects key differentiator for antipsychotics5
Side Effects: Key Differentiator for Antipsychotics
  • Neuroleptic Malignant Syndrome
    • Fever
    • Muscle Rigidity
    • Two of following:
      • Diaphoresis, dysphagia, tremor, incontinence, tachycardia, labile BP, lecuocytosis, incr CPK
    • DDX:
      • Other causes of fever – infection
      • Heat Stroke, Malignant Hyperthermia
      • Parkinsons disease
      • Catatonia
side effects key differentiator for antipsychotics6
Side Effects: Key Differentiator for Antipsychotics
  • Prolactin Elevation
    • Conventional Antipsychotics – common
      • A consequence of D2 Receptor Blockade in Hypothalamus
        • Some used to titrate Conventionals up in dose till prolactin level elevated
    • Atypical Agents
      • Risperdal > Zyprexa >> Clozapine, Seroquel, Geodon > Abilify
    • Consequences of Prolactin Elevation:
      • Amenorrhea, Gynecomastia, Glactorrhea, Impotence, Decreased Bone Density
side effects key differentiator for antipsychotics7
Side Effects: Key Differentiator for Antipsychotics
  • Weight Gain
    • More common in Novel or Atypical agents than in Traditional/Conventional agents
    • Novel agents:
      • Zyprexa = Clozapine >> Risperdal > Seroquel
      • Weight Neutral: Geodon, Abilify
  • Diabetes – Increased risk with atypical antipsychotics!
    • Clozapine & Zyprexa – incr risk of DKA
side effects key differentiator for antipsychotics8
Side Effects: Key Differentiator for Antipsychotics
  • Agranulocytosis
    • Clozapine
    • Rare but occurs 0.5 – 1%
    • More rare with other atypicals
    • Requires WBC checks Q 1-2 weeks
  • Cardiac Side Effects
    • QT Elongation – incr risk of arrythmia
    • Most pronounced with: Mellaril (thioridizine), Inapsine (dorperidol)
    • Mild Increase with Geodon (Ziprasidone)
    • Minimal Increase with Risperdal, Haldol, Zyprexa
efficacy
Efficacy
  • Conventional Agents
    • Solid and Equal efficacy on POSITIVE SX
    • Limited efficacy on NEGATIVE SX
  • All Other Novel / Atypical Agents(except Clozapine)
    • Equal efficacy on POSITIVE SX
    • Better Efficacy on NEGATIVE SX
  • Clozapine
    • Better efficacy on POSITIVE SX
    • Better efficacy on NEGATIVE SX
treatment resistance
Treatment Resistance
  • When Positive Sx do not decrease:
    • Was trial adequate in terms of:
      • Dosing?
      • Duration?
    • If one antipsychotic fails another may work
      • Atypicals are tremendously different in terms of receptor affinity and diversity
    • If two antipsychotics fail chances for success diminish very rapidly
    • Clozapine offers best hope after 2 failures (30-50% Response)
    • Augmentation with mood stabilzers may improve response
    • Supplementation with another atypical is common practice but not evidence based