Treatment of the Psychotic Disorders: Schizophrenia

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Treatment of the Psychotic Disorders
Schizophrenia

• Karl Kashfi

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What is schizophrenia?

• A mental illness among the worlds top ten causes
  of long-term disability
• Develops between the ages of 16 and 30
• Cause is unknown, but various theories have been
  proposed in regards to a biological cause
• In addition to biological causes, studies
  indicate a multitude of genetic and environmental
  factors

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Epidemiology and Prevalence

• Affects 1 of the population at any one time!
• Gender-based variations in prevalence of
  schizophrenia (mengtwomen?)
• Cross-cultural variations in prevalence and the
  nature of the illness?

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Symptoms

• The trademark of schizophrenia is an impairment
  in the perception of reality, though there are
  many other symptoms.
• Three broad types of symptoms
• Psychotic (positive) symptoms
• Delusions and hallucinations
• Negative symptoms
• Diminution of basic emotional and behavioral
  processes
• Cognitive impairment
• Decline in concentration and thinking

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Etiology and Risk factors

• Genetic factors
• Higher rates of illness among relatives of a
  patient than in general population
• Environmental factors
• Prenatal/obstetric complications
• Brain abnormalities
• Poverty and low social class (two reasons)
• Urban residents, migrants, and minorities

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Onset, Course, and Prognosis

• Onset of schizophrenia age 16-30 (usually
  earlier in men than in women)
• Onset lasts 5 years
• Prodrome
• Cognitive impairment
• Psychosis/hospitalization
• Psychosis is episodic over time negative
  symptoms are more stable
• No cure less than average life-expectancy

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Review Neurotransmitters

• Neurotransmitters are the chemical messengers of
  the nervous system
• They relay electrical signals from one neuron to
  the next in a series of steps
• Calcium influx
• Exocytosis from presynaptic neuron
• Diffusion across synapse
• Fusion with postsynaptic neuron and generation of
  impulse
• Neurotransmitters can be excitatory or inhibitory

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Important neurotransmitters

• Biogenic amines play a role in emotional
  behavior
• Dopamine
• Catecholamine (like epinephrine, norepinephrine)
• Synthesized from amino acid tyrosine
• Can be inhibitory or excitatory (depends on
  receptor)
• Feeling good neurotransmitter
• Seritonin (5-HT)
• Indolamine
• Synthesized from amino acid tryptophan
• Sleep, appetite, mood

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History of Drug Discovery

• 1950s Chlorpromazine found to induce neurolepsy
  in animals and reduce psychosis in psychotic
  patients.
• These compounds were found to increase metabolism
  of dopamine (less dopamine)
• Conclusion 1 Good antipsychotic!
• Conclusion 2 If less dopamine means less
  psychosis, then high dopamine must mean more
  psychosis!

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Mechanism of Action

• Inverse relationship found between doses of
  antipsychotics and their affinity for the
  dopamine D2 receptors in the brain.
• The observations of the 1950s led to the Dopamine
  Hypothesis
• Excess dopamine leads to psychosis
• Blockade of postsynaptic D2 receptors should
  provide reversal of psychotic features of
  schizophrenia due to negative feedback reactions.

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Other Hypotheses

• If the dopamine hypothesis is true, then blockade
  of D2 receptors by antipsychotics should provide
  immediate reversal of psychosis, BUT this doesnt
  happen.
• A majority of patients require 2-4 weeks for a
  response
• Some never even improve appreciably after
  prolonged use of antipsychotics.
• WHY?
• Depolarization Inactivation Hypothesis
• Multiple gene action delay

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First Generation Antipsychotics

• The discovery of chlorpromazine set the stage for
  the era of the first-generation antipsychotics
• Not everyone, however, responded equally
• 1/3 of patients improved completely, 1/3
  partially, and 1/3 showed little recovery
• Drug potency inversely related to affinity for
  the D2 receptor sites
• The dose requirements for 1st generation
  antipsychotics follow a sigmoidal curve relative
  to efficacy.
• Antipsychotic effects occur in presence of 70
  occupancy of the D2 receptors.

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• Chlorpromazine

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Side Effects!

• Severe symptoms are associated with 1st
  generation antipsychotics, known as
  Extrapyramidal Symptoms
• Dystonias
• Akathisia
• Pseudo-Parkinsonian symptoms
• Unfortunately, therapeutic doses tend to be quite
  close to those which cause EPS
• Other side effects include prolactin increase and
  tardive dyskinesia.

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More Problems

• Another problem with 1st generation
  antipsychotics They suppress positive
  (psychotic) symptoms of schizophrenia, but the
  negative symptoms remain!
• WHY? Because of NON-SPECIFICITY in dopamine
  receptor blockade.

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Dopaminergic Neural Pathways

• Several neural pathways which utilize dopamine
  are located in the midbrain of the brainstem, and
  they mediate such things as emotion,
  fight-or-flight responses, motivation, etc.
• They are projections from the limbic system
• These include
• Mesolimbic pathway
• Mesocortical pathway
• Nigrostriatal pathway

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Motivational salience

• Mesolimbic dopamine pathways are involved in
  motivational and reward-associated stimuli
• What is the relationship between these pathways
  and the symptoms of schizophrenia?
• Motivational salience theory

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Dopaminergic Neural Pathways

• Blockage by antipsychotics of dopamine receptors
  in mesolimbic pathway reduction of positive
  (psychotic) symptoms
• However, antipsychotics also non-specifically
  block the mesocortical and striatal pathways,
  leading to EPS and prolonging of negative
  symptoms.

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Second generation Antipsychotics

• Clozapine introduced 1970s
• 1st of the second generation antipsychotics
• Second generation antipsychotics atypical
  antipsychotics
• Atypical because EPS is absent!
• Other beneficial properties include reduction of
  negative symptoms
• This is because serotonin receptors are blocked
  as well as dopamine receptors

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Clozapine Side Effects

• Clozapine Gold standard in treating
  schizophrenia
• Has been shown to reduce aggression, substance
  abuse, and treat other mood-related disorders
• Unfortunately, though very potent, its primary
  problem is agranulocytosis.

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2nd generation antipsychotics

• Other 2nd generation antipsychotics exist, which
  work by the same mechanism as clozapine
• Risperidone
• Olanzipine
• Quetiapine
• Ziprasidone
• Unfortunately, these also come with side effects,
  which vary with the medication
• Metabolic disorders (glucose)
• Weight gain
• Increased prolactin release

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Prognosis of treated patients

• The success of outcome is a function of the
  promptness of treatment following onset
• Cognitive function is a relevant parameter in
  prognosis
• Overall, life expectancy is still shortened when
  compared to the general population due to side
  effects, stigma, and decreased quality of life.
• Anosognosia!

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What does the future hold?

• Potentiation techniques
• D-cycloserine
• New receptor targets (NMDA receptor)
• New neurotransmitter systems
• Dopamine-glutamate
• Dopamine-acetylcholine
• Pharmacogenomics