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Treatment of the Psychotic Disorders: Schizophrenia. Karl Kashfi. What is schizophrenia?. A mental illness among the world’s 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

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Treatment of the Psychotic Disorders: Schizophrenia


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what is schizophrenia
What is schizophrenia?
  • A mental illness among the world’s 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
epidemiology and prevalence
Epidemiology and Prevalence
  • Affects 1% of the population at any one time!
  • Gender-based variations in prevalence of schizophrenia (men>women?)
  • Cross-cultural variations in prevalence and the nature of the illness?
symptoms
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
etiology and risk factors
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
onset course and prognosis
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
review neurotransmitters
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
important neurotransmitters
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
history of drug discovery
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!
mechanism of action
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.
other hypotheses
Other Hypotheses
  • If the dopamine hypothesis is true, then blockade of D2 receptors by antipsychotics should provide immediate reversal of psychosis, BUT this doesn’t 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
first generation antipsychotics
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.
side effects
Side Effects!
  • Severe symptoms are associated with 1st generation antipsychotics, known asExtrapyramidal 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.
more problems
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.
dopaminergic neural pathways
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
motivational salience
“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
dopaminergic neural pathways25
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.
second generation antipsychotics
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
clozapine side effects
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.
2 nd generation antipsychotics
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
prognosis of treated patients
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!
what does the future hold
What does the future hold?
  • Potentiation techniques
    • D-cycloserine
    • New receptor targets (NMDA receptor)
  • New neurotransmitter systems
    • Dopamine-glutamate
    • Dopamine-acetylcholine
  • Pharmacogenomics