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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
• In addition to biological causes, studies
indicate a multitude of genetic and
environmental factors
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
• 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
• 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 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
• 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
• 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
• 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
• 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
• 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
• 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.
Chlorpromazine
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.
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
• Several neural pathways which utilize dopamine
are located in the midbrain of the brainstem, and
they mediate such things as emotion, fight-orflight responses, motivation, etc.
• They are projections from the limbic system
• These include:
– Mesolimbic pathway
– Mesocortical pathway
– Nigrostriatal pathway
“Motivational salience”
• Mesolimbic dopamine pathways are
involved in motivational and rewardassociated stimuli
• What is the relationship between these
pathways and the symptoms of
schizophrenia?
• “Motivational salience” theory
Dopaminergic Neural Pathways
• Blockage by antipsychotics of dopamine
receptors in mesolimbic pathway –
reduction of positive (psychotic) symptoms
• However, antipsychotics also nonspecifically block the mesocortical and
striatal pathways, leading to EPS and
prolonging of negative symptoms.
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 – “Gold standard” in treating
schizophrenia
• Has been shown to reduce aggression,
substance abuse, and treat other moodrelated disorders
• Unfortunately, though very potent, its
primary problem is agranulocytosis.
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
• 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?
• Potentiation techniques
– D-cycloserine
– New receptor targets (NMDA receptor)
• New neurotransmitter systems
– Dopamine-glutamate
– Dopamine-acetylcholine
• Pharmacogenomics