Schizophrenia
CLINICAL EXPRESSION AND CORE CONCEPT
A disorder of distorted mental experience, with disruption in how the
brain generates and interprets internal thoughts and external
sensory information.
Core clinical description: distortion of thought and perception,
and sometimes mood.
Typical onset: adolescence/early adulthood -> aligns with late
brain maturation of higher cognitive regions.
Aetiology: strong hereditary component, but not inevitable (genetic
risk increases probability, not certainty).
CLINICAL FEATURES: POSITIVE VS NEGATIVE SYMPTOMS
Positive symptoms (Type I)
Presence of abnormal thoughts/behaviours:
o Delusions, often paranoid (fixed false beliefs).
o Hallucinations (e.g., hearing voices).
o Thought disorder - inserted thoughts (disrupted sense of
thought ownership/agency).
o Disorganised speech (behavioural output of disordered
thought structure).
Negative symptoms (Type II)
Absence of normal responses/behaviours:
o Reduced expression of emotion (blunted affect).
o Social withdrawal.
o Poverty of speech.
Can be harder to detect - look like reduced normal behaviour rather
than obviously abnormal behaviour.
Key:
Not one single uniform illness: it’s heterogeneous, with subtypes
and variable symptom profiles.
Positive symptoms often drive diagnosis (they are “louder”), while
negative/cognitive changes may have been present earlier but only
become obvious in hindsight.
THE DOPAMINE HYPOTHESIS: CURRENT STATUS + LIMITATIONS
What the evidence supports
Dopamine hyperactivity as a real and measurable feature in
schizophrenia.
DA hyperactivity demonstrated in patients.
, Drug-naïve patients show increased DA synthesis (reduces the “it’s
just medication effects” argument).
Basal and amphetamine-induced DA release is elevated.
Correlates with acute episodes and with responsiveness to
antipsychotic treatment.
Why it’s considered overly simplistic
Even if dopamine is involved, it may not be the primary driver of the
disorder.
Neuroleptics take weeks to work - suggests symptom improvement
may depend on slower secondary changes rather than immediate
receptor blockade alone.
They mainly reduce positive symptoms, leaving negative/cognitive
problems less treated.
THE GLUTAMATE/NMDA HYPOTHESIS (PRIMARY DEFECT MODEL)
Reframes schizophrenia as fundamentally a glutamatergic disorder, where
dopamine changes are secondary.
Core claim: glutamatergic hypoactivity is primary, dopamine
hyperactivity is secondary.
NMDA antagonists as a “drug model” of psychosis
NMDA receptor blockade -> reducing NMDA transmission can
reproduce a schizophrenia-like state -> therefore schizophrenia is
correlated with NMDA receptor hypofunction.
PCP is a non-competitive NMDA channel blocker; can be clinically
indistinguishable from acute paranoid schizophrenia.
Produces both Type I and Type II symptoms (vs amphetamine maps
more onto Type I-like effects).
Intensifies psychotic symptoms in schizophrenic patients.
Other antagonists are similar, ketamine noted.
NMDA knockdown mice
Converging evidence that NMDA hypofunction can produce Type II-
like behavioural changes.
Only 5–10% of normal NMDA receptor function vs wild-type.
Behavioural changes described as Type II-like:
o Decreased social interaction
o Decreased mating frequency
o Increased escape behaviour.
Reported as reversed by antipsychotics (possibility).
HOW GLUTAMATE HYPOFUNCTION COULD CREATE “DOPAMINE
IMBALANCE”
CLINICAL EXPRESSION AND CORE CONCEPT
A disorder of distorted mental experience, with disruption in how the
brain generates and interprets internal thoughts and external
sensory information.
Core clinical description: distortion of thought and perception,
and sometimes mood.
Typical onset: adolescence/early adulthood -> aligns with late
brain maturation of higher cognitive regions.
Aetiology: strong hereditary component, but not inevitable (genetic
risk increases probability, not certainty).
CLINICAL FEATURES: POSITIVE VS NEGATIVE SYMPTOMS
Positive symptoms (Type I)
Presence of abnormal thoughts/behaviours:
o Delusions, often paranoid (fixed false beliefs).
o Hallucinations (e.g., hearing voices).
o Thought disorder - inserted thoughts (disrupted sense of
thought ownership/agency).
o Disorganised speech (behavioural output of disordered
thought structure).
Negative symptoms (Type II)
Absence of normal responses/behaviours:
o Reduced expression of emotion (blunted affect).
o Social withdrawal.
o Poverty of speech.
Can be harder to detect - look like reduced normal behaviour rather
than obviously abnormal behaviour.
Key:
Not one single uniform illness: it’s heterogeneous, with subtypes
and variable symptom profiles.
Positive symptoms often drive diagnosis (they are “louder”), while
negative/cognitive changes may have been present earlier but only
become obvious in hindsight.
THE DOPAMINE HYPOTHESIS: CURRENT STATUS + LIMITATIONS
What the evidence supports
Dopamine hyperactivity as a real and measurable feature in
schizophrenia.
DA hyperactivity demonstrated in patients.
, Drug-naïve patients show increased DA synthesis (reduces the “it’s
just medication effects” argument).
Basal and amphetamine-induced DA release is elevated.
Correlates with acute episodes and with responsiveness to
antipsychotic treatment.
Why it’s considered overly simplistic
Even if dopamine is involved, it may not be the primary driver of the
disorder.
Neuroleptics take weeks to work - suggests symptom improvement
may depend on slower secondary changes rather than immediate
receptor blockade alone.
They mainly reduce positive symptoms, leaving negative/cognitive
problems less treated.
THE GLUTAMATE/NMDA HYPOTHESIS (PRIMARY DEFECT MODEL)
Reframes schizophrenia as fundamentally a glutamatergic disorder, where
dopamine changes are secondary.
Core claim: glutamatergic hypoactivity is primary, dopamine
hyperactivity is secondary.
NMDA antagonists as a “drug model” of psychosis
NMDA receptor blockade -> reducing NMDA transmission can
reproduce a schizophrenia-like state -> therefore schizophrenia is
correlated with NMDA receptor hypofunction.
PCP is a non-competitive NMDA channel blocker; can be clinically
indistinguishable from acute paranoid schizophrenia.
Produces both Type I and Type II symptoms (vs amphetamine maps
more onto Type I-like effects).
Intensifies psychotic symptoms in schizophrenic patients.
Other antagonists are similar, ketamine noted.
NMDA knockdown mice
Converging evidence that NMDA hypofunction can produce Type II-
like behavioural changes.
Only 5–10% of normal NMDA receptor function vs wild-type.
Behavioural changes described as Type II-like:
o Decreased social interaction
o Decreased mating frequency
o Increased escape behaviour.
Reported as reversed by antipsychotics (possibility).
HOW GLUTAMATE HYPOFUNCTION COULD CREATE “DOPAMINE
IMBALANCE”
