2 Neuroscience2.11 Integrated neurobiology of syndromes and states
2.11.9 Psychosis
2 min read2 figures
Written by Resident Doctor Committee · Published
Dopamine hypothesis
Version | Claim |
|---|---|
I (1960s to 1970s) | Global dopamine excess, based on dopamine D2 receptor affinity tracking antipsychotic potency and on amphetamine psychosis; it could not explain negative symptoms |
II (revised) | Mesolimbic overactivity causes positive symptoms; mesocortical underactivity causes negative and cognitive symptoms |
III (Howes and Kapur) | Raised presynaptic striatal dopamine synthesis is the final common pathway on which genetic, obstetric, social and drug risks converge |
Aberrant salience (Kapur) is the idea that mesolimbic dopamine overactivity gives irrelevant events importance, and delusions and hallucinations follow.
Raised presynaptic dopamine synthesis capacity on [18F]-DOPA positron emission tomography (PET) is the most consistent dopaminergic abnormality in schizophrenia.
This rise is largest in the associative striatum, which the nigrostriatal pathway supplies.
Amphetamine challenge imaging shows greater presynaptic dopamine release in the striatum, while the prefrontal cortex has a dopamine deficit.
Prefrontal and GABA findings
Hypofrontality (Weinberger and Berman) is failure to activate the dorsolateral prefrontal cortex during executive tasks such as card sorting.
Hypofrontality is linked to reduced mesocortical dopamine, negative symptoms and working memory deficits.
Schizophrenia shows a deficit of small GABA (gamma-aminobutyric acid) interneurones in layer II of the prefrontal cortex, with disturbed GABA release and uptake.
Reduced NMDA (N-methyl-D-aspartate) receptor signalling on interneurones may disinhibit pyramidal cells; ketamine, phencyclidine and anti-NMDA receptor encephalitis support this model.
Structural findings
Finding | Detail |
|---|---|
Enlarged lateral ventricles | The most consistently replicated change, because the surrounding tissue is lost |
Reduced total grey matter | Also consistently replicated |
Hippocampal volume loss | One of the most replicated regional losses; present at first episode, and to a lesser degree in unaffected relatives |
Superior temporal gyrus | Holds auditory cortex and Wernicke's area; its abnormal structure and activity are the correlate of auditory hallucinations |
Caudate enlargement is an effect of antipsychotics, not of the illness.
In at-risk people, raised resting blood volume in the hippocampal CA1 subfield comes before conversion to psychosis and before hippocampal atrophy.
Asymmetry and the planum temporale
The planum temporale is a language region behind Heschl's gyrus that is normally larger on the left.
In schizophrenia this leftward asymmetry is reduced or reversed, a finding shared with developmental dyslexia.
Crow's cerebral torque hypothesis holds that failure of normal right-left asymmetry and language lateralisation is a structural basis of schizophrenia; it remains a hypothesis.
Risk factors
Regular cannabis use in adolescence raises the relative risk of later schizophrenia about two- to fourfold, most when use starts early.
The 22q11.2 deletion carries substantial risk, with about a quarter of carriers developing psychosis.
Other risks include obstetric complications, prenatal infection, urban upbringing, migration and adversity; none is necessary or sufficient.
Prognosis
Poor prognostic factors in schizophrenia are male sex, early and insidious onset, poor premorbid adjustment, negative symptoms, cognitive impairment and enlarged ventricles.