3 Clinical psychopharmacology3.3 Pharmacodynamics

3.3.3.1 The Dopamine Hypothesis

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Written by Resident Doctor Committee · Published

Origins

  • Amfetamine and the dopamine agonists used in Parkinson's disease can cause or worsen psychosis.

  • The dopamine D2 receptor affinity of traditional antipsychotics correlates with their clinical potency.

  • Stimulant psychosis does not reproduce the whole schizophrenia syndrome.

Striatal dopamine excess and positive symptoms

  • The striatum is the site of the dopamine excess that underlies positive symptoms.

  • In schizophrenia, amfetamine provokes exaggerated striatal dopamine release and worsens positive symptoms.

  • The excess is presynaptic: dopamine synthesis capacity, stimulated release and baseline synaptic dopamine are raised. A primary rise in D2 receptor number is less consistently supported.

  • Abnormalities are often greatest in the associative striatum, which receives prefrontal inputs.

  • Kapur's aberrant salience model proposes that inappropriate phasic dopamine release gives neutral events significance, and people then explain that significance with delusions.

The revised hypothesis

Pathway

Dopamine

Symptoms

Subcortical (mesolimbic)

Excess

Positive

Mesocortical, to the dorsolateral prefrontal cortex

Reduced

Cognitive and some negative

Follow the green mesolimbic pathway to the nucleus accumbens and the orange mesocortical pathway to the prefrontal cortex: in the revised hypothesis, dopamine is in excess in the first and reduced in the second. Oscar Arias-Carrión1, Maria Stamelou, Eric Murillo-Rodríguez, Manuel Menéndez-González and Ernst Pöppel. Substantially m, CC BY 2.0, via Wikimedia Commons

  • Prefrontal D1 effects follow an inverted U.

  • The cortical component has weaker evidence than the striatal one, partly because low cortical receptor density makes it hard to measure.

  • D2 antagonists help positive symptoms more than primary negative or cognitive symptoms.

Limits

  • Clozapine can work below 60% striatal D2 occupancy.

  • Dopamine measurements overlap with those of controls, so they cannot diagnose an individual.

  • Glutamate, inflammatory and developmental abnormalities also contribute.

Revision material for the MRCPsych examinations. Not clinical guidance, and not for use in patient care.

3.3.3.1 The Dopamine Hypothesis | MRCPsychiatrist