Antipsychotics Flashcards
What are the three neurobiological theories of psychosis?
- The serotonin Theory: 5HT2A receptor hyperfunction in the cortex
- The glutamate Theory: NMDA receptor hypofunction
- The dopamine Theory: Hyperactive dopamine at D2 receptors in the mesolimbic pathway
Describe the glutamate theory of psychosis
Due to loss of inhibitory GABA interneuron function, descending glutamate neurons become disinhibited and hyperactive.
- In schizophrenia due to genetic GAD mutation (GABA synthesizer)
- by NMDA receptor blockade due to PCP and ketamine
- in neurodegenerative disorders that knock out these GABA interneurons
Describe the dopamine theory of psychosis
Due to hyperactive descending glutamate neurons that innervate VTA, excessive dopamine is released causing the hypothesised positive symptoms of psychosis through mesolimbic dopaminergic pathway. However, in the mesocortical pathway dopamine release is ultimately decreased due to innervation upon another set of GABA interneurons, which explains hypofrontality - negative and cognitive symptoms.
Describe the serotonin hypothesis of psychosis
The theory suggests serotonin hyperfunction upon the 5HT2a receptors present at glutamatergic neurons.
- In parkinson’s disease these receptors are upregulated and hypersensitive due to loss of serotoninergic neurons.
- Hallucinogens like LSD and psilosybin agonise these receptors.
- In dementia, selective loss of GABA interneurons due to lewy-bodies and plaques cause the lack of inhibition of these surviving glutamate neurons.
The imbalance of excitatory 5HT2A receptors overstimulate glutamate pyramidal neurons that directly innervate VTA.
Describe the direct and indirect dopaminergic nigrostriatal pathway that facilitates movement.
Dopamine nerves from the SNc project to D1 and D2 receptors located postsynaptically upon GABA interneurons in the striatum.
Direct pathway: excitatory D1 receptors causing upstream glutamate release -> enhance GO
Indirect pathway: inhibitory D2 receptors causing upstream glutamate release. -> inhibit STOP
What is the effect of D2 antagonists / partial agonists?
Dopamine’s effect will be lower. In the mesolimbic system it has antipsychotic properties. Some side effects:
- D2 antagonists prevent DA from inhibiting the indirect ‘stop’ pathway.
-> Extra pyramidal symptoms, including tardive dyskinesia (involuntary continuous movements, often in face and tongue). - Oversecretion of prolactin
How could you treat dopamine induced Parkisonism?
To treat DIP, anticholinergics that block postsynaptic M1 receptors could help, to compensate for the excessive acetylcholine release that was induced by blocking the inhibitory D2 receptors on striatal acetylcholine releasing nerves.
What are side effects of blocking M1 receptors?
- Dry mouth
- blurred vision
- constipation
- drowsiness
- cognitive dysfunction
How could you treat tardive dyskinesia?
By inhibiting the vescular monoamine transporter type 2 (VMAT2), which ultimately reduces dopamine stimulation without blocking D2 receptors.
What are side effects of first-generation anti-psychotics besides DIP, TD and blocking M1 receptors?
They also often block H1 histamine receptors, which is associated with weight gain and sedation, and/or block α1-adrenergic receptors that are also associated with sedative effects, as well as orthostatic hypotension (low BP).
They often worsen negative symptoms due to hypofrontality, which may cause smoking habbits or drug abuse.
D2 effects in tuberinfundibular pathway - important for prolactin secretion - are hyperprolactinemia and amenorrhea.
What are second generation antipsychotics?
They combine D2 antagonism with 5HT2a antagonism, which improves both efficacy and the side effects.
What three separate populations of the cortical glutamatergic pyramidal neurons contain excitatory postsynaptic 5HT2a receptors, and what is the effect of antagonising 5HT2a receptors at these locations?
- Glutamatergic pyramidal neurons directly innervating mesolimbic dopamine neurons -> decreased positive symproms
- Glutamatergic pyramidal neurons directly innervating nigrostriatal dopamine neurons -> reduces DIP
- Glutamatergic pyramidal neurons indirectly innervating mesocortical dopamine neurons via GABAergic interneurons in the VTA. -> emotional blunting
Describe the role of 5HT1a receptor agonism in relation to 5HT2a antagonism.
5HT1a receptors are inhibitory, so agonism will lead to the same effects as 5HT2 antagonism which is to increase dopamine release in some areas.
5HT1a receptors are also located at:
- Glutamatergic pyramidal neurons directly innervating nigrostriatal dopamine neurons
- Glutamatergic pyramidal neurons indirectly innervating mesocortical dopamine neurons via GAGAergic interneurons in the VTA
What are the 4 types of EPS?
Akathesia, parkisonism (bradykanysia, tremor, movement regidity), dyskinesia, dystonia (constant muscle contraction)
Describe hallucinogen persistent perceptual disorder.
Type 1: experiencing random brief flashback to using psychedelics, usually pleasant.
Type 2: experiencing persistent visual changes, a long term side effect only known after LSD use.
