Psychosis from Stahl Ch 4 (to be updated)

 

• the 3 major hypotheses of psychosis and their nerotransmitter networks
  • dopamine theory
  • glutamate theory
  • serotonin theory

Figure 1 The dopamine hypothesis of psychosis. For half a century, psychosis, particularly auditory hallucinations and paranoid delusions, have been thought to be the result of hyperactivation of the dopaminergic mesolimbic pathway. The mesolimbic pathway projects from the ventral tegmental area (VTA) to the ventral striatum. The dorsal striatum is not thought to be affected by this hyperactivity because it is innervated via the nigrostriatal pathway from the substantia nigra and controls motor movements.

Figure 2 A recent theory suggests that psychosis in schizophrenia may be the result of hypofunctional NMDA receptors on GABA interneurons in the cerebral cortex This hypofunction may lead to overactivation of downstream glutamate signaling to the ventral tegmental area. Overactivation of this pathway may result in turn in excess dopamine in the ventral striatum via the mesolimbic pathway.

Figure 3 Psychosis can be the result of hyperactivation of 5-HT 2A receptors on glutamate neurons. This hyperactivation may be due to excess serotonin, upregulated 5-HT2A receptors, or a psychedelic hallucinogenic 5-HT 2A agonist, all of which could lead to downstream release of glutamate. Glutamate release in the VTA may activate the mesolimbic pathway, resulting in excess dopamine in the ventral striatum.

Figure 4 Excess glutamate signaling in the cerebral cortex, particularly the visual cortex, is thought to be associated with visual hallucinations. Upregulated 5-HT2A receptors on glutamate neurons, excessive serotonin release, or a psychedelic hallucinogenic 5HT1A agonist could all increase signaling to visual cortex and cause visual hallucinations.

Source: Stahl, S. M. (2018). Beyond the dopamine hypothesis of schizophrenia to three neural networks of psychosis: dopamine, serotonin, and glutamate. CNS Spectrums, 23(3), 187–191. doi:10.1017/S1092852918001013

https://www.cambridge.org/core/journals/cns-spectrums/article/beyond-the-dopamine-hypothesis-of-schizophrenia-to-three-neural-networks-of-psychosis-dopamine-serotonin-and-glutamate/3E9E50ED717219011DD1B570365010E8

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• the classic dopamine hypothesis of psychosis and schizophrenia
  • the dopamine NT Network

https://www.mdpi.com/982102

• • classic dopamine pathways and key brain regions
    • tuberoinfundibular DA pathway
    • thalamic DA pathway:x
    • nigrostriatal DA pathway: CTSC loop
    • mesocortical DA pathyway
    • mesolimbic DA pathyway: reward and reinforcement

https://images.app.goo.gl/TVY58zc63excjXPG6

• • the classic dopamine hypothesis of the positive Sx
    • mesolimbic hyperdopaminergia
  • corollary to the classic dopamine hypothesis of SPR
    • mesocortical hypodopaminergia and the cogvnitive, negative, and affective symptoms of SPR

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• the glutamate hypothesis of psychosis and SPR
  • the glutamate NT network
    • cortico-brainstem
    • cortico-strialtal
    • hippocampal-striatal
    • thalamo-cortical
    • cortico-thalamic
    • cortico-cortical(direct/indirect)
  • the NMDA glutamate hypofunction hypothesis of psychosis
    • faulty NMDA neurotransmission at Glutamate synapses on GABA interneurons in prefrontal cortex

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• the serotonin hypothesis of psychosis and SPR
  • the serotonin NT network
    • 5 HT receptors
  • the serotonin hyperfunction hypothesis of psychosis

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summary and conclusions regarding dopamine, NMDA, and serotonin NT in psychosis

1) dopamine hyperactivity at D2 receptors in the mesolimbic/mesotriatal pathyway, from VTA/mesostriatum integrated hub to the ventral striatum

2) NMDA receptor hypoactivity at GABAergic interneurons with loss of GABAergic in hibition in the prefrontal cortex

3) serotonin hyperactivity/imbalance at 5HT-2A receptors on glutamate neurons in the cerebral cortex

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• SPR as the prototypical psychotic disorder
  • beyond the positive and negative sx of SPR
    • positive sx of psychosis and SPR: delusions, hallucinations, distortions or exaggeration in languate and communication , disorganized speech, diorganized behavior, agitation
    • negative sx of SPR(prodrome): blunted affect, emotional ithdrawal, poor rapport, passivity, apathetic social withdrawal, difficulty in abstract thinking, lack of spontaneity, stereotyped thinking alogia, avolition, anhedonia, attentional impairment

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• Other psychotic illnesses
  • mood-related psychosis, psychotic depression, psychotic mania
  • parkinsons's disease psychosis
  • dementia-related psychosis