MESOCORTICAL PATHWAYS

MESOCORTICAL PATHWAY

“Elizabeth will feel worse because there is some evidence that she is a poor or non-metaboliser of Clopixol. A few years ago Susan Bevis paid for tests on some the common liver antigens (P450s) responsible for metabolising psychiatric drugs.  You might want to ask her about this.  

If I recall she was deficient in the two main enzymes mentioned below.  This can and often does lead to toxicity and or treatment failure.  So in a nutshell the drug will not treat the psychotic symptoms but can cause poisoning because the patient cannot evacuate the metabolites fast enough.  Dr Shahpesandy definitely knows the pharmacodynamics and pharmacokinetics here.  See page 47 of the attached slides.

In vitro studies suggest zuclopenthixol is metabolised primarily by CYP2D6 and CYP3A4. The clinical study supports this, demonstrating the impact of co-prescribed inhibitors or inducers. Guidelines should incorporate these interactions noting the potential for zuclopenthixol-related toxicity or treatment failure.

“I’ve read reports where there manufacturers tests these drugs on existing patients and ask them if it makes them feel better or worse.

Elizabeth says it makes her feel worse but Dr Shahpesandy isn’t listening.”

On Wed, 30 Mar 2022 at 19:30,

“The mesolimbic pathway is implicated in schizophrenia.  In paranoid schizophrenia fear and anger are magnified and distorted and might cause disruptions in the mesocortical pathways to the frontal lobe causing psychosis.  

Zuclopenthixol Decanoate (Clopixol) is a mesolimbic antagonist* on D2 receptors in the mesolimbic pathway.  Those with poorly expressed CYP2D6 (poor or non-metabolisers) experience significantly attenuated elimination of Clopixol leaving the drug active in the mesocortical pathways for longer an potentiating increased risk of adverse effect .   

*meaning it depresses the activity of dopamine receptors in the mesocortical pathway between the limbic system and the prefrontal cortex.  This is why it is important to know if there is any sign of inflammation or any lesion in those areas of the brain.  An MRI scan will give the first clue and a search for specific antibodies will conform whether there are any lesions or inflammation.  

It is also why it is necessary to determine if a patient is a poor metaboliser of Clopixol. 

Subject: Limbic Inflammation

“Here is a scan showing limbic related inflammation in the temporal region of the brain.

As you can the pale area on the left temporal area of this patient’s skull that part of the brain is inflamed.  That is the part of the brain where the mesolimbic pathways are found.  That inflammation might stop dopamine D2 signalling and affect thought process, especially anger and fear.

Clopixol is a D2 antagonist on that pathway too.  If a patient had an inflammatory condition it will likely affect neurotransmission and the metabolism of this drug.

Dr Shahpesandy is, from what I can see from his research well aware of P450 metabolism and the effect of inflammation and lesions on neurotransmission.  

Do the MRI and follow up with looking for inflammatory markers.  “simples” as Meerkats say.

B”

>
Sent: Thu, 31 Mar 2022 0:06
Subject: On a final note re; Mesocortical pathways

“That’s why the Martin Harrow study is so important.

That’s why patients on long term anti-psychotics have adverse effects on cognition and not improvements.”

Subject: Brain scan indicating inflammation.

 Further to the earlier comments.  The left temporal lobe of this patients brain is inflamed.  Note that the brain crenelations are closed up and the brain tissue is pale on the scan just before the eyes.  

Above this the mesocortical pathways extend to the pre-frontal cortex where our higher and abstract thoughts occur.   Interruptions in neurotransmission can be caused by this inflammation and interestingly some anti-psychotic medications also interfere with D2 (dopamine) receptors in the mesocortical pathway.  

Ask the doctor if he would agree that ‘upregulation’ and ‘downregulation’ of dopamine might affect presentation of psychotic symptoms.  I would be fascinated by the reply. 

If you look at the diagram of the mesocortical pathway from the limbic system to the pre-frontal cortex pathways (in red on attached diagram) you will see them moving forward of the temporal zones.  

Anti-psychotic medications down regulate those neurotransmitters, that is indeed what they are designed to do. 

B”

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