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Schizophrenia: Designing the Ideal Pharmacological Agent

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Transcript of Schizophrenia: Designing the Ideal Pharmacological Agent

Designing the Ideal Pharmacological Agent Schizophrenia photo (cc) Malte Sörensen @ flickr Dopamine
Seratonin
Norepinephrine
Glutamate
Acetylcholine
Histamine What neurotransmitters are implicated in schizophrenia? Treat and prevent positive symptoms
Treat affective symptoms
Treat cognitive symptoms
Treat negative symptoms
Limited adverse effects
No EPS
No metabolic dysfunction
Low cost
No drug interactions
Receptor and site specificity So what characteristics would an ideal agent have? Increased dopamine or dopamine receptors in the dorsal and/or ventral striatum may be a factor in schizophrenia.

As a result, almost all current therapies antagonize the D2 receptors. However, these therapies can have adverse effects such as EPS.

However, this can't be the complete story. Dopamine Theory Glutamate is a widely utilized neurotransmitter that has multiple functions including memory and cognition.
Glutamate also modulates the release of other neurotransmitters such as dopamine.
In patients with schizophrenia, glutamanergic pathways are hypoactive.
Glutamate antagonists, such as Ketamine and PCP, can induce positive and negative symptoms or exacerbate symptoms.
However, too much glutamate can cause neurotoxicity.
As a result, glutamate must be tightly regulated in the brain. Glutamate Up-regulation of some serotinergic pathways in schizophrenia lead to hypofunction of the dopaminergic pathways.

However, the serotonergic nuclei in the brainstem (and resulting axons) remain unchanged in schizophrenia. Thus, adding to the complexity... Serotonin Nigrastriatal pathway--reduces D2 blockade enough to decrease EPS
Mesolimbic pathway--no affect on antipsychotic effects
Mesocortical pathway--increases the release of dopamine allowing for improved cognition Serotonin 2a Antagonism Should 2a antagonism be a common target? All atypical antipsychotics have relevant 2a antagonism. Histamine H1 blockade may have a negative effect on cognition and contribute to metabolic dysfunction.

Atypical antipsychotics tend to have some H1 blocking properties. Acetylcholine Muscarinic Nicotinic Other targets: 5HT2c--antagonism increases dopamine and epinephrine
5HT1a--presynaptic agonism effects may enhance antidepressant effects
5HT1d--autoreceptor antagonism may enhance antidepressant effects Glutamate receptor targets: There are 100s of glutamate receptors
NMDA modulators
mGluR allosteric modulators
AMPA modulators Other targets: D1--gets down regulated during continuous D2 blockade leading to severe memory/cognitive impairments
D3--appear to be elevated in schizophrenia, but importance to pathophysiology is not known Decreased M1 receptor binding is noted in post-mortem brains
Non selective M1 agonists have shown improved cognition in alzheimer's but low tolerability Nicotine has shown to improve some cognitive measures, but is limited by tachyphylaxis
alpha 7 nicotinic receptors
DMXB-A
AVL-3288 So what is the ideal medication? Treat and prevent positive symptoms
Treat affective symptoms
Treat cognitive symptoms
Treat negative symptoms
Limited adverse effects
No EPS
No metabolic dysfunction
Low cost
No drug interactions
Receptor and site specificity Ideal receptor effects Dopamine D2 antagonism (excluding nigrastriatal pathway)
D1 agonism Serotonin 5HT2a and 1d antagonism
5HT2c and 1a agonism Glutamate NMDA, AMPA, and mGluR modulation Acetylcholine Histamine M1 agonism
alpha 7 nicotinic modulation No H1 blockade Conclusion Schizophrenia is a complex disease affected by multiple neurotransmitters and pathways
An ideal agent aims to treat and prevent all symptom types while minimizing adverse effects
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