This document discusses several hypotheses for the causes of psychosis and schizophrenia. The serotonin hypothesis suggests that excess stimulation of 5-HT2A receptors may underlie hallucinations, while 5-HT2A receptor blockade by atypical antipsychotics is key to their mechanism of action. The dopamine hypothesis proposes that excessive limbic dopaminergic activity causes psychosis, and antipsychotics block D2 receptors. Imaging studies show increased striatal dopamine levels in schizophrenia. The glutamate hypothesis involves hypofunction of NMDA receptors on GABAergic neurons leading to disinhibition and hyperstimulation through other glutamate receptors.

1. Nature of psychosis and
schizophrenia
Domina Petric, MD
https://powerpoint.crystalgraphics.com

2. Psychosis
Hallucinations
Auditory, visual,
tactile, olfactory
Delusions
Defined as
false beliefs.
Disorganized thinking
Grossly disorganized
thinking in a clear
sensorium.
16.3.2018.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.

3. Schizophrenia
• Schizophrenia is a particular
kind of psychosis characterized
mainly by a clear sensorium, but
a marked thinking disturbance.
• Psychosis is not unique to
schizophrenia and it is not
present in all patients with
schizophrenia at all times.
16.3.2018.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.

4. Schizophrenia
• Neurodevelopmental disorder.
• Structural and functional changes in the
brain are present even in utero in some
patients.
• These changes may develop during childhood
and adolescence.
• It is a genetic disorder with high heritability.
• No single gene is involved, but multiple
genes with common and rare mutations,
including large deletions and insertions (copy
number variations).
16.3.2018.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.

5. The serotonin hypothesis of
schizophrenia
5-HT
16.3.2018.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.

6. The serotonin hypothesis
• 5-HT2A and 5-HT2C receptor
stimulation is the basis for the
hallucinatory effects of LSD and
mescaline, both serotonin agonists.
• 5-HT2A receptor blockade is a key
factor in the mechanism of action of
the main class of atypical
antipsychotic drugs.
16.3.2018.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.

7. The serotonin hypothesis
• Atypical antipsychotic drugs are
clozapine, melperone,
risperidone, zotepine,
blonanseine olanzapine,
quetiapine, ziprasidone,
aripiprazole, sertindole,
paliperidone, iloperidone,
asenapine and lurasidone.
16.3.2018.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.

8. The serotonin hypothesis
• Atypical antipsychotic drugs are
inverse agonists of the 5-HT2A
receptors: they block the constitutive
activity of these receptors.
• 5-HT2A receptors modulate the
release of dopamine, norepinephrine,
glutamate, GABA and acetylcholine in
the cortex, limbic region and striatum.
16.3.2018.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.

9. The serotonin hypothesis
• Stimulation of 5-HT2A receptors leads
to depolarization of glutamate
neurons, but also stabilization of
N-methyl-D-aspartate (NMDA)
receptors on postsynaptic neurons.
• Hallucinogens can modulate the
stability of a complex consisting of
5-HT2A and NMDA receptors.
16.3.2018.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.

10. The serotonin hypothesis
• 5-HT2C receptor stimulation provides a
further means of modulating cortical
and limbic dopaminergic activity.
• Stimulation of 5-HT2C receptors leads to
inhibition of cortical and limbic
dopamine release.
• Clozapine, asenapine and olanzapine
are 5-HT2C inverse agonists.
16.3.2018.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.

11. The serotonin hypothesis
Stability of 5-HT2A and NMDA
receptors complex
Hallucinogens can
modulate this stability.
5-HT2C inverse agonists
Clozapine, asenapine,
olanzapine
5-HT2A receptors
Modulate the release of dopamine,
norepinephrine, glutamate, GABA and
acetylcholine.
5-HT2A inverse agonists
Atypical antipsychotic
drugs
5-HT2A and 5-HT2C stimulation
Basis of the hallucinatory
effects of LSD and mescaline.
16.3.2018.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.

12. The dopamine hypothesis of
schizophrenia
Dopamine
16.3.2018.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.

13. The dopamine hypothesis
The dopamine hypothesis is highly
relevant to understanding the major
dimensions of schizophrenia:
• positive symptoms
• negative symptoms (emiotional
blunting, social withdrawal, lack of
motivation)
• cognitive impairment
• depression
16.3.2018.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.

14. The dopamine hypothesis
Dopamine
Positive symptoms
Delusions and
hallucinations
Cognitive impairment
Disorganized
thoughts
Negative symptoms
Emotional blunting,
social withdrawal,
lack of motivation Depression
Provokes or worsens
negative symptoms
16.3.2018.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.
Stigmatization!

15. The dopamine hypothesis
• Excessive limbic dopaminergic activity
plays a role in psychosis.
• Many antipsychotic drugs strongly
block postsynaptic D2 receptors in the
CNS, especially in the mesolimbic and
striatal-frontal system.
• This includes partial dopamine
agonists, such as aripiprazole and
bifeprunox.
16.3.2018.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.

16. The dopamine hypothesis
• Drugs that increase
dopaminergic activity (levodopa,
amphetamines, bromocriptine,
apomorphine) either aggravate
schizophrenia psychosis or
produce psychosis de novo in
some patients.
16.3.2018.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.

17. The dopamine hypothesis
• Dopamine-receptor density has been
found postmortem to be increased in the
brains of schizophrenics who have not
been treated with antipsychotic drugs.
• Some postmortem studies of
schizophrenic subjects have reported
increased dopamine levels and D2-
receptor density in the nucleus
accumbens, caudate and putamen.
16.3.2018.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.

18. The dopamine hypothesis
Imaging studies findings:
• increased amphetamine-induced
striatal dopamine release
• increased baseline occupancy of
striatal D2 receptors by extracellular
dopamine
Increased striatal dopamine synthesis
and release!
16.3.2018.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.

19. The dopamine hypothesis
Blockade of
postsynaptic
D2 receptors
Increased in
shizophrenics
(postmortem
studies)
Nucleus
accumbens,
caudate and
putamen
Increased striatal
dopamine
synthesis and
release
Antipsychotics
Levodopa,
amphetamines…
Dopamine-
receptor density
Increased
dopamine levels
Imaging
studies
Aggravate
schizophrenia or
produce psychosis
de novo
16.3.2018.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.

20. The dopamine hypothesis
Diminished cortical or hippocampal
dopaminergic activity has been suggested to
underlie the cognitive impairment and
negative symptoms of schizophrenia:
• decreased dopaminergic innervation in
medial temporal cortex, dorsolateral
prefrontal cortex and hippocampus
• decreased levels of DOPAC (dopamine
metabolite)
16.3.2018.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.

21. The dopamine hypothesis
• Imaging studies have found increased
prefrontal D1-receptor levels that correlated
with working memory impairments.
• Serotonin receptors, particularly the 5-HT2A,
may mediate synergistic effects or protect
against the extrapyramidal consequences of
D2 antagonism.
• Combined theory of several transmitter-
receptor systems: dopamine + serotonin +
glutamate?
16.3.2018.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.

22. The dopamine hypothesis
The atypical antipsychotic
drugs share the property
of weak D2 receptor
antagonism and more
potent 5-HT2A receptor
blockade.
16.3.2018.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.

23. The glutamate hypothesis of
schizophrenia
Glutamate
16.3.2018.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.

24. The glutamate hypothesis
• Glutamate is the major excitatory
neurotransmitter in the brain.
• Phencyclidine and ketamine are
noncompetitive inhibitors of the
NMDA receptor that exacerbate
both cognitive impairment and
psychosis in patients with
schizophrenia.
16.3.2018.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.

25. The glutamate hypothesis
• Hypofunction of NMDA receptors, located
on GABAergic interneurons, leads to
diminished inhibitory influences on
neuronal funcion and contributes to
schizophrenia.
• The diminished GABAergic activity can
induce disinhibition of downstream
glutamatergic activity.
• This can lead to hyperstimulation of cortical
neurons through non-NMDA receptors.
16.3.2018.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.

26. The glutamate hypothesis
• The NMDA receptor, an ion channel,
requires glycine for full activation.
• It has been suggested that in
patients with schizophrenia, the
glycine site of the NMDA receptor is
not fully saturated: glycine transport
inhibitors as possible antipsychotic
agents.
16.3.2018.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.

27. The glutamate hypothesis
• Ampakines are drugs that potentiate
currents mediated by AMPA-type
glutamate receptor.
• They protect neurons againts
neurotoxic insults, in part by
mobilizing growth factors such as
brain-derived neurotrophic factor
(BDNF).
16.3.2018.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.

28. Literature
• Katzung, Masters, Trevor.
Basic and clinical
pharmacology.
16.3.2018.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.