1. Nature of psychosis and schizophrenia
Domina Petric, MD

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

3. Katzung, Masters, Trevor. Basic and clinical pharmacology.
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.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

4. Katzung, Masters, Trevor. Basic and clinical pharmacology.
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).
Katzung, Masters, Trevor. Basic and clinical pharmacology.

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

11. The serotonin hypothesis
5-HT2C inverse agonists
Clozapine, asenapine, olanzapine
Stability of 5-HT2A and NMDA receptors complex
Hallucinogens can modulate this stability.
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.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

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

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

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.
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.
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.
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!
Katzung, Masters, Trevor. Basic and clinical pharmacology.

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

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

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