Treatment of Psychosis, schizophrenia side effects of antipsychotics

1. Antipsychotics
Dr Nasar Khan
mnsk@queensu.ca

2. The history of antipsychotic drug
development
30`s 40`s 50`s 60`s 70`s 80`s 90`s 00
Ziprasidone
Aripiprazole
Brexpiprazole
Asenapine
Lurasidone
Iloperdone
Paliperidone
Clozapine
Olanzapine
Risperidone
Quetiapione
Clopenthixol
Zuclopenthixol
Flupenthixol
Haloperidol
Fluphenazine
Loxapine
Thioridazine
Perphenazine
CPZAnestheticsECT

3. The history of antipsychotic drug
development
• Often based on chance findings that bear little relationship to the intellectual
background driving observation.
• In 1891, Paul Ehrlich observed the antimalarial effects of methylene blue, a
phenothiazine derivative.
• Later, the phenothiazines were developed for their antihistaminergic
properties.
• In 1951, Laborit and Huguenard administered the aliphatic phenothiazine,
chlorpromazine, to patients for its potential anesthetic effects during surgery.
thereafter, Hamon et al. and Delay et al. extended the use of this treatment in
psychiatric patients and serendipitously uncovered its antipsychotic activity.

4. The history of antipsychotic drug
development
• Between 1954 and 1975, about 15 antipsychotic drugs were introduced in
the United States and about 40 throughout the world.
• Thereafter, there was a hiatus in the development of antipsychotics until
the introduction of clozapine treatment in the United States in 1990
opened the era of"atypical" antipsychotic drugs.

5. Classic and commonly
used terms
Proposed terms by WPA
Neuroleptics or
Typical antipsychotics
First generation
antipsychotics
Atypical antipsychotics
(serotonin –†dopamine
antagonists)
Second generation
antipsychotics
Dopamine partial
agonists
( aripiprazole )
Third generation
antipsychotics
Multi-receptor modulation Next Generation

6. WHY THEY ARE ‘ATYPICAL’ ?
SPECTRUM OF ACTION
Higher ratio of serotonin : dopamine receptor blockade
Appear more specific for mesolimbic than striatal dopamine System
DIFFERENT SIDE EFFECT PROFILE
Lower Risk of EPS

7. Neuroleptic: synonym for antipsychotic drug/
Antipsychotics are the drugs currently used in the prevention
of psychosis. They have also been termed neuroleptics, because the suppress motor activity and
emotionality.

8. Etiology and treatment strategies?

10. Dopamine hypothesis
• Schizophrenia results from excess activity of dopamine
neurotransmission in Mesolimbic and Mesocortical Pathways because:
• All antipsychotic drugs block dopamine receptors. Stimulant drugs which
act through dopamine can produce schizophreniclike behaviors
(eg.amphetamines).
• Levodopa, a dopamine precursor, can exacerbate schizophrenic
symptoms, or occasionally elicit them in non-schizophrenic patients.
• Higher levels of dopamine receptors measured in brains of
schizophrenics by PET.
• Brain [DA] increases during psychotic episodes but not during remissions.

11. The role of dopamine in Schizophrenia is
quite complex :
• Positive Symptoms are thought to be result of OVERACTIVITY in
Mesolimbic pathway ( activating D2 receptors ).
• While, negative symptoms may result from a DECREASE ACTIVITY
in Mesocortical pathway (D1 receptors).
• Nigrostriatal and Tuberoinfundibular pathways appear to be
normal in Schizophrenia.

12. Glutamate Hypothesis; Glutamate :
excitatory Neurotransmitter
• NMDA Receptors : Ionotropic Glutamate Receptors
• It is observed that NMDA hypofunction on one hand
• Decrease DA in Mesocortical Pathway so Increase Negative
Symptoms
• And on the other hand
• Increase DA in Mesolimbic Pathway , hence, Increase Positive
Symptoms.
• Evidence : NMDA rec Antagonists (Phencyclidine,ketamine)
produce both Positive and Negative Psychotic Symptoms.

13. Serotonergic Pathways
• Many effective antipsychotic drugs, in addition to blocking
dopamine receptors, also act as 5-HT-receptor antagonists.
• Many 'atypical‘ antipsychotic drugs produce fewer extrapyramidal
side effects than dopamine-selective compounds, as they also
combine with 5-HT2A-receptors.
• Whether 5-HT2A-receptor blockade accounts directly for their
antipsychotic effects, or merely reduces undesirable side effects
associated with D2-receptor antagonists, remains controversial.

14. Classification
Typical antipsychotics
• Phenothiazines e.g.
chlorpromazine, fluphenazine,
thioridazine
• Butyrophenones e.g.
haloperidol, droperidol
• Thioxanthines e.g.
chlorprotixen, thiothixene
• Atypical antipsychotics
• Clozapine
• Risperidone
• Sulpiride
• Sertindole
• Lurasidone
• Olanzapine
• Quetiapine.

16. Drug Targets
• Dopamine receptors: D1, D2, D3, D4, D5
• Serotonin receptors: 5- HT-1A, 2A, 3, 6, 7
• Norepinephrine: -1 & - 2
• Muscarinic acetylcholine: mACh-1 & 4
• Histamine: H-1 & 2
• Dopamine,
• norepinephrine &
• serotonin transporters
• NMDA-glutamate receptor

17. RECEPTOR OCCUPANCY RECEPTOR AFFINITY

21. Steady State