Download “antipsychotics”?

Reducing Confusion in Naming
Antipsychotics: Pharmacology, Not
Clinical Target for Nomenclature
Stephen M. Stahl, MD, PhD
Professor of Psychiatry,
University of California, San Diego
Honorary Senior Visiting Fellow
University of Cambridge, United Kingdom
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Learning Objectives
• To discuss how antipsychotic nomenclature can be
confusing by using names based upon clinical actions
• To propose nomenclature based upon pharmacologic
mechanisms no matter what the clinical use
• To reduce confusion by addressing:
– When is an antipsychotic not an antipsychotic?
– When is a non antipsychotic an antipsychotic?
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Question 1
• Why are antipsychotics antipsychotics?
–
–
–
–
1. Because they reduce psychosis
2. Because they block D2 dopamine receptors
3. Both
4. Neither
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Current Nomenclature for Conventional
(First-Generation) Antipsychotics
D2
•
•
•
•
•
•
•
D2 antagonists
Dopamine blockers
Neuroleptics
Psycholeptics
Conventional antipsychotics
First Generation antipsychotics
Major tranquilizers
Stahl SM. Stahl’s Essential Psychopharmacology. 4th Ed. Cambridge University Press, 2013.
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Current Nomenclature for Atypical
(Second-Generation) Antipsychotics
•
•
•
•
•
•
•
•
•
D2/5HT2A antagonists
Serotonin dopamine antagonists
Antipsychotics
Anti-manics
Mood Stabilizers
Anti-depressants
Treatment resistant antidepressants
Antidepressant augmenting agents
Bipolar antidepressants
Stahl SM. Stahl’s Essential Psychopharmacology. 4th Ed. Cambridge University Press, 2013.
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Muscarinic Acetylcholine Receptors:
M1
M2
M3
M4
Histamine Receptors:
H1
Adrenergic Alpha
Receptors:
1
2A
2B
2C
Transporters
SERT NET
D2
Dopamine Receptors:
D1
Serotonin Receptors:
5HT1A
2A
5-1
1B
1D
2B
2C
1E
3
5
6
7
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
D2 D3
D4
Question 2
• Why are antipsychotics antidepressants?
–
–
–
–
–
–
–
1. Because they improve depression
2. Because they block dopamine D2 receptors
3. Because of other pharmacologic actions
4. All of the above
5. None of the above
6. 1 and 2
7. 1 and 3
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Lurasidone
5HT7
5-59
D4
D2
5HT
2A
2C
5HT
1A
2A
1
5HT
2C
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Lurasidone
Axis I Class : dopamine multifunctional
Relevant Mechanism: dopamine and serotonin receptor
antagonist
Axis 2 Indications: schizophrenia (USA, Canada, UK, Europe); major
depressive episodes associated with bipolar I disorder
(USA and Canada)
Axis 3 Efficacy: Improvement of psychotic symptoms, improvement in
depressive symptoms
Side Effects: sedation, dizziness, EPS, galactorrhea (low),
weight gain (low). Risk of diabetes (low) but monitoring
recommended as a class warning; class warning for
increased mortality in elderly dementia patients and for
tardive dyskinesia and NMS
Committee notes: Serotonin 7, serotonin 1A and alpha 2 actions may be
relevant especially in bipolar depression
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Lurasidone (cont’d)
Axis 4 Neurobiological description
Neurotransmitter actions: Dopamine and serotonin receptor antagonist
Preclinical: Antagonist at D2 and D3, 5HT2A, 5HT7, NE alpha2
receptors; partial agonist at 5HT1A receptor
Human: Blocks central D2 receptors (PET; human)
Physiological:
Preclinical: Catalepsy, improves cognition in animal models
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Pimavanserin
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Pimavanserin
• 5HT2A inverse agonist antagonist
– Blocks intrinsic activity when no
agonist is present and blocks the
agonist when present
• Recently approved for psychosis
in Parkinson’s disease (PD)
– Reduction in psychotic symptoms
– Unlike antipsychotics, pimavanserin
does not impair motor function or
reduce the efficacy of L-DOPA
Significant improvement on the
Scale for the Assessment of
Positive Symptoms –Parkinson’s
Disease (SAPS-PD)
Cummings et al. The Lancet 2014;383:533-40; Friedman JH. Expert Opin Pharmacother 2013;14(14):1969-75;
Goldman, Holden. Curr Treat Options Neurol 2014;16:281; McFarland et al. Beh Pharmacol 2011;22:681-92;
Meltzer HY et al. Neuropsychopharmacol 2010;35:881-92; Meltzer, Roth. J Clin Invest 2013;123(12):4986-91.
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Question 3
• If an agent like pimavanserin improves psychosis but
doesn’t block D2 dopamine receptors, should it be
classified as an antipsychotic?
– 1. yes
– 2. no
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Question 4
• If an agent improves psychosis but doesn’t block D2
dopamine receptors like pimavanserin, should it get
class warnings for antipsychotics (weight gain, diabetes,
tardive dyskinesia, NMS, mortality in elderly dementia,
etc), be classified as “other antipsychotic” and be used
only second line after other antipsychotics fail?
– 1. yes
– 2. no
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Question 5
If pimavanserin improves sleep and improves behavioral
symptoms of dementia as well as psychosis in
Parkinson’s disease what should it be called?
1. hypnotic
2. antipsychotic hypnotic
3. Parkinsonian antipsychotic
4. anti-dementia agent
5. Antipsychotic for Parkinson’s disease that is not an
antipsychotic because it doesn’t block D2 receptors and
doesn’t have EPS, or other warnings, thus the nonantipsychotic antipsychotic hypnotic antidementia agent
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Question 6
How about calling pimavanserin a selective serotonin
receptor antagonist?
1. yes
2. no
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Summary
• We propose that it is no longer appropriate to name all drugs that
treat psychosis only as “antipsychotics”
• A multi axial classification system is proposed to use for drugs that
treat psychosis, mania and depression based on pharmacologic
mechanism of action
• Mechanism based nomenclature may clarify these differing
mechanisms for individual agents rather than class effects for all
atypical antipsychotics, especially for actions in psychosis versus
mood disorders
• This approach has the potential to better inform those who work with
drugs that treat depression and other conditions to prevent
confusion with other drugs that treat both psychosis and multiple
additional disorders such as depression and sexual dysfunction
• This approach is also a strategy for naming novel drugs yet to be
discovered that target novel mechanisms of action
Copyright © 2011 Neuroscience Education Institute. All rights reserved.