Neuroscience-Based Nomenclature: Focus on Treatment of Psychosis Stephen M. Stahl, MD, PhD Professor of Psychiatry, University of California, San Diego Honorary Senior Visiting Fellow University of Cambridge, United Kingdom
Stephen M. Stahl, MD, PhD Type Consultant Company Acadia; BioMarin; Forum; GenOmind, Jazz; Lundbeck; Orexigen; Otsuka; Pamlab; Servier; Shire; Sprout; Taisho Grant/Research Support Speaker s Bureau Alkermes, Clintara, Eli Lilly, Forext, GenoMind, JayMac, Jazz, Merck, Novartis, Otsuka, PamLambs, Pfizer, Servier, Shire, Sprout, Sunovion, Takeda, Teva, Tonix Forum; Servier; Sunovion; Takeda Shareholder Neuroscience Education Institute
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?
Problems with the Term Antipsychotic for Treatments of Psychosis with Complex Pharmacology All antipsychotics presumed to act by blocking D2 dopamine receptors Other receptors not linked to efficacy in psychosis Psychosis means positive symptoms Treatments of psychosis either cause EPS or metabolic problems Treatments of psychosis require warnings for tardive dyskinesia, neuroleptic malignant syndrome, seizures, death in dementia related psychosis, stroke, leukopenia, orthostasis, dysphagia
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.
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. 4 th Ed. Cambridge University Press, 2013.
Dilemma #1: Nomenclature for drugs that treat psychosis What if they don t block D2 receptors?
Pimavanserin
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.
Dilemma #2: Nomenclature for drugs that treat psychosis What if they treat negative symptoms but not positive symptoms in psychosis? What if they treat cognitive symptoms but not positive symptoms in psychosis?
The Priming Mechanism of Action at α7 Receptors = Acetylcholine = Ca 2+ Extracellular α7 α7 α7 α7 α7 Primer binds, but does not activate the α7 receptor Channel opens = α7 primer With primer bound, only one acetylcholine molecule is needed to open the channel Intracellular Ions flow through freely Acetylcholine dissociates, but the primer stays bound, allowing for reactivation of the receptor by acetylcholine Priming of the α7 receptor allows for a lower concentration of acetylcholine to activate the channel, which results in the channel being able to signal more regularly and reduces the occurrence of rapid desensitization
Dilemma #3: Nomenclature for drugs that treat psychosis What if they treat mania, unipolar depression, bipolar depression, depression with mixed features? Do they now cause suicidality?
Muscarinic Acetylcholine Receptors: M1 M2 M3 M4 Histamine Receptors: H1 Adrenergic Alpha Receptors: 1 2A 2B 2C Transporters SERT NET D2 Dopamine Receptors: Serotonin Receptors: 5HT1A 2A 1B 1D 2B 2C 1E 3 5 6 7 D1 D2 D3 D4 5-1
The Solution: Multi-Axial Nomenclature Axis I Class : Relevant Mechanism: Axis 2 Axis 3 Axis 4 Indications: Efficacy: Side Effects: Neurobiological description Neurotransmitter actions: Preclinical: Human: Physiological: Committee notes:
Haloperidol Axis I Axis 2 Axis 3 Class : dopamine Relevant Mechanism: dopamine D2 receptor antagonist Indications: schizophrenia, mania and hypomania; mental or behavioural problems such as aggression, hyperactivity and self mutilation in the mentally retarded and in patients with organic brain damage; adjunct to short term management of moderate to severe psychomotor agitation Efficacy: Improvement of psychotic symptoms Side Effects: EPS, galactorrhea, sedation, dizziness, weight gain. Risk of tardive dyskinesia, NMS Axis 4 Neurobiological description Neurotransmitter actions: dopamine D2 receptor antagonist Preclinical: antagonist at D1, D2, D3 and alpha 1 norepinephrine receptors Committee notes: depot available
Lurasidone 5HT7 D2 2C 1 5-59 D4 5HT 2A 5HT 1A 2A 5HT 2C
Lurasidone Axis I Axis 2 Axis 3 Class : dopamine multifunctional Relevant Mechanism: dopamine and serotonin receptor antagonist Indications: schizophrenia (USA, Canada, UK, Europe); major depressive episodes associated with bipolar I disorder (USA and Canada) 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
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
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