Program Outline Out with the Old In with the New: Novel, Neuroscience-Based Re-Classification of Psychiatric Medications Rajiv Tandon, MD Professor of Psychiatry University of Florida College of Medicine Gainesville, Florida Current Classification of Psychotropic Medications The Official Nomenclature Why it Does Not Work Why we need a Neuroscience-guided System Proposed International Neuroscience-Based Nomenclature () Description Review and Discussion An Alternative Simpler Mechanistic Classification and its Clinical Application Description Clinical Application Why Nomenclature Matters Organization of information about available medications Synthesis of current knowledge and incorporation of new information Enables practice of Evidence-Based Medicine Framework to better inform pharmacologic treatment decisions What Clinicians Need and Want in a Pharma Nomenclature System that optimally guides informed choices about initial treatment and next pharmacologic step/s for a range of psychiatric conditions Based on contemporary scientific knowledge Allows easy incorporation of new information Provides language for communication about pharmacologic treatment with clinicians and patients Does not conflict with the way medications are used Comprehensive and also Comprehensible Coherent Simple Easy to use Current Nomenclature of Psychotropic Medications (~170 used) The official taxonomy of psychiatric medications (WHO) (ATC CLASSIFICATION SYSTEM AS WITH ALL OTHER MEDICATIONS) The WHO Classification of PSYCHOTROPICS NO5 and NO6 Agents that alter function of the mind What is the classification that clinicians use? Why current terminology is past breaking point!!! What we can learn from the approach taken by other medical disciplines? NO5 Psycholeptics Have a calming effect NO6 Psychoanaleptics Have a stimulating effect ATC = Anatomical Therapeutic Chemical; WHO = World Health Organization. WHO Collaborating Centre for Drug Statistics Methodology, Guidelines for ATC classification and DDD assignment 2016. Oslo, 2016. www.whocc.no/filearchive/publications/2017_guidelines_web.pdf. Accessed August 3, 2017. WHO Collaborating Centre for Drug Statistics Methodology, Guidelines for ATC classification and DDD assignment 2016. Oslo, 2016. www.whocc.no/filearchive/publications/2017_guidelines_web.pdf. Accessed August 3, 2017.
The WHO Classification of PSYCHOLEPTICS NO5 The WHO Classification of PSYCHOANALEPTICS NO6 A. Major tranquilizers. Includes tetrabenazine, reserpine, cannabidiol, pimavanserin B. Anxiolytics Minor Tranquilizers Includes opioids, benzodiazepines, nonbenzodiazepines, barbiturates, gabapentin C. Hypnotics/Sedatives Includes GABA A agonists, GABA B agonists, H 1 antagonists, 5-HT 2A antagonists, melatonin, orexin WHO Collaborating Centre for Drug Statistics Methodology, Guidelines for ATC classification and DDD assignment 2016. Oslo, 2016. www.whocc.no/filearchive/publications/2017_guidelines_web.pdf. Accessed August 3, 2017. A. Antidepressants B. Stimulants and Nootropics D. Anti-Dementia Drugs C. Psycholeptics & Psychoanaleptics in combination WHO Collaborating Centre for Drug Statistics Methodology, Guidelines for ATC classification and DDD assignment 2016. Oslo, 2016. www.whocc.no/filearchive/publications/2017_guidelines_web.pdf. Accessed August 3, 2017. The WHO Classification of ANTIDEPRESSANTS NO6A A. Non-selective E. Others Monoamine Reuptake Inhibitors D. Selective Monoamine Oxidase A Inhibitors B. Selective Serotonin Reuptake Inhibitors C. Non-selective Monoamine Oxidase Inhibitors WHO Collaborating Centre for Drug Statistics Methodology, Guidelines for ATC classification and DDD assignment 2016. Oslo, 2016. www.whocc.no/filearchive/publications/2017_guidelines_web.pdf. Accessed August 3, 2017. Problems with Current WHO Nomenclature Overly complex and yet uninformative Incomplete Indications neither specific to nor exclusive to medication Confusing Misleading to patients Have become less coherent as new medications cannot be easily classified Creative use of language (SGA, SNRI, SSRI) Contribute to stigma SGA = second-generation antipsychotic; SNRI = serotonin-norepinephrine reuptake inhibitor; SSRI = selective serotonin reuptake inhibitor. What Clinicians Need and Want in a Pharma Nomenclature System that optimally guides informed choices about initial treatment and next pharmacologic step/s for a range of psychiatric conditions Based on contemporary scientific knowledge Allows easy incorporation of new information Provides language for communication about pharmacologic treatment with clinicians and patients Does not conflict with the way medications are used Comprehensive and also Comprehensible Coherent Simple Easy to use What Pharma Nomenclature Do Clinicians Currently Use? Emphasis on simplicity and coherence (FGAs and SGAs) Antidepressants (TCAs, SSRIs, SNRIs, MAOIs, Other) Mood Stabilizers (Lithium, Anticonvulsants) Stimulants Benzodiazepines Others FGA = first-generation antipsychotic; TCA = tricyclic antidepressant; MAOI = monoamine oxidase inhibitor.
Can We Learn from Other Medical Disciplines? Though simpler, the clinician system has all the other problems leading to Not useful in guiding pharmacologic treatment choices Highly variable practices Stigma, lack of coherence, confusion So what have the other disciplines done? No longer use the WHO ATC (anatomy, therapeutic application, chemical structure) classification Group medications on the basis of mechanism of action Thereby addressing many of the problems seen with the ATC method Moving to an To keep up with scientific advances and clinical reality, learning from other disciplines, we wish to move to a Neuroscience-based System Leading psychopharmacologic organizations embarked on a 4-year process () ECNP, ACNP, CINP, AsCNP, IUBCPharmacol Formulated a proposal and draft was reviewed and field-tested on the Internet 28 scientific journal editors (all psychopharmacology journals) have endorsed its use in their Journal 6 dimensions on which 108 of the approximately 150 psychotherapeutic medications are classified Dimension 1: (Pharmacologic Domains) - 11 Acetylcholine, Dopamine, GABA, Glutamate, Histamine, Ion channel, Lithium, Melatonin, Norepinephrine, Opioid, Serotonin Dimension 2: (Mode of action) - 10 Agonist, Partial agonist, Antagonist, Positive allosteric modulator (PAM), Reuptake inhibitor, Reuptake inhibitor and Releaser, Reuptake inhibitor and antagonist, ion channel blocker, enzyme inhibitor, enzyme modulator Dimension 3: (Approved Indications) vary across countries based on decisions of local regulatory bodies Dimension 4: (Efficacy and Side Effects) information from guidelines, additional indications Dimension 5: (Practical Notes) clinical knowledge filtered through the taskforce Dimension 6: (Neurobiology) preclinical and clinical All medications should be described in terms of all clinically relevant modes of action, listing them in a hierarchical manner 108 of the approximately 150 psychotherapeutic medications are classified All medications should be described in terms of all clinically relevant modes of action, listing them in a hierarchical manner (based on???) 108 of the approximately 150 psychotherapeutic medications are classified Examples Olanzapine Antagonist; D 2, 5-HT 2A ; same as iloperidone Risperidone Antagonist; D 2, 5-HT 2A, NE α 2 Quetiapine MM; Antagonist; D 2, 5-HT 2A ; Reuptake inhibitor (NE) Aripiprazole Partial Agonist; D 2, 5-HT 2A
Is the System an Advance? Do You Find it Helpful? Neuroscience-Based Experts from across world have developed it Will be required in several scientific publications New information will be communicated with this terminology Appears highly sophisticated Is the System an Advance? Do You Find it Helpful? Not clinician-friendly at all!!! Long, complicated descriptions even essays Overly complex and yet incomplete Requires clinician to have much more sophisticated pharmacologic knowledge Not completely informative (affinity, intrinsic activity, fast/slow dissociation) Mechanisms of action incompletely understood Confusing on what parameters do you decide relevant pharmacology and how do you construct a hierarchy Currently only applicable to adult psychiatry We Need a Better System What Can We Do NOW? What Do Clinicians Need to Make Optimal Use of Medications we have for the Conditions we see A syndromal diagnosis An understanding of the nature of the underlying brain disorder Mechanism of action of the drug Based on contemporary scientific knowledge Allow easy incorporation of new information Language for communication about pharmacologic treatment Does not conflict with the way medications are used As Comprehensive as possible BUT MUST BE COMPREHENSIBLE Not confusing or incoherent Simple and Easy to use Do We Know How Psychotherapeutic Medications Work? Grossly Simplified Based on Common Denominator Stimulants: Increase DA (and NE) : Block DA (D 2 ) receptors Antidepressants: Increase 5-HT and/or NE Anti-dementia: Increase ACh Benzodiazepines: Stimulate GABA Lithium + Anticonvulsants: Second messengers and ion channels (membrane stabilization) Classification of Psychotherapeutic Medications, Circa 2017 A. D 2 Antagonists and Partial Agonists G. Other Lithium H 1 Antagonists Melatonin agonists F. AChE inhibitors E. Catecholamine reuptake inhibitors and release B. Monoamine D. Voltage-gated Calcium and Reuptake Inhibitors, Sodium Ion Channel Blockers Agonists, and MAOIs C. GABA-enhancing Agents (PAMs BDZs) Prior to Antipsychotic Agents Conventional or Typical (First-Generation) Atypical (Second-Generation) 1952 1960s 1980s 1990s 2000s Chlorpromazine Haloperidol Fluphenazine Clozapine Thioridazine Loxapine Perphenazine Trifluoperazine Risperidone Thiothixene Olanzapine Molindone Quetiapine Pimozide Ziprasidone Aripiprazole Paliperidone Iloperidone Asenapine Lurasidone Brexpiprazole Cariprazine
Dopamine Neurotransmitter/Receptor Involvement in Psychotic Disorders DA is believed to play a large role in the pathogenesis of psychotic symptoms All antipsychotics today ACT at postsynaptic DA D 2 receptors DA pathways include Mesolimbic: Too MUCH DA positive symptoms Mesocortical: Too LITTLE DA negative, mood, and cognitive symptoms Nigrostriatal: Blocking DA results in EPS Tuberoinfundibular: Blocking DA results in hyperprolactinemia EPS = extrapyramidal symptoms. Stahl SM. Stahl s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. Fourth Edition. New York: Cambridge University Press; 2013. Dopamine PRESYNAPTIC NEURON Synaptic Vesicle Dopamine Receptor (D2) POSTSYNAPTIC NEURON Why Avoidance of EPS is So Important!!! Fewer EPS Better cognition Fewer negative symptoms Obtaining antipsychotic effect without EPS Less depression Less tardive dyskinesia Less nonadherence Tandon R. Psychiatr Q. 2002;73(4):297-311. EPS: The Atypical Advantage EPS profiles differ among atypical agents Determined by combination of following attributes: 5-HT 2A /DA blockade Affinity for DA D 2 receptor and ease of dissociation from DA D 2 receptor Partial agonism at DA D 2 receptor Intrinsic anticholinergic activity Prior to Antipsychotic Agents Conventional or Typical (First-Generation) Atypical (Second-Generation) 1952 1960s 1980s 1990s 2000s Chlorpromazine Haloperidol Fluphenazine Clozapine Thioridazine Loxapine Perphenazine Trifluoperazine Risperidone Thiothixene Olanzapine Molindone Quetiapine Pimozide Ziprasidone Aripiprazole Paliperidone Iloperidone Asenapine Lurasidone Brexpiprazole Cariprazine Tandon R. Psychiatr Q. 2002;73(4):297-311. D 2 Antagonists and Partial Agonists Therapeutic Applications NOTES 1. Psychosis: All are equally effective with varying side effects, with clozapine being more effective in psychosis refractory to other agents. EPS avoidance is important 2. Depression Bipolar depression those with very low EPS potential quetiapine, lurasidone, clozapine MDD as adjunct High affinity agent 3. Mania All are equally effective 4. OCD as adjunct High affinity agent 5. Neurodevelopmental Disorder with agitation Very high affinity agent MDD = major depressive disorder; OCD = obsessive-compulsive disorder. A. Psychosis B. Depression C. Mania D. OCD E. Neurodevelopmental Disorder with agitation Monoamine Reuptake Inhibitors, Agonists, and MAOIs Therapeutic Applications NOTES A. Depression B. Anxiety C. OCD D. Chronic Pain and Fibromyalgia
Agents in Various Classes of Individual Agents within each class VARY in Pharmacokinetics Pharmacodynamics Drug-drug interactions Range of therapeutic applications Amount of available clinical data and experience Ease of use Pharmacologic Treatment of Any Disease Know the Disease that you are treating Nature: Clinical, Etio-Pathophysiology Treatment targets; Treatment goals Know the Treatments at your disposal What they do; How they compare; Costs Principles of Treatment Measurement-based; Targeted; Individualized THE BEST TREATMENT TODAY Measurement-Based, Individualized* You can t manage what you don t measure. Unknown Specific vulnerabilities and needs of patient interact with specific profile of antipsychotic agent in the context of illness course to determine: Optimal dosing strategy Best benefit-cost differential These are difficult to predict ahead of time Match individual needs/vulnerabilities to agent profile as best as possible at initial selection of antipsychotic Monitor (both benefits and side effects) on ongoing basis There is no best agent or group of agents for all *Example of Schizophrenia. Why Nomenclature Matters Organization of information about available medications Synthesis of current knowledge and incorporation of new information Enables practice of Evidence-Based Medicine Framework to better inform pharmacologic treatment decisions Reconciling and Clinician-Friendly Systems Clinician-friendly system described is useful for broad grouping of psychotherapeutic medications It only approximates current science: greatest common denominator Best balance between precision and applicability is most useful for characterization of individual agents Detailed description of profile and other relevant information Overly cumbersome for grouping of agents Use both together as above Both will need to be reviewed and updated with time