INTO THE PIPELINE: THE LATEST IN PSYCHOPHARMACOLOGY Learning - PowerPoint PPT Presentation

INTO THE PIPELINE: THE LATEST IN PSYCHOPHARMACOLOGY

Learning Objectives • Describe the mechanisms of action of emerging and investigational treatments of mental illnesses • Discuss implications of recent and novel data to clinical practice

Current State of Psychopharmacology

Drug Development Areas for Unmet Needs Drugs that provide improved Drugs that treat options for treatment- more symptoms resistant patients Drugs that Drugs with increase compliance enhanced safety profiles

The Five Molecular Targets of Psychotropic Drugs

Attention deficit/hyperactivity disorder (ADHD)

Treatment Options and Medication

Number of Stimulant Preparations?

Number of Non-Stimulant Preparations? FDA-approved • Atomoxetine • Guanfacine XR • Clonidine XR

In The Pipeline Stimulants in Development • AR19 (manipulation resistant amphetamine) • HLD100 (d-amphetamine DR/ER) • ATS (amphetamine transdermal patch) • KP415 (d-MPH prodrug) • CTX-1301 (d-MPH MLR XR) • KP484 (d-MPH prodrug XR) • CTX-1302 (d-amphetamine MLR XR) Non-Stimulants in Development • centanafadine (NDSRI) • NLS-001 (mazindol) • CX717 (AMPA modulator) • SKL13865 (NDRI) • eltoprazine (5HT1A/1B partial agonist) • SPN-812 (viloxazine XR, SNMA)

Mood Disorders

The Mood Disorder Spectrum DSM-5 Major Depressive Disorder •Although categorical classifications may be useful for clinical practice, the overwhelming majority of the evidence points to a dimensional (spectrum) view of mood disorders •e.g., treatment response (antidepressant vs. mood stabilizing agent) and links with family history of bipolar disorder Benazzi F. Eur Psychiatry 2008;23(1):40-8; Hu J et al. Prim Care Companion CNS Disord 2014;16(2):PCC.13r01599; Sato T et al. J Affect Disord 2004;81(2):103-13; Vieta E, Valenti M. J Affect Disord 2013;148(1):28-36.

Remission After First Antidepressant Only 1 in 3 patients will achieve remission on their first antidepressant 67% of patients require four antidepressant trials before symptoms remit Rush AJ et al. Am J Psychiatry 2006;163:1905-17.

Remission After First Antidepressant

Relapse After First Antidepressant

What percentage of unipolar major depressive episodes remit?

Monotherapies That Target Multiple Receptors Starting Dose Usual Daily Dose Tips and Pearls (mg/day) (mg/day) Evening dosing; increase every 1–2 weeks until 2 mirtazapine 15 15 – 45 desired efficacy is reached; maximum generally 45 5HT3 H1 5HT mg/day 2A 5HT 2C NET 𝜷 1 Increase by 100–200 mg/day each week until nefazodone 100 2x/day 300 – 600 T E R S desired efficacy is reached 5HT 5HT 2C 2A Initial 150 mg/day in divided doses; can increase trazodone 150 150 – 600 H1 1 every 3–4 days by 50 mg/day as needed SERT 5HT 5HT Initial 150 mg/day in divided doses; can increase 2C trazodone ER 150 150 – 375 2A every 3 days by 75 mg/day as needed Increase to 20 mg/day after one week; can 1A vilazodone 10 20 – 40 increase to 40 mg/day after one more week; should SERT be taken with food 1A 1B Can decrease to 5 mg once daily or increase to 20 vortioxetine 10 5 – 20 1D SERT mg once daily depending on patient response 3 7 Stahl SM. Stahl’s Essential Psychopharmacology: The Prescriber’s Guide. 6th ed. 2016.

Beyond Monoamines: The Neuroplasticity Hypothesis of Depression Monoamine levels Changes in neuroplasticity and glutamatergic neurotransmission Depressive symptoms 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 Duration of antidepressant treatment (days)

Other Targets in Depression Treatments Acetylcholine (Ach) Release Inhibitor Glucocorticoid Receptor Antagonists and Neuromuscular Blocking Agent Agent Clinical Trial Phase • Onabotulinumtoxin A—treatment in the glabellar Mifepristone III (forehead) region can treat MDD Metyrapone III • Effects of one injection last up to 16 weeks Org-34517 II Acetylcholine Muscarinic (AChM) Emerging Somatic Treatments Receptor Antagonist • Deep transcranial magnetic stimulation (DTMS) • Repetitive transcranial magnetic stimulation (rTMS) • Scopolamine may exert antidepressant effects by acting on the MTORC1 complex via the • Synchronized transcranial magnetic stimulation (sTMS) mTOR pathway and thereby inducing • Low field magnetic stimulation (LFMS) synaptogenesis • Intermittent theta-burst stimulation (iTBS) Bewernick B et al. F1000Res 2015;4; Drevets WC et al. Biol Psychiatry 2013;73(12):1156-63; Navarria A et al. Neurobiol Dis 2015;82:254-61; Khajavi D et al. J Clin Psychiatry 2012;73(11):1428-33; Dale E et al. Biochem Pharmacol 2015;95(2):81-97; Scarr E et al. Front Cell Neurosci 2013;7:55; Cohen IV et al. Sci Rep 2017;7(1):1450; Magid M et al. J Clin Psychiatry 2014;75(8):837-44; Parsaik AK et al. J Psychiatr Pract 2016;22(2):99-110; Cole EJ et al. Am J Psychiatry. 2020;177(8):716-726.

Dysfunction of Glutamate Signaling •Glutamate is an excitatory neurotransmitter involved in many functions, including synaptic plasticity, learning, and memory •Numerous studies have shown regional changes in glutamate receptors, as well as elevated levels of glutamate in the brains of patients with MDD •Normal glutamatergic activity is thought to be involved in maintaining normal neuroplasticity •Under conditions of stress or depression, glutamate signaling is impaired, leading to a reduction of neuroplasticity

Two Types of GABA-A Mediated Inhibition GABA neuron glial cell cholesterol pregnenolone neurosteroid GABA Benzodiazepine- Benzodiazepine- sensitive GABA-A insensitive GABA-A receptor receptor postsynaptic extrasynaptic Tonic inhibition Phasic inhibition Stahl SM. Stahl's Essential Psychopharmacology. 4th ed. 2013.

In The Pipeline Treatments for MDD • AV-101 (4-Chlorokynurenine, NMDA modulator) • PCN-101 (r-ketamine) • AXS-05 (bupropion/dextromethorphan) • PH10 (pherine nasal spray) • BTRX-335140 (kappa opioid antagonist • Psilocybin • Hydroxynorketamine • REL-1017 (d-methadone), • NV-5138 (mTORC1 activator) • SAGE-217 (GABA-A modulator)

Bipolar Depression Lumateperone : FDA Approved for Schizophrenia on December 23, 2019 NRX-101 (lurasidone/cycloserine) being investigated for bipolar depression with suicidal ideation and behavior Durgam et al. ACNP Ann Meeting 2019; Wilkinson ST et al., Drug Discov Today. 2019;24(2):606-615.

COVID-19 and Psychiatric Disorders

Psychotropic Medications and COVID-19 Table 1. Potential Interactions Between Psychotropics and Organ Systems Affected By COVID-19 Organ System Impacted Psychotropic Utilization • Hematologic Avoid psychotropics that may impact white blood cell production (clozapine, carbamazepine, olanzapine) • Use caution with psychotropics that may increase bleeding risk (valproic acid, SSRIs, SNRIs) • Cardiac Use caution with psychotropics known to prolong QTc (antipsychotics, citalopram, TCAs) • Hepatic Avoid psychotropics that may cause liver injury (chlorpromazine, carbamazepine, valproate, duloxetine, nefazodone) • Renal Dose adjustment may be needed for some psychotropics (lithium, gabapentin, topiramate, pregabalin, paliperidone, duloxetine) • Nervous System Use caution with benzodiazepines, opioids, sedative/hypnotics, and strong anticholinergics in patients with delirium • Use caution with psychotropics that may lower seizure threshold • Pulmonary Use caution with psychotropics that may suppress respiratory drive (benzodiazepine)

Psychotropic Medications and COVID-19 Table 2. Potential Interactions Between Psychotropics and Medications Used to Treat COVID-19 COVID-19 Treatment Psychotropic Utilization • Azithromycin Use caution with psychotropics that may prolong QTc • Use caution with hepatotoxic psychotropics • Chloroquine/ Use caution with psychotropics that may prolong QTc • Hydrochloroquine Use caution with hepatotoxic psychotropics • Potential drug interactions with CYP3A4 inhibitors (fluvoxamine) and inducers (carbamazepine, oxcarbazepine, modafinil) • Use caution with psychotropics that may lower seizure threshold • Colchicine Use caution with PgP and CYP3A4 inhibitors (fluvoxamine) • Convalescent plasma No specific interactions therapy • Corticosteroids Use caution with psychotropics that may lower seizure threshold (bupropion) • Phenytoin increases hepatic metabolism of corticosteroids • Favipiravir Possible QTc prolongation • Interferon Use caution with psychotropics that may lower seizure threshold • Lopinavir/Ritonavir Use caution with CYP3A4, CYP2D6, CYP1A2, and CYP2B6 substrates • Contraindicated with pimozide, midazolam, and triazolam • Lowers concentration of some psychotropics (bupropion, methadone, lamotrigine, olanzapine) • Remdesivir No information available • Tocilizumab No major interactions reported • Vitamin C Coadministration with barbiturates may decrease the effects of vitamin C

Schizophrenia

Therapeutic Mechanisms of Drugs for Psychosis D2 antagonist 5HT2A/D2 antagonist 5HT2A antagonist D2/5HT1A partial agonist