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 treat more symptoms Drugs that provide improved

• ptions for treatment-

resistant patients Drugs with enhanced safety profiles Drugs that increase compliance

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

• Although categorical classifications may be useful for clinical practice, the
• verwhelming 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.

DSM-5 Major Depressive Disorder

Remission After First Antidepressant

Only 1 in 3 patients will achieve remission on their first antidepressant Rush AJ et al. Am J Psychiatry 2006;163:1905-17.

67% of patients require four antidepressant trials before symptoms remit

Remission After First Antidepressant

Relapse After First Antidepressant

What percentage of unipolar major depressive episodes remit?

Monotherapies That Target Multiple Receptors

Starting Dose (mg/day) Usual Daily Dose (mg/day) Tips and Pearls

mirtazapine 15 15 – 45

Evening dosing; increase every 1–2 weeks until desired efficacy is reached; maximum generally 45 mg/day

nefazodone 100 2x/day 300 – 600

Increase by 100–200 mg/day each week until desired efficacy is reached

trazodone 150 150 – 600

Initial 150 mg/day in divided doses; can increase every 3–4 days by 50 mg/day as needed

trazodone ER 150 150 – 375

Initial 150 mg/day in divided doses; can increase every 3 days by 75 mg/day as needed

vilazodone 10 20 – 40

Increase to 20 mg/day after one week; can increase to 40 mg/day after one more week; should be taken with food

vortioxetine 10 5 – 20

Can decrease to 5 mg once daily or increase to 20 mg once daily depending on patient response

Stahl SM. Stahl’s Essential Psychopharmacology: The Prescriber’s Guide. 6th ed. 2016.

5HT 2A 5HT 2C 5HT3 2 H1 5HT 2A 5HT 2C SERT 1 H1 SERT 1A SERT 1A 1B 1D 3 7 5HT 2A 5HT 2C S E R T 𝜷1 NET

Duration of antidepressant treatment (days)

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

Monoamine levels Depressive symptoms Changes in neuroplasticity and glutamatergic neurotransmission

Beyond Monoamines: The Neuroplasticity Hypothesis of Depression

Other Targets in Depression Treatments

Emerging Somatic Treatments

• Deep transcranial magnetic stimulation (DTMS)
• Repetitive transcranial magnetic stimulation (rTMS)
• Synchronized transcranial magnetic stimulation (sTMS)
• Low field magnetic stimulation (LFMS)
• 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.

Glucocorticoid Receptor Antagonists

Agent Clinical Trial Phase Mifepristone III Metyrapone III Org-34517 II

Acetylcholine Muscarinic (AChM) Receptor Antagonist

• Scopolamine may exert antidepressant effects

by acting on the MTORC1 complex via the mTOR pathway and thereby inducing synaptogenesis

Acetylcholine (Ach) Release Inhibitor and Neuromuscular Blocking Agent

• Onabotulinumtoxin A—treatment in the glabellar

(forehead) region can treat MDD

• Effects of one injection last up to 16 weeks

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

• f 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

Tonic inhibition Phasic inhibition

GABA

Benzodiazepine- sensitive GABA-A receptor

extrasynaptic

Benzodiazepine- insensitive GABA-A receptor

postsynaptic

Stahl SM. Stahl's Essential Psychopharmacology. 4th ed. 2013.

neurosteroid cholesterol pregnenolone

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

Durgam et al. ACNP Ann Meeting 2019; Wilkinson ST et al., Drug Discov Today. 2019;24(2):606-615.

Lumateperone: FDA Approved for Schizophrenia on December 23, 2019 NRX-101 (lurasidone/cycloserine) being investigated for bipolar depression with suicidal ideation and behavior

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/ Hydrochloroquine

• Use caution with psychotropics that may prolong QTc
• 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 therapy

• No specific interactions

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,
• lanzapine)

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 D2/5HT1A partial agonist 5HT2A antagonist

Schizophrenia Marketplace: Drug Development Areas for Unmet Needs

Drugs that enhance cognition Drugs that treat negative symptoms Drugs that provide improved

• ptions for treatment-

resistant patients Drugs with enhanced safety profiles Drugs that increase compliance Fellner et al. Pipeline Plus 2017;42(2):130-4.

Match Each Symptom to Hypothetically Malfunctioning Brain Circuits

Dopamine Pathways Relevant to Schizophrenia Symptoms

Efficacy: Beyond D2 Hypothesis

• Schizophrenia has been primarily associated with

dopamine dysfunction

• All effective treatments directly target the dopamine D2

receptor

• Core pathophysiology may also involve dysfunction of

glutamatergic, serotonergic, cholinergic, and gamma- aminobutyric acid (GABA) signaling

• Imbalance within any of these may influence the entire

system

• Novel treatment development is focusing on targets beyond

dopamine, including glutamate, serotonin, acetylcholine, GABA, and inflammatory cytokines

Yang et al. International Journal of Molecular Sciences 2017;18(8):1-14.

Summary: Antipsychotic Binding at Dopamine Receptors

brexpiprazole paliperidone aripiprazole risperidone ziprasidone iloperidone lurasidone quetiapine asenapine

• lanzapine

clozapine cariprazine blonanserin D2

D1 D2 D3

predominantly D2

D2 D1 D1 D2 D3

Plus D1

D2 D3 D1 D2 D3

Plus D3

Stahl SM. CNS Spectrums 2017;22:375-84.

Dopaminergic Antipsychotics in Development

Ballester and Frankel. The American Journal of Psychiatry Residents’ Journal 2016;11(1):5-8.

Drug Mechanism Status Company Clinical Trial AMG579 OMS643762 PDE 10A inhibitor PDE10A inhibitor Phase 2 Amgen NCT01952132 DAAOI-1 DAAO catalyzes D-serine and glycine POC ongoing NCT01390376 Eltoprazine 5-HT1A/1B agonist POC ongoing NCT01266174 L-DOPA Dopamine stabilization POC ongoing NCT01636037 Stepholidine D2 antagonist/D1 agonist/5HT1A agonist POC ongoing University of Toronto YKP1358 D2/D3/5HT2A antagonist Phase 2 SK Bio- Pharmaceuticals

Beyond Dopamine: Lumateperone

• FDA Approved December 23, 2019

Beyond D2: Drugs in Development

• Lu AF35700
• Lu AF11167
• Pimavanserin
• KarXT (xanomeline + trospium
• SEP-363856

Treatment of Negative Symptoms: Glutamatergic Strategies

• Topiramate
• Multiple meta-analyses show efficacy
• Lamotrigine, memantine, amantadine, NMDA agonists
• Inconsistent or disappointing results
• Metabotropic glutamate receptor (mGluR) 2/3 agonists
• Disappointing results
• mGluR positive allosteric modulators
• Efficacious in animal studies; currently Phase II

Veerman SRT et al. Drugs 2017;77:1423-59.

Treatment of Negative Symptoms: Other Strategies

• Anti-inflammatory agents
• Disappointing results for NSAIDs
• Meta-analysis showed efficacy for minocycline
• Anti-oxidant
• Mixed results for N-acetylcysteine (NAC)
• Meta-analysis shows moderate efficacy for ginkgo

biloba

• Hormone treatment
• Preliminary evidence for raloxifene (selective estrogen

receptor modulator)

• HMG CoA reductase inhibitors
• Small positive trial of adjunct simvastatin

Veerman SRT et al. Drugs 2017;77:1423-59; Tajik-Esmaeeli S et al. Int Clin Psychopharmacol 2017;32(2):87-94.

Clinical Translation: Treatment Mechanisms Beyond Dopamine

• Neurobiological data: rationale for why current

antipsychotics don't seem to improve cognition

• Prospect of novel mechanisms
• Glutamatergic
• GABA-ergic
• Cholinergic
• Anti-inflammatory

Glutamate and Schizophrenia

• NMDA hypofunction hypothesis of

schizophrenia

• Neurodevelopmentally abnormal glutamate

synapses

• Hypofunctional NMDA receptors
• Overstimulation of downstream glutamate

receptors

Glutamate neuron Glycine transporter Postsynaptic metabotropic receptor AMPA receptor NMDA receptors glutamate

Direct acting glycine site agonists d-cycloserine d-serine glycine

Glial cell

AMPA modulators CX-516 piracetam cyclothiazide LY404187 Glycine transporter inhibitors sarcosine bitopertin (RG1678) mGlu receptor modulators LY354740 LY2140023

Novel Treatment Mechanisms: Glutamate

Summary: Novel Therapies Targeting Total Symptoms

• Therapies targeting total symptoms include:
• Cannabidiol
• D3 antagonist/5-HT1A partial agonist F17464
• Phosphodiesterase 10A (PDE10A) inhibitors MK-

8189 and TAK-063

• Sodium nitroprusside
• Trace amine-associated receptor-1 (TAAR1)

agonist RO5263397 and SEP-363856

• KarXT (xanomeline + trospium)

Sleep Disorders

Pharmacological Treatments for Insomnia

Pharmacological Agent FDA-Approved for Insomnia Benzodiazepine Hypnotics Estazolam ✓ Flurazepam ✓ Quazepam ✓ Temazepam ✓ Triazolam ✓ Nonbenzodiazepine Hypnotics Eszopiclone ✓ Zaleplon ✓ Zolpidem ✓ Antidepressants Doxepin ✓ Trazodone Pharmacological Agent FDA-Approved for Insomnia Hypocretin/Orexin Antagonist Suvorexant ✓ Lemborexant ✓ Melatonin Receptor Agonists Melatonin Ramelteon ✓ Tasimelteon Antipsychotics Quetiapine Olanzapine Anticonvulsants Clonazepam Gabapentin Tiagabine

Stahl SM, Morrissette DA. Stahl's Illustrated Sleep and Wake Disorders 2016.

Blocking Orexin Receptors With Antagonist Agents May Help to Promote Sleep

• Binding of orexin to

OXR1 and OXR2 receptors promotes wakefulness; orexin antagonists promote sleep by blocking these receptors

Blocking Orexin Receptors With Antagonist Agents May Help to Promote Sleep

• Lemborexant blocks the orexin

(aka hypocretin) system

• FDA-approved treatment of

insomnia characterized by difficulties with sleep onset and/or sleep maintenance in adults

• Approved at both 5 and 10 mg

doses for insomnia

• Other FDA-approved DORA is

suvorexant

Lemborexant Lemborexant Orexin A Orexin B

Summary

• The neurobiology and molecular underpinnings of sleep are

complex

• The quality and quantity of sleep can greatly affect our physical

and mental health

• There are numerous pharmacological and nonpharmacological

treatment options available that target various components of the sleep/wake circuit to improve sleep/wake

Posttest Question

For ADHD, there are how many FDA-approved stimulant medications?

• 1. 6
• 2. 13
• 3. 19
• 4. 29
• 5. 33

Posttest Question

The majority of currently available atypical antipsychotics:

• 1. Have higher affinity for dopamine 2 receptors than for

serotonin 2A receptors

• 2. Have higher affinity for serotonin 2A receptors than for

dopamine 2 receptors

• 3. Have comparable affinity for dopamine 2 and serotonin 2A

receptors

Posttest Question

A 32-year-old man with bipolar disorder has had a partial response to divalproex and is now being augmented with an atypical antipsychotic. The effects of atypical antipsychotics in nonpsychotic mania may be due to:

• 1. Indirect effects on GABA release via D2 receptor antagonism
• 2. Indirect effects on glutamate release via serotonin 2A

antagonism

• 3. Direct effects on voltage-sensitive sodium channels
• 4. Direct effects on voltage-sensitive calcium channels