Ketamine

Mujeeb U Shad, M.D., M.S.C.S.

Residency Program Director, Valley Health System, Las Vegas, NV

Adjunct Professor of Psychiatry

University of Nevada, Las Vegas, NV

Adjunct Professor of Psychiatry,

Touro University Nevada, Las Vegas, NV

What is New in Psychopharmacology for the Primary Physicians to Know?

Ketamine Beyond Monoamines – Mechanism of Action

Aims & Objectives

The audience will be presented with an update on recently and relatively recently approved psychopharmacological medications for major and minor psychiatric indications. The information presented will be relevant to the primary care physicians

New Psychotropics New Antidepressants

Esketamine – Intransal Vortioxetine (Trintellix) Levomilnacipran (Fetzima) Brexanolone (Zelpresso)

New antipsychotics Aristada Initio Risperidone LAI Brexpiprazole (Rexulti) Cariprazine (Vraylar)

Non-Stimulant ADHD medication Viloxazone (Qelbree)

Sleep aids Suvorexant (Belsomra)

Lemborexant (Dayvigo)

Ramelteon (Rozerem)

New Psychotropics Novel Indications:

Medications for Parkinson’s Psychosis

Pimavanserin (Nuplazid)

Medication to treat post-partum depression

Brexanolone (Zulresso)

Medications to treat Tardive Dyskinesia

Valbenazine (Ingrezza)

Deutetrabenazine (Austedo)

Medication for Hypoactive Sexual Desire Disorder (HSSD) in females

Flibanserin (Addyi)

Medication to treat Pseudo-bulbar Affect

Dextromethorphan/Quinidine (Nuedexta)

Ketamine

Synthesized in 1962, first used in humans in 1965, released for clinical use in 1970 Only 20% bioavailability after oral use.To be used in conjunction with an oral antidepressant for treatment-resistant depression.

First medication for depression with a new mechanism of action since fluoxetine was approved in 1988.

Because of risks dissociation and misuse, subject to Risk Evaluation and Mitigation Strategy (REMS) program with a black-box warning.

To be given only under supervision by a certified physician and must be monitored for at least two hours post-administration.

Why Esketamine and Why Intranasal?

• Esketamine is 3-4 times more potent than arketamine

• Thus, lower dose volume

• Easier to take intranasally

Efficacy Differences Between IV and Intranasal Esketamine

Changes in Mean MADRS Score in the Open Label Phase

• Patients continued taking esketamine were 51% less likely to relapse than those on placebo.

During open-label period esketamine was continued to be given twice/wk. followed by once/wk. followed by once every month.

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Clinician-Administered Dissociative States Scale (CADSS) (Panel A)

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Vortioxetine: Receptor Action Profile

Vortioxetine Effect on Cognition Levomilnacipran

(Fetzima)

Latest SNRI approved for the treatment of major depression

Only SNRI with greater noradrenergic than serotonergic effects.

Dose start 20 mg QD x 2 days then increase to 40 mg QD

Half-Life: 12 hours

No effect of food on absorption

SERT

NET

Conclusions Intranasal 28, 56, and 84 mg, but not 14 mg, were significantly better than placebo in reducing depressive symptoms as demonstrated by the changes in MADRS total score.

The antidepressant effects of esketamine persist for at least 8-weeks after the last dose in the open label follow up period

Esketamine can produce number of transient adverse effects, such as nausea, dizziness, dysgeusia, and dissociation.

Of note, dissociative symptoms were limited to the immediate post-administration period and attenuated after repeated dosages over time.

Paradigm Shift – Polypharmacy in a Single Pill

The first effective antidepressant, imipramine was nonselective with multiple adverse effects. This resulted in a quest for selectivity resulting in development of SSRIs and SNRIs. However, despite being selective, SSRIs and SNRIs still have multiple adverse effects and unmet needs in the management of treatment-refractory depression. This has made clinicians to use augmentation and/or combination strategies. At the same time, a paradigm shift has occurred from selectivity to a multimodal approach to improve efficacy and tolerability. Vortioxetine is one of the first antidepressants to represent a multimodal approach within a single molecule.

ARISTADA INITIO™: Reduces Oral Aripiprazole Supplementation to 1 Day

ARISTADA INITIO (aripiprazole lauroxil) [prescribing information]. Waltham, MA: Alkermes; 2018.

STEP 2 Select one ARISTADA® dose and give

on the same day or up to 10 days later if desired

DAY 1

FIRST ARISTADA DOSE

441 mg 662 mg 882 mg 1064 mg

STEP 1 After establishing tolerability with oral aripiprazole, give patients a

one-time ARISTADA INITIO injection and a single 30 mg dose of

oral aripiprazole

1 ARISTADA INITIO dose and a single dose of 30 mg ORAL ARIPIPRAZOLE

DAY 1

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With 1 injection of ARISTADA INITIO and a single dose of 30 mg oral aripiprazole plus the first dose of ARISTADA® (1064 mg), you can fully dose on day 1 for 2 months

Not to scale. For illustration purposes only.

ARISTADA INITIO has smaller crystals (faster release)

ARISTADA has larger crystals (slower release)

The proprietary LinkeRx® technology allows for consistent and sustained medication levels throughout the dosing period1,2

The Science Behind ARISTADA INITIO™ and ARISTADA®

1. Turncliff R et al. Schizophr Res. 2014;159:404-410; 2. Remenar JF et al. Mol Pharm. 2014;11:1739-1749; 3. Data on file. Waltham, MA: Alkermes, Inc; 4. ARISTADA INITIO (aripiprazole lauroxil) [prescribing information]. Waltham, MA: Alkermes; 2018.

• ARISTADA INITIO and ARISTADA are created using the same LinkeRx technology, and their conversion processes are the same3

• Both ARISTADA and ARISTADA INITIO are comprised of aripiprazole lauroxil crystals3

• ARISTADA INITIO is a formulation of aripiprazole lauroxil that also utilizes NanoCrystal®

technology, allowing for smaller crystal formation and faster dissolution properties3

• ARISTADA INITIO and ARISTADA are not interchangeable because of differing pharmacokinetic profiles4

1000 nanometers (nano) = 1 micrometer (micron)

Consistent and Sustained Medication Levels

q4wks=every 4 weeks; q8wks=every 8 weeks. 1. Data on file. Waltham, MA: Alkermes, Inc.; 2. ARISTADA INITIO (aripiprazole lauroxil) [prescribing information]. Waltham, MA: Alkermes; 2018.

Median simulated aripiprazole plasma concentrations for the ARISTADA INITIO™ regimen* and ARISTADA® (1064 mg) 2-month dose1

*The ARISTADA INITIO regimen is defined as a single injection of ARISTADA INITIO given in conjunction with a single 30 mg dose of oral aripiprazole.2

0 4 8 12 16 20 24 Time (weeks)

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100

200

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Arip

ipra

zole

Con

cent

ratio

n (n

g/m

L)

1 ARISTADA INITIO 675 mg injection + single-dose 30 mg oral aripiprazole + ARISTADA 441 mg q4wks

Aripiprazole concentration range for the 441 mg and 882 mg q4wks dose regimens

1 ARISTADA INITIO 675 mg injection + single-dose 30 mg oral aripiprazole + ARISTADA 1064 mg q8wks

1 ARISTADA INITIO 675 mg injection + single-dose 30 mg oral aripiprazole + ARISTADA 882 mg q4wks

Viloxazine (Qelbree) Viloxazine (Qelbree)

Novel Indications for Psychotropics

• Indication: Treatment of hallucinations and delusions associated with Parkinson's disease psychosis

• Approval Date: April 29, 2016 • MOA: Antagonist/inverse agonist with high affinity for

5HT2A receptors and low affinity for 5HT2C receptors and sigma 1 receptors

• No affinity for dopamine receptors • Dose: 34 mg by mouth once daily (two 17 mg tablets) • However, 17 mg a day should be used if CYP3A4

inhibitors are used concomitantly • Cost: $2340/month

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Pimavanserin (Nuplazid)

Product Information: NUPLAZID (pimavanserin) oral tablet. Acadia Pharmaceuticals, Inc. San Diego, CA. 2017.

HL: 9-10 hours

Clemson et al. American Journal of Obstetrics & Gynecology 2019 220, S69-S70.

(Zulresso)

Brexanolone IV was generally well tolerated and showed statistically significant greater reductions of depressive symptoms in women with PPD compared to PBO, as measured by MADRS within 48 hours.

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• dry mouth

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Dextromethorphan

Valbenazine (Ingrezza)

• Dose:

• Indication: Tardive dyskinesia (TD) in adult patients • Approval Date: April 11, 2017 • MOA: Novel, highly selective vesicular

monoamine transporter 2 inhibitor • Similar MOA as tetrabenazine

• Initial: 40 mg orally once daily • After 1 week, increase to 80 mg once daily

Product Information: INGREZZA (valbenazine) oral tablet. Neurocrine Biosciences, Inc. San Diego, CA, 2017.

Deutetrabenzine (Austedo)

Fewer tolerability issues than with tetrabenazine

Lower sedation rates than with valbenzine

No effects on mood parameters or rates of pseudoparkinsonion symptoms

Maximum dose of 18 mg two times a day in poor metabolizers for CYP2D6

In an RCT, AIMS score were reduced significantly from baseline by 24 as well as 36 mg/day versus placebo

Flibanserin (ADDYI)

• Indication: hypoactive sexual desire disorder (HSDD) in premenopausal women

• Approval Date: August 18, 2015 • MOA: Serotonin (5-HT) receptor 1A agonist and

5-HT2A • Dose: 100 mg PO once daily at bedtime

• Discontinue treatment after 8 weeks if no improvement

Product Information: ADDYI (flibanserin) oral tablets. Sprout Pharmaceuticals, Inc. Raleigh, NC, 2015.

Brexanolone (Zulresso): FDA Approved for Post-Partum Depression (PPD)

Brexanolone is a neuroactive metabolite of progesterone It is more commonly known as allopregnanolone It is produced by cortical and hippocampal pyramidal neurons as well as by the pyramidal-like neurons of the BL amygdala It is an positive allosteric modulator for GABA A receptors

Allopregnanolone Allopregnanolone is reported to have:

antidepressant, anxiolytic, stress-reducing, rewarding, prosocial, anti-aggressive, pro-sexual, sedative, cognitive, memory-impairing,analgesic, anesthetic, anticonvulsant, and neuroprotective effects.

But allopregnanolone has short half life and poor oral bioavailability.

Flibanserin (ADDYI) Black Box Warning: Contraindicated with alcohol, moderate-strong CYP3A4 inhibitors, or hepatic impairment due to increased risk of severe hypotension and syncope

Thus, only available though ADDYI Risk Evaluation and Mitigation System (REMS) program.

Adverse Effects: Dizziness, somnolence, nausea, fatigue, insomnia,

Approval based on BEGONIA trial, which resulted in significant improvements in the number of satisfying sexual events and sexual desire versus placebo.

Product Information: ADDYI (flibanserin) oral tablets. Sprout Pharmaceuticals, Inc. Raleigh, NC, 2015.

Flibanserin (ADDYI)

signifi

• Place in Therapy: • Suboptimal benefit vs. risk trade-off

• Systematic review published in JAMA Internal Medicine: • “Treatment with flibanserin, on average, resulted in one-half additional

satisfying sexual event per month while statistically and clinically cantly increasing risk of dizziness, somnolence, nausea, and fatigue.”

• Quality of evidence was graded as very low

Jaspers L, et al. Efficacy and safety of flibanserin for the treatment of hypoactive sexual desire disorder in women: a systematic review and meta-analysis. JAMA Intern Med. 2016 Feb 29. doi: 10.1001/jamainternmed.2015.8565. [Epub ahead of print]

Mechanism of Action

Dextromethorphan/Quinidine (Nuedexta)

Dextromethorphan/Quinidine (Nuedexta) Approved in U.S. and Europe for treatment of pseudobulbar affect (involuntary/uncontrollable episodes of crying +/- laughing)

Cases of improvement of agitation in pts with dementia

Serotonin and norepinephrine reuptake inhibitor

Low-affinity N-methyl-D-aspartate receptor antagonist