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

Associate Professor of Psychiatry

Oregon Heath & Science University, Portland Oregon

Supervising Psychiatrist, Resident Outpatient Clinic at Samaritan Mental Health,

Corvallis Oregon

Staff Psychiatrist,

Oregon State Hospital, Salem Oregon

An Update on Psychiatric

Medications

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Aims & Objectives

The audience will be presented with an update on recently

and relatively recently approved psychopharmacological

medications for major and minor psychiatric indications.

It is NOT a review of efficacy or tolerability of psychotropic

medicationsOHSU

New Psychotropics

New Antidepressants

Extended-Release trazodone (Oleptro)

Desvenlafaxine (Pristiq)

Duloxetine (Cymbalta)

Vilazodone (Viibryd)

Levomilnacipran (Fetzima)

Vortioxetine (Trintellix)

Esketamine – Intransal

New antipsychotics

Brexpiprazole (Rexulti)

Cariprazine (Vraylar)

Pimavanserin (Nuplazid)

Sleep aids

Suvorexant (Belsomra)

Ramelteon (Rozerem)

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New Psychotropics

Novel Indications:

Medications to treat “adverse effects” such as Tardive Dyskinesia

Valbenazine (Ingrezza)

Deutetrabenazine (Austedo)

New medication for Hypoactive Sexual Desire Disorder (HSSD) in females

Flibanserin (Addyi)

New medication to treat Pseudo-bulbar Affect

Dextromethorphan/Quinidine (Nuedexta)OHSU

Vilazodone (Viibryd)

SERTSPARI

serotonin partial agonist / reuptake inhibitor

5HT1A

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Vilazodone: Pharmacokinetics

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Vilazodone: Dosing and Administration

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Vilazodone: Drug Interactions

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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 OHSU

Levomilnacipran (Fetzima)

• Metabolized by CYP3A4

• Lower dose in patients with renal impairment

• Nausea was most common adverse effect

• Increased heart rate by 7.4 BPM

• Increased BP 3.0 mm Hg in SBP and 3.2 mm Hg in

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Levomilnacipran (Fetzima):

Adverse Effects

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SERT

venlafaxine

NET

desvenlafaxine

SERT

NET

CYP

2D6

Venlafaxine (Effexor) Vs.

Desvenlafaxine (Pristiq)

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Weight Gain with Desvenlafaxine in 5 RCT in MDD

*P < .001 within-group change from baseline. †P < .001 desvenlafaxine versus placebo. ‡P < .01 versus desvenlafaxine 50 mg.§P ≤ .001 versus desvenlafaxine 50 mg. ‖P < .05 within-group change from baseline. **P < .001 versus desvenlafaxine 100 mg. ††P <

.05 versus desvenlafaxine 200 mg. ‡‡P < .05 desvenlafaxine versus placebo. §§P < .01 desvenlafaxine versus placebo.

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Duloxetine

SERT

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Comparison of SNRIs

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Trazodone XR (Oleptro) vs Placebo: Treatment for Major Depression

• 412 pts randomized with 202 in the

trazodone XR group and 204 in the

placebo group.

• 105/412 prematurely discontinued the

study.

• A two week titration to trazodone 150,

225, 300, or 375 mg/d vs. placebo

followed by 42 d of post-titration dose.

• Average post-titration dose = 310 mg for

the trazodone XR group and 355 mg for

the placebo group.

• Significantly greater improvement in

mean HAM-D 17 score in the trazodone

XR group versus placebo by the first

week of the double blind phase (day 7

of titration) maintained throughout the

trial (P<.005, LOCF).

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Relative Binding Affinities of Trazodone

Stahl SM. CNS Spectr. Vol 14, No 10.

2009

• Relative selectivity for trazodone for four keybinding sites: with the highest bars being themost selective actions of trazodone.

• Although 50 mg may fully saturate 5-HT2A

receptors, most of α1 receptors, about half ofH1 receptors & 5HT pump, antidepressanteffects require 5HT pump saturation (i.e., 300mg).

Trazodone affinities for receptors

and transporters.

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• Trazodone IR given as 100 mg 3x/day for 9 days

generates a saw tooth pattern of levels greatly sur-

passing the minimum antidepressant concentration

required all night long.

• This results in adverse effects such as sedation

extending into next morning. By contrast, 300mg XR

a day generates smoother peak and trough levels

above minimum antidepressant concentration.

Lower peaks levels from XR than IR are more

tolerable.

Stahl SM. CNS Spectr. Vol 14, No 10. 2009.

Trazodone XR at 300 mg a day addresses sedation as

well as antidepressant effects. Trazodone IR used at the

usual sedating dosages can only be sedating. Peak

levels of 100 mg IR are almost equal to 300 mg of XR.

Trazodone IR (Desyrel) vs Trazodone XR (Oleptra)

Given Once Nightly

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• 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.

Paradigm Shifts

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Vortioxetine: Receptor Action Profile

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Vortioxetine Effect on Montgomery-Asberg

Depression Rating Scale (MADRS) Score

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Vortioxetine Effect on Cognition

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• Vortioxetine is metabolized by CYP2D6 and 3A4.

• Thus, inhibitors of CYP2D6 will inhibit metabolism

• Inducers of CYP3A4 will increase the metabolism

of vortioxetine.

Drug Interaction with

Vortioxetine

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Ketamine

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KETAMINE

Synthesized in 1962, first used in humans in 1965, released

for clinical use in 1970

Antagonist to NMDA Receptor.

Racemic mixture of S and R ketamine.

S isomer is 3 x more potent and has fewer

psychotomimetic effects.

Only 20% bioavailability after oral use.OHSU

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FDA Approves Fast-Acting

Esketamine for Treatment-Resistant

Depression

• Esketamine (Spravato) nasal spray to be used in conjunction with an oral antidepressant for treatment-

resistant depression.

• Esketamine is the first medication for depression with a new mechanism of action since fluoxetine was

approved in 1988.

• Because of risks dissociation and misuse, esketamine is subject to a comprehensive Risk Evaluation and

Mitigation Strategy (REMS) program and carries a black-box warning.

• Patients can take esketamine only under supervision by a certified physician and must be monitored for at

least two hours post-administration.

• In preclinical trials, 223 patients with treatment-resistant depression were randomized to receive twice

weekly doses of intranasal esketamine or placebo.

• Those on active nasal spray experienced greater improvement in their depression symptoms at 4-weeks

compared to placebo nasal spray.

• In a longer study, patients who continued taking esketamine were 51% less likely to relapse than those on

placebo.

• Two other short-term trials did not meet prespecified statistical tests for demonstrating effectiveness.

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Why Esketamine?

• Esketamine is 3-4

times more potent

than arketamine

• Thus, lower dose

volume OHSU

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Change in MADRS Score from baseline

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Change in MADRS Score from baseline

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Changes in Mean MADRS Score in the

Open Label Phase

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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Most Frequently Reported Adverse Effects

Canuso et al. AJP 2018

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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.

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Brexpiprazole (Rexulti)

H1

15HT2A

5HT2C

D4

5HT1A

D2D3

5HT1B

5HT7

5HT2B

5HT6

D1

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Cariprazine

H1

15HT2A

5HT2C

5HT1A

D2D3 5HT7

5HT2B

• Schizophrenia dose range =

starting with 1.5 mg and then

increasing to 6 mg once daily

• Can be increased to 3 mg on

Day 2

• Manic or Mixed Episodes dose

range is 3 to 6 mg once daily

• CYP3A4 is responsible for the

formation and elimination of

active metabolites of

cariprazine.

• Dose adjustments required For

CYP3A4 inhibitors and inducers

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Novel Indications for

Psychotropics OHSU

• 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.

Flibanserin (ADDYI)

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• Black Box Warning: Contraindicated with alcohol, moderate-

strong CYP3A4 inhibitors, or hepatic impairment due to increased risk of severe hypotension and syncope (only available though

ADDYI REMS program)

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

dry mouth

• 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)

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• Place in Therapy: first FDA-approved treatment option

for HSDD in premenopausal women

• 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 significantly 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]

Flibanserin (ADDYI)

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• 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

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

2017.

Pimavanserin (Nuplazid)

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Pimavanserin (Nuplazid): Adverse Effects

• Avoid in dementia-related psychosis due to increase in

mortality rate

• Serious adverse reaction is QTc prolongation

• Common adverse effects include: peripheral edema,

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• Black Box Warning (BBW): Increased mortality in elderly

patients with dementia-related psychosis

• Adverse Effects: Peripheral edema, confusion, nausea

• Approval: based on a randomized, double-blind,

placebo-controlled phase III study for hallucinations• May benefit patients with Parkinson’s disease psychosis for

whom few other treatment options exist

• Emphasized need to remove dependency on antipsychotic

drugs

Cummings, et al. Pimavanserin for patients with Parkinson’s disease psychosis: a randomized,

placebo-controlled phase 3 trial. The Lancet Journal. 1 Nov. 2017. 383: 533–40

Pimavanserin (Nuplazid)

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Valbenazine (Ingrezza)

• 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

• Dose:

• 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.

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Deutetrabenzine (Austedo)

Fewer tolerability issues than with tetrabenazine

Lower sedation rates than with valbenzine

No effects on mood parameters or rates of pseudoparkinsonion symptoms

HL: 9-10 hours

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

In a RCT, AIMS score were reduced significantly from baseline by 24 as well

as 36 mg/day versus placebo OHSU

Dextromethorphan (Austedo)

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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

Mechanism of Action

Serotonin and norepinephrine reuptake inhibitor

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