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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
DBPOHSU
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
NETOHSU
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,
nausea and confusionOHSU
• 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