www.mghcme.org
George I. Papakostas, M.D.
Scientific Director, MGH CTNI. Director, Treatment-Resistant Depression Studies, MGH DCRP
Associate Professor of Psychiatry, Harvard Medical School
New Treatments for Major Depressive Disorder
www.mghcme.org
• Dr. Papakostas has served as a consultant for Abbott Laboratories, AstraZeneca PLC, Avanir Pharmaceuticals, Brainsway Ltd, Bristol-Myers Squibb Company, Cephalon Inc., Dey Pharma, L.P., Eli Lilly Co., Genentech, Inc, GlaxoSmithKline, Evotec AG, H. Lundbeck A/S, Inflabloc Pharmaceuticals, Janssen Global Services LLC, Jazz Pharmaceuticals, Johnson & Johnson Companies, Novartis Pharma AG, One Carbon Therapeutics, Inc, Otsuka Pharmaceuticals, PAMLAB LLC, Pfizer Inc., Pierre Fabre Laboratories, Ridge Diagnostics (formerly known as Precision Human Biolaboratories), Shire Pharmaceuticals, Sunovion Pharmaceuticals, Takeda Pharmaceutical Company LTD, Theracos, Inc., and Wyeth, Inc.
• Dr. Papakostas has received honoraria from Abbott Laboratories, Astra Zeneca PLC, Avanir Pharmaceuticals, Bristol-Myers Squibb Company, Brainsway Ltd, Cephalon Inc., Dey Pharma, L.P., Eli Lilly Co., Evotec AG, Forest Pharmaceuticals, GlaxoSmithKline, Inflabloc Pharmaceuticals, Jazz Pharmaceuticals, H. Lundbeck A/S, Medichem Pharmaceuticals, Inc, Novartis Pharma AG, Otsuka Pharmaceuticals, PAMLAB LLC, Pfizer, Pierre Fabre Laboratories, Ridge Diagnostics, Shire Pharmaceuticals, Sunovion Pharmaceuticals, Takeda Pharmaceutical Company LTD, Theracos, Inc., Titan Pharmaceuticals, and Wyeth Inc.
• Dr. Papakostas has received research support from AstraZeneca PLC, Bristol-Myers Squibb Company, Forest Pharmaceuticals, the National Institute of Mental Health, PAMLAB LLC, Pfizer Inc., Ridge Diagnostics (formerly known as Precision Human Biolaboratories), Sunovion Pharmaceuticals, and Theracos, Inc.
• Dr. Papakostas has served (not currently) on the speaker’s bureau for BristolMyersSquibb Co and Pfizer, Inc.
Disclosures
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Focus
• Oral pharmacologic agents as monotherapy – Expanding database
• Adjunctive treatments – Medications
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Vortioxetine has a multimodal action that combines receptor activity and reuptake inhibition, leading to modulation of neurotransmission in several systems1-3
Vortioxetine Mechanism of Action
aIn the forebrain; the precise contribution of the individual targets to the observed pharmacodynamic profile remains unclear and caution should be applied when extrapolating animal data directly to man GABA=gamma-aminobutyric acid; 5-HT=serotonin; SERT=serotonin transporter
1. Bang-Anderson 2011; 2. Mørk 2012; 3. Vortioxetine SPC 2013; 4. Westrich et al. Poster at IFMAD 2012;
5. Mørk et al. Poster at ECNP 2011; 6. Mørk et al. Poster at SOBP 2011; 7. Pehrson et al. Poster at ECNP 2013; 8. Mørk et al. Poster at APA 2013;
4
Direct effects1,4 5-HT1B partial agonist
5-HT3 antagonist
5-HT7 antagonist
SERT inhibitor
5-HT1D antagonist
5-HT1A agonist
Indirect effects5-8a
↑ serotonin neurotransmission
↑ noradrenaline neurotransmission
↑ acetylcholine neurotransmission
↑ dopamine neurotransmission
↑ histamine neurotransmission
↑ glutamate neurotransmission
↓ GABA neurotransmission
Receptor activity
Reuptake inhibition
Neurotransmitter system modulation
Vortioxetine
5-HT7
SERT 5-HT1A
5-HT1B
5-HT1D
5-HT3
Uptake inhibitor Agonist
Partial agonist Antagonist
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Vortioxetine in MDD Meta-Analysis of Placebo-Controlled Trials
Vortioxetine vs Pbo (SMD)
Pae CU et al. J Psychiatry Neurosci. 2015; 40(3):174-186
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Vortioxetine in MDD Meta-Analysis of Placebo-Controlled Trials
Vortioxetine vs Comparators (SMD)
Pae CU et al. J Psychiatry Neurosci. 2015; 40(3):174-186
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Vortioxetine 10mg versus Venlafaxine XR 150mg for MDD (Asia Pacific)
p > 0.05
Papakostas GI and Shelton RC. In Preparation.
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p > 0.05
Papakostas GI and Shelton RC. In Preparation.
Vortioxetine 10mg versus Venlafaxine XR 150mg for MDD (Asia Pacific)
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Nausea with Vortioxetine treatment
Incidence of nausea reported as an AE in 10 short-term clinical trials1
Studies included: HLu 11492A, HLu 11984A, TAK 303, TAK 304, TAK 305, HLu 13267A, TAK 315, TAK 316, TAK 317 and HLu 12541A (elderly). AE=adverse event; DUL=duloxetine; VEN=venlafaxine
1. Baldwin et al. Poster at IFMAD 2013; 2. Vortioxetine. Summary of Product
Characteristics, 2013
Placebo 5 mg 10 mg 15 mg 20 mg DUL 60 mg
VEN 225 mg
Vortioxetine
Inci
denc
e of
nau
sea
(%)
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Vortioxetine and sleep disturbance
Studies included: HLu 11492A, HLu 11984A, TAK 303, TAK 304, TAK 305, HLu 13267A, TAK 315, TAK 316, TAK 317 and HLu 12541A (elderly). AE=adverse event; DUL=duloxetine; VEN=venlafaxine
10
1. Vortioxetine. Summary of Product Characteristics, 2013; 2. Baldwin et al. Poster at IFMAD 2013
Inci
denc
e of
inso
mni
aa (%
)
Placebo 5 10 15 20
Vortioxetine (mg)
Inci
denc
e of
som
nole
nce
(%)
60 mg DUL
225 mg VEN
Placebo 5 10 15 20
Vortioxetine (mg)
60 mg DUL
225 mg VEN
Incidence of insomnia-related AEs reported in 10 short-term clinical trials2
Incidence of somnolence reported as an AE in 10 short-term clinical trials2
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Vortioxetine and Weight Gain
Short-term treatment: •In randomised, double-blind, placebo-controlled, active referenced, studies of vortioxetine (5 mg, 10 mg, 15 mg and 20 mg/day) in adults with MDD, there were no clinically relevant weight changes over time or differences between treatment groups1-4
•In a study in elderly patients with MDD, the changes in weight associated with vortioxetine were at placebo level5
Long-term treatment: •In the double-blind period of a relapse-prevention study in MDD, the mean weight increase for vortioxetine was 0.4 kg and for placebo 0.6 kg6
11
1. Vortioxetine. Summary of Product Characteristics, 2013; 2. Boulenger et al. Int Clin Psychopharmacol 2013. [Epub ahead of print];
3. Alvarez et al. Int J Neuropsychopharmacol 2012;15,589–600; 4. Henigsberg et al. J Clin Psychiatry 2012;73(7):953–959
5. Katona et al. Int Clin Psychopharmacol 2012;27:215–223; 6. Vortioxetine EPAR
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Prevalence of Cognitive and Physical Impairment
Fava M et al. J Clin Psychiatry. 2006.
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Definitions
• Cognitive Functioning – Broad measure – Conscious activity – Integration of Sensory Input and Memory – Purposeful and goal-oriented (Output)
• In Psychiatry: Similarly Broad • In MDD
– Execution and completion of mental tasks. • DSM: Difficulty Concentrating and Making Decisions.
– Perception and processing of affect.
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Components
• Immediate Memory • Delayed Memory • Attention • Cognitive Speed • Executive Functioning
Papakostas GI. J Clin Psychiatry. 2014 and 2015.
www.mghcme.org
Executive Functioning
– Engaging in meaningful goal-directed behavior – Task focused. – Requires
• Being able to harness motivational input – Positive affect, i.e. wanting something, anticipating enjoyment.
• Being able to ignore negative affective stimuli – More linked to fight or flight type behaviors than organized planned action.
• Being able to ignore neutral and irrelevant (to the task) stimuli
– The “Maestro”. – Medial and Lateral Prefrontal cortex. – Gateway to restoration of psychosocial functioning
Papakostas GI. J Clin Psychiatry. 2014 and 2015
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Duloxetine Effects on Depression in Elderly MDD
Raskin J et al. Am J Psychiatry. 2007.
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Digit Symbol Substitution Test (DSST)
• Widely used instrument of cognitive performance as part of the Wechsler Adult Intelligence Scale (WAIS)
• Participants match symbols with a corresponding number based on a 9-digit coding table
• Score is based on the number of symbols correctly coded in 90 seconds; higher scores indicate a better performance
• Measure of global cognitive functioning heavily weighed on executive functioning (set shifting, response inhibition).
Wechsler D: Wechsler Adult Intelligence Scale, 3rd ed. San Antonio, Tex. Psychosocial Corporation, 1997
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Digit Symbol Substitution Test (DSST)
Kim CJ, Hong SH, Kim BS, et al. Korean J Anesthesiol. 2008;55(3):291–297. http://dx.doi.org/10.4097/kjae.2008.55.3.291
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Rey Auditory Verbal Learning Test (RAVLT)
• Participants are given a list of 15 unrelated words, read aloud by the examiner or audio recording, and asked to recall as many as they can
• Then asked to repeat words after a period of time • Measures immediate recall, verbal learning, and
memory • Score is equal to the total number of words
recalled
Rey A: L’examen psychologique dans les cas d’encephalopathie tramatique. Archives de Psychologie. 1941; 286-340.
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Duloxetine Effects on Cognition in Elderly MDD
Raskin J et al. Am J Psychiatry. 2007. * p<0.05 only for RAVLT immediate and delayed.
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SSRI (Citalopram) vs Placebo in Elderly MDD: Effects on DSST
p>0.05 vs placebo for change Culang ME et al. Am J Geriatr Psychiatry. 2009.
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Vortioxetine Efficacy in Elderly (65-88 years of age) Patients with MDD (8 weeks, n=452)
Katona C et al, Int Clin Psychopharmacol. 2012.
%
* *
*p<0.05 vs placebo
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Effects on Cognition in Elderly MDD: Standardized Effect Sizes
Katona C et al, Int Clin Psychopharmacol. 2012.
* * * *
*
*p<0.05
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Cognitive Functioning in Younger MDD Patients
• Randomised, double-blind, placebo-controlled study to assess
cognitive function in MDD Primary objective: • To evaluate the efficacy of acute (8 weeks’) treatment with fixed-dose
vortioxetine 10 mg/day and 20 mg/day versus placebo on cognitive function and depressive symptoms, in adults (18–65 years) with recurrent moderate-to-severe MDD
• Primary efficacy endpoint: –Change from baseline in cognitive function composite z-score for
vortioxetine versus placebo at Week 8
Composite z-score=weighted sum of the z-scores for DSST, RAVLT acquisition, and RAVLT delayed recall DSST=Digit Symbol Substitution Test; MMRM=mixed model for repeated measures; RAVLT=Rey Auditory Verbal Learning Test
McIntyre et al. Int J Neuropsychopharmacol. In press.
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Vortioxetine Antidepressant Efficacy
Mean change from baseline in MADRS total score (FAS; OC, MMRM by visit; LOCF, ANCOVA)
*p<0.05; **p<0.01; ***p<0.001 vs placebo LOCF=last observation carried forward
Treatment week Endpoint
LOCF
**
***
*** ***
Mea
n ch
ange
from
bas
elin
e in
MAD
RS
tota
l sco
re
***
***
***
McIntyre et al. Int J Neuropsychopharmacol. In press.
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Vortioxetine and Cognitive Functioning
Standardised effect size (Cohen’s d) for the neuropsychological tests (FAS, OC)
*p<0.05, **p<0.01, ***p<0.001 vs placebo acq=acquisition; con=congruent; CRT=Choice Reaction Time task; delay=delayed recall; DSST=Digit Symbol Substitution Test; FAS=full analysis set; incon=incongruent; OC=observed cases; RAVLT=Rey Auditory Verbal Learning Test; SRT=Simple Reaction Time task; TMT=trail Making Test
Stan
dard
ised
effe
ct si
ze v
s pla
cebo
DSST RAVLT acq RAVLT delay TMT-B Stroop con
Stroop incon TMT-A SRT CRT
0.23
0.13
0.51 0.52
0.31 0.28 0.29 0.35
0.33
0.37 0.35 0.34 0.29 0.29
0.41
0.26
0.38
0.10
*** ***
** **
*
** ***
** *** ** ** ** **
***
*
***
Memory Attention Speed of processing Executive function
McIntyre et al. Int J Neuropsychopharmacol. In press.
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Cognitive Functioning in Younger MDD Patients: Comparison with Duloxetine
• Recent data from a randomised, double-blind, placebo-controlled
study to assess cognitive function in MDD Primary objective: • To evaluate the efficacy of acute (8 weeks’) treatment with flexible-
dose Vortioxetine 10 mg/day-20 mg/day versus Fixed-dose Duloxetine 60mg/day versus placebo on cognitive function and depressive symptoms, in adults (18–65 years) with recurrent moderate-to-severe MDD
• Primary efficacy endpoint: –Change from baseline in DSST score for vortioxetine and duloxetine
versus placebo at Week 8
Mableshwarkar AR et al. Neuropsychopharmacology. 2015; 40: 2025-2037.
www.mghcme.org
Cognitive Functioning in Younger MDD Patients: Comparison with Duloxetine
Mableshwarkar AR et al. Neuropsychopharmacology. 2015; 40: 2025-2037.
p < 0.05
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MGH CPFQ
• 7-item self-report scale, Items: • Motivation • Wakefulness • Energy • Focus • Recall • Word-finding difficulty • Mental acuity
Fava M et al. J Clin Psychiatry. 2006.
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Vortioxetine and sexual side effects
ASEX=Arizona Sexual Experiences Scale; TEAE=treatment emergent adverse event; TESD=treatment-emergent sexual dysfunction
1. Vortioxetine EPAR; 2. Vortioxetine Summary of Product
Characteristics, 2013
Sexual dysfunction, reported as TEAEs •Sexual dysfunction, reported as TEAEs during treatment with vortioxetine was low (1.6%) and similar to that in the placebo group (0.9%)1
Sexual dysfunction, assessed using the ASEX scale •No difference from placebo for 5 mg to 15 mg doses of vortioxetine2 •Increase in TESD from 5 mg to 20 mg vortioxetine, but there was no clear dose–response relationship1 •Vortioxetine 20 mg was associated with an increase in TESD (46%)1
30
Inci
denc
e of
TES
D (%
)
Placebo Vortioxetine (5–20 mg)
Duloxetine (60 mg)
Incidence of TESD based on ASEX scoring1
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• Randomized, Double-blind, Multi-Center Trial (US) • Men and women ages 18-55 • On stable dose of Sertraline, Paroxetine, or Citalopram • MDD with CGI-S<4 (mild, borderline, or no symptoms) • Sexually active qo week before onset of episode and/or
SSRI • Sexual dysfunction due to SSRI or MDD only • CSFQ <42 (women) or <48 (men)
Switching to Vortioxetine versus Escitalopram
Clayton A et al. J Sex Med. (In press).
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• Abrupt switch to either (1:1) • Vortioxetine 10mg x1 week then 20mg for 7 • Escitalopram 10mg x1 week then 20mg for 7
Switching to Vortioxetine versus Escitalopram
Clayton A et al. J Sex Med. (In press).
www.mghcme.org
Vortioxetine (N=225) Escitalopram (N=222) Age (years) 39.3 +/- 9.9 40.2 +/- 10.1 Women N (%) 128 (56.9%) 135 (60.8%) CSFQ score 36.5 +/- 5.8 36.3 +/- 5.6 MADRS score 7.9 +/- 6.2 8.3 +/- 6.5 CGI-S score 2.0 +/- 0.8 2.0 +/- 0.8 Completion % 169 (75.1%) 179 (80.6%)
Switching to Vortioxetine versus Escitalopram
Clayton A et al. J Sex Med. (In press).
www.mghcme.org Clayton A et al. J Sex Med. (In press). *P < 0.05, **P < 0.01 vs. Escitalopram
Switching to Vortioxetine versus Escitalopram
www.mghcme.org Clayton A et al. J Sex Med. (In press).
*P < 0.05 vs. escitalopram.
Switching to Vortioxetine versus Escitalopram
www.mghcme.org Clayton A et al. J Sex Med. (In press).
Switching to Vortioxetine versus Escitalopram
www.mghcme.org Clayton A et al. J Sex Med. (In press).
Switching to Vortioxetine versus Escitalopram
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• Randomized, Double-blind, Multi-Center Trial (US) • Men and women ages 18-70 • MDD 8 weeks to 12 months • MDD with MADRS>25 • Fewer than 2 antidepressant trials during the current
episode
Vilazodone vs Citalopram in MDD
Mathews M et al. Int Clin Psychopharmacol. 2015; 30:67-74.
www.mghcme.org
• Randomization to either (1:1:1:1) • Placebo • Vilazodone 10mg x1 week then 20mg for 9 weeks • Vilazodone 10mg x1 week then 20mg for 1 week then
40mg for 8 weeks • Citalopram 20mgx 2 weeks then 40mg x 8 weeks
Vilazodone vs Citalopram in MDD
Mathews M et al. Int Clin Psychopharmacol. 2015; 30:67-74.
www.mghcme.org
Pbo V20 V40 Cit Age (years) 42.0 41.7 40.8 42.6 Women N (%) 56.2% 57.6% 57.1% 58.5% CSFQ score 42.0 42.2 41.3 41.0 MADRS score 31.3 31.0 30.8 31.1 HAMA 15.7 15.8 15.7 14.8 Completion % 74.7% 69.1% 65.9% 70.9%
Mathews M et al. Int Clin Psychopharmacol. 2015; 30:67-74.
Vilazodone vs Citalopram in MDD
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* p<0.05 for V20mg vs Pbo t p<0.05 for V40mg vs Pbo # p<0.05 for Cit vs Pbo
Mathews M et al. Int Clin Psychopharmacol. 2015; 30:67-74.
Vilazodone vs Citalopram in MDD
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Vilazodone vs Citalopram in MDD
*
* p < 0.05 LOCF
Mathews M et al. Int Clin Psychopharmacol. 2015; 30:67-74.
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p > 0.05 LOCF
Mathews M et al. Int Clin Psychopharmacol. 2015; 30:67-74.
Vilazodone vs Citalopram in MDD
www.mghcme.org
p > 0.05 LOCF
Mathews M et al. Int Clin Psychopharmacol. 2015; 30:67-74.
Vilazodone vs Citalopram in MDD
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p > 0.05 LOCF
Mathews M et al. Int Clin Psychopharmacol. 2015; 30:67-74.
Vilazodone vs Citalopram in MDD
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Levomilnacipran SR Short-Term, Placebo-Controlled Published* RCTs
Asnis GM et al. J Clin Psychiatry. 2013. 40mg 80mg 120mg Montgomery SA et al. J Clin Psychiatry. 2013 75mg 100mg Sambunaris A et al. J Clin Psychopharmacol. 2014 40-120mg Bakish D et al. J Psychiatry Neurosci. 40mg 80mg
*Pubmed as of June 7th, 2014 utilizing search criteria “Levomilnacipran” and “placebo” ** Not within FDA approved dose-range
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Improvements in Fatigue-Related Items
***P<.001 versus placebo. ER, extended-release; HAMD17, Hamilton Depression Rating Scale; LOCF, last observation carried forward; MADRS, Montgomery-Åsberg Depression Rating Scale.
Freeman M et al. APA Poster. 2014.
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Patients With No or Minimal Fatigue Symptomsa
**P<.01; ***P<.001 versus placebo. aPatients who had fatigue symptoms at baseline and no/minimal symptoms after double-blind treatment, defined as follows: MADRS item 7 and HAMD17 item 7 (score ≥2 at baseline, <2 at end of treatment); HAMD17 item 8 and item 13 (score ≥1 at baseline, <1 at end of treatment). ER, extended-release; HAMD17, Hamilton Depression Rating Scale; LOCF, last observation carried forward; MADRS, Montgomery-Åsberg Depression Rating Scale; OR, odds ratio. Freeman M et al. APA Poster. 2014.
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Adjunctive Treatments
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Ziprasidone (20-80BiD) Augmentation of Escitalopram in MDD(N=139)
• N=139 outpatients (98 women, mean age 44 years) with Escitalopram non-remitters. – Mean dose 20.4mg
• Double-blind, placebo-controlled, 8-week adjunctive trial of ziprasidone augmentation (mean dose 98mg).
• HAMD17 1o outcome measure (MMRM). • QIDS-SR and CGI 2o outcome measures.
Papakostas GI et al. Am J Psychiatry. (In press).
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p = 0.04 MMRM
Papakostas GI et al. Am J Psychiatry. (In press).
Ziprasidone (20-80BiD) Augmentation (N=139)
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Ziprasidone (20-80BiD) Augmentation (N=139)
p = 0.03 MMRM
Papakostas GI et al. Am J Psychiatry. (In press).
www.mghcme.org
p = 0.02 MMRM
Papakostas GI et al. Am J Psychiatry. (In press).
Ziprasidone (20-80BiD) Augmentation (N=139)
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Conclusion
• Vortioxetine • Expanded Efficacy Data • Expanded Cognition Data • Switching for Sexual AEs Data
• Vilazodone • Equivalent antidepressant efficacy to one SSRI • ? Anxiety in MDD • SexFx inconclusive data
• Levomilnacipran • Adjunctive Medications: Ziprasidone
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Thank you
Psychopharmacology Friday, September 28 – Sunday, September 30, 2012
The Westin Copley Place
39th Annual Psychopharmacology Conference Thursday – Sunday, October 22– 25, 2015
The Westin Copley Place MGHCME.ORG
Massachusetts General Hospital Department of Psychiatry
Presents
39th Annual Psychopharmacology
Conference
THURSDAY-SUNDAY, OCTOBER 22-25, 2015 THE WESTIN COPLEY PLACE
BOSTON, MA
