KEEPING UP WITH THE CLINICAL ADVANCES: DEPRESSION

Learning Objective

• Describe the molecular targets of novel agents, including adjunctive treatments, currently being investigated

50% of Patients Respond to MonoaminergicAntidepressants

Deficiency in monoamines

Increase monoamine levels with an antidepressant

50% of Patients DO NOT Respond to Monoaminergic Antidepressants

Adequate monoamines

Increase monoamine levels with an antidepressant

Downstream dysfunction in glutamatergic neurotransmission or

neuroplasticity

Pharmacological modulation of downstream dysfunction in glutamatergic

neurotransmission or neuroplasticity

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 neuroplasticityand glutamatergicneurotransmission

Beyond Monoamines: The NeuroplasticityHypothesis of Depression

Beyond Monoamines: The Neuroplasticity Hypothesis of Depression

• The depressed brain shows signs of inadequate neuroplasticityand excessive glutamate

• Acting on monoaminergic systems, currently available antidepressants may lead to downstream improvement in neuroplasticity and glutamatergic neurotransmission

• Directly targeting glutamatergic neurotransmission or neuroplasticity may:

• Lead to faster treatment response (e.g., ketamine, rapastinel, SAGE-547, SAGE-217)

• Improve response and remission ratesRacagni G, Popoli M. Dialogues Clin Neurosci 2008;10(4):385-400; Crupi R, Marino A, Cuzzocrea S. Curr Med Chem 2011;18(28):4284-98; Sanacora G, Treccani G, Popoli M. Neuropharmacology 2012;62(1):63-77; Vidal R, Pilar-Cuellar F, dos Anjos S et al. Curr Pharm Design 2011;17(5):521-33; Banasr M, Dwyer JM, Duman RS.

Curr Opinion Cell Biol 2011;23(6):730-7; Duman RS, Aghajanian GK. Science 2012;338(6103):68-72.

Neuroplasticity: Monoamine Signaling and Brain-Derived Neurotrophic Factor Release

CREB

synaptogenesis

neuroplasticity

cell survival

neurogenesis

BDNF: brain-derived neurotrophic factor

CREB: cAMP response element-binding protein

CaMK: calcium/calmodulin-dependent protein kinasePKA: protein kinase A

monoamine

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

Genes turned on

Increased neuroplasticity and reduced glutamatergic neurotransmission

Decreased release of glutamate

Increased proteins involved in neuroplasticity

Activation of cAMP response element binding protein (CREB)

Racagni G, Popoli M. Dialogues Clin Neurosci 2008;10(4):385-400;Barbon A et al. Neurochem Int 2011;59(6):896-905.

Downregulation of NMDA receptors

Increased expression of AMPA receptor subunits

Downstream Improvement in Neuroplasticity and Glutamatergic Neurotransmission

DA 5HT NEMonoamine regulation

PKCRSKCaMK

GSK-3Wnt/FrzcAMP

MAPKSignaling cascades

The Three G's Glutamate, GABA, and Glycine

Impaired Neuroplasticity Due to Imbalanced GABA and Glutamate signaling

• Abnormalities in glutamatergic neurotransmission via the N-methyl-D-aspartate receptor (NMDA-R) have a key role in the pathophysiology of depression

Hashimoto K et al. Transl Psychiatry. 2016;6:e744.

NMDA-R

Dysfunction of Glutamate Signaling

• Glutamate is an excitatory neurotransmitter involved in many functions, including synaptic plasticity, learning, and memory

• Studies have shown regional changes in glutamate receptors, as well as elevated levels of glutamate in the brains of 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

Hashimoto K et al. Transl Psychiatry. 2016;6:e744; Inoshita M et al. Neuropsychiatr Dis Treat. 2018;14:945-953; Sanacora G et al. Neuropharmacology. 2012;62(1):63-77.

Directly targeting glutamatergic

neurotransmission or neuroplasticity may lead to faster treatment response

and may improve response and

remission rates

Ketamine

NMDA receptorCa2+

Bunney BG, Bunney WE. Int J Neuropsychopharmacol 2012;15:695-713.

Ketamine Directly Targets Glutamate Neurotransmission

Ketamine

• Ketamine (anesthetic)

• Blocks NMDA receptors, evokes glutamate release

• Induces schizophrenia-like symptoms in normal volunteers and exacerbates them in patients

• Short-term, low-dose intravenous ketamine does not induce full range of psychotic symptoms in experimental setting

Ketamine Increases Synaptic Plasticity

AMPARs

Increased synaptic plasticity

mTOR

Bunney BG, Bunney WE. Int J Neuropsychopharmacol 2012;15:695-713.

mammalian Target Of Rapamycin: a critical

intracellular protein that mediates neuroplasticity and

neurotrophic processes

glu

AMPAreceptor

NMDAreceptorblocked byketamine

ERK, AKT

mTOR

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

Ketamine’s Antidepressant Effects May Also Be Due to Activation of AMPA Receptors, not the Blocking of NMDA Receptors

Attenuation of Antidepressant Effects of Ketamine by Opioid Receptor Antagonism

Williams NR et al. Am J Psychiatry. 2018; Epub ahead of print.

Recent study showed that ketamine may work to treat depression, at least in part, by activating opioid receptors

Ketamine Placebo

Reduction in symptoms of depression

Naltrexone(opioid-blocking drug)Ketamine

Almost no effect on symptoms of

depression

• Underlying antidepressant mechanism for ketamine may be due to the metabolite (2R,6R)-HNK acting through activation of AMPA receptors, instead of blocking NMDA receptors

• More effective at reducing depression-like symptoms, even though the (S)-form is about 3–4 times more potent at blocking NMDA receptors

• Lacks the negative side effects and potential for abuse that ketamine has

• Future research aims to test the effectiveness of (2R,6R)-HNK for the treatment of depression in humans.

Utility of (2R,6R)-Hydroxynorketamine viaDirect AMPA Activation

Abdallah CG et al. Depress Anxiety 2016; 33: 689-697; Stahl SM. Stahl's Essential Psychopharmacology. 4th ed. 2013; Zanos P et al.

Nature 2016; 533: 481-486; Zhao X et al. Br J Clin Pharmacol. 2012;74(2):304-14.

(2R,6R)-Hydroxynorketamine (HNK)—a metabolite of ketamine

Antidepressant Effect of Ketamine Within Hours in Patients With Treatment-Resistant Depression

* indicates P<.05; †, P<.01; ‡, P<.001

21-It

em H

DR

S Sc

ore

15

25

0

5

10

30

20

-60min

40min

90min

110min

230min

Day 1

Day 2

Day 3

Day 7

Ketamine

*

*

†‡

‡ ‡

Placebo

Zarate CA Jr et al. Arch Gen Psychiatry 2006;63:856-64.

HDRS: Hamilton Depression Rating Scale

Dose of intravenous ketamine consistently decreases

symptoms of depression in patients with treatment-resistant depression in a

rapid (within hours), robust(across many symptoms of depression), and relatively sustained (typically 7-14

days) manner

Rapid Antidepressant Effect of Ketamine in 18 Patients With Treatment-Resistant Depression

29% were considered to be in remission,with an HDRS score of 7 or below (data not shown)

40min

90min

110min

230min

Day 1

Day 2

Day 3

Day 7

Prop

ortio

n W

ith 5

0% C

hang

e in

Sc

ore

From

Bas

elin

e (H

DR

S)

0.8

0

0.2

0.6

KetaminePlacebo

0.4

1.0

HDRS: Hamilton Depression Rating Scale

Zarate CA Jr et al. Arch Gen Psychiatry 2006;63:856-64.

Safety and Efficacy of Repeated-Dose Intravenous Ketamine

• Repeated doses (six infusions over the course of several weeks) have shown promise from an efficacy and safety standpoint

• Even when dose is escalated

• No advantage in efficacy in sustaining the initial antidepressant effects for two times verses three times a week intravenous ketamine in patients (n=67)

Aan het rot M et al. Biol Psychiatry. 2010;67(2):139-45; Cusin C et al. Aust N Z J Psychiatry. 2017;51(1):55-64; Singh JB et al. Biol Psychiatry. 2016;80(6):424-31.

Ketamine Formulations• Ketamine intranasal administration 50 mg vs saline placebo (n=27)−Effective, easier to administer1

• Intranasal esketamine (S-enantimer of racemic ketamine)− 0.20 mg/kg and 0.40 mg/kg intravenous esketamine exhibited significant

reductions in MADRS scores compared with placebo (n=30)2

−After a 1-week period, all three intranasal esketamine treatment groups (28 mg, 56 mg, or 84 mg) changes in MADRS total scores were statistically superior to placebo on Day 8 (n=67)3

• Efficacy and safety of intravenous, intramuscular and subcutaneous routes for treating depression with ketamine4

−All three had comparable antidepressant effects; Subcutaneous has fewest adverse effects

Lapidus KA et al. Biol Psychiatry. 2014;76(12):970-6; Singh JB et al. Am J Psychiatry. 2016;173(8):816-26; Daly EJ et al. Presented at the 54th Annual Meeting of the ACNP; Dec.

2015; Hollywood, FL; Loo CK et al. Acta Psychiatr Scand. 2016;134(1):48-56.

MADRS: Montgomery-AsbergDepression Rating Scale

A Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders

Recommendations from the American Psychiatric Association Council of Research Task Force on Novel Biomarkers and Treatment Recommendations for Clinical Use of Ketamine

Patient Selection • Strongest evidence for major depressive disorder• Less evidence in other mood disorders• Baseline symptom assessment• Antidepressant treatment history• Physical and laboratory • Informed consent including discussion of potential risks and benefits

Clinical Experience and Training

• Currently no recommendations or guidelines• Clinicians should be prepared to manage potential cardiovascular events and behavioral effects of ketamine

Treatment Setting • Setup for monitoring of cardiovascular and respiratory function

Medication Delivery • Most studies use 0.5 mg/kg of IV ketamine delivered over 40 minutes• Dose may need to be adjusted for patients with BMI>30

Follow-up and Assessments • Use rating instruments to assess clinical response and evaluate risk:benefit ratio of continued treatment

Efficacy of Longer-term Repeated Administration

• Studies suggest that repeated dosing may extend the duration of ketamine effects• Ketamine administration 2X/week over 2-3 weeks seems as effective as 3X/week over 2-3 weeks• Taper or discontinue treatment based on an individual patient basis

Safety Measures and Continuation of Treatment

• Risk of cognitive impairment and cystitis are associated with chronic ketamine use• Substance abuse liability• Frequent ketamine administration is not recommended

Future Directions • Major knowledge gaps remain regarding long-term efficacy and safety • Further, large-scale studies are needed • Clinicians providing ketamine treatment are encouraged to participate in coordinated systems of data collection

Sanacora G et al. JAMA Psychiatry. 2017;74(4):399-405.

Other Glutamatergic ModulatorsFailed to Show Efficacy or No

Longer in Development

1. Mathew SJ et al. Neuropsychopharmacology. 2017; 2. Zarate CA et al. Am J Psychiatry. 2006;163(1):153-5; 3. Smith EG et al. J Clin Psychiatry 2013; 74: 966–973; 4. Sanacora G et al. Neuropsychopharmacology. 2017;42(4):844-853; 5. Preskorn SH et al. J

Clin Psychopharmacol. 2008;28(6):631-7; 6. Heresco-levy U. et al. Int J Neuropsychopharmacol. 2013;16(3):501-6; 7. Liu RJ et al. Neuropsychopharmacology. 2017;42(6):1231-1242; 8. Nagele P et al. Biol Psychiatry. 2015;78(1):10-8.

Agent TargetRiluzole Voltage-gated sodium

channelsDid not out-preform placebo on mean MADRS1.05

Memantine NMDA receptor Trials for depression unsuccessful2,3

Lanicemine NMDA receptor Failed to show superior efficacy4

CP-101,606 NMDA-NR2B subunit Ceased due to association with cardiac conduction abnormalities5

EVT-101 NR2B selective antagonist

Clinical hold issued by the FDA

MK-0657 NMDA-NR2B subunit Weak evidence of efficacy

AZD-6423 NMDA receptor Weak evidence of efficacy

AVP-923 NMDA receptor, Sigma-1 receptor, SERT, NET

Alzheimer, no TRD efficacy

AVP-786 NMDA receptor, Sigma-1 receptor, SERT, NET

Alzheimer, no TRD efficacy

Agent Target

d-Cycloserine NMDA receptor Moderate evidence6

GLYX-13 (rapastinel)

NMDA receptor Currently in Phase III; Moderate evidence7

AXS 05 dextro-methorphan +

bupropion

Currently in Phase III; Moderate evidence

Nitrous oxide NMDA receptor Preliminary evidence of efficacy for MDD8

Still in Development

Rapastinel: An NMDA Receptor Glycine-Site Functional Partial Agonist vs Positive Allosteric Modulator

• Allosteric modulator of both glutamate and glycine at novel binding site

• Functional partial agonist of the glycine site of the NMDA receptor

• In preclinical studies, rapastinel showed robust antidepressant effects with rapid onset and appeared to increase neuroplasticity and enhance synaptic function

Moskal JR et al. Expert Opin Investig Drugs. 2014;23(2):243-54; Preskorn S et al. J PsychiatrPract. 2015;21(2):140-9; Liu RJ et al. Neuropsychopharmacology. 2017;42(6):1231-1242.

NMDA receptor

Glutamate Glycine

Novel binding site

Rapastinel: An NMDA Receptor Glycine-Site Functional Partial Agonist vs Positive Allosteric Modulator

• Produces rapid antidepressant effects−Single Dose Study Phase IIA (n=116): Single IV dose of rapastinel

dose of 1, 5, 10, or 30 mg, or placebo1

• At 1-week post-infusion, 5 and 10 mg of rapastinel showed significant antidepressant response

−Repeated Dose Study Phase IIB (n=116): Weekly infusion of IV rapastinel (at doses of 1, 5, or 10 mg) or placebo, with follow-up on days 3, 7, and 142

• IV rapastinel 5 or 10 mg showed a reduction in HAM-D scores on days 1 through 7, but no effects were observed thereafter

• No ketamine-like side effects• Currently in large phase III trials for MDD

1. Moskal JR et al. Expert Opin Investig Drugs. 2014;23(2):243-54; 2. Preskorn S et al. J Psychiatr Pract. 2015;21(2):140-9; Liu RJ et al. Neuropsychopharmacology. 2017;42(6):1231-1242.

Novel Positive Allosteric Modulators

• SAGE-547 (brexanolone), is a intravenous (IV) formulation of allopregnanolone, a naturally occurring neuroactive steroid that acts as a positive allosteric modulator of GABA-A receptors, including both synaptic and extrasynapticpopulations

• SAGE-217, a novel, oral neuroactive steroid that, like SAGE-547, is a positive allosteric modulator of GABAA receptors, targeting both synaptic and extrasynaptic GABA-A receptors

Extrasynaptic Benzodiazepine-Insensitive GABA-A Receptor

4∝

6∝

𝛽

𝛿𝛽

GABA binding site Neurosteroid

binding site

GABA-A Complex Receptorcontain 𝛿 subunit

Two Types of GABA-A Mediated InhibitionGABA neuron

glial cell

Tonic InhibitionPhasic Inhibition

GABA

Benzodiazepine-sensitive GABA-A

receptor

extrasynaptic

Benzodiazepine-insensitive GABA-A

receptorpostsynaptic

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

neurosteroid

cholesterol

pregnenolone

Allosteric Modulation of ExtrasynapticGABA-A Receptors

4∝

6∝

𝛽𝛿𝛽

GABA binding site Novel PAM

binding sitePositive Allosteric

Modulation (PAM) can increase receptor efficiency

and/or potency

PAM

Increased tonicGABAergic current

Stahl SM. Stahl's Essential Psychopharmacology. 4th ed. 2013; Tuem KB, Atey TM. Front Neurol. 2017;8:442.

Extrasynpatic GABA-A contain 𝛿 subunit

SAGE-547: Positive Allosteric Modulator of GABA-A Receptors for PPD

Two Double-Blind, Placebo-Controlled, Phase-III Studies• Women (age 18 – 45) with severe postpartum depression (PPD) for ≤6

months • 3 groups administered a continuous inpatient infusion for 60 hours

• (brexanolone IV 90 g/kg/hour; brexanolone IV 60 g/kg/hour; and placebo)

• Results: Both brexanolone groups experienced a greater mean reduction in HAM-D score compared with placebo after 60 hours

− brexanolone IV 90 g/kg/hour: 17.7 points; P = 0.0252− brexanolone IV 60 g/kg/hour: 19.9 points; P = 0.0013

• Effects observed at 60 hours was maintained at the 30-day follow-up• Brexanolone was well-tolerated overall, and the most common adverse events

were headache, dizziness and somnolence.Meltzer-Brody SE, et al. Poster P5-168. and Meltzer-Brody SE, et al. Poster P5-169.

Presented at: American Psychiatric Association Annual Meeting; May 5-9, 2018; New York.

SAGE-217: Positive Allosteric Modulator of GABA-A Receptors for MDD

• Phase II Clinical Trial: randomized, double blind, placebo controlled clinical trial − 89 subjects with moderate-to-severe major depressive disorder

(MDD); ages 18-65

• Onset of action is within 24 hours after first dose• At the end of 14 days patients receiving 30mg of SAGE-217 had

a 17.6-point reduction from baseline in HAM-D scale vs. 10.7 point on placebo (p<0.0001)

• Most common adverse events were headache, dizziness, nausea, somnolence− AE rates were 53% on SAGE-217 and 46% on placebo

Gunduz-Bruce H et al. Biol. Psychiatry. 2018;83:S108-128.

The Endogenous Opioid System

Identified Phases of Reward Processing

Keren H et al. Am J Psychiatry. 2018; Epub ahead of print.

Reward Phase Associated Symptom Translational Term Example

Experimental Task

Prediction Anticipatory anhedonia

Reward/loss anticipation

Monetary incentive delay task

Decision Impaired decision making Choice Iowa gambling task

Action Low energy Effort expenditure Effort expenditure for rewards task

Experience Consummatoryanhedonia

Reward/loss feedback

Monetary incentive delay task

Neural Aberrations During Reward Processing in Depression

• Meta-analyses of 38 fMRI and 12 EEG studies• fMRI studies revealed significantly reduced striatal activation in

depressed compared with healthy individuals during reward feedback.

• When region-of-interest analyses were included, reduced activation was also observed in reward anticipation, effect stronger in individuals <18

• EEG studies involved mainly the FRN event-related potential• FRN was also significantly reduced in depression, with pronounced

effects in individuals under age 18. In longitudinal studies, reduced striatal activation in fMRI and blunted FRN in EEG were found to precede the onset of depression in adolescents.

Keren H et al. Neuroimage. 2018;178:266-276.

EEG: electroencephalogram; fMRI: functional magnetic resonance imaging; FRN: feedback-related negativity

receptorμ

δreceptor

κreceptor

Endogenous Opioid Receptors

Stahl SM. Stahl's Essential Psychopharmacology. 4th ed. 2013; Benarroch EE. Neurology. 2012;79(8):807-14.

Opioid Peptides𝛽-endorphinenkephalindynorphin

Opioid ReceptorsMu (μ) àDelta (δ) à

Kappa (κ) à

Location of Opioid Receptors

Nummenmaa L, Tuominen L. Br J Pharmacol. 2018;175(14):2737-2749.

Location of Mu-Receptors in the Brain Overlap of human emotion circuit

Partial Agonist(e.g. buprenorphine)

Full Agonist(e.g. methadone)

Dose of Opioid

Opioid Effect

Mu opioid receptor

partialagonist

Partial agonist binds to the opioid receptor and causes it to open more frequently than the resting

state but less frequently than with a full agonist

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

Opioid Receptor

Main Endogenous

Agonists

Effect on Pain

Effects on Behavior

Mu (μ) 𝛽-Endorphin

Metenkephalin

analgesia (spinal)

• antidepressant-like behavior

• euphoria• reward and physical

dependence• improved mood• respiration• sedation

Mu-opioid receptor agonists may also have antidepressant potential

Mu opioid receptor

agonist

Opioid Receptor

Main Endogenous

Agonists

Effect on Pain

Effects on Behavior

Delta (δ) Enkephalins Analgesia (supraspinal

& spinal analgesia)

• sedation• inhibition of

dopamine release• modulation of mu-

opioid receptors

Delta-opioid receptors may have antidepressant and anti-anxiety actions

agonist

Delta opioid

receptor

Opioid Receptor

Main Endogenous

Agonists

Effect on Pain

Effects on Behavior

Kappa (κ) Dynorphin A Analgesia (spinal)

• worsened mood• diuresis• dysphoria

Kappa neurons may interact to block Mu neurons and thus, kappa agonists worsen

depression and cause dysphoria in animal models

agonist

Kappa opioid

receptor

Kappa opioid

receptor Currently being studied for their potential antidepressant actions

antagonist

Kappa antagonist, especially if combined with a small degree of

mu agonist, will potentiate possible antidepressant effects by a novel non

monoaminergic mechanism

Endogenous Opioid Receptors

• κ-opioid receptor antagonists have antidepressant potential• Likely to be implicated in mood regulation• All 3 opioid receptors modulate BDNF activity and neurogenesis in the hippocampus

Opioid Receptor

Main Endogenous Agonists

Reward Mechanisms

Effect on Pain AgonismEffects on Behavior

Mu (μ) 𝛽-EndorphinMet-enkephalin

Facilitates Analgesia (spinal)

Improved mood, reward anddependence, euphoria,

antidepressant-like behavior, sedation

Delta (δ) Enkephalins Facilitates Analgesia (supraspinal &

spinal analgesia)

Improved mood; antidepressant and antianxiety-like behavior, sedation

Kappa (κ) Dynorphin A Inhibits Analgesia (spinal) Worsened mood; dysphoria, anti-reward, sedation

Benarroch EE. Neurology. 2012;79(8):807-14; Lutz PE, Kieffer BL. Trends Neurosci. 2013;36(3):195-206.

dynorphin

This leads to an increase in dopamine release in nucleus accumbens

Nucleusaccumbens

Ventraltegmentalarea

Mesolimbic dopamine

pathway

𝛽-endorphin

GABA interneuron

In contrast, the activation of kappa (𝜿) receptors located presynaptically in the nucleus accumbens inhibits dopamine

release

VTA

NA

Activation mu (𝝁) receptors located on GABA interneurons

leads to a disinhibition of dopaminergic neurons projecting

the nucleus accumbens

Spanagel R et al. Proc Natl Acad Sci USA. 1992;89(6):2046-50.

Mu and Kappa Systems Appear to Counteract, Especially in the Mesolimbic Dopaminergic System

DA

Buprenorphine

• Partial mu opioid agonist• Kappa antagonist• Currently used in addiction treatment• Open label, positive data in refractory depression• Low Dose Buprenorphine Reduces Suicidal Ideation−Double-blind, placebo-controlled trial 88 patients received either

0.1-0.8 mg/day (mean dose 0.44 mg/day) or placebo for 4 weeks−Very low dosages of buprenorphine were associated with

decreased suicidal ideation in a group of severely suicidal patients without substance abuse

Yovell Y et al. Am J Psychiatry. 2016;173(5):491-8.

ALKS 5461: Buprenorphine & Samidorphan• Combination of buprenorphine

(partial μ-opioid agonist, kappa antagonist) and samidorphan (μ antagonist)

• Samidorphan added to counteract the μ-opioid agonist activity of buprenorphine & reduce its addictive potential

• Kappa antagonism has shown antidepressant activity in animal models

• Possible adjunct to ongoing antidepressant

Fava M et al. Am J Psychiatry. 2016;173(5):499-508.

Study 205• Ph III Double-blind, placebo controlled • 11 week trial in AD non-responders

(n=814)• Doses of buprenorphine/ samidorphan−0.5/0.5 mg−2/2 mg

• Neither dose was statistically superior to placebo on primary endpoint (MADRS at week 5)−Post hoc analysis showed significance

for the 2/2 mg dose at other time points

ALKS 5461: Buprenorphine & Samidorphan

Ehrich E et al. Biol Psychiatry. 2017;81(10):S23.

• Ph III Multicenter, randomized, double-blind, pbo-controlled (n=407)

• Doses of buprenorphine/samidorphan− 1/1 mg− 2/2 mg

• Evidence of antidepressant activity in both groups

• Statistically significant for the 2/2mg group only

Study 207

The most common AEs:− Nausea− Dizziness− Fatigue

2/2mg Superior to Placebo− Improving core symptoms of

depression (MADRS-6, p=0.018)− Overall symptoms of depression

(MADRS-10, p=0.026)

No pattern of AEs indicative of abuse potential

ALKS 5461 as Adjunct in MDD

• Study 208: ongoing long-term phase 3b will evaluate the efficacy, safety, and tolerability of ALKS 5461 as adjunctive treatment in patients with MDD

• Agonist-antagonist opioid modulation represents a novel approach to the treatment of MDD

• May be an alternative to adjunct treatment with antipsychotics

Ehrich E et al. Neuropsychopharmacology. 2015;40(6):1448-55; Fava M et al. Am J Psychiatry. 2016;173(5):499-508.

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)

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.

Glucocorticoid Receptor Antagonists

Agent Clinical Trial PhaseMifepristone IIIMetyrapone IIIOrg-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 - yreatment in the glabellar (forehead) region can treat MDD

• Effects of one injection last up to 16 weeks

Summary

• Neurobiological substrates of depression may go beyond monoaminergic circuits

• Glutamatergic targets like ketamine, esketamine, and rapastinel have shown promise in treatment of MDD

• Opioid agents like buprenorphine and ALKS 5461 have shown efficacy in treatment of MDD

• Additional research is needed to validate these targets