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Home , Dextromethadone, Esketamine

OUT OF THE PIPELINE: WHAT NEXT? OPTIMIZING OUTCOMES FOR TREATMENT-RESISTANT DEPRESSION Learning Objectives

• Explore the hypothesized neurobiological bases of major depressive disorder

• Describe novel treatments for major depressive disorder Pharmacological Treatment Algorithm

First LEVEL 1 Inefficacy or intolerability

Switch Transition/Combination Augment

LEVEL 2 Inefficacy or intolerability

Switch Transition/Combination Augment LEVEL 3 Inefficacy or intolerability

MAOI LEVEL 4 Inefficacy or intolerability

LEVEL 5 Augment Remission After First Antidepressant Relapse After First Antidepressant What percentage of unipolar major depressive episodes remit? What are the most common residual symptoms in nonremitters?

concentration/interest most common fatigue/pain insomnia

psychomotor retardation least common depressed mood Theory of Multiple Mechanisms

• Multiple symptoms likely means that multiple brain circuits are involved • Theoretically, it's possible that changing more than one neurotransmitter's release in more than one site can affect multiple symptoms linked to multiple circuits

• However, the etiology of depression remains speculative, and choosing antidepressant based on has yet to be shown effective Monotherapies That Target Multiple Receptors

Starting Dose Usual Daily Dose (mg/day) (mg/day) Tips and Pearls

2 Evening dosing; Increase every 1–2 weeks until 5HT3 H1 desired efficacy is reached; maximum generally 45 5HT 15 15 – 45 2A 5HT mg/day

Increase by 100–200 mg/day each week until 100 2x/day 300 – 600 desired efficacy is reached

H1 Initial 150 mg/day in divided doses; can increase 150 150 – 600 every 3–4 days by 50 mg/day as needed Initial 150 mg/day in divided doses; can increase trazodone ER 150 150 – 375 every 3 days by 75 mg/day as needed

1A Increase to 20 mg/day after one week; can SERT 10 20 – 40 increase to 40 mg/day after one more week; should be taken with food

1A 1B 1D Can decrease to 5 mg once daily or increase to 20 10 5 – 20 3 mg once daily depending on patient response 7

Stahl SM. Stahl’s Essential Psychopharmacology: The Prescriber’s Guide. 6th ed. 2016. Factors to Consider When Choosing Between Switching or Augmenting

Consider switching to another Consider an adjunctive antidepressant when: medication when: • There have been two or more antidepressant • It is the first antidepressant trial trials • There are poorly tolerated side effects to the • The initial antidepressant is well tolerated initial antidepressant • There is partial response (>25% • There is no response (<25% improvement) to improvement) to the initial antidepressant the initial antidepressant • There are specific residual symptoms or side • There is more time to wait for a response effects to the initial antidepressant that can be (less severe, less functional impairment) targeted • Patient prefers to switch to another • There is less time to wait for a response antidepressant (more severe, more functional impairment) • Patient prefers to add on another medication

Kennedy SH et al. Can J Psychiatry 2016;61(9):540-60. Beyond Monoamines: The Neuroplasticity Hypothesis of Depression

Monoamine levels

Changes in neuroplasticity and neurotransmission

Depressive symptoms

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 Duration of antidepressant treatment (days) Beyond Monoamines: The Neuroplasticity Hypothesis of Depression (cont’d) • The depressed brain shows signs of inadequate neuroplasticity and excessive glutamate

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

• Directly targeting glutamatergic neurotransmission or neuroplasticity may: • Lead to faster treatment response (e.g., , , SAGE-547, SAGE-217, AXS-05, ) • Improve response and remission rates

Racagni 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

monoamine

synaptogenesis

neuroplasticity

cell survival CREB

neurogenesis CaMK: calcium/calmodulin-dependent protein kinase PKA: protein kinase A CREB: cAMP response element-binding protein BDNF: brain-derived neurotrophic factor Downstream Improvement in Neuroplasticity and Glutamatergic Neurotransmission

Monoamine regulation DA 5HT NE

Signaling cascades cAMP Wnt/Frz CaMK MAPK RSK PKC GSK-3

Activation of cAMP response element binding protein (CREB)

Genes turned on

Increased expression of Downregulation of Increased proteins Decreased release AMPA receptor subunits NMDA receptors involved in neuroplasticity of glutamate

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

The Three Gs: Glutamate, GABA, and Dysfunction of Glutamate Signaling

• Glutamate is an excitatory neurotransmitter involved in many functions, including synaptic plasticity, learning, and memory • Numerous 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 Ketamine Directly Targets Glutamate Neurotransmission

Directly targeting glutamatergic Ketamine Ca2+ neurotransmission or NMDA receptor neuroplasticity may lead to faster treatment response and may improve response and remission rates

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

• Ketamine () • 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

mammalian target of rapamycin: a critical intracellular protein that mediates neuroplasticity and mTOR neurotrophic processes

AMPARs

Increased synaptic plasticity

Bunney BG, Bunney WE. Int J Neuropsychopharmacol 2012;15:695-713. Ketamine’s Antidepressant Effects May Also Be Due to Activation of AMPA Receptors, Not the Blocking of NMDA Receptors

glu

NMDA AMPA receptor receptor blocked by ketamine

ERK, AKT

mTOR

Stahl SM. Stahl's Essential Psychopharmacology. 4th ed. 2013. Attenuation of Antidepressant Effects of Ketamine by Receptor Antagonism

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

Ketamine Placebo Ketamine (opioid-blocking drug)

Reduction in Almost no effect symptoms of on symptoms of depression depression

Williams NR et al. Am J Psychiatry 2018;175(12):1205-121. Utility of (2R,6R)- via Direct AMPA Activation

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

Abdallah CG et al. Depress Anxiety 2016;33:689-97; Stahl SM. Stahl's Essential Psychopharmacology. 4th ed. 2013; Zanos P et al. Nature 2016;533:481-6; Zhao X et al. Br J Clin Pharmacol. 2012;74(2):304-14. 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)

1.0 Placebo Ketamine 0.8

0.6

0.4

0.2 score from baseline (HDRS) score from baseline Proportion with with in 50% change Proportion 0 40 90 110 230 Day Day Day Day min min min min 1 2 3 7 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 1,2 • Even when dose is escalated 2

• No advantage in efficacy in sustaining the initial antidepressant effects for two times verses three times a week intravenous ketamine in patients (n=67) 3

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 (S- 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

MADRS: Montgomery-Asberg Depression Rating Scale 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. Intranasal Esketamine

• S-enantiomer of racemic ketamine • has a higher affinity for the NMDA receptor than the R-enantiomer

• FDA Approved March 5, 2019 • Indicated in conjunction with an oral antidepressant for TRD

Intranasal Induction Phase Maintenance Phase Maintenance Phase • 28mg/device; each nasal spray Week 9 and after Weeks 1–4 Weeks 5–8 device delivers 2 sprays that • Administer q2Week or once • Administer twice per week • Administer once weekly total 28mg weekly; individualize dosing • Day 1 starting dose: 56 mg • 56 mg or 84 mg • Available as a 56mg kit (two 28- frequency to the least • Subsequent doses: 56 mg mg nasal spray devices) or an frequent dosing to maintain or 84 mg 84mg kit (three 28-mg nasal remission/response spray devices) • 56 mg or 84 mg has to be administered in a clinic

NEI Prescribe. 2020 Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in TRD: Phase III Study Results

Short -Term Studies (28-days) 2-sided p-value fixed dose: New AD + Intranasal Placebo (n=113) vs. Esketamine TRANSFORM-1 (3001) not56 mg statistically + New AD (n=115) positive vs. Esketamine 84 mg + Newp =AD 0.088 (n=114) flexible dose: New AD + Intranasal Placebo (n=109) vs. TRANSFORM-2 (3002) statisticallyEsketamine Flex dosepositive (56 or 84 mg) + New AD (n=114)p = 0.020

TRANSFORM-3 (3005) flexible dose: New AD + Intranasal Placebo (n=65) vs.pEsketamine (patients ≥65 years) notFlex dosestatistically (28, 56, or 84 positive mg) + New AD (n=72) = 0.059

Maintenance of Effect (16 weeks) 2-sided p-value

SUSTAIN-1 (3003) Relapsestatistically prevention positive study p = 0.003

Long Term Open Label Safety

SUSTAIN-2 (3004) long-term safety study

Ongoing Studies

TRD3006 Short-Term Study AD: antidepressant TRD: treatment-resistant depression SUSTAIN-3 (3008) - Continuation Phase 3 Study TRANSFORM-2 (3002): Randomized Double-Blind Active-Controlled Study

Change in MADRS score from Baseline to Day 28 • Treatment with esketamine nasal spray (56 or 84 mg twice weekly) plus an AD or placebo nasal spray plus AD • Change in MADRS score with esketamine plus AD was significantly greater than with placebo plus AD at day 28 (difference of least square means=−4.0, SE=1.69, 95% CI=−7.31, −0.64) • AEs in the esketamine plus AD group generally appeared shortly after dosing and resolved by 1.5 hours after dosing

AD: antidepressant MADRS: Montgomery-Asberg Depression Rating Scale

Popova V et al. Am J Psychiatry 2019;176(6):428-38. Two Phase III Long-Term Esketamine Nasal Spray Studies

SUSTAIN-1 (3003) SUSTAIN-2 (3004) (Maintenance of Effect) (Long-Term Open Label Safety)

• Primary• 705 patients: Endpoint: 16 time weeks to relapse of intranasal among • 802 adult patients received esketamine patientsesketamine who were+ oral in stableAD showed remission a nasal spray (28 mg, 56 mg, or 84 mg) aftersignificant 16 weeks delay to relapse plus with repeated, intermittent dosing • Amongcompared the 297 with adults placebo, who enteredwith the the for up to one year randomizedrisk of relapse maintenance decreasing phase, in favor 176 of • Most common treatment-emergent adverse achieved stable remission events during the treatment phases (≥10% intranasal esketamine by 51% patients) were: • Among• Adverse stable events remitters, included: the following experienced relapse (two-sided p=0.003): • dizziness (32.9%) • vomiting (10.8%) • dysgeusia • headache • dissociation (27.4%) • metallic taste and oral • 24• vertigo(26.7%) in the esketamine• nausea plus AD group • nausea (25.1%) hypoaesthesia (11.8% • dissociation • blurred vision • headache (24.9%) each) • 39• somnolence(45.3%) in the placebo• oral hypoesthesia. plus AD group • drowsiness (16.7%), • viral upper respiratory tract • dizziness • vertigo (11.0%) infection (10.2%) Symptoms resolved around 1.5 hours post-dose

AD: antidepressant MADRS: Montgomery-Asberg Depression Rating Scale Daly EJ et al. JAMA Psychiatry 2019; Epub ahead of print; ClinicalTrials.gov Identifier: NCT02493868; ClinicalTrials.gov Identifier: NCT02497287 Mechanism of Action of Classic • All classic hallucinogens exert effects primarily via prefrontal cortical 5HT2A receptor agonism – Downstream effects on glutamate, serotonin, and neurotransmission

Vollenweider FX, Kometer M. Nature Rev Neurosci 2010;11:642-51. , Classified as a , Is a Plant Alkaloid and 5-HT2A Receptor

The 5-HT2A receptor is known to play a key role in regulating mood, anxiety, schizophrenia, and consciousness Psilocybin Receives Breakthrough Therapy Designation for TRD and MDD

• Currently being investigated for both major depressive disorder (MDD) and treatment- resistant depression (TRD)

• Compass Pathway is examining the use of psilocybin psilocybin-assisted therapy addressing TRD

• Usona Institute is looking at psilocybin potential therapy that targets major depressive disorder (MDD)

• Both programs currently in phase 2 Psilocybin for Treatment-Resistant Depression • Twelve patients with moderate to severe unipolar depression • Two doses of psilocybin administered with psychological support • No control group

Carhart-Harris RL et al. Lancet Psychiatry 2016;3:619-27. Psilocybin for Treatment-Resistant Depression

Decreased Quick Inventory of Depressive Symptoms (QIDS) at 1 week through 3 months

Mean depression severity (QIDS) over time

Carhart-Harris RL et al. Lancet Psychiatry 2016;3:619-27. Other Glutamatergic Modulators

Failed to show efficacy or are no longer in development

Agent Target Riluzole 18 Voltage-gated sodium channels Did not out-perform placebo on mean MADRS1 NMDA receptor Trials for depression unsuccessful2,3 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 Alzheimer’s, no TRD efficacy receptor, SERT, NET AVP-786 NMDA receptor, Sigma-1 Alzheimer’s, no TRD efficacy receptor, SERT, NET GLYX-13 NMDA receptor Phase III failed to differentiate from placebo on (rapastinel) the primary and key secondary endpoints

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;74:966-73; 4. Sanacora G et al. Neuropsychopharmacology 2017;42(4):844-53; 5. Preskorn SH et al. J Clin Psychopharmacol 2008;28(6):631-7. Other Glutamatergic Modulators

Still in development Agent Target d- NMDA receptor Moderate evidence1 AGN-241751 NMDA receptor Currently in Phase II; Moderate evidence2 AXS 05 NMDA receptor Currently in Phase III; Moderate (dextro- and others evidence3 + ) NMDA receptor Preliminary evidence of efficacy for MDD4 dextromethadone NMDA receptor Currently in Phase II; Moderate evidence

1. Heresco-levy U et al. Int J Neuropsychopharmacol 2013;16(3):501-6; 2. Liu RJ et al. Neuropsychopharmacology 2017;42(6):1231-42; 3. Banerjee P et al. Biol Psychiatry 2019:85(10):S348; 4. Nagele P et al. Biol Psychiatry 2015;78(1):10-8. Novel Positive Allosteric Modulators

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

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

GABA binding site 4 binding site

∝ 6 𝛽𝛽 𝛽𝛽 ∝ 𝛿𝛿

GABA-A complex receptor contain subunit

𝛿𝛿 Two Types of GABA-A Mediated Inhibition

GABA neuron glial cell cholesterol

pregnenolone

GABA neurosteroid

Benzodiazepine- sensitive GABA-A Benzodiazepine- receptor insensitive GABA-A postsynaptic receptor extrasynaptic

Phasic inhibition Tonic inhibition

Stahl SM. Stahl's Essential Psychopharmacology. 4th ed. 2013. Allosteric Modulation of Extrasynaptic GABA-A Receptors

GABA PAM binding site Novel PAM binding site 4 Positive Allosteric ∝ 6 𝛽𝛽 Modulation (PAM) can 𝛽𝛽 increase receptor efficiency ∝ 𝛿𝛿 and/or potency

Extrasynpatic GABA-A contain subunit

𝛿𝛿 Increased tonic GABAergic current

Stahl SM. Stahl's Essential Psychopharmacology. 4th ed. 2013; Tuem KB, Atey TM. Front Neurol 2017;8:442. SAGE-217: Positive Allosteric Modulator of GABA-A Receptors for MDD • Phase II : randomized, double blind, placebo controlled − 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, and somnolence − AE rates were 53% on SAGE-217 and 46% on placebo

Gunduz-Bruce H et al. Biol. Psychiatry 2018;83:S108-28. The Endogenous Opioid System Identified Phases of Reward Processing

Associated Example Reward Phase Translational Term Symptom Experimental Task Anticipatory Reward/loss Monetary incentive Prediction anhedonia anticipation delay task Impaired decision Decision Choice Iowa gambling task making Effort expenditure Action Low energy Effort expenditure for rewards task Consummatory Reward/loss Monetary incentive Experience anhedonia feedback delay task

Keren H et al. Am J Psychiatry 2018;175(11):1111-20. 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 feedback-related negativity (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

EEG: electroencephalogram; fMRI: functional magnetic resonance imaging

Keren H et al. Neuroimage 2018;178:266-76. Anhedonia in MDD

• Emotional blunting phenotypically overlaps with anhedonia,1,2 a common symptom of MDD reported in ~75% of patients3 • Anhedonia has been implicated in disturbances of central , mesolimbic, and mesocortical reward circuit pathways4 • Anhedonia and impaired reward circuit pathways are associated with a poorer prognosis and suboptimal treatment response5 • Given its multimodal mechanism of action as well as the cognitive effects, vortioxetine may contribute towards alleviating anhedonia2 MDD=major depressive disorder

1. Loas G et al. Compr Psychiatry 1994;35:366-72; 2. McIntyre R et al. Front Psychiatry 2019;10. DOI: 10.3389/fpsyt.2019.00017; 3. Franken IH et al. J Affect Disord 2007;99:83-9; 4. Pan Z et al. Curr Pharm Des 2017;23:2065-72; 5. Buckner JD et al. 2008159:25-30. Anhedonia Improvements Correlated With General Function and Health-Related Quality of Life Improvements (Post-hoc Analysis)

Correlations of the endpoint changes between functional impairment, well-being, and anhedonia from baseline

SDS total score SDS work SDS social life SDS family life WHO-5 Correlations r p-value r p-value r p-value r p-value r p-value

MADRS total score 0.527 <0.001 0.422 <0.001 0.46 <0.001 0.486 <0.001 -0.604 <0.001

SHAPS score 0.392 <0.001 0.309 0.006 0.403 <0.001 0.365 0.001 -0.336 0.002

MADRS anhedonia factor score 0.511 <0.001 0.423 <0.001 0.41 <0.001 0.507 <0.001 -0.570 <0.001

MADRS=Montgomery and Asberg Depression Rating Scale SDS=Sheehan Disability Scale. SHAPS=Snaith-Hamilton Pleasure Scale WHO-5=World Health Organisation – Five Well-being.

Cao B et al. Front Psychiatry 2019;10:17. Effort Expenditure for Rewards Task (EEfRT)

A 20-minute, computer-based task designed to explore how effort expenditure influences decision-making and reward-seeking behaviour.

Subramaniapillai M et al. Psychiatry 2019;94:152113. Vortioxetine Improves Cognition: Cognition is Associated With Choosing More Complex Tasks = Greater Motivation

Subramaniapillai M et al. Psychiatry 2019;94:152113. Endogenous Opioid Receptors

Opioid Receptors Opioid Peptides Mu (μ)  -endorphin Delta (δ)  enkephalin 𝛽𝛽 Kappa (κ)  dynorphin

κ δ receptor receptor μ receptor

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

Location of Mu-Receptors in the Brain Overlap of Human Emotion Circuit

Nummenmaa L, Tuominen L. Br J Pharmacol 2018;175(14):2737-49. Endogenous Opioid Receptors

Opioid Receptor Main Endogenous Reward Effect on Pain Agonism Mechanisms Effects on Behavior

Mu (μ) -Endorphin Facilitates Analgesia Improved mood, reward and dependence, Met-enkephalin (spinal) euphoria, antidepressant-like behavior, sedation 𝛽𝛽 Delta (δ) Enkephalins Facilitates Analgesia (supraspinal Improved mood; antidepressant and antianxiety- & spinal analgesia) like behavior, sedation

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

• κ- antagonists have antidepressant potential • Likely to be implicated in mood regulation • All three opioid receptors modulate BDNF activity and neurogenesis in the hippocampus Benarroch EE. Neurology 2012;79(8):807-14; Lutz PE, Kieffer BL. Trends Neurosci 2013;36(3):195-206. Mu and Kappa Systems Appear to Counteract, Especially in the Mesolimbic Dopaminergic System

NA In contrast, the activation of kappa ( ) receptors located presynaptically in the Nucleus DA nucleus accumbens inhibits dopamine𝜿𝜿 accumbens release dynorphin

Mesolimbic dopamine Activation mu ( ) receptors pathway located on GABA interneurons VTA leads to a disinhibition𝝁𝝁 of dopaminergic neurons projecting Ventral the nucleus accumbens tegmental area -endorphin

GABA 𝛽𝛽 This leads to an increase in dopamine interneuron release in nucleus accumbens

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

• 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 &

Study 207 2/2mg Superior to Placebo − Improving core symptoms of • Ph III Multicenter, randomized, depression (MADRS-6, p=0.018) double-blind, pbo controlled (n=407) − Overall symptoms of depression • Doses of buprenorphine/samidorphan (MADRS-10, p=0.026) − 1/1 mg − 2/2 mg The most common AEs: − Nausea • Evidence of antidepressant activity in − Dizziness both groups − Fatigue • Statistically significant for the 2/2mg group only No pattern of AEs indicative of abuse potential

Ehrich E et al. Biol Psychiatry 2017;81(10):S23. Other Targets in Depression Treatments

Acetylcholine (Ach) Release Inhibitor Glucocorticoid Receptor Antagonists and Neuromuscular Blocking Agent Agent Clinical Trial Phase • Onabotulinumtoxin A—treatment in the glabellar III (forehead) region can treat MDD Metyrapone III • Effects of one injection last up to 16 weeks Org-34517 II

Acetylcholine Muscarinic (AChM) Emerging Somatic Treatments • Deep transcranial magnetic stimulation (DTMS) • may exert antidepressant effects • Repetitive transcranial magnetic stimulation (rTMS) by acting on the MTORC1 complex via the • Synchronized transcranial magnetic stimulation (sTMS) mTOR pathway and thereby inducing • Low field magnetic stimulation (LFMS) synaptogenesis

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. Summary

• Neurobiological substrates of depression may go beyond monoaminergic circuits • Glutamatergic targets like ketamine, esketamine, and rapastinel have shown promise in treatment of MDD • Hallucinogens targeting 5HT2A receptor agonism have shown promise for both MDD and TRD • Opioid agents like buprenorphine and ALKS 5461 have shown efficacy in treatment of MDD • Additional research is needed to validate these targets Posttest Question

What percentage of unipolar major depressive episodes remit?

1. 67% after 4 treatments 2. 50% after 4 treatments 3. 90% after 4 treatments Posttest Question

When a SPARI is administered, about half of serotonin transporters (SERTs) and half of ______receptors are occupied immediately.

1. dopamine (D2) 2. dopamine (D3) 3. serotonin 1A (5HT1A) 4. serotonin 3A (5HT3A) Posttest Question

Extrasynaptic GABA-A receptors:

1. Are the primary targets of benzodiazepines 2. Are the primary targets of 3. Are involved in phasic inhibition 4. All of the above