BEYOND MONOAMINES: NOVEL APPROACHES TO ANTIDEPRESSANT TREATMENT

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 NeuroplasticityHypothesis of Depression

• The depressed brain shows signs of inadequate neuroplasticity and excessive glutamate

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

• Directly targeting glutamatergic neurotransmission or neuroplasticitymay:

• Lead to faster treatment response (e.g., ketamine)• 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 BDNF

CREB

synaptogenesisneuroplasticity

cell survival

neurogenesis

BDNF: brain-derived neurotrophic factor

CREB: cAMP response element-binding protein

CaMK: calcium/calmodulin-dependent protein kinase

PKA: protein kinase A

monoamine

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

Directly targeting glutamatergic

neurotransmission or neuroplasticity may lead to faster treatment response

and may improve response and

remission rates

KetamineNMDA receptor

Ca2+

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

Ketamine Directly Targets Glutamate Neurotransmission

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

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

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HDRS: Hamilton Depression Rating Scale

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

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

• 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

1. Lapidus KA et al. Biol Psychiatry. 2014;76(12):970-6. 2. Singh JB et al. Am J Psychiatry. 2016;173(8):816-26.

3. Daly EJ et al. Presented at the 54th Annual Meeting of the ACNP; Dec. 2015; Hollywood, FL.4. 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 channels

Did not out-preform placebo on mean MADRS10.05

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

Agent Target

d-Cycloserine NMDA receptor Moderate evidence6

GLYX-13 (rapastinel)

NMDA receptor Currently in Phase III; Moderate evidence7

AVP-786 NMDA receptor, Sigma-1 receptor,

SERT, NET

Phase II clinical trial in MDD) as adjunct

AVP-923 NMDA receptor, Sigma-1 receptor,

SERT, NET

Phase II clinical trial in MDD

Nitrous oxide NMDA receptor Preliminary evidence of efficacy for MDD8

Still in Early Development

Rapastinel: An NMDA Receptor Glycine-Site Functional Partial Agonist vs Postive 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 infusions 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 MDD1. 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.

Endogenous Opioid Receptors

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

δ κμ

receptorreceptor

receptor

Opioid Peptides𝛽-endorphinenkephalindynorphin

Opioid ReceptorsMu (μ)Delta (δ)Kappa (κ)

Endogenous Opioid Receptors

• δ-opioid receptor agonists and 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 and dependence, 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.

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

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

• Both doses not 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.

Onabotulinumtoxin A•Acetylcholine (Ach) release inhibitor and neuromuscular blocking agent

•2 positive randomized-controlled trials in MDD

•Effects of one injection last up to 16 weeks

•Treatment in the glabellar (forehead) region can treat MDD

•3 groups (n=101)−Statistically significant reduction in depressive symptoms in those

who received botulinum toxin A versus placebo injections in the frown muscles.

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.

Increased Cholinergic Activity Associated with Depression

•Depression may be associated with hyperactivation of the cholinergic system and, as a consequence, decreased activity in the noradrenergic system

•Anticholinergic agents have been associated with antidepressant effects−These antidepressant effects are thought to be mediated through

downstream increase in neuroplasticity

•Typical anticholinergic adverse side effects, such as dry mouth, blurred vision, and drowsiness may imply limitation to its broad clinical use

Dale E et al. Biochem Pharmacol. 2015;95(2):81-97; Scarr E et al. Front Cell Neurosci. 2013;7:55.

Rapid Antidepressant Actions of Scopolamine

•Acetylcholine muscarinic (AChM) receptor antagonist

•Double-blind, placebo-controlled, crossover clinical trial (n=18)−Scopolamine infused at 4.0 μg/kg intravenously produced robust antidepressant effects versus placebo, which were evident within 3 days after the initial infusion1

•Scopolamine may exert antidepressant effects by acting on the MTORC1 complex via the mTOR pathway and thereby inducing synaptogenesis

1. 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.

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

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