KEEPING UP WITH THE CLINICAL ADVANCES: DEPRESSION

Transcription

1 KEEPING UP WITH THE CLINICAL ADVANCES: DEPRESSION

2 Learning Objective Describe the molecular targets of novel agents, including adjunctive treatments, currently being investigated

3 50% of Patients Respond to Monoaminergic Antidepressants Increase monoamine levels with an antidepressant Deficiency in monoamines

4 50% of Patients DO NOT Respond to Monoaminergic Antidepressants Increase monoamine levels with an antidepressant Adequate monoamines Downstream dysfunction in glutamatergic neurotransmission or neuroplasticity Pharmacological modulation of downstream dysfunction in glutamatergic neurotransmission or neuroplasticity

5 Beyond Monoamines: The Neuroplasticity Hypothesis of Depression Monoamine levels Changes in neuroplasticity and glutamatergic neurotransmission Depressive symptoms Duration of antidepressant treatment (days)

6 Beyond Monoamines: The Neuroplasticity Hypothesis 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 neuroplasticity may: Lead to faster treatment response (e.g., ketamine, rapastinel, SAGE- 547, SAGE-217) Improve response and remission rates Racagni G, Popoli M. Dialogues Clin Neurosci 2008;10(4): ; Crupi R, Marino A, Cuzzocrea S. Curr Med Chem 2011;18(28): ; 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.

7 Stahl SM. Stahl's Essential Psychopharmacology. 4th ed Neuroplasticity: Monoamine Signaling and Brain- Derived Neurotrophic Factor Release monoamine synaptogenesis neuroplasticity CREB cell survival neurogenesis CaMK: calcium/calmodulin-dependent protein kinase PKA: protein kinase A CREB: camp response element-binding protein BDNF: brain-derived neurotrophic factor

8 Downstream Improvement in Neuroplasticity and Glutamatergic Neurotransmission Monoamine regulation DA 5HT NE Signaling cascades MAPK RSK camp PKC Wnt/Frz GSK-3 CaMK Activation of camp response element binding protein (CREB) Genes turned on Increased expression of AMPA receptor subunits Downregulation of NMDA receptors Increased proteins involved in neuroplasticity Decreased release of glutamate Increased neuroplasticity and reduced glutamatergic neurotransmission Racagni G, Popoli M. Dialogues Clin Neurosci 2008;10(4): ; Barbon A et al. Neurochem Int 2011;59(6):

9 The Three G's Glutamate, GABA, and Glycine

10 Impaired Neuroplasticity Due to Imbalanced GABA and Glutamate signaling Hashimoto K et al. Transl Psychiatry. 2016;6:e744. Abnormalities in glutamatergic neurotransmission via the N-methyl- D-aspartate receptor (NMDA-R) have a key role in the pathophysiology of depression NMDA-R

11 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: ; Sanacora G et al. Neuropharmacology. 2012;62(1):63-77.

12 Ketamine Directly Targets Glutamate Neurotransmission Directly targeting glutamatergic neurotransmission or neuroplasticity may lead to faster treatment response and may improve response and remission rates NMDA receptor Ca2+ Ketamine Bunney BG, Bunney WE. Int J Neuropsychopharmacol 2012;15:

13 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

14 Ketamine Increases Synaptic Plasticity mtor mammalian Target Of Rapamycin: a critical intracellular protein that mediates neuroplasticity and neurotrophic processes AMPARs Increased synaptic plasticity Bunney BG, Bunney WE. Int J Neuropsychopharmacol 2012;15:

15 Ketamine s Antidepressant Effects May Also Be Due to Activation of AMPA Receptors, not the Blocking of NMDA Receptors glu AMPA receptor NMDA receptor blocked by ketamine ERK, AKT mtor Stahl SM. Stahl's Essential Psychopharmacology. 4th ed

16 Attenuation of Antidepressant Effects of Ketamine by Opioid Receptor Antagonism Recent study showed that ketamine may work to treat depression, at least in part, by activating opioid receptors Ketamine Placebo Ketamine Naltrexone (opioid-blocking drug) Reduction in symptoms of depression Almost no effect on symptoms of depression Williams NR et al. Am J Psychiatry. 2018; Epub ahead of print.

17 Utility of (2R,6R)-Hydroxynorketamine 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: ; Stahl SM. Stahl's Essential Psychopharmacology. 4th ed. 2013; Zanos P et al. Nature 2016; 533: ; Zhao X et al. Br J Clin Pharmacol. 2012;74(2):

18 Antidepressant Effect of Ketamine Within Hours in Patients With Treatment-Resistant Depression 21-Item HDRS Score min 40 min 90 min * indicates P<.05;, P<.01;, P<.001 HDRS: Hamilton Depression Rating Scale * 110 min 230 min Day 1 Day 2 Day 3 * Day 7 Placebo Ketamine Dose of intravenous ketamine consistently decreases symptoms of depression in patients with treatmentresistant depression in a rapid (within hours), robust (across many symptoms of depression), and relatively sustained (typically 7-14 days) manner Zarate CA Jr et al. Arch Gen Psychiatry 2006;63:

19 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) Proportion With 50% Change in Score From Baseline (HDRS) HDRS: Hamilton Depression Rating Scale min 90 min 110 min 230 min Day 1 Day 2 Day 3 Placebo Ketamine Day 7 Zarate CA Jr et al. Arch Gen Psychiatry 2006;63:

20 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):

21 Ketamine Formulations Ketamine intranasal administration 50 mg vs saline placebo (n=27) Effective, easier to administer 1 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 ketamine 4 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.

22 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 Clinical Experience and Training Treatment Setting Medication Delivery Follow-up and Assessments Efficacy of Longer-term Repeated Administration Safety Measures and Continuation of Treatment Future Directions 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 Currently no recommendations or guidelines Clinicians should be prepared to manage potential cardiovascular events and behavioral effects of ketamine Setup for monitoring of cardiovascular and respiratory function 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 Use rating instruments to assess clinical response and evaluate risk:benefit ratio of continued treatment 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 Risk of cognitive impairment and cystitis are associated with chronic ketamine use Substance abuse liability Frequent ketamine administration is not recommended 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):

23 Other Glutamatergic Modulators Agent Riluzole Failed to Show Efficacy or No Longer in Development Target Voltage-gated sodium channels Did not out-preform placebo on mean MADRS 1.05 Memantine NMDA receptor Trials for depression unsuccessful 2,3 Lanicemine NMDA receptor Failed to show superior efficacy 4 CP-101,606 NMDA-NR2B subunit Ceased due to association with cardiac conduction abnormalities 5 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 evidence 6 GLYX-13 (rapastinel) AXS 05 Still in Development NMDA receptor dextromethorphan + bupropion Currently in Phase III; Moderate evidence 7 Currently in Phase III; Moderate evidence Nitrous oxide NMDA receptor Preliminary evidence of efficacy for MDD 8 AVP-923 AVP-786 NMDA receptor, Sigma- 1 receptor, SERT, NET NMDA receptor, Sigma- 1 receptor, SERT, NET Alzheimer, no TRD efficacy Alzheimer, no TRD efficacy 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: ; 4. Sanacora G et al. Neuropsychopharmacology. 2017;42(4): ; 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): ; 8. Nagele P et al. Biol Psychiatry. 2015;78(1):10-8.

24 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 Glutamate NMDA receptor Glycine Novel binding site Moskal JR et al. Expert Opin Investig Drugs. 2014;23(2):243-54; Preskorn S et al. J Psychiatr Pract. 2015;21(2):140-9; Liu RJ et al. Neuropsychopharmacology. 2017;42(6):

25 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 placebo 1 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 14 2 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):

26 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 extrasynaptic populations 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

27 Extrasynaptic Benzodiazepine-Insensitive GABA-A Receptor GABA binding site β 4 6 β δ Neurosteroid binding site GABA-A Complex Receptor contain δ subunit

28 Two Types of GABA-A Mediated Inhibition GABA neuron glial cell cholesterol pregnenolone GABA neurosteroid Benzodiazepinesensitive GABA-A receptor postsynaptic Benzodiazepineinsensitive GABA-A receptor extrasynaptic Phasic Inhibition Tonic Inhibition Stahl SM. Stahl's Essential Psychopharmacology. 4th ed. 2013

29 Allosteric Modulation of Extrasynaptic GABA-A Receptors GABA binding site β 4 6 β PAM δ Novel PAM binding site Positive Allosteric Modulation (PAM) can increase receptor efficiency and/or potency Extrasynpatic GABA-A contain δ subunit Increased tonic GABAergic current Stahl SM. Stahl's Essential Psychopharmacology. 4th ed. 2013; Tuem KB, Atey TM. Front Neurol. 2017;8:442.

30 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 = brexanolone IV 60 g/kg/hour: 19.9 points; P = 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 P and Meltzer-Brody SE, et al. Poster P Presented at: American Psychiatric Association Annual Meeting; May 5-9, 2018; New York.

31 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 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 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:S

32 The Endogenous Opioid System

33 Identified Phases of Reward Processing Reward Phase Prediction Decision Associated Symptom Anticipatory anhedonia Impaired decision making Translational Term Reward/loss anticipation Choice Action Low energy Effort expenditure Experience Consummatory anhedonia Reward/loss feedback Example Experimental Task Monetary incentive delay task Iowa gambling task Effort expenditure for rewards task Monetary incentive delay task Keren H et al. Am J Psychiatry. 2018; Epub ahead of print.

34 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. EEG: electroencephalogram; fmri: functional magnetic resonance imaging; FRN: feedback-related negativity Keren H et al. Neuroimage. 2018;178:

35 Endogenous Opioid Receptors Opioid Receptors Mu (μ) à Delta (δ) à Kappa (κ) à Opioid Peptides β-endorphin enkephalin dynorphin κ δ receptor receptor μ receptor Stahl SM. Stahl's Essential Psychopharmacology. 4th ed. 2013; Benarroch EE. Neurology. 2012;79(8):

36 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):

37 partial agonist Full Agonist (e.g. methadone) Mu opioid receptor Opioid Effect Partial Agonist (e.g. buprenorphine) Dose of Opioid 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

38 agonist Opioid Receptor Main Endogenous Agonists Effect on Pain Effects on Behavior Mu opioid receptor 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

39 agonist Opioid Receptor Main Endogenous Agonists Effect on Pain Effects on Behavior Delta opioid receptor Delta (δ) Enkephalins Analgesia (supraspinal & spinal analgesia) sedation inhibition of dopamine release modulation of muopioid receptors Delta-opioid receptors may have antidepressant and anti-anxiety actions

40 agonist Opioid Receptor Main Endogenous Agonists Effect on Pain Effects on Behavior Kappa opioid receptor 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

41 antagonist Kappa opioid receptor Kappa antagonist, especially if combined with a small degree of mu agonist, will potentiate possible antidepressant effects by a novel non monoaminergic mechanism Currently being studied for their potential antidepressant actions

42 Endogenous Opioid Receptors Opioid Receptor Main Endogenous Agonists Reward Mechanisms Effect on Pain Agonism Effects on Behavior Mu (μ) β-endorphin Met-enkephalin Facilitates κ-opioid receptor antagonists have antidepressant potential Likely to be implicated in mood regulation Analgesia (spinal) Delta (δ) Enkephalins Facilitates Analgesia (supraspinal & spinal analgesia) Improved mood, reward and dependence, euphoria, antidepressant-like behavior, sedation Improved mood; antidepressant and antianxiety-like behavior, sedation Kappa (κ) Dynorphin A Inhibits Analgesia (spinal) Worsened mood; dysphoria, antireward, sedation All 3 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):

43 Mu and Kappa Systems Appear to Counteract, Especially in the Mesolimbic Dopaminergic System Nucleus accumbens NA DA dynorphin In contrast, the activation of kappa (κ) receptors located presynaptically in the nucleus accumbens inhibits dopamine release Ventral tegmental area Mesolimbic dopamine pathway VTA β-endorphin Activation mu (μ) receptors located on GABA interneurons leads to a disinhibition of dopaminergic neurons projecting the nucleus accumbens GABA interneuron This leads to an increase in dopamine release in nucleus accumbens Spanagel R et al. Proc Natl Acad Sci USA. 1992;89(6):

44 Partial mu opioid agonist Kappa antagonist Buprenorphine 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 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.

45 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 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) Fava M et al. Am J Psychiatry. 2016;173(5): Post hoc analysis showed significance for the 2/2 mg dose at other time points

46 ALKS 5461: Buprenorphine & Samidorphan Study 207 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 2/2mg Superior to Placebo Improving core symptoms of depression (MADRS-6, p=0.018) Overall symptoms of depression (MADRS-10, p=0.026) The most common AEs: Nausea Dizziness Fatigue No pattern of AEs indicative of abuse potential Ehrich E et al. Biol Psychiatry. 2017;81(10):S23.

47 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): ; Fava M et al. Am J Psychiatry. 2016;173(5):

48 Other Targets in Depression Treatments 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 Glucocorticoid Receptor Antagonists Agent Clinical Trial Phase Mifepristone III Metyrapone III Org 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 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): ; Navarria A et al. Neurobiol Dis. 2015;82:254-61; Khajavi D et al. J Clin Psychiatry. 2012;73(11): ; 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):

49 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