Novel Treatments for Major Depression

Transcription

1 Novel Treatments for Major Depression Dan V. Iosifescu, M.D., M.Sc. Associate Professor of Psychiatry and Neuroscience Icahn School of Medicine at Mount Sinai Consultant in Psychiatry, Massachusetts General Hospital

2 Dan V. Iosifescu, M.D. Disclosures (12 Months) My spouse and I have the following relevant financial relationships with a commercial interest to disclose: Consultant (Honoraria) Axsome, CNS Response, Lundbeck, Sunovion Research Funding (though the Icahn School of Medicine at Mount Sinai) Alkermes, Brainsway This talk contains references to off label or non-fda approved treatments

3 STAR*D: Current Antidepressant Medications Have Modest Efficacy 60 % remission % 30.6% % 13.0% 10 0 Level 1 (N=3671) Level 2 (N=1439) Level 3 (N=390) Level 4 (N=123) Rush AJ et al. Am J Psych 2006

4 Efficacy (response rate) drug vs. fluoxetine Favors comparator Meta-Analysis on the Comparative Efficacy of 12 New-Generation Antidepressants RCTs (25,928 patients) Odds Ratio Fluoxetine as Reference * * * * * Favors fluoxetine *p<0.05 Cipriani et al., Lancet 2009

5 FDA-Approved Antidepressants in the Last Five Years Vilazodone (2011) Levomilnacipran ER (2013) Vortioxetine (2013)

6 Vilazodone Blocks Serotonin Transporters and is a Partial Agonist of 5HT 1A Receptors Presynaptic Postsynaptic 1 2 Vilazodone Serotonin 5-HT Transporter (SERT) 5-HT 1A Receptors Other 5-HT Receptors Only serotonergic neurotransmission is depicted here. 1. Selective inhibition of serotonin reuptake 2. Partial agonist at 5-HT 1A receptors

7 Vilazodone Clinical Efficacy Lower Rates of Sexual AEs than SSRIs, similar to BUP 3 2 1) Rickels K et al. Per Med. 2009; 6(2): ; 2) Khan A et al. J Clin Psychiatry. 2011; 72(4):441-7; 3) Clayton AH et al. Postgrad Med. 2014; 126(2):91-9

8 Levomilnacipran-ER SNRI Two-fold greater selectivity for NE vs. 5- HT Starting dose = 20 mg/day Effective Dose = mg/day NE 5-HT 5-HT NE IC 50, ng/ml IC 80, ng/ml IC 90, ng/ml Inhibition of 5-HT and NE Transporters by Levomilnacipran

9 Levomilnacipran ER Clinical Efficacy 1) Asnis GM et al. J Clin Psychiatry. 2013; 74(3): ) Bakish D et al. J Psychiatry Neurosci. 2014; 39(1): 40-9; 3) Sambunaris A et al. J Clin Psychopharmacol. 2014; 34(1):47-56.

10 Number Needed to Treat or Harm vs. Placebo Safety and Efficacy of Levomilnacipran 100 Efficacy - NNT Tolerability - NNH Response Remission Nausea Hyperhidrosis Constipation Heart rate increased Erectile dysfunction (males) Vomiting Tachycardia PalpitationsD/C because of AE Citrome L. Int J Clin Pract. 2013; 67 (11): Citrome L. Int J Clin Pract. 2015; 69 (2): NNT for response/remission, NNH for adverse events where incidence with levomilnacipran 5% and 2 times the rate for placebo as identified in product labelling (3), and NNH for discontinuation because of an adverse event, with 95% Cls, for pooled short-term studies comparing levomilnacipran vs. placebo. AE, adverse event; D/C, discontinuation; NNH, number needed to harm; NNT, number needed to treat.

11 Levomilnacipran ER: Impact on Improved functional outcomes (Sheehan Disability Scale) vs. placebo in 4/5 studies Only antidepressant with FDA approval for functional improvement Functional Disability Sambunaris A et al. Int Clin Psychopharmacol. 2014; 29(4):

12 Receptor occupancy (%) Vortioxetine - Serotonin Receptor Modulator at Clinically Relevant Doses 100 Clinical dose range gives 50-90% SERT occupancy Simulated human affinity Vortioxetine dose (mg/kg) Affinity (nm) Receptor Rat Human 5-HT HT HT 1B HT 1A SERT Pehrson AL et al. Eur Neuropsychopharmacol 2012; Bang-Andersen B et al. J Med Chem 2011;54:

13 Vortioxetine Clinical Efficacy 7/11 placebo-controlled trials were positive Thase E et al. Eur Neuropsychopharmacol. 2016;26(6):979-93

14 Number Needed to Treat or Harm vs. Placebo Relative Efficacy/Safety of Vortioxetine Efficacy - NNT Tolerability - NNH Citrome L. Int J Clin Pract. 2014; 68(1): Citrome L. Int J Clin Pract. 2015; 69(2):

15 Vortioxetine Effects on Cognition Meta-Analysis of 3 RCTs Efficacy on the DSST (Digit Symbol Substitution Test) Also positive on the self-report PDQ (Perceived Deficits Questionnaire) McIntyre RS et al. Int J Neuropsychopharmacol Aug 24 [Epub ahead of print]

16 Treatment-Resistant Depression Failure to respond to 2+ antidepressant trials of adequate dose and duration Constitutes ~1/3 of patients with MDD Remission rates in TRD<<20% Contributes significant costs, morbidity, mortality Important Steps in Evaluation: Diagnostic reassessment (unipolar vs. bipolar) Psychiatric and medical comorbidities Previous trials adequate in dose and duration? Pharmacokinetic factors (metabolic inducers; rapid/fast metabolizers)

17 Promising Next-Generation Pharmacological Strategies for TRD Glutamatergic receptors modulators Opioid receptors modulators Scopolamine Anti-inflammatory agents

18 The Glutamate Synapse Sanacora et al. Nat Rev Drug Discovery 2008

19 Glutamate Signaling is Abnormal in Depression Acute stress increases glutamate signaling in cortex Chronic stress leads to alterations in glutamate receptors and synapses Glial cell loss in human postmortem cortex in MDD is related to glutamate toxicity Altered glutamate in MDD detected by brain H 1 -MRS Ketamine: a dissociative anesthetic agent Glutamate NMDA receptor antagonist Rapid antidepressant effects Abuse liability Rajkowska and Miguel-Hidalgo, 2012; Luykx et al. Neurosci Biobehav Rev 2012

20 RCT IV Ketamine vs. Saline (N=18) Rapid Antidepressant Effect Zarate et al. Arch Gen Psych 2006

21 RCT IV Ketamine vs. Midazolam (N=72) Rapid Antidepressant Effect Mean diff = 7.95 points [95%CI: 3.2,12.7] P = KET RR = 64% MID RR = 28% OR = 2.18, P = Murrough*, Iosifescu* et al. Am J Psychiatry. 2013

22 Meta-Analysis of Ketamine Efficacy in TRD At 1 day At 1 week Newport DJ et al. Am J Psychiatry. 2015

23 Acute Behavioral and Hemodynamic Effects of Ketamine in TRD Review of 205 IV ketamine infusions: No significant increase in psychotic symptoms Measurable small and transient increase in dissociative symptoms Transient increase in blood pressure Wan et al. J Clin Psych. 2015

24 MADRS Next steps: Repeated IV Ketamine and Repeated dose IV ketamine effective, but mean duration of improvement is 18 days Intranasal Ketamine Intranasal ketamine effective, easier to administrate Janssen is developing IN esketamine for TRD (currently in phase 3 studies) Figure 1. Change in Depression Severity Over 1 Week Following Intranasal Ketamine or Placebo *p<0.05, Sig. vs. baseline #p<0.05, Sig. responders vs. nonresponders Control Ketamine Murrough et al. Biological Psychiatry. 2013; Lapidus et al. Biological Psychiatry min 40 min 240 min 24 h Time 48 h 72 h 7 days

25 Lanicemine (AZ6765) - a Novel NMDA Receptor Antagonist Positive Phase II Results, Development Terminated in Phase III Sanacora G et al. Mol Psych

26 No Ketamine-Like Agent Has Yet Demonstrated Efficacy in Phase III Failed to Show Efficacy Memantine Lamotrigine Lanicemine (AZ 6765) MK 0657 (NR2B Antag) EVT 101 (NR2B) CP-101,606 Org (AMPA) Riluzole Still Early in Development D-cycloserine Rapastinel (GLYX-13) Glycine site Is there another mechanism that explains the effects of ketamine?

27 RCT of the NMDA Receptor Partial Agonist D-Cycloserine (1g/d) Augmentation for TRD Heresco-Levy et al. Int J Neuropsychopharm. 2013

28 GLYX 13 Has Ketamine-like Effects in Several Animal Models of Depression Moskal JR et al. Neuropharmacology 2005;49(7):

29 GLYX 13 Phase 2A Single-Dose Study U shaped dose response: max effect at 5 and 10 mg N = 116 Preskorn S, et al. J Psychiatr Pract. 2015;21(2):

30 GLYX 13 Phase 2B Repeated-Dose Study Weekly IV dosing (5 mg, 10 mg, or PBO) Burch et al. Poster presented at ACNP, 2014 HDRS-17 decreased after GLYX-13 and increased after PBO

31 6 weeks post GLYX-13 withdrawal HDRS-17 did not return to baseline GLYX mg/kg weekly performed less well than other dosing regimens Burch et al. Poster presented at ACNP, 2014 No psychotomimetic adverse events

32 Endogenous Opioids and Their Receptors - Abnormal in MDD Sadness and chronic stress lead to alterations in opioid receptors neurotransmission 1-4 The opioid system: mu-, delta-, and kappa receptors (G protein-coupled) mu-receptors: analgesia, reward, and dependence 2 delta-receptors: anti-depressant and anti-anxiety-like behavior 3 kappa receptors: anti-reward, dysphoria, pro-depression 4 Reductions in mu-opioid receptor mediated neurotransmission during a sustained sadness state 1 1) Zubieta et al, Arch Gen Psychiatry, ) Moles et al. Science ) Filliol et al. Nat Genet 2000; 4) Lutz and Kieffer. Trends Neurosci. 2013

33 Opioid Receptors Regulate Monoaminergic Systems Relevant to Mood Control Lutz PE, Kieffer BL. Trends Neurosci. 2013;36(3):

34 Buprenorphine Partial mu opioid agonist Kappa antagonist Used in addiction treatment Open label, positive data in refractory depression RCT of Low Dose Buprenorphine for Suicidal Ideation N=88 patients with clinically significant suicidal ideation Buprenorphine mg/day (mean 0.44 mg/day) or placebo for 4 weeks Buprenorphine superior to PBO for reducing suicidal ideation at 2 and 4 weeks No withdrawal symptoms after treatment discontinuation Yovell Y et al. Am J Psychiatry. 2016;173(5):491-8

35 RCT of ALKS 5461 (buprenorphine + mu antagonist ALKS 33) in SSRI non-responders Fava M et al, Am J Psychiatry. 2016;173(5):

36 ALKS-5461 As Adjunct in MDD FORWARD-3 and FORWARD patients in DB, PBO controlled 11 week trials in antidepressant non-responders Doses of buprenorphine/samidorphan (0.5/0.5 mg and 2/2 mg) Both doses not superior to PBO FORWARD-5 (1/1 mg and 2/2 mg) continues Alkermes PR release, Jan 21, 2016

37 A Kappa Opioid Receptor Agonist Increases Anhedonia and Depression Intracranial Self-Stimulation Thresholds U Forced Swim Test (FST) Selective kappa agonist U produces anhedonia (increase in reward threshold on FST) and depression (FST) Todtenkopf et al 2004 ; Mague et al 2003

38 Selective Kappa Antagonists Normalize Reward and Produce Antidepressant-Like Effects Intracranial Self-Stimulation Thresholds Kappa Opioid Antagonist ANTI Forced Swim Test CERC 501 a novel kappa opioid receptor antagonist currently evaluated as treatment for depression and anhedonia Todtenkopf et al 2004 ; Mague et al 2003; Lowe et al. J Clin Pharmacol. 2014

39 The Cholinergic System and Mood Disorders Elevated cholinergic function is implicated in the pathophysiology of mood disorders. 1 Physostigmine (an anticholinesterase inhibitor) exacerbates depressive symptoms in MDD and BD patients 1 Muscarinic receptor gene polymorphisms are associated with an elevated incidence of depression. 2 Scopolamine (an acetylcholine muscarinic receptor antagonist), produces rapid antidepressant effects in MDD patients 3 1) Janowsky and Overstreet. The Role of Acetylcholine Mechanisms in Mood Disorders. Raven Press 1995; 2) Wang JC et al. Hum Mol Genet 2004; 3) Furey and Drevets. Arch Gen Psych. 2006

40 RCT of IV Scopolamine (4 μg/kg) in TRD (n=18) IV Scopolamine has rapid antidepressant effects 1 Mechanism associated with increased mtor and synaptogenesis 2 (like ketamine) 1) Furey and Drevets. Arch Gen Psych. 2006; 63: ; 2) Voleti B et al. Biol Psychiatry. 2013; 74(10):742-9

41 RCT of Oral Scopolamine (1 mg/d) Augmentation of Citalopram in MDD Khajavi et al. J Clin Psych. 2012; 73:

42 High Prevalence of Inflammation in Depression Meta-analysis of Cytokine Levels in MDD Controls Depressed IL-1β TNF-α CRP (Studies / Pts) IL-1β (14 / 1000) TNF-α (31 / 2476) CRP (20 / 1425) IL-6 (13 / 2022) Cytokines = non-antibody proteins released by cells on contact with antigens 1 Cytokines induce depressive symptoms and HPA axis activation 2 Depressed patients have high levels of cytokines 3 IL Standard Difference in Means 1) Dunn AJ et al. Neurosci Biobehav Rev. 2005; 2) Yirimya R et al, Ann NY Acad Sci, 2000; 3) Haapkoski et al. Brain Behav Immun. 2014

43 RCT of Adjunctive Cyclooxygenase-2 inhibitor Celecoxib in MDD Akhondzadeh et al. Depression and Anxiety. 2009, 26:

44 pg/ml Adding NSAIDs to SSRIs is Associated with Worsening of Antidepressant-Like Effects Tail Suspension Test Forced Swim Test Warner-Schmidt JL et al. PNAS

45 pg/ml TNF-α Antagonist Infliximab Effective Only for TRD Subjects with Pre-Existing Inflammation (high CRP) Raison CL et al. JAMA Psychiatry. 2013;70(1):31-41.

46 Somatic Treatments for TRD Repetitive Transcranial Magnetic Stimulation (rtms) Deep Transcranial Magnetic Stimulation (DTMS) Synchronized Transcranial Magnetic Stimulation (stms) Low Field Magnetic Stimulation (LFMS)

47 Right Unilateral Ultrabrief ECT + Venlafaxine in Geriatric MDD Kellner C et al, Am J Psychiatry Jul 15 [Epub ahead of print]

48 Continuation ECT + Venlafaxine + Lithium for Maintenance of Treatment Response Kellner C et al, Am J Psychiatry Jul 15 [Epub ahead of print]

49 ECT Superior to Pharmacotherapy in Treatment-Resistant Bipolar Depression Response Rates ECT 73.9% Pharmacotherapy 35.0% Schoeyen et al. Am J Psychiatry. 2015;172(1):41-51

50 Meta-analysis of Repetitive TMS (rtms) for MDD Slotema CW et al. J Clin Psychiatry. 2010; 71(7):873-84

51 Deep TMS: Improved Remission Rates in TRD Remission Rates Stratified by Treatment Resistance Levkovitz et al. World Psych. 2015

52 Comparison of FDA-approved device treatments ECT rtms Deep TMS Efficacy in TRD ++ +/- + Adverse events ++ +/- +/- Most concerning AE Cognitive deficits (sometimes chronic) Seizures (rare) Seizures (rare) Duration of acute treatment 2-4 weeks (3/week) 4-6 weeks (5/week) 4-6 weeks (5/week)

53 RCT of Synchronized TMS (stms) in MDD Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6 * = p < Frequency of stimulation = intrinsic alpha rhythm of the individual * Low intensity of magnetic field Potential to become a take-home TMS device SHAM n=61 stms n=59 Leuchter et al. Brain Stimulation

54 Low Field Magnetic Stimulation Rohan et al. Biol Psychiatry. 2014;76:

55 Conclusions A variety of novel pharmacological and somatic treatments, with new mechanisms of action, currently undergoing validation for TRD Ketamine replicated, rapid efficacy GLYX 13 with promising data Unclear why many other glutamategic strategies have failed Early promising data for Opioid agents: CERC 501,? ALKS 5461 Scopolamine Anti inflammatory agents: possibly helpful in subset with high inflammation Somatic treatments: ECT gold standard; novel methods of delivery rtms - well tolerated, lower efficacy ; DTMS possibly improved efficacy for TRD Many other under development: LFMS, stms, Onabotulinumtoxin A Vibrant area of research, other treatments under development

56 Thank you!