#CHAIR2016. September 15 17, 2016 The Biltmore Hotel Miami, FL. Sponsored by

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1 #CHAIR2016 September 15 17, 2016 The Biltmore Hotel Miami, FL Sponsored by

2 #CHAIR2016 Ketamine: Promising Path or False Prophecy in the Development of Novel Therapeutics for Mood Disorders Alan F. Schatzberg, MD Stanford University School of Medicine Stanford, CA

3 Alan F. Schatzberg, MD Disclosures Research/Grants: Janssen Pharmaceuticals Consultant: Alkermes; Clintara; Forum Pharmaceuticals, Inc.; McKinsey & Company; Takeda Pharmaceuticals U.S.A., Inc. Stockholder: (Directly Purchased): Corcept Therapeutics; Titan Pharmaceuticals, Inc.; Seattle Genetics, Inc.; Incyte Corporation; Gilead; Merck & Co., Inc.

4 #CHAIR2016 Learning Objective 1 Describe the mechanisms of action for ketamine in major depressive disorder

5 #CHAIR2016 Learning Objective 2 Evaluate the data on efficacy and safety of ketamine in major depressive disorder

6 MOA of Known or Putative Antidepressants Enhanced NE and 5-HT monoaminergic synaptic activity Second generation antipsychotics Glutamatergic transmission Hormone/peptide regulators Opioid modulators Onabotulinumtoxin-A (OBA) Deep brain stimulation (DBS) MOA = Mechanism of Action

7 Mechanisms of Action: Glutamatergic Agents NMDA antagonism e.g., ketamine Other glutamate effects e.g, GLYX-13; D- cycloserine, etc.

8 Ketamine* Anesthetic agent Used intravenously primarily Used for chronic pain N-methyl-D-aspartate antagonist; Mu opioid agonist; stimulant (?) Psychotomimetic; dissociation Acute antidepressant efficacy not sustained *Not approved by the US FDA for MDD

9 Ketamine*: Change in the Hamilton Depression Rating Scale The 21-item Hamilton Depression Rating Scale (HDRS) over 1 week (n = 18) *Not approved by the US FDA for MDD Zarate CA, et al. Arch Gen Psychiatry 2006;63:

10 Rationale for OPT KET NIMH Trial in TRD Several single-site studies supported the rapid antidepressant efficacy of ketamine in TRD; however, uncertainties remained Small sample size Crossover design Saline as control condition Response persistence Safety and tolerability Would a single infusion of ketamine prove superior to an active placebo in a parallel-arm randomized controlled trial? Ketamine (N = 47); midazolam (N = 25) *Not approved by the US FDA for MDD, TRD = treatment resistant depression

11 Ketamine* Primary Efficacy Outcome MADRS Score Study Drug Primary Outcome *** Midazolam Ketamine 0 Baseline Inpatient Day 1 Day 2 Day 3 Time *Not approved by the US FDA for MDD Murrough JW, et al. Am J Psychiatry. 2013;170(10): Outpatient Day 4 Day 5 Day 6 Day 7

12 Adverse Event Adverse Events on Infusion Day Ketamine Midazolam Ketamine Midazolam New Onset or Worsening Distressing Number of Patients (Percent) Dizziness 21 (45) 5 (20) 6 (13) 1 (4) Blurred Vision 20 (43) 2 (8) 5 (11) 1 (4) Nausea/Vomiting 16 (34) 3 (12) 3 (6) 1 (4) Headache 15 (32) 5 (20) 4 (8) 1 (4) Dry Mouth 12 (26) 4 (16) 2 (4) 2 (8) Dizziness on Standing 10 (21) 2 (8) 3 (6) 0 (0) Palpitation 5 (10) 0 (0) 2 (4) 0 (0) Ringing in Ears 2 (4) 1 (4) 0 (0) 0 (0) Frequent Urination 0 (0) 0 (0) 0 (0) 0 (0) Painful Urination 0 (0) 0 (0) 0 (0) 0 (0) Murrough JW, et al. Am J Psychiatry (10):

13 Response to Repeated Ketamine* Infusions a p <.05. *This agent is not approved by the FDA for MDD. Murrough JW, et al. Am J Psychiatry. 2013;170(10):

14 A Double-Blind, Randomized, Placebo-Controlled, Dose- Frequency Study of IV Ketamine in Patients With TRD Objective: Ketamine (KET), an N-methyl-D-aspartate glutamate receptor antagonist, has demonstrated a rapid-onset antidepressant effect in patients with TRD. This study evaluated the efficacy of twice- and thrice-weekly intravenous administration of KET in sustaining initial antidepressant effects in pts with TRD. Method: In a multicenter, double-blind study, adults (ages yrs) with treatment-resistant depression were randomized to receive either IV KET (0.5 mg/kg of body weight) or IV PBO, administered over 40 mins, either 2 or 3 times weekly, for up to 4 wks. Patients who discontinued double-blind treatment after at least 2 wks for lack of efficacy could enter an optional 2-wk open-label phase to receive KET with the same frequency as in the double-blind phase. The primary outcome measure was change from baseline to day 15 in total score on the Montgomery-Åsberg Depression Rating Scale (MADRS). Results: In total, 67 (45 women) of 68 randomized patients received treatment. In the twice-weekly dosing groups, mean change in MADRS score at day 15 was 18.4 (SD = 12.0) for KET and 5.7 (SD=10.2) for PBO; in the 3x-weekly groups, it was 17.7 (SD = 7.3) for KET and 3.1 (SD = 5.7) for PBO. Similar observations were noted for KET during the open-label phase (twice-weekly, 12.2 [SD = 12.8] on day 4; thrice-weekly, 14.0 [SD = 12.5] on day 5). Both regimens were generally well tolerated. Headache, anxiety, dissociation, nausea, and dizziness were the most common ( 20%) treatment-emergent adverse events. Dissociative symptoms occurred transiently and attenuated with repeated dosing. Conclusions: Twice-weekly and thrice-weekly administration of KET at 0.5 mg/kg similarly maintained antidepressant efficacy over 15 days. Singh AB, et al. Am J Psychiatry. 2016;173:8.

15 Anxiety Predicts Response to Ketamine* *Not approved by the FDA for MDD Ionescu DF, et al. J Clin Psychitary. 2014;75(9) e932-8.

16 Anxiety Predicts Recurrence After IV Ketamine* Day to relapse based on MADRS scores. Median ± SE day on which patients with anxious depression relapsed (19.0 ± 17.9 days) was significantly longer than the median ± SE day on which patients with nonanxious depression relapsed (1.0 ± 0.0 days, x 2 = 9.30, p =.002). *Not approved by the FDA for MDD Ionescu DF, et al. J Clin Psychitary. 2014;75(9) e932-8.

17 Intranasal S-Ketamine Under development for acute suicidal activity and refractory major depression Phase II data promising

18 Memantine* for Late-Life Depression and Apathy After Disabling Medical Event: HDRS Effect Hamilton Depression Score memantine (N-17) placebo (N=19) low-risk comparisons (N=19) Week *Not approved by the US FDA for MDD Lenze EJ, et al. Int J Geriatr Psychiatry. 2012;27(9):

19 AZD 6765 in Major Depression Synaptic glutamate binder Recent multicenter trials failed to demonstrate efficacy in multiple doses per week protocols over several weeks Program reportedly canceled

20 GLYX-13 in Major Depression U shaped dose response in rat models and in Phase 2A study No ketamine-like side effects Phase 2A study 1,5,10 or 30 mg or placebo; i.v. 5 mg. and 10 mg. separated from placebo at day 7 but not at day 14; other doses did not Effect size for single dose 0.58 Burch RM. Presented at the ACNP Annual Meeting, December 2-6, 2012.

21 Randomized Add-On Trial of High-Dose D-cyloserine (DCS) for TRD Abstract Antagonism of N-methyl-d-aspartate glutamatergic receptors (NMDAR) may represent an effective antidepressant mechanism. d-cycloserine (DCS) is a partial agonist at the NMDAR-associated glycine modulatory site that at high doses acts as a functional NMDAR antagonist. 26 treatment-resistant MDD pts participated in a DBPC, 6-wk parallel group trial with a gradually titrated high dose (1000 mg/d) of DCS added to their antidepressant medication. DCS treatment was well tolerated, had no psychotomimetic effects and led to improvement Hamilton Depression Rating Scale (HAMD; p = 0.005) and Beck Depression Inventory (p =.046). Of the 13 subjects treated with DCS, 54% had a 50% HAMD score reduction vs. 15% of the 13 patients randomized to placebo (p =.039). A significant (p =.043) treatment pretreatment glycine serum levels interaction was registered. These findings indicate that NMDAR glycine site antagonism may be a cost-effective target for development of mechanistically novel antidepressants. Larger-sized DCS trials are warranted. Heresco-Levy U, et al. Int J Neuropsychopharmacol 2013;16(3):

22 Other Possible MOA s for Ketamine AMPA flooding 2o to NMDA antagonism Rabamycin (m-tor) increased signalling mu-opioid receptor agonism Dopaminergic release-stimulant Kappa opioid receptor antagonism GSK-3B inhibition Tropomyosin receptor Kinase B (TrkB)

23 Mechanisms of Action Opioid Modulators Mu partial or full agonists buprenorphine; ketamine Mixed mu agonist antagonist buprenorphine/sam Kappa antagonists

24 Buprenorphine* Partial mu opioid agonist Kappa antagonist Used in addiction treatment Open label, positive data in refractory depression Being developed (in combination with samidorphan, a mu antagonist) for treatment of refractory major depression 1 *Not approved by the US FDA for MDD

25 Low Dose Buprenorphine* Reduces Suicidal Ideation 88 patients with clinically significant suicidal ideation Buprenorphine mg/day (mean dose 0.44 mg/day) or placebo for 4 weeks Buprenorphine superior to placebo for reducing suicidal ideation at 2 and 4 weeks No withdrawal symptoms after treatment discontinuation *Not approved by the US FDA for MDD Yovell Y, et al Am J Psychiatry in Advance /aapi.ajp

26 RCT of ALKS 5461 (Buprenorphine + Mu Antagonist ALKS 33) in SSRI Non- Responders MADRS Change from Baseline at Week 4 0 MADRS LS Means Stage 1 Stage 1 baseline MADRS (all subjects): Stage 2 Stage 2 baseline MADRS (all subjects): 23.8 Placebo ALKS /2 ALKS /8 Fava M, et al. Am J Psychiatry. 2016;173(5):

27 ALKS-5461 As Adjunct in MDD FORWARD-3 and FORWARD patients in DB, PBO controlled, 11 wk trial 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 Press Release 2016.

28 Ketamine and Morphine in OCD IV ketamine significantly more effective than placebo in refractory OCD; effects last one week in some patients 1 Oral morphine significantly more effective than placebo in refractory OCD; effects seen the next day and last for 5 days 2 1. Rodriguez C, et al. Neuropsychopharm. 2013;38(12): Koran L, et al. J Clin Psychopharm. 2005;66(3):

29 Antagonism Induced by Intracerebroventricular Administration of Naloxone (a), Clocinnamox (b) or Naltrindole (c) on the Central Antinociception Produced by Ketamine Pachecho D, et al. Brain Research. 2014;1562:69-75.

30 Effects of Methoxetamine and Ketamine on Condition Place Preference in Rats **p =.01 significantly different from the SAL/control group Botanas et al. Pharmacol Biochem and Behav, 2015;133:31 36.

31 Withdrawal from Acute Amphetamine Induces an Amygala-Driven Attenuation of Dopamine Neuron Activity: Reversal by Ketamine Abstract Drug addiction is a chronic disorder characterized by a cycle composed of drug seeking, intoxication with drug taking and withdrawal associated with negative affect. Numerous studies have examined withdrawal/negative affect after chronic use; however, very few have examined the effect of acute administration on the negative affective state after acute drug withdrawal. One dose of amphetamine was injected into Sprague-Dawley rats. Despair behavior using the modified forced swim test (FST) and dopamine (DA) activity in the ventral tegmental area using in vivo electrophysiological recordings were studied 18, 48 and 72 h after injection of amphetamine. The effects of inactivation of the basolateral amygdala (BLA) and ketamine administration on VTA DA neuron activity and passivity in the modified FST were examined. Eighteen hours following amphetamine withdrawal, there was a substantial decrease in the number of active DA neurons, as well as an increase in time spent immobile in the modified FST, which returned to baseline after 72 h. Inactivation of the BLA after acute amphetamine prevented the decrease in DA neuron tonic activity. Injection of ketamine also prevented the decrease in DA population activity but had no effect on immobility measured in the modified FST. Belujon P, et al. Neuropsychopharmacology. 2016;41(2):

32 Implications for other MoA s Combination of NMDA antagonism, mu opioid agonism, and dopamine release/stimulant properties could be problematic Have we found an iatrogenic, one compound speedball?

33 Call to Action Abuse liability of ketamine in depression needs to be studied Opioid MOA of ketamine needs to be studied in depressed patients MOA = mechanism of action

34 #CHAIR2016 Questions Answers &