Outline Background on Ketamine The Promise and Perils of Ketamine - - PDF document

The Promise and Perils of Ketamine in Psychiatric Practice

Sanjay J. Mathew, MD

Professor of Psychiatry & Behavioral Sciences Johnson Family Chair for Research in Psychiatry Menninger Department of Psychiatry & Behavioral Sciences Baylor College of Medicine Staff Physician, Michael E. Debakey VA Medical Center Houston, Texas

Outline

TRD = treatment-resistant depression; PTSD = posttraumatic stress disorder.

• Background on Ketamine
• The Promise

– Single Infusion Therapy for TRD, Suicidal Ideation, PTSD – Continuation Therapy

• The Perils
• Ketamine in Clinical Practice: Towards Best

Practice Patterns for Off-label Use

Case Study: Ms. B

ECT = electroconvulsive therapy. Nichols SD, et al. Current Psychiatry. 2015;15(5):48-51.

• Age 31, first depressive episode age 24 in law school
• 2 episodes/year, with loss of function, marked

anhedonia, and suicidal ideation

• Past adequate trials of antidepressants:

– Sertraline (200 mg) – Venlafaxine XR (300 mg) – Bupropion XL (450 mg) – Vortioxetine (20 mg)

• Adjunctive lithium and aripiprazole not well tolerated
• ECT effective but suffered severe memory impairment

WOULD YOU CONSIDER A TRIAL OF KETAMINE?

Ketamine: History

PCP = phencyclidine. US Food and Drug Administration. www.accessdata.fda.gov/scripts/cder/daf/.

• Synthesized in 1962 by Calvin Stevens, a Parke-Davis

chemist seeking an alternative anesthetic to PCP

• FDA approved for human use since 1970 (Schedule III)
• Approved indications

– “…the sole anesthetic agent for diagnostic and surgical procedures that do not require skeletal muscle relaxation.” – “…the induction of anesthesia prior to the administration of

• ther general anesthetic agents.”

– “…to supplement low-potency agents, such as nitrous

• xide.”

Ketamine and NMDA Receptor

NMDA = N-methyl-D-aspartate. Du J, et al. Dialogues Clin Neurosci. 2004;6(2):143-155.

• Dissociative anesthetic (2–3

mg/kg — 2000–3000 ng/mL peak plasma concentrations)

• Uncompetitive high-affinity

NMDAR antagonist

• Binds to PCP “angel dust” site

within ion channel

• Membrane depolarization

relieves Mg block, and with co-agonist binding, Ca2+ and Na+ enters cell

Antidepressant Mechanism of Action

• f NMDA Receptor Modulators

Murrough JW, et al. Nat Rev Drug Discov. 2017;[Epub ahead of print].

Are the Antidepressant Actions of Ketamine Independent of NMDA Receptor Activity?

Zanos P, et al. Nature. 2016;533(7604):481-486. Malinow R. Nature. 2016;533(7604):477-478.

Metabolic Pathways of Ketamine

Zarate CA Jr, et al. Mol Psychiatry. 2017;22(3):324-327. 70–200 ng/mL peak plasma concentration. *P ˂ .05; **P ˂ .01; ***P ˂ .001. HAM-D = Hamilton Rating Scale for Depression; SSRI = selective serotonin reuptake inhibitor; TRD = treatment-resistant depression. Zarate CA Jr, et al. Arch Gen Psychiatry. 2006;63(8):856-864.

Single Ketamine Infusion (0.5 mg/kg over 30 minutes) Rapidly Effective in TRD: Replication Study (N = 17)

MADRS = Montgomery-Åsberg Depression Rating Scale. Murrough JW, et al. Am J Psychiatry. 2013;170(10):1134-1142.

Single Ketamine Infusion is Superior to Psychoactive Control in TRD: Baylor/Mt Sinai Study (N = 72)

Reduction in MADRS score 24 hours after infusion was the primary outcome measure and was significantly greater for the ketamine group than for the midazolam group (P ≤ .002).

Ketamine dose = .5 mg/kg

Single Infusion of Ketamine – Efficacy in TRD (N = 147)

Newport DJ, et al. Am J Psychiatry. 2015;172(10):950-966.

At 1 week At 1 day

Short-Term Effect Sizes for Single Infusion Ketamine

Bobo WV, et al. Depress Anxiety. 2016;33(8):698-710.

Add-on Trial of Ketamine in Treatment-Resistant Bipolar Depression

*P < .001; †P < .01. Diazgranados N, et al. Arch Gen Psychiatry. 2010;67(8):793-802.

Dose: 0.5 mg/kg ketamine

Depressive symptoms significantly improved in participants receiving ketamine compared with placebo

*** ** *** **

Effect of Ketamine on Suicidal Ideation:

Individual Patient Meta-Analysis

Wilkinson S, et al. Presented at: Society of Biological Psychiatry – 72nd Annual Meeting; May 18–20, 2017; San Diego, CA.

Single Dose Efficacy in PTSD

Feder A, et al. JAMA Psychiatry. 2014;71(6):681-688.

• Ms. A: “I feel good, I want to get out

and do things, like get a haircut. I haven’t felt like this in a year. I tried to think about (the assault) but couldn’t. That was strange… I feel more connected to others, less afraid.”

• Mr. B: “I feel much better, the sirens
• utside on the street no longer bother
• me. I called several friends that I hadn’t

spoken with in a while. I feel calm, not so jumpy.”

• Ms. C: “I feel energetic, not stressed
• ut or anxious, I feel good, refreshed. I

enjoyed going outdoors briefly for a

• smoke. I haven’t dwelled on thoughts

about (the trauma), I let it go. I feel happy, upbeat, my mind is clear. Interacting with others no longer takes so much effort, I don’t feel like I have to fake.”

Double-Blind, Placebo-Controlled, Dose-Ranging Trial of Intravenous Ketamine as Adjunctive Therapy in TRD

Fava M, et al. Presented at: American Society of Clinical Psychopharmacology Annual Meeting; May 29–June 2, 2017; Miami, FL.

Ketamine .1 mg/kg n = 18 Ketamine .5 mg/kg n = 22 Ketamine 1.0 mg/kg n = 20 Midazolam .045 mg/kg n = 19 Ketamine .2 mg/kg n = 20 SCREEN RANDOMIZE DAY DAY 3 DAY 30 PRIMARY ENDPOINT ASSESSMENTS STUDY COMPLETION

HAM-D-6 Scores for Different IV Ketamine Doses vs Midazolam

Fava M, et al. Presented at: American Society of Clinical Psychopharmacology Annual Meeting; May 29–June 2, 2017; Miami, FL.

HAM-D-6 Response Rates

Fava M, et al. Presented at: American Society of Clinical Psychopharmacology Annual Meeting; May 29–June 2, 2017; Miami, FL.

Take-Home Message:

Dose-Response Trial of IV Ketamine in TRD

Fava M, et al. Presented at: American Society of Clinical Psychopharmacology Annual Meeting; May 29–June 2, 2017; Miami, FL.

• Both low dose (0.1 mg/kg) and higher doses (0.5 mg/kg

and 1 mg/kg) of IV ketamine superior to active placebo

• Limitations:

– Lack of racial diversity in study sample – Unclear reasons for failure of 0.2 mg/kg dose arm – No assessment of response durability beyond 72 hours or speed of response at 4 hours

Continuation and Maintenance Therapy

• Repeated ketamine infusions
• Maintenance ketamine protocols in combination

with drugs, ECT, or psychotherapy

Thrice-Weekly Ketamine Infusions in TRD: Mt Sinai Sample (N = 24)

Murrough JW, et al. Biol Psychiatry. 2013;74(4):250-256.

18 days until relapse

Thrice-Weekly Ketamine Infusions in TRD: Minneapolis VA Sample (N = 14)

Shiroma PR, et al. J Affect Disord. 2014;155:123-129.

Mean time to relapse = 16 days 92% responded; 67% remitted Dose = 0.5 mg/kg over 40 minutes

Repeated Ketamine Infusions in TRD: Mayo Clinic Sample (N = 12)

Vande Voort JL, et al. J Affect Disord. 2016;206:300-304.

Dose = 0.5 mg/kg over 100 minutes 58% responded, 42% remitted Thrice-weekly up to 6 infusions

12-Month Naturalistic Observation of 3 Patients Receiving Ketamine Infusions for TRD

Szymkowicz SM, et al. J Affect Disord. 2013;147(1-3):416-420.

Patient 1’s response to ketamine infusions Patient 2’s response to ketamine infusions Patient 3’s response to ketamine infusions

Twice-Weekly Dosing as Effective as Thrice-Weekly Dosing in TRD

Singh JB, et al. Am J Psychiatry. 2016;173(8):816-826.

Ket: 69% responded, 38% remitted PBO: 15% responded; 7.7% remitted Ket: 54% responded; 23% remitted PBO: 6% responded; 0% remitted

RCT of the NMDA Receptor Partial Agonist D-Cycloserine (1 g/day) Augmentation for TRD

RCT = randomized controlled trial. Heresco-Levy U, et al. Int J Neuropsychopharmacol. 2013;16(3):501-506.

Enrolment, randomization, withdrawals and completion

• f the study (N = 26).

(CONSORT flow diagram.)

Proportion of responders [≥ 50% improvement on 21-item HAMD] during 6 week adjuvant treatment with D-cycloserine (n = 13) and placebo (n = 13). *P = .039

47 Assessed for eligibility Enrolment 26 Randomized 13 Placebo 1 Discontinued study due to chest pain 13 D-cycloserine 3 Discontinued study 1 Hearing discomfort 1 Non-compliance 1 Tiredness Analyzed 13 Intent to treat 12 Completers Analyzed 13 Intent to treat 10 Completers

D-Cycloserine for Relapse Prevention Post-IV Ketamine in Treatment-Resistant Bipolar Depression

Kantrowitz JT, et al. J Clin Psychiatry. 2015;76(6):737-738.

NRX-101 for the Treatment of Acute Suicidal Ideation and Behavior in Bipolar Depression

DCS = D-cycloserine. ClinicalTrials.gov Identifier: NCT02974010.

• NRX-101: Fixed dose combination of DCS + lurasidone
• Primary outcome of Phase 2b Trial:

– Time to relapse following IV ketamine infusion

• Randomized Arms following single IV Ketamine infusion:

– NRX-101 (DCS + lurasidone) – Lurasidone + placebo

Randomized-Controlled Trial of Low-Dose Ketamine Adjunctive to ECT in TRD

Anderson IM, et al. Lancet Psychiatry. 2017;4(5):365-377.

• No benefit of 0.5 mg/kg ketamine bolus (n = 40) in

conjunction with standard anesthetic agent during a course of bitemporal ECT compared with placebo (n = 39)

• Primary Outcome: Hopkins Verbal Learning Test,

Delayed Verbal Recall

• No benefit vs placebo on any efficacy outcome, including

time-to-response and response at endpoint

Electroconvulsive Therapy (ECT) vs Ketamine in Patients with Treatment Resistant Depression (TRD) Leveraging Neuroplasticity Changes to Create Synergistic Interventions with Both Rapidity and Durability

Price RB. NIMH R01 Grant.

Introduce a neurocognitive training intervention during this window of opportunity

Perils

BP = blood pressure; HR = heart rate; MDD = major depressive disorder. Wan LB, et al. J Clin Psychiatry. 2015;76(3):247-252. Sassano-Higgins S, et al. Depress Anxiety. 2016;33(8):718-727.

• Short duration of effect
• Dissociative and other psychological side effects
• Impact on hemodynamics

– Transient increases in systolic and diastolic BP – BPs > 180/100 mmHg or HR > 110 bpm in 30% of MDD patients

• Nausea/vomiting
• Impact on Cognition
• “Ketamine Bladder”
• Addiction/Ketamine Use Disorder

Dissociative Side Effects

CADSS = Clinician Administered Dissociative States Scale. Murrough JW, et al. Am J Psychiatry. 2013;170(10):1134-1142.

Dissociative properties

– Things in slow motion – Things seem unreal – Disconnected from body – Sense of body changed

Dose Dependence of Dissociative Side Effects

Fava M, et al. Presented at: American Society of Clinical Psychopharmacology Annual Meeting; May 29–June 2, 2017; Miami, FL.

Comparison of Side Effects:

0.5 mg/kg vs 0.75 mg/kg

Cusin C, et al. Aust N Z J Psychiatry. 2017;51(1):55-64.

Side Effects Infusion 1–3 (0.5 mg/kg) Infusion 4–6 (0.75 mg/kg)

Physical side effects Headaches 4/14 (29%) 3/13 (23%)a Tiredness/sleepiness/sedation/spaciness 1/14 (7%) 3/13 (23%)b Dizziness/lightheadedness 1/14 (7%) 3/13 (23%)b Cold/cough/sinus congestion 2/14 (14%) 1/13 (8%)a Diarrhea 1/14 (7%) 1/13 (8%) Nausea 1/14 (7%) 1/13 (8%) Weepiness/crying 1/14 (7%) 1/13 (8%) Nosebleed 1/14 (7%) 1/13 (8%) Hypoglycemia 1/14 (7%) 1/13 (8%) Panic 1/14 (7%) 0/13 (0%)a Transient palpitations 1/14 (7%) 0/13 (0%)a Shortness of breath 0/14 (0%) 1/13 (8%)b Difficulty starting urination 1/14 (7%) 0/13 (0%)a Bursitis/tendinitis 1/14 (7%) 0/13 (0%)a Easy bruising 1/14 (7%) 0/13 (0%)a Dissociative side effects (CADSS) Amnesia 5/14 (36%) 4/13 (31%)a Depersonalization 9/14 (64%) 4/13 (31%)a Derealization 10/14 (41%) 8/13 (62%)b Average blood pressure increase (mmHg) Systolic +13 +18 Diastolic +9 +10

Baylor/Mt Sinai Study: Treatment during Ketamine Infusion

*15% of participants at BCM, 12% of participants at MSSM required anesthesiologist intervention. Participant ID Max or Min BP (Systolic) Max or Min BP (Diastolic) Reason for Intervention Course of Action Infusion Discontinued? MSSM01 150 101 Hypertension Nitroglycerin (50 mg x 3) No MSSM03 73 40 Hypotension/ Bradycardia Atropine, Ephedrine Yes (SAE) MSSM16 118 75 Emesis Ondansetron 4 mg No BCM01 176 102 Hypertension Esmolol x 2 (20 mg, 30 mg) No BCM05 181 104 Hypertension Esmolol x 1 (30 mg), Nitroglycerine (50 mg) No BCM22 183 97 Hypertension Esmolol (20 mg, 30 mg, 50mg) x 3 No BCM32 168 112 Hypertension Esmolol x 2 (20 mg, 30 mg) No BCM40 175 111 Hypertension Esmolol x 2 (20 mg, 30 mg) No BCM45 187 91 Hypertension Esmolol x 3 (20 mg, 30 mg, 50 mg) Yes BCM47 151 88 Hypertension Esmolol x 2 (20 mg, 30 mg) No

Ketamine Infusions (Weekly or Twice Weekly) Not Associated with Memory Impairments in TRD

ECT-MQ = ECT Memory Questionnaire. Diamond PR, et al. J Psychopharmacol. 2014;28(6):536-544.

Dose = 0.5 mg/kg over 40 min

“Ketamine Bladder”

Shahani R, et al. Urology. 2007;69(5):810-812. Winstock AR, et al. BJU Int. 2012;110(11):1762-1766. McGirr A, et al. Psychol Med. 2015;45(4):693-704.

• Hemorrhagic or ulcerative

cystitis associated with chronic use

• Extremely painful and frequent

urination

• Recreational abusers tend to use

much higher doses (one study showed 12 g/week)

• No reports associated with

intermittent subanesthetic dose

– Urinary track Sx no greater than placebo in meta-analysis

Ketamine in Real-World Practice Settings

Ketamine Advocacy Network.

Rapid Growth in Ketamine Providers

Wilkinson S, et al. Am J Psychiatry. In press.

Most common off-label indications— MDD (72%), bipolar (15%), PTSD (6%)

Survey Responses of Providers Offering Off-label Ketamine (N = 57)

Wilkinson S, et al. Am J Psychiatry. In press.

Provider Specialty Route of Administration Monitoring at east every 15 min during IV infusion Frequency of maintenance treatments Psychiatry (67%) Intravenous (88%) Heart rate (78%) Monthly (30%) Anesthesiology (23%) Oral (23%) Pulse oximetry (80%) Once per 3 weeks (21%) Emergency Medicine (3.5%) Intranasal (19%) Blood pressure (76%) Once per 2 weeks (12%) Family Medicine (3.5%) Less than monthly (16%)

Ketamine Infusion Set-Up

Pictures from: Ketamine Clinic Los Angeles.

Patient Selection

• Comprehensive diagnostic assessment

– Evaluate for Hx of psychosis and SUDs/AUDs – Past medical and psychiatric records – Medical contraindications and relative contraindications

• Uncontrolled HTN, CAD, severe OSA, CVA,

dementia, poor anesthesia candidate

• For MDD diagnosis:

– Severity of depression (QIDS or PHQ9) and episode duration – Previous treatment history

• ECT history (Cleveland Clinic example)
• For Obese patients (BMI > 30) consideration should be

made to adjust dosing to ideal body weight

Informed Consent Process

MAOI = monoamine oxidase inhibitor; TCA = tricyclic antidepressant; TMS = transcranial magnetic stimulation; VNS = vagus nerve stimulation. Sanacora G, et al. JAMA Psychiatry. 2017;74(4):399-405.

• Limits of available information pertaining to the potential

benefits of ketamine therapy

• Acknowledgement of Off-label use of ketamine
• Discussion of alternative treatment options

– Lithium augmentation – MAOIs/TCAs – ECT/TMS/VNS – Clozapine (refractory bipolar disorder)

• Essential to have written informed consent before

initiating treatment

Clinician Experience and Training

ACLS = Advanced Cardiovascular Life Support. Sanacora G, et al. JAMA Psychiatry. 2017;74(4):399-405.

• Clinical specialty not as important as ability to manage

potential cardiovascular events should they occur

• Reasonable standard — Licensed clinician who can

administer a DEA Schedule III medication with ACLS certification

• On-site clinician available to treat psychiatric

emergencies

Treatment Delivery

Sanacora G, et al. JAMA Psychiatry. 2017;74(4):399-405.

• Assessment of Respiratory Status (oxygen saturation or

end-tidal CO2)

• Assessment of cardiovascular function (BP, HR) at

regular intervals

• Assessment of level of consciousness (Modified

Observer’s Assessment of Alertness/Sedation Scale)

• Criteria for stopping infusion
• Crash cart availability for hemodynamic instability

Post-Infusion Monitoring and Discharge

Sanacora G, et al. JAMA Psychiatry. 2017;74(4):399-405.

• IV line in place for approximately 1 hour following

infusion

• Generally monitor for up to 2 hours after the end of

infusion

• Documentation of return to baseline physiological and

mental status by clinician on-site

• Ensure that a responsible individual is available to

transport patient home

Oral Ketamine in a Large Health Care System: The Kaiser Experience

McInnes A. Kaiser Permanente, San Francisco.

• Long wait times for IV ketamine prompted exploration of

po forms of ketamine – 31/44 patients with a 50% reduction in QIDS after 6 to 8 administrations; Average dose 100 mg (1 mg/kg)

• Side effects minimal

– Systolic BP increase 10 mm/Hg; slightly less increase in diastolic BP; no changes in HR – Patient ready for discharge in 45 to 60 minutes

Case Study: Ms. B

Nichols SD, et al. Current Psychiatry. 2015;15(5):48-51.

• Reasonable consideration for severe TRD with functional

disability

• Should also be presented with full range of approaches,

including drug, neurostimulation, psychotherapy alternatives — – Drug: MAOI, TCA, Liothyronine – Cognitive-behavioral therapy – Neurostimulation: rTMS (including Deep TMS); VNS

Resources / Additional Reading

• Mathew SJ, Zarate CA Jr (Eds). Ketamine for Treatment-

Resistant Depression. The First Decade of Progress. Adis; 2016.

• Sanacora G, et al. A Consensus Statement on the Use of

Ketamine in the Treatment of Mood Disorders. JAMA

• Psychiatry. 2017;74(4):399-405.
• Sanacora G, et al. Balancing the Promise and Risks of

Ketamine Treatment for Mood Disorders.

• Neuropsychopharmacology. 2017;42(6):1179-1181.
• Murrough JW, et al. Targeting glutamate signalling in

depression: progress and prospects. Nat Rev Drug

• Discov. 2017;[Epub ahead of print].