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KETAMINE:NEW FRONTIERS IN PHARMACOTHERAPY

C. SCOTT JENNISCH, MD

IOWA PSYCHIATRY, LLC

MANAGING PARTNER

DISCLOSURES:

SPEAKERS BUREAU: SUNOVION, ALLERGAN, TAKEDA, LUNDBECK/OTSUKA

PARTIAL OWNERSHIP, IOWA KETAMINE CLINIC, LLC

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OBJECTIVES:

WHY DO WE NEED MORE TREATMENT OPTIONS?REVIEW THE HISTORY OF KETAMINE

CLINICAL APPLICATION - INFORMATION TO USE ON MONDAY

RISKS PROFILE AND REASONS FOR CAUTION

EXPERIENCE AT IOWA KETAMINE CLINIC, LLC

WHAT DOES THE FUTURE HOLD?TO NOT EMBARRASS MYSELF IN FRONT OF DR. CORYELL

THE NEED FOR MORE TREATMENT OPTIONSSTAR*D DATA1 – CUMULATIVE REMISSION RATE OF 67%ONSET OF ACTION/TIME TO REMISSION WITH CURRENT TREATMENTS1

SUICIDE RATES ARE RISING2 – 1999-2016 INCREASED: NATIONWIDE BY 25%, IOWA BY 36%DEPRESSION IS THE LEADING CAUSE OF DISABILITY WORLDWIDE WITH AN 18% INCREASEFROM 2005-20153

EFFECTIVE TREATMENT ALTERS THE COURSE OF ILLNESS1

END ORGAN DAMAGE4,5,6,7 - HIPPOCAMPUS, INFORMATION PROCESSING, GENETIC, CHANGES AND INFLAMMATORY MARKERS

American Journal of Psychiatry 163:1905–1917, 2006 2. CDC Vital Signs, June 2018 3. WHO 4. Journal of psychiatry & neuroscience: JPN, 34(1), 41, 2009 5. Journal of affective disorders, 130(1), 66-74, 2011 6. JAMA psychiatry, 71(4), 454-456, 2014 7. Psychoneuro-endocrinology Volume 95, September 2018, Pages 43-49

HISTORY:•FIRST DEVELOPED IN 1962 AND WAS FIRST APPROVED FORHUMAN USE IN THE 1970S.•DURING THE VIETNAM WAR, KETAMINE WAS USED AS ANANESTHETIC TO HELP WOUNDED SOLDIERS.•IN THE LATE 1970S THE ABUSE OF KETAMINE BEGAN TO RISE. MARCIA MOORE WROTE JOURNEYS INTO THE BRIGHT WORLDAND JOHN LILLY WROTE THE SCIENTIST.•IN THE 1990S KETAMINE BEGAN TO BE POPULARLY ABUSED INTHE CLUB SCENE.•THE MOST COMMON WAY FOR PEOPLE TO GET KETAMINE ISTHROUGH THEFT OF LEGAL PHARMACEUTICALS OR FROMROBBING VETERINARIAN CLINICS.•IN 1999, KETAMINE BECAME A SCHEDULED III CONTROLLEDSUBSTANCE.

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KETAMINE QUIZ

KETAMINE IS A SHORT ACTING MEDICATION?

TRUE OR FALSE?

KETAMINE IS ON THE WHO MODEL LIST OF ESSENTIAL MEDICATIONS?

TRUE OR FALSE?

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KETAMINE WILL GIVE A FALSE POSITIVE FOR PCP ON A URINE DRUG SCREEN?

TRUE OR FALSE?

STREET NAMES FOR KETAMINE INCLUDE ALL OF THE FOLLOWING:

SPECIAL K, K, VITAMIN K, KIT KAT, CAT VALIUM, FIGHTING IRISH, AND K-HOLE?

TRUE OR FALSE?

KETAMINE IS A HORSE TRANQUILIZER?

TRUE OR FALSE?

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MECHANISM OF ACTION:

•NMDA RECEPTORANTAGONIST/GLUTAMATE1

•G PROTEIN MIGRATION2

•MAPK/ERK PATHWAY3

•OPIOID SYSTEM ACTIVATION4

1. Nature. 2011;475:91–5 2. Mol Psychiatry. 2016 Mar; 21(3): 313–319 3. Biological Psychiatry Jan 2018;83:2-4 4. Am J Psychiatry. 2018 Aug 29

SIDE EFFECT PROFILE:CARDIOVASCULAR: BLOOD PRESSURE AND PULSE RATE ARE FREQUENTLY ELEVATED FOLLOWING ADMINISTRATION OF KETAMINEHYDROCHLORIDE ALONE. HOWEVER, HYPOTENSION AND BRADYCARDIA HAVE BEEN OBSERVED. ARRHYTHMIA HAS ALSOOCCURRED.

RESPIRATION: ALTHOUGH RESPIRATION IS FREQUENTLY STIMULATED, SEVERE DEPRESSION OF RESPIRATION OR APNEA MAY OCCURFOLLOWING RAPID INTRAVENOUS ADMINISTRATION OF HIGH DOSES OF KETAMINE HYDROCHLORIDE. LARYNGOSPASMS AND OTHERFORMS OF AIRWAY OBSTRUCTION HAVE OCCURRED DURING KETAMINE HYDROCHLORIDE ANESTHESIA.

EYE: DIPLOPIA AND NYSTAGMUS HAVE BEEN NOTED FOLLOWING KETAMINE HYDROCHLORIDE ADMINISTRATION. IT ALSO MAYCAUSE A SLIGHT ELEVATION IN INTRAOCULAR PRESSURE MEASUREMENT.

GENITOURINARY: SEVERE IRRITATIVE AND INFLAMMATORY URINARY TRACT AND BLADDER SYMPTOMS INCLUDING CYSTITIS HAVEBEEN REPORTED IN INDIVIDUALS WITH HISTORY OF CHRONIC KETAMINE USE OR ABUSE.

PSYCHOLOGICAL: EMERGENT PHENOMENA THAT HAVE BEEN DESCRIBED AS A FLOATING SENSATION, VIVID PLEASANT DREAMS, NIGHTMARES, HALLUCINATIONS AND DELIRIUM.

NEUROLOGICAL: IN SOME PATIENTS, ENHANCED SKELETAL MUSCLE TONE MAY BE MANIFESTED BY TONIC AND CLONIC MOVEMENTSSOMETIMES RESEMBLING SEIZURES (K CRAMPS) ABUSERS HAVE NOTED COGNITIVE IMPAIRMENT.

GASTROINTESTINAL: ANOREXIA, NAUSEA AND VOMITING HAVE BEEN OBSERVED; HOWEVER, THIS IS NOT USUALLY SEVERE ANDALLOWS THE GREAT MAJORITY OF PATIENTS TO TAKE LIQUIDS BY MOUTH SHORTLY AFTER REGAINING CONSCIOUSNESS

SIDE EFFECT PROFILE:SYSTEMATIC ANALYSIS OF 60 PRIOR STUDIES ON THE USE OF KETAMINE TO TREATDEPRESSION, WHICH INCLUDED 899 PATIENTS IN TOTAL.

THE MOST COMMON SIDE-EFFECTS WERE ANXIETY, HEADACHE, DIZZINESS, DISSOCIATION, ELEVATED BLOOD PRESSURE, AND BLURRED VISION. MOST SIDE-EFFECTSSPONTANEOUSLY RESOLVED SHORTLY AFTER KETAMINE WAS ADMINISTERED.

“OUR FINDINGS SUGGEST A SELECTIVE REPORTING BIAS WITH LIMITED ASSESSMENT OFLONG-TERM USE AND SAFETY AND AFTER REPEATED DOSING…”

Lancet Psychiatry. 2018 Jan;5(1):65-78

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DOSING:

INDUCTION: KETAMINE 1-4.5MG/KG IVKETAMINE 3-9MG/KG INTRANASAL

DEPRESSION: KETAMINE 0.5MG/KG PER 40 MINUTES IV1

ESKETAMINE 28 MG, 56 MG, 84 MG INTRANASAL2

1. Int J Neuropsychopharmacol. 2016;19(4):pyv124 2. AMA Psychiatry. 2018;75(2):139-14

KETAMINE INFUSION MDD:

DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL OF KETAMINE THERAPY IN TREATMENT-RESISTANT DEPRESSION:PRIMARY OBJECTIVE IS TO INVESTIGATE WHETHER ALL DOSES (0.1 MG/KG, 0.2 MG/KG, 0.5 MG/KG, AND 1.0 MG/KG) OF KETAMINE ARE SUPERIOR TO ACTIVE PLACEBO(MIDAZOLAM 0.045 MG/KG) THERAPY IN THE ACUTE TREATMENT OF PATIENTS WITHTREATMENT RESISTANT DEPRESSION WITHIN 72 HOURS (DAY 3), WHEN ADDED TOONGOING AND STABLE ANTIDEPRESSANT THERAPY. (N=99)

ClinicalTrials.gov Identifier: NCT01920555 / Maurizio Fava, MD, Massachusetts General Hospital

KETAMINE INFUSION MDD:

ClinicalTrials.gov Identifier: NCT01920555 / Maurizio Fava, MD, Massachusetts General Hospital

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KETAMINE INFUSION MDD:

RESULTS:GROUPS: ALL GROUPS

STATISTICAL TEST TYPE: SUPERIORITY

STATISTICAL METHOD: MIXED MODELS ANALYSIS

P VALUE : <0.01

MEAN DIFFERENCE (FINAL VALUES): -4.79

95% CONFIDENCE INTERVAL: -7.35 TO -2.24

ClinicalTrials.gov Identifier: NCT01920555 / Maurizio Fava, MD, Massachusetts General Hospital

KETAMINE INFUSION MDD:

KETAMINE AUGMENTATION FOR OUTPATIENTS WITH TREATMENT-RESISTANT DEPRESSION: PRELIMINARY EVIDENCE FOR TWO-STEP INTRAVENOUS DOSE ESCALATION.FOURTEEN PATIENTS WITH TREATMENT-RESISTANT DEPRESSION WERE ELIGIBLE TO RECEIVE AUGMENTATION WITH SIXOPEN-LABEL INTRAVENOUS KETAMINE INFUSIONS OVER 3 WEEKS. FOR THE FIRST THREE INFUSIONS, KETAMINE WASADMINISTERED AT A DOSE OF 0.5 MG/KG OVER 45 MINUTES; THE DOSE WAS INCREASED TO 0.75 MG/KG OVER45 MINUTES FOR THE SUBSEQUENT THREE INFUSIONS. THE PRIMARY OUTCOME MEASURE WAS RESPONSE AS MEASUREDON HAMILTON DEPRESSION RATING SCALE-28 ITEMS.

AFTER THE COMPLETION OF THREE KETAMINE INFUSIONS, 7.1% (1/14) RESPONDED; AFTER ALL SIX KETAMINEINFUSIONS, 41.7% (5/12) COMPLETERS RESPONDED AND 16.7% (2/12) REMITTED. INTENT-TO-TREAT RESPONSEAND REMISSION RATES AT THE END OF THE FINAL INFUSION WERE 35.7% (5/14) AND 14.3% (2/14). HOWEVER, ALL BUT ONE RESPONDER RELAPSED WITHIN 2 WEEKS AFTER THE FINAL INFUSION.

REPEATED, ESCALATING DOSES OF INTRAVENOUS KETAMINE AUGMENTATION WERE PRELIMINARILY FOUND TO BEFEASIBLE, EFFICACIOUS AND WELL TOLERATED.

Aust N Z J Psychiatry. 2017 Jan;51(1):55-64

KETAMINE INFUSION MDD:SINGLE-DOSE INFUSION KETAMINE AND NON-KETAMINE N-METHYL-D-ASPARTATERECEPTOR ANTAGONISTS FOR UNIPOLAR AND BIPOLAR DEPRESSION: A META-ANALYSISOF EFFICACY, SAFETY AND TIME TRAJECTORIES:NINE RCT, KETAMINE STUDIES: N = 234; KETAMINE REDUCED DEPRESSION SIGNIFICANTLY MORE THANPLACEBO/PSEUDO-PLACEBO BEGINNING AT 40 MIN, PEAKING AT DAY (95% CI -1.28 TO -0.73, P<0.001), ANDLOOSING SUPERIORITY BY DAYS 10-12.

COMPARED WITH PLACEBO/PSEUDO-PLACEBO, KETAMINE LED TO SIGNIFICANTLY GREATER RESPONSE (40 MIN TODAY 7) AND REMISSION (80 MIN TO DAYS 3-5).

ALL-CAUSE DISCONTINUATION WAS SIMILAR BETWEEN KETAMINE (P = 0.34) AND PLACEBO. ALTHOUGH SOMEADVERSE EFFECTS WERE MORE COMMON WITH KETAMINE THAN PLACEBO, THESE WERE TRANSIENT AND CLINICALLYINSIGNIFICANT.

Psychol Med. 2016;46(7):1459

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KETAMINE INFUSION MDD:

SYSTEMATIC REVIEW OF SEVEN TRIALS COMPARED KETAMINE WITH A CONTROL IN 172 PATIENTS WITHUNIPOLAR OR BIPOLAR MAJOR DEPRESSION. A SINGLE DOSE OF KETAMINE (0.5 MG/KG) OR THECONTROL WAS ADMINISTERED INTRAVENOUSLY (SIX TRIALS) OR INTRANASALLY (ONE TRIAL)

RESPONSE AT MULTIPLE POSTTREATMENT TIME POINTS OCCURRED IN MORE PATIENTS WHO RECEIVEDKETAMINE THAN THE CONTROL:

TWO HOURS – 51% VERSUS 2% OF PATIENTS

ONE DAY – 53% VERSUS 7%

SEVEN DAYS – 31% VERSUS 7%

BY DAY 14, RESPONSE WAS PRESENT IN ONLY 11 PERCENT OF THE PATIENTS WHO RECEIVED KETAMINE.

Am J Psychiatry. 2015 Oct;172(10):950-66

ELECTROCONVULSIVE THERAPY:

SIGNIFICANT TREATMENT EFFECT OF ADD-ON KETAMINE ANESTHESIAELECTROCONVULSIVE THERAPY IN DEPRESSIVE PATIENTS: A META-ANALYSIS1

16 STUDIES WITH 346 PATIENTS/329 CONTROLS. ANTIDEPRESSANT TREATMENT EFFECT OF ADD-ON KETAMINE SIGNIFICANTLYHIGHER THAN OTHER ANESTHETICS (P< 0.001). SIGNIFICANCE PERSISTED AT 1 - 2 WEEKS AND 3 - 4 WEEKS. SIDE EFFECT PROFILESAND RECOVERY TIME SIGNIFICANTLY WORSE THAN CONTROL GROUP P<0.05).

KETAMINE IN ELECTROCONVULSIVE THERAPY FOR DEPRESSIVE DISORDER: A SYSTEMATICREVIEW AND META-ANALYSIS2

16 STUDIES INCLUDING 928 PATIENTS. KETAMINE AND ECT SHOWED NO BETTER RESPONSE AND REMISSION RATES WITHINCREASED ADVERSE EVENTS, INCLUDING CARDIOVASCULAR AND PSYCHIATRIC SYMPTOMS.

1. Eur Neuropsychopharmacol, 2017 Jan;27(1):29-41 2. J Psychiatr Res, 2018 Sep;104:144-156

ELECTROCONVULSIVE THERAPY:

RAPID ANTIDEPRESSANT EFFECTS OF REPEATED DOSES OF KETAMINE COMPAREDWITH ELECTROCONVULSIVE THERAPY

BLIND, RANDOMIZED STUDY, 18 PATIENTS WERE DIVIDED INTO TWO GROUPS WHICH RECEIVED EITHER THREEINTRAVENOUS INFUSIONS OF KETAMINE HYDROCHLORIDE (0.5 MG/KG OVER 45 MIN) OR ECT ON 3 TEST DAYS (EVERY48 H). THE PRIMARY OUTCOME MEASURE WAS THE BECK DEPRESSION INVENTORY AND HAMILTON DEPRESSIONRATING SCALE, WHICH WAS USED TO RATE OVERALL DEPRESSIVE SYMPTOMS AT BASELINE, 24 H AFTER EACHTREATMENT, 72 H AND ONE WEEK AFTER THE LAST (THIRD) KETAMINE OR ECT. WITHIN 24 H, DEPRESSIVE SYMPTOMSSIGNIFICANTLY IMPROVED IN SUBJECTS RECEIVING THE FIRST DOSE OF KETAMINE COMPARED WITH ECT GROUP. THISIMPROVEMENT REMAINED SIGNIFICANT THROUGHOUT THE STUDY. DEPRESSIVE SYMPTOMS AFTER THE SECOND DOSEKETAMINE WAS ALSO LOWER THAN THE SECOND ECT. KETAMINE IS AS EFFECTIVE AS ECT IN IMPROVING DEPRESSIVESYMPTOMS IN MDD PATIENTS AND HAVE MORE RAPID ANTIDEPRESSANT EFFECTS COMPARED WITH THE ECT.

Psychiatry Res. 2014;215(2):355. Epub 2013 Dec 13

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OTHER PSYCHIATRIC CONSIDERATIONS:BIPOLAR AFFECTIVE DISORDER

SUICIDAL IDEATION

OCDPTSDGAD/SOCIAL ANXIETY DISORDER

HOSPICE CARE

CHEMICAL DEPENDENCY

TRAUMATIC BRAIN INJURY, AUTISM SPECTRUM DISORDER, EATING DISORDERS

SUICIDAL IDEATION:

KETAMINE MAY BE USEFUL FOR SHORT-TERM TREATMENT OF SUICIDAL IDEATION.

A META-ANALYSIS OF PATIENT LEVEL DATA FROM EIGHT RANDOMIZED TRIALS COMPARED A SINGLEINTRAVENOUS INFUSION OF KETAMINE (0.5 MG/KG) WITH A CONTROL CONDITION IN 167 PATIENTS WITHACTIVE OR PASSIVE SUICIDAL IDEATION AT STUDY ENTRY.

MOST OF THE PATIENTS WERE DIAGNOSED WITH UNIPOLAR MAJOR DEPRESSION (77 PERCENT); OTHERDIAGNOSES INCLUDED BIPOLAR DISORDER AND POSTTRAUMATIC STRESS DISORDER. APPROXIMATELY 50 PERCENT OF PATIENTS WERE CONCURRENTLY TREATED WITH PSYCHOTROPIC MEDICATIONS.

GREATER IMPROVEMENT WITH KETAMINE BEGAN WITHIN ONE DAY OF TREATMENT, AND RESOLUTION OFSUICIDAL IDEATION BY DAY SEVEN OCCURRED IN MORE PATIENTS WHO RECEIVED KETAMINE THANCONTROLS (60% VERSUS 32%).

Am J Psychiatry 2018; 175:150.

CHILD/ADOLESCENT:INTRANASAL KETAMINE IN PEDIATRIC BIPOLAR DISORDER/FEAR OF HARM PHENOTYPE: RETROSPECTIVE CHART REVIEW OFA CASE SERIES OF 12 TREATMENT REFRACTORY YOUTH – AGES 6-19. SUBSTANTIAL REDUCTION IN MANIA, FEAR OF HARM, AGGRESSION, DEPRESSION, ANXIETY, BEHAVIORAL SYMPTOMS, ATTENTION/EXECUTIVE FUNCTION AND SLEEP PROBLEMS. THE MEDICATION WAS WELL TOLERATED.1

CLINICAL EXPERIENCE USING INTRANASAL KETAMINE IN THE LONGITUDINAL TREATMENT OF JUVENILE BIPOLAR DISORDERWITH FEAR OF HARM PHENOTYPE: RETROSPECTIVE CHART REVIEW OF 12 YOUTH TREATED EVERY 2 – 5 DAYS FOR 3 MONTHS TO 6.5 YEARS. NEARLY ALL PATIENTS HAD A MARKED REDUCTION IN CGI RATED AS "MUCH." OR "VERY MUCH" IMPROVED WITH MILD ADVERSE EVENTS THAT DECREASED OVER TIME WITHOUT LOSS OF BENEFIT.2

INTRAVENOUS KETAMINE FOR ADOLESCENTS WITH TREATMENT RESISTANT DEPRESSION: AN OPEN LABEL STUDY. 13 PARTICIPANTS AGE 14 – 18 RECEIVED SIX IV KETAMINE TREATMENTS (0.5 MG/KG) OVER TWO WEEKS. FIVE RESPONDERS. THREE SHOWED SUSTAINED BENEFIT AT SIX WEEKS. HIGHER DOSE PREDICTED TREATMENT RESPONSE.3

1. J Affect Disord. 2013 May;147(1-3):431-6 2. J Affect Disord. 2018 Jan 1;225:545-551 3. J Child Adolesc Psychopharmacol. 2018 Sep;28(7):437-444

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PREDICTORS OF KETAMINE RESPONSE:PREDICTORS OF KETAMINE RESPONSE STUDIES NUMBER OF SUBJECTS

SOCIODEMOGRAPHIC NONE NONE NONE

CLINICAL FAMILY HISTORY OF ALCOHOL DISORDER IN A FIRST-DEGREE RELATIVE (FHP) PHELPS ET AL. 2009 [17]. MDD (N = 26)

LUCKENBAUGH ET AL. 2012 [18]. MDD AND BD (N = 33)

NICIU ET AL. 2014 [19]. MDD (N = 52)

HIGH BMI NICIU ET AL. 2014 [19]. MDD (N = 108)

NO PRIOR SUICIDE HISTORY NICIU ET AL. 2014 [19]. MDD (N = 108)

PERIPHERAL BIOCHEM LOW BASELINE ADIPONECTIN LEVELS MACHADO-VIEIRA ET AL. 2017 [20]. MDD (N = 49)

BD (N = 31)

HIGH BASELINE PERIPHERAL B12 LEVEL PERMODA-OSIP ET AL. 2013 [21]. BD (N = 20)

POLYSOMNOGRAPHY LOW BASELINE DELTA SLEEP RATIO DUNCAN ET AL. 2013 [22]. MDD (N = 30)

NEUROCHEMISTRY LOW GLX/GLUTAMATE RATIO SALVADORE ET AL. 2012 [23]. MDD (N = 14)

NEUROIMAGING INCREASED PRETREATMENT ANTERIOR CINGULATE CORTEX ACTIVITY SALVADORE ET AL. 2009 [24]. MDD (N = 11

GENETICS VAL66MET BDNF ALLELE LAJE ET AL. 2012 [25]. MDD (N = 62)

COGNITION POOR BASELINE NEUROCOGNITIVE SCORE MURROUGH ET AL. 2013 [26]. MDD (N = 25)

Int J Environ Res Public Health. 2018 Apr; 15(4): 771

CONTRAINDICATIONS:

ACTIVE PSYCHOTIC SYMPTOMS, MANIC SYMPTOMS, OR A HISTORY OFA PRIMARY PSYCHOTIC DISORDER

UNCONTROLLED HYPERTENSION

PREGNANCY - RELATIVE

HISTORY OF KETAMINE ABUSE OR DEPENDENCE

HISTORY OF SEVERE, ONGOING ALCOHOL OR SUBSTANCE ABUSE ORDEPENDENCE

KNOWN HYPERSENSITIVITY TO KETAMINE OR ITS COMPONENTS

IOWA KETAMINE CLINIC, LLC:

ONE OF TWO KETAMINE CLINICS IN THE STATE OF IOWA

OPENED IN SEPTEMBER 2017TREATMENT FOR PSYCHIATRIC CONDITIONS – NO PAIN MANAGEMENT

APPROXIMATELY 75 PATIENTS TREATED TO DATE

RESPONSE RATE 75% IN MDD (PHQ-9, - 15) (GAD-7, -10.5)MAINTENANCE TREATMENT 20% IN MDD

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ESKETAMINE:

ALSO KNOWN AS (S)-KETAMINE, KETANEST AND KETANEST S, AN ENANTIOMER OFKETAMINE

INTRODUCED IN GERMANY IN 1997 JOHNSON & JOHNSON/JANSSEN DEVELOPED A NASAL SPRAY FORMULATION FORMDD

BREAKTHROUGH DESIGNATION FROM THE FDA FOR TREATMENT RESISTANT DEPRESSIONAND MDD WITH SUICIDAL IDEATION

ONGOING PHASE III CLINICAL TRIALS

Janssen Pharmaceutical Companies of Johnson & Johnson

ESKETAMINE NASAL SPRAY - AUGMENTATION:

ADULTS WITH TREATMENT RESISTANT DEPRESSION (TRD) – 28 DAYS

RESPONSE TX 69%, PLACEBO 52% REMISSION TX 53%, PLACEBO 31%

RELAPSE PREVENTION IN ADULTS WITH TRD IN REMISSION AFTER 16 WEEKS51% LOWER RISK OF RELAPSE (27% RELAPSE TX GROUP, 45% PLACEBO RELAPSE)

LONG- TERM SAFETY STUDYTREATMENT EMERGENT ADVERSE EVENTS – DIZZINESS (33%), DISSOCIATION (27%), NAUSEA (25%), HEADACHE (25%), DROWSINESS (17%). 6.9% RATE OF TEAE

ELDERLYMADRS CHANGE NOT STATISTICALLY SIGNIFICANT

Janssen Pharmaceutical Companies of Johnson & Johnson

ESKETAMINE NASAL SPRAY - AUGMENTATION:

EFFICACY AND SAFETY OF INTRANASAL ESKETAMINE ADJUNCTIVE TO ORAL ANTIDEPRESSANT THERAPYIN TREATMENT-RESISTANT DEPRESSION: A RANDOMIZED CLINICAL TRIALDESIGN: THE STUDY CONSISTED OF 4 PHASES: (1) SCREENING, (2) DOUBLE-BLIND TREATMENT (DAYS 1-15), COMPOSED OF TWO 1-WEEK PERIODS, (3) OPTIONAL OPEN-LABELTREATMENT (DAYS 15-74), AND (4) POSTTREATMENT FOLLOW-UP (8 WEEKS). ONE HUNDRED TWENTY-SIX ADULTS WITH A DSM-IV-TR DIAGNOSIS OF MDD AND HISTORY OFINADEQUATE RESPONSE TO 2 OR MORE ANTIDEPRESSANTS.

INTERVENTIONS IN PERIOD 1, PARTICIPANTS WERE RANDOMIZED (3:1:1:1) TO PLACEBO (N = 33), ESKETAMINE 28 MG (N = 11), 56 MG (N = 11), OR 84 MG (N = 12) TWICEWEEKLY. IN PERIOD 2, 28 PLACEBO-TREATED PARTICIPANTS WITH MODERATE-TO-SEVERE SYMPTOMS WERE RERANDOMIZED (1:1:1:1) TO 1 OF THE 4 TREATMENT ARMS; THOSEWITH MILD SYMPTOMS CONTINUED RECEIVING PLACEBO. PARTICIPANTS CONTINUED THEIR EXISTING ANTIDEPRESSANT TREATMENT DURING THE STUDY. DURING THE OPEN-LABELPHASE, DOSING FREQUENCY WAS REDUCED FROM TWICE WEEKLY TO WEEKLY, AND THEN TO EVERY 2 WEEKS.

THE PRIMARY EFFICACY END POINT WAS CHANGE FROM BASELINE TO DAY 8 IN THE MADRS TOTAL SCORE.

RESULTS: SIXTY-SEVEN PARTICIPANTS. CHANGE IN MADRS TOTAL SCORE IN ALL 3 ESKETAMINE GROUPS WAS SUPERIOR TO PLACEBO (ESKETAMINE 28 MG: -4.2 [2.09], P = .02; 56 MG: -6.3 [2.07], P = .001; 84 MG: -9.0 [2.13], P < .001), WITH A SIGNIFICANT ASCENDING DOSE-RESPONSE RELATIONSHIP (P < .001). IMPROVEMENT INDEPRESSIVE SYMPTOMS APPEARED TO BE SUSTAINED (-7.2 [1.84]) DESPITE REDUCED DOSING FREQUENCY IN THE OPEN-LABEL PHASE. THREE OF 56 (5%) ESKETAMINE-TREATEDPARTICIPANTS DURING THE DOUBLE-BLIND PHASE VS NONE RECEIVING PLACEBO AND 1 OF 57 PARTICIPANTS (2%) DURING THE OPEN-LABEL PHASE HAD ADVERSE EVENTS THATLED TO STUDY DISCONTINUATION.

CONCLUSIONS: ANTIDEPRESSANT EFFECT WAS RAPID IN ONSET AND DOSE RELATED. RESPONSE APPEARED TO PERSIST FOR MORE THAN 2 MONTHS WITH A LOWER DOSINGFREQUENCY.

JAMA Psychiatry. 2018;75(2):139

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REASON FOR CAUTION:

VULNERABLE PATIENT POPULATION

SAFETY PROFILE OF LONG TERM USE UNKNOWN

CONSIDERED EXPERIMENTAL/OFF LABEL

POTENTIAL FOR ABUSE

FUTURE DEVELOPMENTS:

ESKETAMINE

RAPASTINEL

BREXANOLONE/SAGE – 217ALKS-5461 – BUPRENORPHINE 2 MG / SAMIDORPHAN 2 MG

PSYCHEDELICS - PSYILOCYBIN

SUMMARY:

UNMET NEED ABOUNDS

WE CAN DO BETTER

KETAMINE HAS MUCH PROMISE…BUT THERE IS MUCH WE DO NOT KNOW

FUTURE DEVELOPMENTS ARE PROMISING

WE HAVE HOPE TO OFFER OUR PATIENTS

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THANK YOU!

QUESTIONS?