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Rapid Treatments for Psychiatric Disorders:

focus on rapid antidepressant treatments

Cristina Cusin, MDDepression Clinical and Research

ProgramAssistant Professor HMS

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Disclosures

Cristina Cusin 2012-2017:

– Speaking/CME/Consulting: Janssen, Takeda, Boehringer

– Equity: None

– Royalty/patent: PCT/US15/56192; 070919.00032 Acyliccucurbit[N]uril type molecular containers to treat intoxication and substance abuse

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Definition of rapid?

• What does it mean “rapid”?

• “Rapid” compared to what?

• How do we compare with other specialties? (cardiology, anesthesia, neurology - stroke, pain, infectious disease)

• If you had acute pain from kidney stone and the only ‘effective’ treatment was a drug with a chance of improvement of 45% in 6 weeks how would you feel?

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“Rapid treatments” at MGH in 1976

Rapid treatment of acute psychosis• 24 patients with acute functional psychoses

(schizophrenia or mania) were treated with IM haloperidol in a three-hour period.

• 5mg -> +10 mg Q30min vs 5mg-> +5mgQhr• There was almost complete remission of cardinal

symptoms (thought disorder, hallucinations, and delusional activity) in this period for 11 patients. “Acute dystonia, easily reversed, was the only significant side effect”

Anderson WH, American Journal Psychiatry, 1976, 133 (9) 1076-1078

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Rapid for what problem?(Hint: Think emergency room setting)

• Violent behavior

• Psychosis

• Intoxication/Overdose

• Withdrawal

• Drug reaction or interaction

• Anxiety/Panic

• Depression /Suicidality

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Rapid for what problem? - II

• Route of administration of drugs (IV/IM)

• Contain/restrain/stabilize

• Administer something that solve the problem (i.e. naloxone for opiate OD) or stabilize (IV benzodiazepine for alcohol withdrawal)

• We have “treatments” for conditions with known etiology

• Do we have treatments for conditions of unknown etiology?

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How do we treat acute psychiatric problems?

• Etiology not known

• Acute onset or worsening

• Old (cheap) drugs vs new expensive drugs ($$)

• What treatment is more efficacious?

• Do we have guidelines?

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When rapid treatment is a BAD idea

• Hyponatremia:

• Hyperglycemic crisis

• Patient delirious and agitated

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Rapid “treatment” of agitation?

• Still need to rule out organic causes of delirium/agitation/psychotic symptoms (check lytes, CBT, toxins, PE, stroke, etc)

• What is the best pharmacologic treatment for non-organic psychosis?

• comparative effectiveness

are very hard to conduct

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Rapid tranquillization for agitated patients in emergency psychiatric rooms: a randomized trial of midazolam versus

haloperidol plus promethazine.

• 301 aggressive patients randomized to receive IM midazolam (15 mg) or IM haloperidol (10 mg) + promethazine (50 mg).

• At 20’ were tranquil or asleep 89% of patients given midazolam vs 67% of those given haloperidol plus promethazine.

• By 40 minutes, midazolam still had a statistically and clinically significant 13% relative advantage.

• After 1 hour, about 90% of both groups were tranquil or asleep.

TREC collaborative group BMJ 2003 Sep 27; 327(7417): 708–713.

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Rapid tranquillization of violent or agitated patients in a psychiatric emergency setting. Pragmatic randomized trial of intramuscular lorazepam v. haloperidol plus promethazine.

• 200 patients randomized to receive IM lorazepam (4 mg) or IM haloperidol (10 mg) + promethazine (25-50 mg mix).

• 4 h later, equal numbers in both groups were tranquil or asleep.

• 76% given the haloperidol-promethazine were asleep compared with 45% of those on lorazepam (RR=2.29,95% CI 1.59-3.39; NNT=3.2,95% CI 2.3-5.4). The haloperidol-promethazine mix produced a faster onset of tranquillization/sedation and more clinical improvement over the first 2 h.

• Neither intervention differed significantly in the need for additional intervention or physical restraints, numbers absconding, or adverse effects

Alexander et al. Br J Psychiatry 2004 Jul;185:63-9..

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A practical clinical trial comparing haloperidol, risperidone, and olanzapine for the acute treatment of first-episode

nonaffective psychosis.

• 172 patients, practical clinical trial, haloperidol (N = 56), risperidone (N = 61), and olanzapine (N = 55). Mean modal daily doses were 5.4 mg/day for haloperidol, 4 mg/day for risperidone, and 15.3 mg/day for olanzapine; 98.3% of subjects were drug naive at baseline.

• All 3 treatments showed similar effectiveness in reducing the severity of general, negative, and positive sx after 6 weeks. No statistical differences among groups.

• extrapyramidal symptoms and concomitant anticholinergic medication use was greater with haloperidol than olanzapine or risperidone.

• Olanzapine-treated patients had significantly more weight gain vs haloperidol and risperidone groups.

Crespo-Facorro B, et al. J Clin Psychiatry. 2006 Oct;67(10):1511-21.

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Rapid tranquilization of severely agitated patients with

schizophrenia spectrum disorders: a naturalistic, rater-blinded,

randomized, controlled study with oral haloperidol, risperidone, and olanzapine

• 43 severely agitated patients

• randomly assigned to either daily haloperidol 15 mg, olanzapine 20 mg, or risperidone 2 to 6 mg over 5 days.

• All drugs were effective for rapid tranquilization within 2 hours. Over 5 days, the course differed between agents (P < 0.001), but none was superior.

• Dropouts occurred only in the risperidone and olanzapinegroups.

Walther et al, J Clin Psychopharmacol. 2014 Feb;34(1):124-8.

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Olanzapine IM or velotab for acutely disturbed/agitated people with suspected serious mental illnesses

• 4 trials olanzapine IM vs. IM placebo (total n=769, 217 placebo).

• olanzapine IM >placebo at 2 hours (4 RCTs, n=769, RR 0.49 CI 0.42 to 0.59, NNT 4 CI 3 to 5) and olanzapine IM was as acceptable as placebo.

• olanzapine IM did not seem associated with extrapyramidal effects

• 2 trials olanzapine IM vs haloperidol IM (total n=482, 166 allocated to haloperidol). No differences between olanzapine IM and haloperidol by 2 hours for the outcome of 'no important clinical response’

• 2 trials compared olanzapine IM with lorazepam IM (total n=355, 119 allocated to lorazepam). For the outcome of 'no important clinical response' , there was no difference at 2 hours

• No studies reported outcomes related to hospital and service use, satisfaction with care or suicide, self-harm or harm to others.

• No studies evaluated the oro-dispersable form of olanzapine.

Belgamwar RB. Cochrane Database Syst Rev. 2005 Apr 18;(2):CD003729.

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Olanzapine IM or velotab for acutely disturbed/agitated people with suspected serious mental illnesses

• “Data relevant to the effects of olanzapine IM are taken from some studies that may not be considered ethical in many places, all are funded by a company with a pecuniary interest in the result. These studies often poorly report outcomes that are difficult to interpret for routine care. Other important outcomes are not recorded at all.”

Belgamwar RB. Cochrane Database Syst Rev. 2005 Apr 18;(2):CD003729.

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Review: Haloperidol for psychosis-induced aggression or agitation (rapid tranquillization)

• 41 studies comparing haloperidol with other treatments.

• Few studies reflect real world practice, most were small and carried considerable risk of bias.

• Compared with placebo, more people in the haloperidol group were asleep at two hours (2 RCTs, n=220, RR 0.88, 95%CI 0.82 to 0.95, very low-quality evidence) and experienced dystonia (2 RCTs, n=207, RR 7.49, 95%CI 0.93 to 60.21, very low-quality evidence)

• The haloperidol group required fewer injections than those in the aripiprazole group (2 RCTs, n=473, low-quality evidence). More people in the haloperidol group experienced dystonia (very low-quality evidence)

• Four trials (n=207) compared haloperidol with lorazepam with no significant differences with regard to number of participants asleep at one hour (very low-quality of evidence) or those requiring additional injections (very low-quality of evidence).

Ostinelli Cochrane Database Syst Rev. 2017 Jul 31;7:CD009377

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Haloperidol for psychosis-induced aggression or agitation (rapid tranquillization)

• Where additional drugs are available, sole use of haloperidol for extreme emergency is considered unethical.

• Addition promethazine is supported by evidence from within randomized trials.

• Use of an alternative antipsychotic drug is only partially supported by fragmented and poor-grade evidence.

• Adding a benzodiazepine to haloperidol does not have strong evidence of benefit and carries risk of additional harm.

• After six decades of use for emergency rapid tranquillization, this is still an area in need of good independent trials relevant to real-world practice

Ostinelli Cochrane Database Syst Rev. 2017 Jul 31;7:CD009377

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De-escalation techniques for psychosis-induced aggression or agitation

• De-escalation is a psychosocial intervention for managing people with disturbed or aggressive behavior.

• Of the 345 citations that were identified using the search strategies, we found only one reference to be potentially suitable for further inspection. However, after viewing the full text, it was excluded as it was not a randomized controlled trial.

• Using de-escalation techniques for people with psychosis induced aggression or agitation appears to be accepted as good clinical practice but is not supported by evidence from randomized trials. It is unclear why it has remained such an under-researched area.

Du M Cochrane Database Syst Rev. 2017 Apr 3;4:CD009922

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Aripiprazole for mania

• Aripiprazole alone or in combination for acute mania.• 10 studies (N=3340). 7 studies (aripiprazole versus placebo (2239 participants);

2 of these included a third arm-one lithium (485 participants) and haloperidol (480 participants). 2 studies compared aripiprazole as an adjunctive treatment to valproate or lithium versus placebo (754 participants), and one study compared aripiprazole versus haloperidol (347 participants).

• The overall risk of bias was unclear. A high dropout rate from most trials (> 20% for each intervention)

• aripiprazole alone was more effective than placebo in reducing manic symptoms in adults and children/adolescents at three and four weeks but not at six weeks (YMRS mean difference at three weeks -3.66, moderate quality evidence and a modest difference)

• Aripiprazole was compared with other drug treatments. No statistically significant differences between aripiprazole and other drug treatments at any time point up to and including 12 weeks.

Brown Cochrane Database Syst Rev. 2013 Dec 17;(12):CD005000

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Ziprasidone IM

• approved by the Food and Drug Administration in 2002 for the treatment of agitation in patients with schizophrenia

• Intramuscular ziprasidone compared with intramuscular haloperidol in the treatment of acute psychosis (J Clin Psychiatry. 2000 Dec;61(12):933-41.) - 19 centers, 7 countries, sponsor Pfizer

– 3 days of flexible-dose ziprasidone i.m. (N = 90) or haloperidol i.m. (N = 42) followed by oral treatment to day 7. Ziprasidone IM was significantly more effective in reducing the symptoms of acute psychosis and was better tolerated than haloperidol IM, particularly in movement disorders.

• Intramuscular ziprasidone versus haloperidol for managing agitation in Chinese patients with schizophrenia. Zhang H et al J Clin Psychopharmacol. 2013 Apr;33(2):178-85.

– ziprasidone had a favorable tolerability profile and comparable efficacy and safety compared to haloperidol.

• randomized, rated-blind trial of 4 intramuscular interventions (J Clin Psychopharmacol. 2013 Jun;33(3):306-12.) 100 agitated patients were assigned to receive: haloperidol (2.5 mg) + promethazine (25 mg) (HLP + PMZ), haloperidol (2.5 mg) + midazolam (7.5 mg) (HLP + MID), ziprasidone (10 mg) (ZIP), or olanzapine (10 mg) (OLP). All treatment options promoted a reduction in agitation

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Rapid acute treatment of agitation in individuals with

schizophrenia: multicentre, randomised, placebo-controlled

study of inhaled loxapine

Michael D. Lesem et al. BJP 2011;198:51-58

©2011 by The Royal College of Psychiatrists

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Inhaled Loxapine for mania

• Rapid acute treatment of agitation in patients with bipolar I disorder: a multicenter, randomized, placebo-controlled clinical trial with inhaled loxapine. Kwentus J, et al. Bipolar Disord. 2012 Feb;14(1)

• RCT , 17 psychiatric facilities. • Agitated patients (N=314) with bipolar I disorder (manic or mixed episodes)

were randomized (1:1:1) to inhaled loxapine 5 mg or 10 mg, or inhaled placebo em

• both doses of inhaled loxapine significantly reduced agitation compared with placebo.

• patients were confirmed to be in good general health, as assessed by medical history, physical examination, a 12-lead electrocardiogram, and standard serum chemistry, hematology, and urinalysis tests.

• no history of drug or alcohol dependence in the previous two months

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Rapid acute treatment of agitation in patients with bipolar I disorder: a multicenter, randomized, placebo‐controlled clinical trial with inhaled loxapine

Bipolar DisordersVolume 14, Issue 1, pages 31-40, 13 FEB 2012 DOI: 10.1111/j.1399-5618.2011.00975.xhttp://onlinelibrary.wiley.com/doi/10.1111/j.1399-5618.2011.00975.x/full#f4

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Loxapine - Results and limitations

• The people who need this medication are generally medically complex, may have street drugs in their system, are generally cigarette smokers and their pulmonary and in many cases their cardiac status may be unknown. It can only be given in a registered health care facility by personnel who can assess and manage any pulmonary complications.

• 60 capsules of loxapine 10mg (generic) 32.84 $• average wholesale price for ONE 10-mg package of

Adasuve $145 -> often not on formulary• If the initial dose is not effective, the question becomes

- now what?

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Planning another study?

• Rationale and design of the PLACID study: a randomised trial comparing the efficacy and safety of inhaled loxapine versus IM aripiprazole in acutely agitated patients with schizophrenia or bipolar disorder.

• San L, Estrada G, Oudovenko N, Vieta E.BMC Psychiatry. 2017 Apr 4;17(1):126. doi: 10.1186/s12888-017-1291-5.

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Rapid Improvement of Acute Schizophrenia Symptoms After Intravenous Sodium Nitroprusside

A Randomized, Double-blind, Placebo-Controlled Trial

• Single low-dose sodium nitroprusside IV (0.5 μg/kg/min for 4 hours) to 20 patients with schizophrenia taking antipsychotics

• Outcome: changes in positive, negative, anxiety, and depressive symptoms during the following 4 weeks.

• (0.5 to 10 μg/kg/min dose rates for hypertension)

• Mechanism? modulate the NMDA–nitric oxide–cGMP pathway

JC Hallak et al. JAMA Psychiatry. 2013;70(7):668-676.

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Date of download: 9/12/2015Copyright © 2015 American Medical

Association. All rights reserved.

From: Rapid Improvement of Acute Schizophrenia Symptoms After Intravenous Sodium Nitroprusside: A

Randomized, Double-blind, Placebo-Controlled Trial

JAMA Psychiatry. 2013;70(7):668-676. doi:10.1001/jamapsychiatry.2013.1292

Mean Total 18-Item Brief Psychiatric Rating Scale ScoresA, Scores during the first 12 hours; B, scores at 4 weeks. Asterisks

indicate statistically significant P values as given in the text; error bars, SEMs.

Figure Legend:

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“Rapid” antidepressant in 1991

A Preliminary, Open Study of the Combination of Fluoxetine and Desipramine for Rapid Treatment of Major Depression• 14 inpatients, responses were retrospectively compared

with those of 52 inpatients treated with desipramine alone• One week after treatment began, the mean change in

Hamilton Depression Rating Scale scores was 42% in the group that received Fl+D and 20% in the group that received D alone (Mann-Whitney U Test, P =.007).

• At 2 weeks, the mean change in scores of the group that received Fl+D was 60%, while a 30% change was noted in the patients treated with D alone (P=.001).

• 10/14 patients remitted

Nelson, et al. Arch Gen Psychiatry.1991

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Ketamine vs. Placebo in Unipolar and Bipolar Depression

Zarate et al. Arch. Gen. Psychiatry, 2006.Diazgranados et al. Arch. Gen. Psychiatry, 2010.

Dotted Line = PlaceboSolid Line = Ketamine

Courtesy Dr Ionescu

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Ketamine Safety and tolerability

• Transient euphoria, perceptual disturbances, dissociative and psychotomimetic effects (Berman et al. Biol. Psychiatry, 2000; Zarate et al. Arch Gen. Psychiatry, 2006).

• Moderate anxiety, irritability, headache, increased libido.

• brief hyper- or hypotensive episodes, tachycardia or bradycardia, bradypnea (aan het Rot et al. Biol. Psychiatry, 2010).

• Significant cardiorespiratory adverse events rare

• Most adverse effects peaked within 40 minutes and ceased within 80 minutes post-infusion (Zarate et al., 2006).

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Ketamine and suicide

• Price et al. (Biological Psychiatry, 2009): patients with TRD have reduced MADRS suicide subscale scores 24 hrs after a single ketamine infusion (n=26,).

• DiazGranados et al.(J of Clin Psych, 2010): 33 patients with TRD received a single ketamine infusion: suicidal ideation scores decreased at 40 minutes, remained significantly decreased for 4 hours.

• Larkin et al. (Int. J of Neuropsychoph 2011) reported similar findings in an emergency room setting in patients with depression and SI. Patients received single ketamine bolus, with changes in MADRS scores at 40 minutes that persisted 10 days. (n=14, open-label).

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Ketamine and suicide II

• Murrough et al. Ketamine for rapid reduction of suicidal ideation: a randomized controlled trial. (Psychol Med 2015 Dec;45(16):3571-80.)

• RCT N=24 patients with mood and anxiety spectrum disorders with clinically significant SI, single infusion of ketamine or midazolam

• SI measured using the Beck Scale for Suicidal Ideation (BSI) 24 h post-treatment represented the primary outcome

• BSI score was not different between the treatment groups at 24 h (p = 0.32); however, a significant difference emerged at 48 h (p = 0.047). MADRS-SI score was lower in the ketamine group compared to midazolam group at 24 h (p = 0.05). The treatment effect was no longer significant at the end of the 7-day.

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Ketamine in PTSD

• randomized, double-blind, crossover trial ketamine vs midazolam

• 41 pts with PTSD, free of concomitant psychotropic medications for 2 weeks - 29 of them completed both infusions and ratings

• Significant and rapid reduction in PTSD symptom severity at 24 hours after infusion

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Ketamine in OCD

• open-label trial of ketamine (.5 mg/kg IV over 40 min) in 10 subjects with treatment-refractory OCD- very mild improvement in OCD and improvement in comorbid depression

• randomized, double-blind, placebo-controlled, crossover design, drug-free OCD adults (n=15)

• saline and one of ketamine (0.5 mg/kg), spaced at least 1-week apart

• ketamine's effects within the crossover design showed significant (p<0.005) carryover effects (ie, lasting longer than 1 week)

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Rodriguez et al. Neuropsychopharmacology. 2013;38(12):2475-83.

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Ketamine Mechanism(s) of action

• Neurobiological mechanisms of ketamine’s antidepressant actions are more complex than NMDA receptor blockade.

• primary mechanism of action is blockage of the NMDA receptor at the PCP site within the ionotropic channel.

• -> disinhibition of GABAergic inputs and enhancing the firing rate of glutamatergic neurons, increases the presynaptic release of Glu

• This increase in Glu release then preferentially favors AMPA receptors over NMDA receptors because the latter are blocked by ketamine

• The net effect of ketamine on a cellular level is an increased glutamatergic throughput of AMPA relative to NMDA

• increased glutamatergic activity (Maeng et al. Biol. Psychiatry, 2008)

www.mghcme.orgDwyer and Duman, Biological Psychiatry, 2013

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Ketamine studies at MGH

• Ketamine as ADD-on to treatment-as-usual• OPEN –LABEL• 14 depressed patients very treatment-resistant

with suicidal ideation• 6 infusions of ketamine over 3 weeks. • Escalating dose if no response• 5 patients out of 12 completers (41.7%) were

responders, and 2 out of 12 were in remission (16.7%).

• 5/12 had no suicidal ideation• Response lasted approximately 2-3 weeks

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Repeated-Dose Ketamine for Suicidal Ideation

Ionescu et al, J Clin Psych 2015

2.29

1.71 1.5

1.08

1.08

0.67

0.42

-0.5

0

0.5

1

1.5

2

2.5

3

3.5

4

Baseline(n=14)

Infusion 1(n=14)

Infusion 2(n=14)

Infusion 3(n=13)

Infusion 4(n=13)

Infusion 5(n=12)

Infusion 6(n=12)

CSS

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p<0.001

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2-Group Comparison

5-Group Comparison

A.

B.

RAPID studyFava et al in pressMolecular PsychiatryKetamine studies at MGH

Ketamine dose?

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IV Ketamine in Adult Patients with Treatment-Resistant Depression: A Dose-Frequency Study*Singh et al, ASCP Annual Meeting, 2014

Ketamine frequency?

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More questions…

• Ketamine interaction with medications?

• Ketamine long-term safety?

• Ketamine response predictors?

• Ketamine addiction?

• Ketamine tachiphylaxis?

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The search for ketamine-likeEsketamine (Janssen)

• The S(+) enantiomer of ketamine, approximately twice as potent as an anesthetic, eliminated more rapidly

• inhibits dopamine transporters eight times more than R-ketamine and it increases dopamine activity in the brain

• for use in combination with an oral antidepressant in patients with TRD who have been unresponsive to treatment

• three short-term studies; one withdrawal maintenance of effect study; and one long-term safety study (52 wks).

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A Double-Blind, Doubly-Randomized, Placebo-Controlled Study of Intranasal Esketamine in TRD*

*Singh et al, Biol Psychiatry. 2016 Sep 15;80(6):424-31.

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JAMA Psychiatry. 2018;75(2):139-148.

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Esketamine (cont.)

• In September 2018 Janssen submitted the results to FDA

• The geriatric trial was halted

• Study in patients 68 with MDD and acute suicidality, in need of hospitalization, as adjunct to TAU

• At four hours, MADRS scores had improved by a mean of 13.4 in the esketamine group and by 9.1 in the placebo group (P=0.015). The difference remained significant at 24 hours after treatment, but by day 25 there was no statistical difference between the two groups in MADRS score improvement.

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NOT-ketamine like but still rapid..ALKS 5461

Bupernorphine is a partial agonist of μ receptors and opioid receptor-like (ORL-1)with κ-opioidergic receptor antagonistic properties. the antidepressant effect of

buprenorphine is correlated to its antagonistic activity at κ-opiodergic receptors (by blocking the release of dynorphin could increase glutamate)

Samidorphan is a μ-opioid receptor antagonist)

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ALKS-5461

• 2 phase III studies (also known as Forward-3 and Forward-4), or placebo an adjunctive therapy to SSRIs or SNRIs.

• Forward-3 (N=329): double blind placebo lead and 6-week (2/2 mg of bup/sam) HIGH PLACEBO

• Forward-4 (N=385) was a parallel design study where the effect of ALKS 5461 (2/2 or 0.5/0.5 mg) was studied against the placebo-control group

(missed primary endpoint – post-hoc)• Forward-5 (N=407) used SPCD, MADRS-6

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ALKS-5461 (cont.)

• open-label phase III trial (N=1452) found 52.5% of patients achieved remission of major depression within 12 months of treatment, with a median time to remission of 59 days

• FDA has accepted to review it in April – still under review

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The search for ketamine-likeAZ 6765 (lanicemine)

• 22 medication-free pts with TRD, single infusion of lanicemine 150mg significantly reduced depression scores within 80 minutes

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The search for ketamine-like:AZ 6765 (lanicemine)

• 34 pts with MDD (n=34) randomized to single infusion of lanicemine 100mg vs placebo. Change in MADRS scores at 24 hrs did not differ significantly from placebo. Placebo response was an average of more than 14 points

• 125 medicated patients with MDD randomized to repeat infusions of adjunctive lanicemine 100 mg, 150 mg, or placebo –both doses efficacious

• Large multi-site trial was negative, as the placebo response rate was 39% at primary endpoint

• AZ shut down the pipeline

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Lanicemine (AZD6765)

Patients with Major Depressive Disorder and History of Inadequate Response to Antidepressants: A Randomized, Placebo-Controlled Study

Sanacora G et al. Neuropsychopharmacology. 2017 Mar;42(4):844-853.

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The search for ketamine-like:RG7090 Basimglurant (Roche)

• Selective metabotropic glutamate subtype 5 (mGlu5) receptor–negative allosteric modulator

• colocalized and functionally interacting with NMDA receptors by potentiating NMDA-induced currents in the brain

• 333 pts, 59 sites, as adjunctive of TAU (1-3 failed AD)• the placebo group had a 14.6-point reduction on

the MADRS, and 46.8% of the participants assigned to placebo experienced a response by week 6.

• Unique subjective effects associated with this novel class of medications may not be appreciated by measures such as the physician-rated MADRS

Quiroz al. JAMA Psychiat. 2016 Dec;26(6):653-6.

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Basimglurant

6 weeks, not rapid

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The search for ketamine-like:CP-101,606 Traxoprodil (Pfizer)

• NR2B subunit-selective N-methyl-D-aspartate receptor antagonist• Pts who had failed 1-3 AD prior• 6-week open-label trial of paroxetine and a single-blind,

intravenous placebo infusion. Period 1 nonresponders (n = 30) then received a randomized double-blind single infusion of CP-101,606 or placebo

• Significant antidepressant effect 8.4-point greater reduction in the MADRS score in patients receiving CP-101,606 versus those receiving placebo at 5 days

• Development was stopped due to incidence of QTc prolongation• (study completed in 2006)

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Note about CP-101,606 (Pfizer)

• 1272 went through a thorough screening via telephone, 192 went through a face-to-face interview to yield a total of 47 patients who were entered to period 1. A total of 30 subjects (15 subjects per group) were randomized to period 2

• 17 responded to single blind placebo (36%)

• How generalizable the results in this sample?

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The search for ketamine-like:Rislenemdaz (CERC-301, MK-0657) (Cerecor)

• Another NR2B selective NMDA-antagonist • Fast track designation from FDA• randomized, double blind, placebo-controlled

crossover study, oral, 135 patients diagnosed with MDD who were resistant to SSRI/SNRI treatment.

• 8 mg/day by day 7, no significant changes were noted between drug and placebo on the primary outcome measure

• A second double blind, randomized, placebo controlled phase II trial studying the effects of 12 mg/day and 20 mg/day doses of rislenemdazon patients with MDD

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The search for ketamine-like:Rislenemdaz (CERC-301, MK-0657) (Cerecor)

• 3 week, SPCD design , 115 pts • Did not achieve primary efficacy endpoint at day

2 or day 7 (2016)• Unclear future for this molecule

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The search for ketamine-like:Rapastinel (Glyx-13, Allergan)

• Functional partial agonist at the glycine-binding site on the NMDA receptor

• shown to enhance memory and learning in both young adult and learning-impaired, aging rat models

• randomized, double-blind trial (n=116) with MDD, pts had failed 1 AD, rapastinel (at doses 1, 5, 10, or 30 mg/kg) or placebo.

• Long-term safety and efficacy research is ongoing. Rapastinel has received the FDA’s breakthrough therapy designation

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The search for ketamine-like:Rapastinel (Glyx-13)

• Ongoing phase III; Target enrollment 690 pts at 40 sites

• Monotherapy; 450mg vs 900mg vs placebo

• IV administration, not orally available• Paving the way for Apimostinel (NRX-1074), 100-

fold more potent by weight and orally active• An intravenous formulation of apimostinel is in a

phase II clinical trial for MDD,and an oral formulation is concurrently in phase I trials for MDD.

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The search for ketamine-like:Tulrampator (S-47445, CX-1632) RespireRx

• positive allosteric modulator of the AMPA receptor which is under development of major depressive disorder (as an adjunct), and also Alzheimer's disease, dementia, and mild cognitive impairment.

• may be a rapid-acting antidepressant similarly to ketamine but without its dissociative/hallucinogenic and other adverse effects

• phase II clinical trials for depression• in animals enhances cognition and

memoryantidepressant-, antianhedonic-, and anxiolytic-like effects, and neurotrophic and neuroplasticity-promoting activities

www.mghcme.org

The search for ketamine-like:NS 189 (Neuralstem Inc)

• The compound's activity was discovered using phenotypic screening with a library of 10,269 compounds to identify compounds that promoted neurogenesis in vitro

• effective in animal models of major depression and shown to enhance the neurogenesis

• In a phase IB, double blind, placebo-controlled study* NSI-189 was found to be efficacious as an antidepressant agent in two of the depression scales (SDQ and CPFQ) –negative on the MADRS

• 18 with MDD administered 40 mg, 2–4 times a day for a total of 28 days

• n July 2017, it was announced that a pase II clinical trial with 220 patients failed to meet its primary effectiveness endpoint in MDD

*Fava M, Johe K, Ereshefsky L, et al. Mol Psychiatry. 2016;21:1372–1380

www.mghcme.org

The search for ketamine-like:Dextromethorphan combos

• AVP-786 (dextromethorphan/quinidine “Nuedexta”) Avanir

– Noncompetitive NMDA receptor antagonist, as well as a sigma-1 receptor agonist

– Results of clinical trial pending-Phase II

• AXS-05 (dextromethorphan/bupropion) Axsome

– Currently in Phase III

www.mghcme.org

The search for ketamine-like:4-Chlorokynurenine (AV-101 Vistagen/Pherin)

• oral, non-opioid, non-sedating NMDA receptor glycine B antagonist. It appears to be a rapid-acting antidepressant– Phase II trial for MDD

PH94B Similar drug investigated for SAD

www.mghcme.org

The search for ketamine-like:Xenon gas

• has been used as a general anesthetic. Although it is expensive, anesthesia machines that can deliver xenon are expected to appear on the European market because advances in recovery and recycling of xenon have made it economically viable.

• Xenon interacts with many different receptors and ion channels, a high-affinity glycine-site NMDA receptor antagonist.

• not neurotoxic and it inhibits the neurotoxicity of ketamine and nitrous oxide, while actually producing neuroprotective effects

• does not stimulate a dopamine efflux in the nucleus accumbens.

• activates the two-pore domain potassium channel TREK-1. • competitive inhibitor of the serotonin 5-HT3 receptor.

While neither anesthetic nor antinociceptive, this reduces anesthesia-emergent nausea and vomiting