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New treatments for schizophrenia

Oliver Freudenreich, MD, FACLPCo-Director

MGH Schizophrenia Clinical and Research Program

www.mghcme.org

Outline

• Unmet needsA. Symptoms

• Positive symptoms – TDM, nitroprusside, Lu AF35700, cannabidiol• Negative symptoms – cariprazine, L-methylfolate, MIN-101, AVP-786• Cognition – exercise (sic!)

B. Tolerability• Extrapyramidal symptoms- pimavanserine, lumateperone• Weight gain - ALKS 3831, MELT, liraglutide

C. Adherence• Initiation aripiprazol lauroxil, RBP-7000, Proteus sensor

• Thinking outside the box– Targeting neurocircuits– Targeting the microbiome– Targeting the immune system

• Prominent failures

PARS PRO TOTO

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What are the unmet needs?

A. Schizophrenia is a syndrome with dimensions

• Refractory positive symptoms

• Prominent negative symptoms*

• Neurocognitive impairment*

B. Long-term tolerability of antipsychotics

• Extrapyramidal symptoms

• Weight gain

C. Adherence

*Contributor tofunctional impairment

Fellner C. P&T. 2017;42(2):130-4.

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A. SYMPTOMS

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Treatment-resistant schizophrenia (TRS)

• Consensus guidelines on diagnosis and terminology developed by TRRIP Working Group– Clinical subspecifiers for positive, negative, cognitive

symptom domains

– Time-course (i.e., early, medium, late onset)

– Ultra-treatment resistant (i.e., clozapine)

• Minimum requirements for TRS:– Current symptoms

• Symptom threshold at least moderate severity (rating scale!)

• Symptom duration at least 12 weeks

• Functional impairment at least moderate (rating scale!)

– Adequate treatment• At least two trials of at least 6 weeks of at least 600 CPZ-EQ

• At least 80% adherence

TRRIP = Treatment Response and Resistance in PsychosisHowes OD et al. Am J Psychiatry. 2017;174(3):16-229.

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Antipsychotic Therapeutic Drug

Monitoring (TDM)

• Long history in psychiatry– Lithium

– Tricyclic antidepressants

• Currently underutilized

• Renewed interest– First guideline for TDM published by TDM

taskforce of AGNP in 2004 (update 2011 and 2017)

– Development of new assays for antipsychoticsAGNP = Arbeitsgemeinschaft fur Neuropsychopharmakologie und PharmakopsychiatrieHiemke C, et al. Pharmacopsychiatry. 2017 Sep 14. [Epub ahead of print]Horvitz-Lennon M, et al. Am J Psychiatry. 2017;174(5):421-426.Schoretsanitis G, et al. Expert Rev Clin Pharmacol. 2017;10(9):965-981.

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Evolution of laboratory testing

Today’s specialty lab is tomorrow’s POC testing

Fast is not always better (or necessary)– Regulatory issues– Quality control– Higher cost– Integration with downstream systems

Specialty lab

•Send out

Core lab

•At hospital

Stat lab

•At hospital

POC

•At CMHC

POC = Point of careCMHS = Community Mental Health CenterQuinn AD et al. Crit Rev Clin Lab Sci. 2016;53:1-12.

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Point-of-care (POC) testing

• Performance of a diagnostic laboratory test outside of a traditional central laboratory and near the site of patient care (“bedside testing)– Despite name, who performs the

test is different, not where– Best established for diabetes and

anticoagulation

• Offers alternative for patients who cannot go to a regular lab or refuse blood work– Global medicine (pathogen

testing)!– Fingerstick!

• Possible integration with electronic medical records

Yip PM et al. Clin Biochem. 2018 Jan 29 [Epub ahead of print]

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Sodium nitroprusside infusion

Hallak JEC et al. JAMA Psychiatry 2013;70(7):668-76.

Single intravenous administrationsodium nitroprusside0.5 μg/kg/min for 4 hours

EFFICACY

SAFETY

ES 1.7

Hypotension, cyanide toxicity

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Sodium nitroprusside for schizophrenia

• Nitroprusside– Indication: malignant hypertension

– Mechanism: nitric oxide (NO) donor

• Clinical trials– Positive proof of concept trial1

– Failed replication trial2

– MGH Clinical Trials Network and Institute (CTNI) multi-site trial completed3

• See also PDE inhibitors4

1Hallak JEC et al. JAMA Psychiatry 2013;70(7):668-76.2Stone JM et al. Psychol Med. 2016 ;46(16):3443-50.3ClinicalTrials.gov Identifier: NCT02164981.4Maurice DH et al. Nature reviews Drug discovery. 2014;13(4):290-314.

Molecule of The Year1992

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Lu AF35700

• Mechanism of action– Predominant D1 vs. D2 receptor antagonist

• Profile comparable to clozapine

– High occupancy 5-HT2A and 5-HT6 serotonin receptors

• Phase III development program initiated by Lundbeck (“DayBreak”)– Target population: treatment-refractory schizophrenia

patients– FDA fast-track designation for treatment-refractory

schizophrenia

ClinicalTrials.gov Identifier: NCT02717195

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Cannabidiol (CBD)

• First case report1

• 6-week add-on RTC2

– 1000 mg/d CBT (N=43)

– Placebo (N=45)

• Positive symptoms– PANSS -1.4, [95% CI=-2.5,

-0.2]

• Cognition– BACS not significant

• Adverse events similar

1Zuardi AW et al. J Clin Psychiatry. 1995;56:485-6.2McGuire P et al. Am J Psychiatry. 2018;175(3):225-231.

Non-dopamine antipsychotic?

• Cannabis sativa

– THC

– CBD

• Endocannabinoids

• Anandamine* (“bliss”)

• CB receptors

*N-arachidonoylethanolamine or AEA

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Symptom domains and functional outcome

Fervaha G et al. Acta Psychiatr Scand. 2014;130(4):290-9.Rabinowitz J et al. Schizophr Res. 2012;137(1-3):147-50.Galderisi S et al. World Psychiatry. 2014;13(3):275-87.

Negative symptoms Cognitive impairment

FUNCTIONALOUTCOMEP

osi

tive

sym

pto

ms

An

tip

sych

oti

cs

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Cariprazine for negative symptoms

• Cariprazine is high-affinity D3 preferring D3/D2 partial agonist

• 26-week double-blind phase III RCT– Cariprazine 3 to 6 mg/d (N=227) versus risperidone 4

mg/d (N=229) as active reference antipsychotic

– Stable schizophrenia patients with prominent negative symptoms but no prominent psychosis or depression

– Minimum score of 24 on the PANSS-negative factor score (NFS)

• Outcome variables– Primary endpoint: PANSS-NFS

– Secondary endpoint: Personal and Social Performance Scale (PSP)

Nemeth G et al. Lancet. 2017;389:1103-13.Nemeth G et al. Lancet. 2017;389(10074):1103-13.

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PANSS-NFS change from baseline to week 26* in cariprazine for negative symptoms trial

LSM

Ch

ange

fro

m B

asel

ine

(MM

RM

)

-8.9

-7.4

-12

-10

-8

-6

-4

-2

0

Cariprazine 3-6 mg/d (n=227) Risperidone 4 mg/d (n=229)

**

Imp

rove

me

nt

Nemeth G et al. Lancet. 2017;389(10074):1103-13.

*Primary efficacy endpoint** p < 0.01 vs. risperidone

LSM = least squares mean; MMRM = Mixed-Effects Model for Repeated MeasuresBased on ITT population

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The D3 story1

• D3 has interesting brain distribution– Limbic system (ventral striatum) and thalamus

• D3 is of interest for several areas of psychiatry– Negative symptoms– Drug addiction– Mood disorders– Cognition

• Interesting observation that a pure D2/3 antagonist [amisulpride] does not cause EPS– Full D3 antagonists: antipsychotic without causing EPS?

• D3 agonist drugs [pramipexole, ropinirole; signal for aripiprazole] increased risk for pathological gambling, hypersexuality, compulsive shopping3,4

1Sokoloff P and Le Foll B. Eur J Neurosci. 2017;45:2-19.2Seeman P. Synapse. 2015;69:183-9.3Moore TJ et al. JAMA Intern Med. 2014;174:1930-3.

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D2/3 Partial Agonist AntipsychoticsIndications Typical dose

rangeBindingaffinities (Ki)

Comments

Aripiprazole SchizophreniaBipolar disorderAdjunct depressionTouretteAutism

10 to 30 mg/d D2/3 0.21/0.93D2/D3 = 0.225-HT1a 1.75-HT 2a 3.4

Half-life 94 h**CYP3A4CYP2D6High affinity for 5-HT 2c

Brexpiprazole SchizophreniaAdjunct depression

2 to 4 mg/d0.5 to 2mg/d

D2/3 0.30/1.1D2/D3 = 0.275-HT1a 0.125-HT 2a 0.47

Half-life 91 hCYP3A4CYP2D6

Cariprazine*** SchizophreniaAcute mania/mixedNegative symptoms*

1.5 to 6 mg/d3 to 6 mg/d

D2/3 0.49/0.09D2/D3 = 5.765-HT 1a 2.65-HT 2a 18.8

Longest half-life (1-3 weeks)**CYP3A4

*Not FDA-approved **Half-life including active metabolite***Cariprazine metabolite has very high D3 selectivity D2/D3 = 24.87Frankel JS and Schwartz TL. Ther Adv Psychopharmacol. 2017;7:29–41.Kiss B et al. J Pharmacol Exp Ther. 2010;333:328-40.

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L-methylfolate for negative symptoms

• Folate metabolism– MTHFR gene polymorphism

• MTHFR C677 T

– L-methylfolate• Fully reduced, active form of folate

• 12-week RTC– 15 mg L-methylfolate (N=29; 26 placebo)

– Improved PANSS total (d=0.61, p=0.03)

– Increased thickness of mPFC and reduced limbic connectivity

Roffman JL et al. Mol Psychiatry. 2018;23(2):316-322.Review: Brown HE and Roffman JL. Harv Rev Psychiatry. 2016;24(2):e1-7.

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MIN-101

• 5-HT2A and σ2 receptor antagonist

• Positive phase II trial

– Primary end point: negative symptoms1

– Secondary end point: cognition2

• Phase III trials announced by Minerva Neurosciences

– Primary end point: negative symptoms

1Davidson M et al. Am J Psychiatry. 2017;174:1195-1202.2Keefe RSE et al. J Clin Psychiatry. 2018;79:e1-e6.http://www.minervaneurosciences.com/innovation-pipeline/min-101/

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Deuterated medicines

• Hydrogen isotopes– Hydrogen (H); “heavy” H = deuterium (D); tritium (T)– D is stable (not radioactive!) and not toxic (1-2 gm)– (Remember “heavy water”)

• Deuteration of a molecule– Same 3-D structure!

• Preserves pharmacodynamic properties

– C-D bond 10x stronger than C-H bond• Changes pharmacokinetics: slows metabolism = longer half-

life

• First FDA-approved deuterated product: Austedo

http://www.concertpharma.com/news/documents/IPT32ConcertPharma.pdf

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AVP-786

• “Broad-spectrum psychotropic”• AVP-786 = deuterated (d6)-dextromethorphan + ultra-low

dose quinidine– Dextromethorphan is uncompetitive NMDA receptor antagonist,

sigma-1 receptor agonist, and inhibitor of serotonin and norepinephrine transporters

– Increase half-life• Deuterated dextromethrophan molecule• Added (low-dose) quinidine which is inhibitor of CYP 2D6

• Avanir clinical development programs– Phase III: Agitation in Alzheimer’s disease– Phase II: Residual symptoms of schizophrenia*

• Primary outcome: NSA 16

* ClinicalTrials.gov Identifier: NCT02477670

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Treatment for CIAS

• Avoid adding insult to injury– Reduce anticholinergic burden– Quit smoking!1

• Consider cognitive training if available2

• Numerous pharmacological strategies including enhancing glutamatergic activity, cholinesterase inhibitors, and stimulants have failed3

• Recent failures include alpha-7 receptor nicotinic agonists like encenicline (EVP-6124) in phase III and bradanicline (TC-1659) in phase II– Maybe nelonicline (ABT-126) positive (?) phase II4,5

1Vermeulen JM et al. Am J Psychiatry. 2018 (in press). 2Keshavan MS et al. Am J Psychiatry. 2014;171(5):510-22. Review3Citrome L. J Clin Psychiatry. 2014;75 Suppl 1:21-6. 4Haig GM et al. Am J Psychiatry. 2016;173(8):827-35. 5Haig GM et al. J Clin Psychiatry. 2018;79(3):28-36.

CIAS = Cognitive Impairment Associated with Schizophrenia

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Exercise for CIAS

• The challenge– Cardiovascular morbidity and mortality in SMI patients– Sedentary life-style associated with poor cognition1

• The simple solution– Exercise is “neuroprotective”– Exercise has broad effects on well-being2

• Improves global cognition3

• Key pathways: inflammatory pathways, BDNF (hippocampus)

• Challenges– Implementation: supported exercise– Maintaining gains: sustaining exercise

• Need clinical trial with physical activity as end-point

1Hamer M et al. Psychol Med. 2009;39:3-11.2Noordsy DL et al. Am J Psychiatry. 2018;175(3):209-214.3Firth J et al. Schizophr Bull. 2017;43:546-556.

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B. TOLERABILITY

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Pimavanserin

• Mechanism1

– Antagonist/inverse agonist at serotonin 5HT2A receptors

– Less potent antagonist/inverse agonist at 5HT2C receptors

• 2016 FDA-approval for psychosis in Parkinson’s disease (Nuplazid)2,3

• Ongoing phase III 6-week add-on trial in schizophrenia (Acadia’s ENHANCE-1)4

1Stahl SM. CNS Spectr. 2016;21:271-5.2Cummings J et al. Lancet. 2014;383(9916):533-40.3Mathis MV et al. J Clin Psychiatry. 2017 (in press).4ClinicalTrials.gov Identifier: NCT02970292.See Marek GJ. Curr Pharm Des. 2015;21(26):3788-96.

5-HT2A inverse agonist

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Lumateperone (ITI-007)

• Mechanism of Action1

– 5-HT2A antagonist (Ki=0.54 nM)*– “Dopamine receptor phosphoprotein

modulator” (DPPM)• Pre-synaptic partial agonist and post-

synaptic antagonist at D1/D2

• Intra-Cellular-Therapies program– Positive phase II (‘005)2

• Positive for 60 mg dose and 4 mg risperidone

• Effect size 0.40 for 60 mg dose• Dopamine occupancy <50%• Negative for 120 mg dose

– Positive phase III (‘301)• Effect size 0.30 for 60 mg dose

– Negative phase III (‘302)3

• Positive for comparator drug (risperidone)

• High placebo response rate

1Davis RE and Correll CU. Exp Rev Neurotherapeutics. 2016;16(6):601-614.2Lieberman JA et al. Biol Psychiatry. 2016;79(12):952-61.3https://globenewswire.com/news-release/2016/09/28/875435/0/en/

Intra-Cellular-Therapies-Announces-Top-Line-Results-from-the-Second-Phase-3-Trial-of-ITI-007-in-Patients-with-Schizophrenia-Study-302.html

*Very high affinity. 60-fold higher than for D2

Lower dose (10 mg) preferentially 5-HT2A

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The day the music died

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Samidorphan/olanzapine (ALKS 3831)

• ALKS 3811 = samidorphan + olanzapine

– Samidorphan1

• 3-carboxamido-4-hydroxynaltrexone

• Potent mu-opioid receptor antagonist

• Alkermes development program

– ENLIGHTEN phase III development program

• Short-term ENLIGHTEN-1 (completed)2,3

• Long-tem ENLIGHTEN-24

– Schizophrenia with alcohol use disorder5

1Turncliff R et al. Clin Ther. 2015 Feb 1;37(2):338-48.2ClinicalTrials.gov Identifier: NCT02634346 3Silverman BL et al. Schizophr Res. 2018;195:245-251.4ClinicalTrials.gov Identifier: NCT02694328 5ClinicalTrials.gov Identifier: NCT02161718

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MELT trial

• Phase IV trial• 52-week RTC comparing

– lorcaserin/metformin combination treatment• Lorcaserin 10 bid• Metformin 1000 bid

– lorcaserin monotherapy– Placebo

• Target population– Chronic, treated schizophrenia (overweight, no diabetes)

• Lorcaserin (Belviq) is 5-HT2c agonist anorectic– Schedule IV drug– Serotonin syndrome unlikely1

– Valvulopathy less likely than with fenfluramine2

ClinicalTrials.gov Identifier: NCT02796144 1Nguyen CT et al. Clin Ther. 2016;38(6):1498-509.2Halpern B and Halpern A. Expert Opin Drug Saf. 2015;14(2):305-15.3Greenway FL et al. Clin Obes. 2016;6(5):285-95.

MELT = MEtformin and Lorcaserin for WeighT Loss in Schizophrenia

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GLP-1 receptor agonists

• Pharmacology– Gastric incretin hormone effect– Secreted if oral glucose– Deficient GLP-1 secretion in

DM– Low risk of hypoglycemia

• Administration– SC

• Available in US– Exenatide (first, 2005) – bid– Liraglutide – qd– Lixisenatide - qd– Exenatide ER – Qweek– Albiglutide – Qweek– Dulaglutide – Qweek

Stimulate insulin release in response to mealDecrease glucagon secretionDecrease hepatic gluconeogenesisDelay gastric emptyingPromote central satiety

Weight loss + improved glucose control Yanai H et al. J Med Cases. 2011;2(2):76-80.

GLP-1 = glucagon-like peptide-1

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Liraglutide for schizophrenia

• Marketed in US as Saxenda (lower-dose: Victoza)• 16-week RTC in schizophrenia patients1

– 97 subjects (prediabetes, overweight/obese, clozapine/olanzapine)

– Primary end-point: glucose tolerance (via OGTT)• Normalized fasting glucose: 64% versus 16% (NNT 2)

– Placebo-subtracted weight loss: - 5.3 kg– Improvement in HbA1c: - 0.2

• Tolerability– GI tract– REMS (thyroid carcinoma; acute pancreatitis)– Role of antibodies?

• However: negative RTC with once-weekly exenatide2

ES = 1.0

ES = 1.1

1Larsen JR et al. JAMA Psychiatry. 2017;74(7);719-28.2Ishoy PL et al. Diabetes Obes Metab. 2017;19(2):162-171.

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C. ADHERENCE

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Initiation of aripiprazole lauroxil

• Conventional approach

– Give Aristada injection

– Administer 21 days of oral aripiprazole

• New initiation path with Aristada Initio (brand name)

– Give 675 mg IM extended release injection + single 30 mg oral aripiprazole dose

– Give desired Aristada dose (same day OK)

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RBP-7000 (brand name Perseris)

• Long-acting formulation of risperidone– Once-a-month subcutaneous (SC) injection– Atrigel delivery system (in situ gel-forming system, like

implant)1

• FDA-approval 7/27/18• Pivotal, placebo-controlled phase-III trial2

– 8-week duration– 90 mg and 120 mg effective– Most frequent TAE somnolence, weight gain, akathisia

• Secondary analysis showed improved heath-related quality of life with treatment compared to placebo3

1Sali SR et al. Int J Curr Pharmaceutical Res. 2018;10(2):38-42.2Nasser AF et al. J Clin Psychopharmacol. 2016;36(2):130-140.3Isitt JJ et al. Schizophr Res. 2016;174(1-3):126-131.

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New long-acting risperidone

• Monthly risperidone

– Risperidone in situ microparticles (ISM) [Rovi]

• 6-month risperidone

– Drug-eluting implant [Braeburn Pharmaceuticals]

– Phase 2/3 study comparable efficacy, safety and plasma levels between oral risperidone and BB0817

https://braeburnpharmaceuticals.com/braeburn-achieves-primary-endpoint-study-implant-schizophrenia/

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Technological solutions: digital medicine for adherence monitoring

• Inevitably, new and innovative technologies are applied to adherence monitoring (“digital medicine”)1,2

• New acronyms– IEM = Ingestible Event Marker– DMS = Digital Medicine System– DHFS = Digital Health Feedback System

• How does a DMS work?3

– Patient ingests pill with sensor embedded in that pill (i.e., IEM)– Wearable sensor patch on left lower ribcage detects stomach-

acid activated signal from IEM– Signal then sent to mobile device app which sends information

to cloud-based server– Patient (or whoever else is granted access) reviews data

1Elenko E et al. Nat Biotechnol. 2015;33:456-61.2Kvedar JC et al. Nat Biotechnol. 2016;34:239-46.3https://www.proteus.com/press-releases/otsuka-and-proteus-announce-the-first-us-fda-approval-of-a-digital-medicine-system-abilify-mycite/

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Digital adherence monitoring:Proteus sensor

• FDA-approves first DMS in November 2017: generic aripiprazole with IEM (brand name Abilify MyCite)

• Very small, very brief, IIa open-label study– 67 adult patients with schizophrenia (majority mildly ill)– Three-visit training phase followed by five-week treatment

phase– Outcomes

• Participants wore sensor median 78% of time• 78% were at least “somewhat satisfied” with the system• A significant minority (27%) did not finish this trial (!)

• Study shows that DMS works for those patients who might need it the least

Peters-Strickland T et al. Neuropsychiatr Dis Treat. 2016;12:2587-94.

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Unresolved questions about digital adherence monitoring in psychiatry

• Does it actually improve adherence in real patients with psychosis, both in short- and long-term?

• How palatable is it for paranoid patients to “swallow a spy?”1

• Will the average patient with serious mental disorders be able to use this technology?2,3

• Which patient group might benefit the most?3

– As always in medicine, patient selection is key• Active substance use, memory problems, no routines

– Monitoring for court-ordered treatment can reduce catastrophic outcomes in selected cases (non-adherence leading to violence)

– Might increase autonomy in community-treated patients who need some medication supervision

1Rosenbaum, L. N Engl J Med. 2018;378:101-3.2Miller BJ et al. Psychiatry Res. 2015;225:458-63.3Hatch A et al. J Clin Psychiatry. 2017;78:e803-e812.

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Societal context and risks of digital adherence monitoring

• Is a technological solutions always progress?– Perhaps inevitable in an age of ubiquitous monitoring

– Is there a generational divide?

• Risks– Medical privacy

– Increasing health disparities (misuse and lack of access)

– Technology could replace meaningful other interventions• Increasing health literacy

• Spending time with patients to understand adherence difficulties

• Working with patients towards accepting evidence-based treatments (clozapine, long-acting injectables)

Masand P et al. Exp Rev Neurotherapeutics. 2017;17:319-21.Hatch A et al. J Clin Psychiatry. 2017 Jul;78(7):e803-e812.

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THINKINGOUTSIDETHE BOX

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Targeting circuits

• Lesion-based module disruption– Critical lesion takes out brain module– Classical neurology

• Distributed yet delineated circuit dysfunction– Alexander’s parallel, segregated circuits1

– Neuropsychiatry

• Large-scale network disruption– The search for specific cellular pathology (e.g.,

chandelier interneurons and GABA2)

• TMS for schizophrenia3

1Alexander GE et al. Annu Rev Neurosci 1986;9:357.2Lewis DA. Dev Neurobiol 2011;71:118.3Dougall N et al. Cochrane Database Syst Rev. 2015 Aug 20;(8):CD006081

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Targeting the microbiome

• Microbial dysbiosis– Microbiome and immune system– Microbiome-gut-brain axis1

• Intervention trials across medicine2

– Fecal microbiota transplantation for GI disorders– Probiotic for Alzheimer’s disease3

– Antibiotics for neuropsychiatric disorders4

• Pilot probiotic intervention trial for schizophrenia (in planning phase)– Characterize microbiome (metagenomic sequencing)– Assess peripheral markers of inflammation– Introduce therapeutic agent to alter gut microbiota

1Burokas A et al. Adv Appl Microbiol. 2015;91:1-62.2Mangiola F et al. World J Gastroenterol. 2016;22:361-8. 3Akbari E et al. Front Aging Neurosci. 2016;8:256.4Dickerson F. Brain Behav Immun. 2017;62:46-52.

“Psychobiotics”

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Targeting the immune system

• Peripheral cytokine abnormalities1

• Neuroinflammation2,3

• Examples

– Antioxidants4

– Antiinflammatory drugs5,6

• Inflammatory markers in CATIE predict PANSS7

1Balotsev R et al. Eur Psychiatry. 2017;39:1-10.2Howes OD and McCutcheon R. Transl Psychiatry. 2017;7(2):e1024.3Mondelli V et al. Lancet Psychiatry. 2017;4:563-72. [microglia review]4Magalhaes PV et al. Cochrane Database Syst Rev. 2016 Feb 5;2:CD008919.5Solmi M et al. CNS Spectr. 2017 Feb 9:1-12. [minocycline review]6Khandaker GM et al. Lancet Psychiatry. 2015;2(3):258–70.7Miller BJ et al. Schizophr Res. 2018;195:275-282.

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“However beautiful the strategy*, you should occasionally look at the results.**”

-Sir Winston Churchill

* = your drug mechanism

** = how effective your drug is Haas LF. JNNP 1996;61:465.

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Glycine Reuptake Inhibitors

• Negative symptoms

• “Area of therapeutic need”

• Glycine reuptake inhibitors

– NMDA hypofunction

– Glycine as allostericmodulator (agonist)

Bitopertin1

1Umbricht D et al. JAMA Psychiatry. 2014;71:637.2Goff DC. JAMA Psychiatry. 2014;71:621. Editorial: 2 negative phase III trials.3Bugarski-Kirola D et al. Biol Psychiatry. 2017:82:8-16. [FlashLyte, DayLyte trials]

Bad news2,3

Good news

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Alpha-7 nicotinic agonists

• Alpha-7 nicotinic agonists– Encenicline, nelonicline (ABT-126), bradanicline (TC-1659), et al – Under development for Alzheimer’s disease and schizophrenia1

• Mechanism of action2,3

– Alpha7nAChR modulates pre-synaptic glutamate release– Kynurenic acid is endogenous alpha-7 nicotinic receptor

antagonist– Nicotinic agonist restores glutamatergic tone if KYNA increased

• Encenicline– FDA Fast Track Designation for “Unmet Medical Need”– Positive phase II trial (d=0.257, P=0.034)4

– Two negative phase III trials

1Barbier AJ et al. Clin Ther 2015;37:311.2Wu HQ et al. J Mol Neurosci 2010;40:204.3Albuquerque EX and Schwarcz R. Biochem Pharmacol 2013:85:1027.4Keefe RSE et al. Neuropsychopharmacology 2015; 40:30523.

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Nelonicline (ABT-126)

• Potent α7 nAChR agonist

• AbbVie development program

– Alzheimer’s dementia

• Phase II: negative for primary outcome variable1

• Phase IIb (adaptive trial design): negative2

– Schizophrenia

• Phase II: some effect in non-smokers3

• Phase IIb: negative for non-smokers4 and smokers5

1Gault LM et al. Alzheimers Res Ther. 2016 Oct 18;8(1):44.2Florian H et al. J Alzheimers Dis. 2016;51(4):1237-47.3Haig GM et al. Am J Psychiatry. 2016;173(8):827-35.4Haigh G et al. Neuropsychopharmacology. 2016;41(12):2893-2902.5Haigh G et al. J Clin Psychiatry. 2018;79(3). pii: 16m11162.

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Omega-3 fatty acids for indicated prevention

STUDY DESIGN• Ultra-high risk patients• Intervention: omega-3 PUFA x 6

months• All participants received Cognitive

Behavioral Case ManagementRESULTS• N=304 randomized• ¼ lost to follow-up• 6-month transition rates (CAARMS):

– Placebo 5.1% (=15)– PUFA 6.7% (=17)

• 12-month transition rates:– Placebo 11.2%– PUFA 11.5%

• No effect of adherence (40%!)

NEURAPRO = ?

McGorry PD et al. JAMA Psychiatry. 2017;74:19-27.Editorial: Kane JM and Correll CU. JAMA Psychiatry. 2017;74:11-2.

1.4 g omega-3 FA (840 mg EPA/560 mg DHA

www.mghcme.org

Why is CNS drug development so hard?

• Schizophrenia as a syndrome– One drug does not fit all psychopathology– One drug does not fit all illness stages– Unknown pathophysiology– No biomarkers1

• Schizophrenia as a circuit disorder– One drug target paradigm could be wrong

• Clinical trials methodology– Placebo response2

– Heterogeneity problem (subgroups)– Deception and professional patients3

– Non-linear dosing– Measuring improvement and ceiling effects (function)

1Goff DC et al. Eur Neuropsychopharmacology. 2016;26(6):923-37.2Leucht S et al. Am J Psychiatry. 2017;174(10):927-942.3Devine EG et al. Clin Trials. 2013;10(6):935-48.