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Home , Amitifadine, Apimostinel, Desvenlafaxine, Tedatioxetine

Novel Treatments for Mood Disorders

Michael E. Henry, MD Medical Director Bipolar Clinic and Research Program Director Somatic Therapy Massachusetts General Hospital

www.mghcme.org Disclosures

My spouse/partner and I have the following relevant financial relationship with a commercial interest to disclose: Spouse is an employee of Roche Pharmaceuticals

www.mghcme.org MDD Statistics

• 12 month prevalence U.S.: 9% • Mortality from : 20+ x gen pop • Increased risk of CV death. • Economic Costs to U.S: $36.6 Billion

Lepine JP, Briley M. Neuropsychiatr Dis Treat 2011; 7(suppl 1) 3-7.

www.mghcme.org Network Depression Model: must accommodate defining clinical symptoms

attention-cognition-action

PF9 PM6 P40 pCg

hippocampus

mF9/10 self emotion- mood cognition aCg24 salience cd-vs thal mb-sn state integration oF11 reward

Cg25 a-ins am hth pag/dr

arousal-autonomic-circadian www.mghcme.org Depression Model

Adapted from Mayberg, 2003

www.mghcme.org Potential Mechanisms For New Treatments

Monoamines Augmentation

Glutamate/GABA Inflammation /Metabolic Neuromodulation

www.mghcme.org Monoamine Projections

Neurowiki2012 –MAO in depression www.mghcme.org Modulators

• FKB01 MD - SSRI (TCA’s) - 5-HT2; 5-HT1A agonist; 5-HT1D - Speed of onset may be faster.

• Lumateperone ITI-007 - Bipolar Depression; ; Dementia - SSRI; 5-HT2A, D2 antagonist; presynaptic D2 partial agonist. - Negative symptoms. - Phase III

• Min-117 - SDRI - Targets “Anxio-Depressive symptoms”.

www.mghcme.org Triple Reuptake Inhibitors (SNDRI’s) • Ideal Profile: Strong SERT; intermediate NET;

and mild DAT inhibition. S. Stahl 2013 • • •

• Ginkgo biloba extract (EGb761) Wikipedia 2017

www.mghcme.org SNDRI’s

• : -SERT:NET:DAT:12:23:96 -Positive - phase IIa trial -Negative - phase IIb/IIIa trial - ? Dosing -Weight loss development program • Ansofaxine -Prodrug of -SERT:NET:DAT: 4:5:3 -Phase I trials completed.

www.mghcme.org SNDRI’s

• Liafensine: - Comparable efficacy to - Abuse potential • : -SERT:NET:DAT:11:1.7:65 - Weight loss • : -SERT:NET:DAT:N/A; - Acetylcholine; 5-HT3, 5-HT2c - chosen

www.mghcme.org Acetylcholine

• JNJ-39393406 - Alpha -7 Nicotinic acetylcholine PAM - Phase II for MDD, smoking - D/C’d AD and schizophrenia.

www.mghcme.org Second Generation - FDA Mood Indications

• - TRD - or Mixed • - Mania and Mixed episodes - Augmentation of MDD • - Bipolar I depression • - Bipolar I Manic and Mixed episodes • - Bipolar I Manic and Mixed episodes - Bipolar I Adjunct to Li or Valproate

• DSP-1200 - Alpha -2, D2, 5-HT2A antagonism - Phase I

www.mghcme.org Opiates and Monamines

Lutz PE, Kieffer BL., Trends Neurosci 2013; 195- 206

www.mghcme.org Opiate Receptors

• Mu - Increased GABA tone on 5-HT neurons • Kappa - Agonists are potent analgesics - Dysphoria, hallucinations, dissociation - Antagonists reverse learned helplessness. - Dynophan: decreases Glu and DA - BDNF • Delta - BDNF • Receptor Like 1 (ORL1) -Nociceptin

Dhir A. Expert Opinion on Investigational Drugs; 2016 www.mghcme.org Opiate Candidates

• - MOR partial agonist; KOR antagonist - Used off label for TRD - Abuse potential • ALKS-5461 - buprenorphine/samidorphan - KOR antagonist - NDA Filed.

www.mghcme.org CERC - 501

• Short acting KOR antagonist. • 30 fold selectivity for k receptors relative to mu and delta OR’s. • 2017 sold to Janssen

www.mghcme.org BTRX-246040

• Selective Nociceptin (ORL-1) antagonist. • Increases Monoamines; enhances neurogenesis; and activates the HPA axis.

www.mghcme.org Glutamate

www.mghcme.org NMDA

• Ketamine/Esketamine –NDA filed. • AV-101: Prodrug; B antagonist. - Neuroprotective in animal models. - Phase II trials underway. • GLYX-13: MoAB, NMDA-glycine partial agonist - Phase II separated from PBO. • : NMDA-glycine partial agonist. Phase II trials of oral agent.

Dhir A. Expert Opinion on Investigational Drugs; 2016

www.mghcme.org NMDA/NR2B/AMPA

• CERC-301 - NR2B selective NMDA antagonist. - Phase II (despite fast track status FDA). • - 2016 Breakthrough Therapy designation from FDA - NR2B triggers influx of intracellular calcium - Increased AMPA

www.mghcme.org Combination

• AXS – 05 - Buproprion/ - DM: NMDA and sigma-1 agonist, SNRI

www.mghcme.org GABA Modulators

• Ganaxolone - GABA-A Allosteric modulator-hyperpolarizes • SAGE-217 - GABA-A Allosteric modulator • Brexanolone - GABA-A Allosteric modulator - Post partum depression.

www.mghcme.org Neuromodulation

Henry et al., J. ECT 2001

www.mghcme.org Neuromodulation

• TMS: Theta burst - 5 RCT’s, 221 subjects

- pooled RR 35.6% v 17.5% p=0.005 Berlim MT et al. , 2017 • ECT- FEAST - Open label, 20 depressed adults

- HDRS 58.1% decrease (p< 0.0001) Sahlem GL et al., 2016 • Magnetic Seizure and iLAST Therapy

www.mghcme.org Inflammation and Depression

Inflammatory HPA Axis Cytokines

BDNF Monoamine IDO reuptake

Adapted from Nekovarova T. et al., Depression Front Behav Neurosci 2014; 8:99 epub

www.mghcme.org Inflammatory Markers and Depression

Meta Analysis 1967 - 2008 • Interleukin-1 d=0.35 (95%CI:0.03-0.67) p=0.03 • Interleukin-6 d=0.25 (95%CI:0.18-0.31) p<0.001 • C-Reactive Protein d=0.15 (95%CI:0.10-0.21) p<0.001 Howren M, et al. Psychosomatic Medicine 2009; 71:171-186.

www.mghcme.org

• 2 Trials in MDD - Dean et al.(2017): 71 MDD, 36 randomized to minocycline. Excluded if failed 3 or more antidepressant trials Week 12 MADRS -4, p = 0.624 - Husain et al. (2017): 41 MDD, 21 randomized to minocycline. Included if failed at least 2 Week 12 HAM-D17 -18, d=-1.21 p<0.001.

www.mghcme.org Celecoxib

• 4 RCT’s in MDD • 200 -400 mg/day • , , (p=0.058) • OR: 6.607 (2.729, 15,994) z= 4.186, p<0.001.

• Bipolar: 1 RCT • Antidepressant response rapid but short lived.

Husain MI. et al., Journal of Psychopharmacology 2017; 31:1137-48. Faridhoseini F et al., Human Psychopharmacology 2014; 29:216-213.

www.mghcme.org Pioglitazone

• 1 RCT, 6 weeks • BP-I • 2015: Pioglitazone = 22; HDRS p=0.006

Rosenblat JD et al., Bipolar Disorder 2016; 18:89-101

www.mghcme.org Infliximab

• Tumor Necrosis Factor (TNF) • 60 subjects, 30 Infliximab, 3 infusions. • No Difference in HAM-D scores. • Sugestion that elevated CRP may define treatment responsive subtype.

Rosenblat JD et al., Bipolar Disorder 2016; 18:89-101.

www.mghcme.org Purine Antagonists

• JNJ-54175446 -P2X7 -Gene in area identified as susceptible to mood disorders - Receptor highly expressed in microglia

Neuroscience and Behavioral Reviews, 2018:192-205

www.mghcme.org Nutrition/weight loss

• First module (sessions 1-6) • Two Goals

1.) Enhance Nutrition • Review “Harvard” food plate • Teach serving size/portion control • Discussion of vitamins and minerals

2.) Promote Weight Loss • Monitor weight and vitals weekly • Discuss obstacles to losing weight and problem solving strategies • Tips for creating low-fat meals and making diet substitution • Functional analysis of poor eating behaviors

www.mghcme.org Weight Loss/Obesity

NEW Tx associated with nearly 10 lb weight loss (5.7% of body weight) Associated with improved mood and quality of life Obesity associated with depression and poor quality of life Weight loss associated with improved depression, quality of life., and cognition

Daumit et al. N Engl J Med. 2013; Napoli et al., Am J Clin Nutr. In press; Sylvia et al. Int J Bipolar Disord. 2013; Vannucchi et al., J of Affect Disord. 2014.

www.mghcme.org Botox

• Corrugator and Procerus muscles injections • Facial nerve signaling shifts.

www.mghcme.org Conclusions

• Opiates and Glutamate/GABA are the predominant themes. • Opiates will have to show abuse potential is not an issue. • The immune/inflammation hypothesis of mood disorders may be directly targetable.

www.mghcme.org References

1. Individual Company websites. 2. Clinical trials.gov 3. FDA.gov 4. Wikipedia; 9/23/2018 List of Investigational Antidepressants. 5. Mental Health Daily; 30+ New Antidepressants (2018): Drugs in Clinical Trials.

www.mghcme.org