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 Suicide: 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 Antidepressant Treatments Monoamines Augmentation Opioids Glutamate/GABA Inflammation /Metabolic Neuromodulation www.mghcme.org Monoamine Projections Neurowiki2012 –MAO in depression www.mghcme.org Serotonin Modulators • FKB01 MD - SSRI (TCA’s) - 5-HT2; 5-HT1A agonist; 5-HT1D - Speed of onset may be faster. • Lumateperone ITI-007 - Bipolar Depression; Schizophrenia; 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 • Cocaine • Phencyclidine • Ketamine • Ginkgo biloba extract (EGb761) Wikipedia 2017 www.mghcme.org SNDRI’s • Amitifadine: -SERT:NET:DAT:12:23:96 -Positive - phase IIa trial -Negative - phase IIb/IIIa trial - ? Dosing -Weight loss development program • Ansofaxine -Prodrug of desvenlafaxine -SERT:NET:DAT: 4:5:3 -Phase I trials completed. www.mghcme.org SNDRI’s • Liafensine: - Comparable efficacy to Duloxetine - Abuse potential • Tesofensine: -SERT:NET:DAT:11:1.7:65 - Weight loss • Tedatioxetine: -SERT:NET:DAT:N/A; - Acetylcholine; 5-HT3, 5-HT2c -Vortioxetine 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 Antipsychotics - FDA Mood Indications • Olanzapine - TRD - Mania or Mixed • Aripiprazole - Mania and Mixed episodes - Augmentation of MDD • Lurasidone - Bipolar I depression • Cariprazine - Bipolar I Manic and Mixed episodes • Ziprasidone - 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 • Opioid Receptor Like 1 (ORL1) -Nociceptin Dhir A. Expert Opinion on Investigational Drugs; 2016 www.mghcme.org Opiate Candidates • Buprenorphine - 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; glycine B antagonist. - Neuroprotective in animal models. - Phase II trials underway. • GLYX-13: MoAB, NMDA-glycine partial agonist - Phase II separated from PBO. • Apimostinel: 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). • Rapastinel - 2016 Breakthrough Therapy designation from FDA - NR2B triggers influx of intracellular calcium - Increased AMPA www.mghcme.org Combination Medication • AXS – 05 - Buproprion/dextromethorphan - 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 Minocycline • 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 antidepressants Week 12 HAM-D17 -18, d=-1.21 p<0.001. www.mghcme.org Celecoxib • 4 RCT’s in MDD • 200 -400 mg/day • Sertraline, Fluoxetine, Reboxetine (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 receptor antagonist -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.