Novel Treatments for Mood Disorders

Transcription

1 Novel Treatments for Mood Disorders Michael E. Henry, MD Medical Director Bipolar Clinic and Research Program Director Somatic Therapy Massachusetts General Hospital

2 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

3 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.

4 Network Depression Model: must accommodate defining clinical symptoms attention-cognition-action PF9 PM6 P40 pcg hippocampus emotioncognition integration mf9/10 acg24 of11 self salience reward cd-vs thal mb-sn mood state Cg25 a-ins am hth pag/dr arousal-autonomic-circadian

5 Depression Model Adapted from Mayberg, 2003

6 Depression Model Adapted from Mayberg, 2003

7 Potential Mechanisms For New Antidepressant Treatments Monoamines SNDRI s Augmentation Second Generation Antipsychotics Opioids Kappa antagonists Buprenorphine Glutamate -Ketamine -S-Ketamine - Memantine Neuromodulation TMS ECT- FEAST DBS MST Inflammation /Metabolic Statins Minocycline Exercise

8 Monoamine Projections Neurowiki2012 MAO in depression

9 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

10 SNDRI s Amitifadine: -SERT:NET:DAT:12:23:96 -Positive - phase IIa trial -Negative - phase IIb/IIIa trial -? Dosing -Weight loss development program Ansofaxime -Prodrug of desvenlafaxine -SERT:NET:DAT: 4:5:3 -Bioavailability studies completed. Clinical trials.gov

11 SNDRI s Tesofensine: -SERT:NET:DAT:11:1.7:65 Tedatioxetine: -SERT:NET:DAT:N/A; - Acetylcholine; 5-HT3, 5-HT2c -Vortioxetine chosen

12 Second Generation Antipsychotics - FDA Mood Indications 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

13 Opiate Receptors Mu - Increased GABA tone on 5-HT neurons Kappa - Dynophan: decreases Glu and DA - BDNF Delta - BDNF Opioid Receptor Like 1 (ORL1) Dhir A. Expert Opinion on Investigational Drugs; 2016

14 Opiate Candidates Buprenorphine (µ, ORL-1 partial agonist; k antagonist) ALKS buprenorphine/samidorphan (µ antagonist) - Phase III negative to date. CERC-501 (selective k antagonist). - Currently in Phase II trials.

15 Glutamate

16 NMDA Ketamine/Esketamine AV-101: glycine B antagonist. - Phase II trials underway. AVP-786: D-Dextromethorphan/quinidine - Phase II trials underway. GLYX-13: MoAB, NMDA-glycine partial agonist - Phase II separated from pbo. Dhir A. Expert Opinion on Investigational Drugs; 2016

17 Neuromdulation 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< ) Sahlem GL et al., 2016 Magnetic Seizure and ilast Therapy

18 Inflammatory Markers and Depression Meta Analysis Interleukin-1 d=0.35 (95%CI: ) p=0.03 Interleukin-6 d=0.25 (95%CI: ) p<0.001 C-Reactive Protein d=0.15 (95%CI: ) p<0.001 Howren M, et al. Psychosomatic Medicine 2009; 71:

19 Inflammatory Cytokines HPA Axis BDNF Monoamine reuptake IDO Depression Adapted from Nekovarova T. et al., Front Behav Neurosci 2014; 8:99 epub

20 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 = 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.

21 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:

22 Celecoxib 4 RCT s in MDD mg/day Sertraline, Fluoxetine, Reboxetine (p=0.058) OR: (2.729, 15,994) z= 4.186, p< Bipolar: 1 RCT Antidepressant response rapid but short lived. Husain MI. et al., Journal of Psychopharmacology 2017; 31: Faridhoseini F et al., Human Psychopharmacology 2014; 29:

23 N-Acetylcysteine 2 RCT s, 24 weeks duration BPI and BPII 2008: NAC = 38; MADRS p= : NAC = 76; MADRS NS. Rosenblat JD et al., Bipolar Disorder 2016; 18:

24 Pioglitazone 1 RCT, 6 weeks BP-I 2015: Pioglitazone = 22; HDRS p=0.006 Rosenblat JD et al., Bipolar Disorder 2016; 18:89-101

25 Nutrition/weight loss Module 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

26 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

27 Conclusions Multiple Modalities are under active exploration. Glutamate system offers an array of targets. Metabolic consequences of illness/medications suggests some acute treatments may worsen long-term course of illness. Convergence of effects suggests combination of therapies/targets are worth exploring.