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 Potential Mechanisms For New Antidepressant Treatments Monoamines Augmentation Opioids Glutamate/GABA Inflammation /Metabolic Neuromodulation

7 Monoamine Projections Neurowiki2012 MAO in depression

8 Serotonin Modulators FKB01 MD - SSRI (TCA s) - 5-HT2; 5-HT1A agonist; 5-HT1D - Speed of onset may be faster. Lumateperone ITI Bipolar Depression; Schizophrenia; Dementia - SSRI; 5-HT2A, D2 antagonist; presynaptic D2 partial agonist. - Negative symptoms. - Phase III Min SDRI - Targets Anxio-Depressive symptoms.

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 Ansofaxine -Prodrug of desvenlafaxine -SERT:NET:DAT: 4:5:3 -Phase I trials completed.

11 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

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

13 Second Generation Antipsychotics - 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 Alpha -2, D2, 5-HT2A antagonism - Phase I FDA Mood Indications

14 Opiates and Monamines Lutz PE, Kieffer BL., Trends Neurosci 2013;

15 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

16 Opiate Candidates Buprenorphine - MOR partial agonist; KOR antagonist - Used off label for TRD - Abuse potential ALKS buprenorphine/samidorphan - KOR antagonist - NDA Filed.

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

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

19 Glutamate

20 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

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

22 Combination Medication AXS 05 - Buproprion/dextromethorphan - DM: NMDA and sigma-1 agonist, SNRI

23 GABA Modulators Ganaxolone - GABA-A Allosteric modulator-hyperpolarizes SAGE GABA-A Allosteric modulator Brexanolone - GABA-A Allosteric modulator - Post partum depression.

24 Neuromodulation Henry et al., J. ECT 2001

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

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

27 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:

28 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.

29 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:

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

31 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:

32 Purine Antagonists JNJ P2X7 receptor antagonist -Gene in area identified as susceptible to mood disorders - Receptor highly expressed in microglia Neuroscience and Behavioral Reviews, 2018:

33 First module (sessions 1-6) Two Goals Nutrition/weight loss 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

34 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

35 Botox Corrugator and Procerus muscles injections Facial nerve signaling shifts.

36 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.

37 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.