novel treatments for mood disorders · novel treatments for mood disorders michael e. henry, md...
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Novel Treatments for Mood Disorders
Michael E. Henry, MDMedical Director
Bipolar Clinic and Research ProgramDirector
Somatic Therapy Massachusetts General Hospital
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Disclosures
My spouse/partner and I have the following relevant financial relationship with a commercial
interest to disclose:
Speaker Sunovion Pharmaceuticals
Consultant ITI Pharmaceuticals
Spouse is an employee of Roche
Pharmaceuticals
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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.
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Network Depression Model:
must accommodate defining clinical symptoms
attention-cognition-action
emotion-cognition
integration
arousal-autonomic-circadian
oF11
aCg24
selfmF9/10
salience
reward
PF9
thalcd-vs
Cg25
P40
hippocampus
hth pag/dr
a-ins
am
pCg
moodstatemb-sn
PM6
Mayberg, 2003
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Depression Model
Adapted from Mayberg, 2003
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Potential Mechanisms For New Antidepressant Treatments
Monoamines Opioids
Glutamate/GABA
Augmentation
Inflammation /Metabolic Neuromodulation
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Monoamine Projections
Neurowiki2012 –MAO in depression
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Norepinephrine
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Serotonin Modulators
• Gepirone- 5-HT1A partial agonist; metabolite A2 antagonist- Low dose - anxiolytic; Hypoactive Sexual Desire Disorder- High dose –antidepressant; - Twice rejected by FDA
• Min-117- SDRI- Targets “Anxio-Depressive symptoms”.- Phase IIB (2015) -? efficacy
https://fabrekramer.com/company
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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
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SNDRI’s
• Amitifadine:-SERT:NET:DAT:12:23:96-Positive - phase IIa trial-Negative - phase IIb/IIIa trial - ? Dosing-Smoking cessation
• Ansofaxine-Prodrug of desvenlafaxine (DA)-SERT:NET:DAT: 4:5:3-Phase III trials underway in China and U.S.
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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- Bipolar I Depression
• Ziprasidone- Bipolar I Manic and Mixed episodes- Bipolar I Adjunct to Li or Valproate
• DSP-1200- Alpha -2, D2, 5-HT2A antagonism- Phase I
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Opiates and Monamines
Lutz PE, Kieffer BL., Trends Neurosci 2013; 195- 206
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Opiate Receptors
• Mu- Increased GABA tone on 5-HT neurons
• Kappa- Agonists are potent analgesics- Dysphoria, hallucinations, dissociation- Antagonists reverse learned helplessness.- BDNF
• Delta- BDNF/Neuroprotective- Persistent pain/stress not acute pain
• Opioid Receptor Like 1 (ORL1) -Nociceptin
Dhir A. Expert Opinion on Investigational Drugs; 2016
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Opiate Candidates
• Buprenorphine
- MOR partial agonist; KOR antagonist
- Used off label for TRD
- Abuse potential
• BTRX – 335140
- Selective K opioid antagonist
- Phase I
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JNJ-67953964
• Short acting KOR antagonist.
• 30 fold selectivity for k receptors relative to mu and delta OR’s.
• 2017 sold to Janssen (CERC-501)
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BTRX-246040
• Selective Nociceptin (ORL-1) antagonist.
• Increases Monoamines; enhances neurogenesis; and activates the HPA axis.
• MDD – IIA study did not meet primary or secondary endpoints.
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Glutamate
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NMDA
• Ketamine/Esketamine –Approved.
• 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
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NMDA/NR2B/AMPA
Rapastinel
- 2016 Breakthrough Therapy designation
from FDA
- NR2B triggers influx of intracellular calcium
- Increased AMPA
- Phase III trials negative.
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Combination Medication
• AXS – 05
- Buproprion/dextromethorphan
- DM: NMDA and sigma-1 agonist, SNRI
- Breakthrough Therapy
- Phase III (GEMINI)
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GABA Modulators
• Ganaxolone- GABA-A Positive allosteric modulator-- Hyperpolarizes- Epilepsy, Anxiety- Phase II Post-Partum Depression
• SAGE-547 - Brexanolone- GABA-A Allosteric modulator- Intravenous- Post partum depression – Approved.
• SAGE 217- Oral formulation- Phase III PPD – positive;- Phase III MDD - underway
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Genotyping
• Cytochrome P450 Isoenzymes
• SERT (S)
• Antidepressant transport
• Individual Receptors -5-HT1A; 5-HT-2A
• BDNF – Val 66Met – decreased hippocampalvolume
• IL-1b - mRNA levels higher in non-responders.
• IL-6 (rs 7801617) – escitalopram response.
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Genotyping
FDA: October 31, 2018:
• “… the relationship between DNA variations and the effectiveness of antidepressant medications has never been established.”
• “There are a limited number of cases for which at least some evidence does exist to support a correlation between a genetic variant and drug levels within the body, and this is described in the labeling of FDA cleared approved genetic test and FDA approved medications.”
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Inflammatory Cytokines
HPA Axis
BDNF Monoamine reuptake
IDO
Depression Adapted from Nekovarova T. et al., Front Behav Neurosci 2014; 8:99 epub
Inflammation and Depression
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Weight Loss/Obesity
◼Obesity associated with depression and poor quality of life
◼Weight loss associated with improved depression, quality of life., and cognition
- Exercise v Diet
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.
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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<0.001Howren M, et al. Psychosomatic Medicine 2009; 71:171-186.
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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.
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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.
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Pioglitazone
• 1 RCT, 6 weeks
• BP-I
• 2015: Pioglitazone = 22; HDRS p=0.006
Rosenblat JD et al., Bipolar Disorder 2016; 18:89-101
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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.
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Purine Antagonists
• JNJ-54175446
- P2X7 receptor antagonist:Blocks IL 1B, IL18
- Gene in area identified as susceptible to
mood disorders
- Positive in animal models.
- Phase I
Neuroscience and Behavioral Reviews, 2018:192-205
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Botox
• Corrugator and Procerus muscles injections
• Facial nerve signaling shifts.
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Neuromodulation
Henry et al., J. ECT 2001
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Neuromodulation
• Deep TMS
• TMS: Theta burst
- 5 RCT’s, 221 subjects
- pooled RR 35.6% v 17.5% p=0.005 Berlim MT et al. , 2017.
• ECT- Multifocal Stimulation
• Magnetic Seizure and iLAST Therapy
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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.
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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.