BEYOND MONOAMINES: NOVEL APPROACHES TO ANTIDEPRESSANT TREATMENT
Learning Objective
• Describe the molecular targets of novel agents, including adjunctive treatments, currently being investigated
50% of Patients Respond to MonoaminergicAntidepressants
Deficiency in monoamines
Increase monoamine levels with an antidepressant
50% of Patients DO NOT Respond to Monoaminergic Antidepressants
Adequate monoamines
Increase monoamine levels with an antidepressant
Downstream dysfunction in glutamatergic neurotransmission or
neuroplasticity
Pharmacological modulation of downstream dysfunction in glutamatergic
neurotransmission or neuroplasticity
Duration of antidepressant treatment (days)0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28
Monoamine levels
Depressive symptoms
Changes in neuroplasticityand glutamatergicneurotransmission
Beyond Monoamines: The NeuroplasticityHypothesis of Depression
Beyond Monoamines: The NeuroplasticityHypothesis of Depression
• The depressed brain shows signs of inadequate neuroplasticity and excessive glutamate
• Acting on monoaminergic systems, currently available antidepressants may lead to downstream improvement in neuroplasticity and glutamatergic neurotransmission
• Directly targeting glutamatergic neurotransmission or neuroplasticitymay:
• Lead to faster treatment response (e.g., ketamine)• Improve response and remission rates
Racagni G, Popoli M. Dialogues Clin Neurosci 2008;10(4):385-400; Crupi R, Marino A, Cuzzocrea S. Curr Med Chem 2011;18(28):4284-98; Sanacora G, Treccani G, Popoli M. Neuropharmacology 2012;62(1):63-77; Vidal R, Pilar-Cuellar F, dos Anjos S et al. Curr Pharm Design 2011;17(5):521-33; Banasr M, Dwyer JM, Duman RS. Curr
Opinion Cell Biol 2011;23(6):730-7; Duman RS, Aghajanian GK. Science 2012;338(6103):68-72.
Neuroplasticity: Monoamine Signaling and Brain-Derived Neurotrophic Factor Release BDNF
CREB
synaptogenesisneuroplasticity
cell survival
neurogenesis
BDNF: brain-derived neurotrophic factor
CREB: cAMP response element-binding protein
CaMK: calcium/calmodulin-dependent protein kinase
PKA: protein kinase A
monoamine
Genes turned on
Increased neuroplasticity and reduced glutamatergic neurotransmission
Decreased release of glutamate
Increased proteins involved in neuroplasticity
Activation of cAMP response element binding protein (CREB)
Racagni G, Popoli M. Dialogues Clin Neurosci 2008;10(4):385-400;Barbon A et al. Neurochem Int 2011;59(6):896-905.
Downregulation of NMDA receptors
Increased expression of AMPA receptor subunits
Downstream Improvement in Neuroplasticity and Glutamatergic Neurotransmission
DA 5HT NEMonoamine regulation
PKCRSKCaMK
GSK-3Wnt/FrzcAMP
MAPKSignaling cascades
Directly targeting glutamatergic
neurotransmission or neuroplasticity may lead to faster treatment response
and may improve response and
remission rates
KetamineNMDA receptor
Ca2+
Bunney BG, Bunney WE. Int J Neuropsychopharmacol 2012;15:695-713.
Ketamine Directly Targets Glutamate Neurotransmission
Ketamine Increases Synaptic Plasticity
AMPARs
Increased synaptic plasticity
mTOR
Bunney BG, Bunney WE. Int J Neuropsychopharmacol 2012;15:695-713.
mammalian Target Of Rapamycin: a critical intracellular protein
that mediates neuroplasticity and
neurotrophic processes
glu
AMPAreceptor
NMDAreceptorblocked byketamine
ERK, AKT
mTOR
Stahl SM. Stahl's Essential Psychopharmacology. 4th ed. 2013.
Ketamine’s Antidepressant Effects May Also Be Due to Activation of AMPA Receptors, not the Blocking of NMDA Receptors
Rapid Antidepressant Effect of Ketamine in 18 Patients With Treatment-Resistant Depression
29% were considered to be in remission,with an HDRS score of 7 or below (data not shown)
40min
90min
110min
230min
Day 1
Day 2
Day 3
Day 7
Prop
ortio
n W
ith 5
0% C
hang
e in
Sc
ore
From
Bas
elin
e (H
DR
S)
0.8
0
0.2
0.6
KetaminePlacebo
0.4
1.0
HDRS: Hamilton Depression Rating Scale
Zarate CA Jr et al. Arch Gen Psychiatry 2006;63:856-64.
Ketamine Formulations• Ketamine intranasal administration 50 mg vs saline placebo (n=27)− Effective, easier to administer
• Intranasal esketamine (S-enantimer of racemic ketamine)−0.20 mg/kg and 0.40 mg/kg intravenous esketamine exhibited significant
reductions in MADRS scores compared with placebo (n=30)2
−After a 1-week period, all three intranasal esketamine treatment groups (28 mg, 56 mg, or 84 mg) changes in MADRS total scores were statistically superior to placebo on Day 8 (n=67)3
• Efficacy and safety of intravenous, intramuscular and subcutaneous routes for treating depression with ketamine4
−All three had comparable antidepressant effects; Subcutaneous has fewest adverse effects
1. Lapidus KA et al. Biol Psychiatry. 2014;76(12):970-6. 2. Singh JB et al. Am J Psychiatry. 2016;173(8):816-26.
3. Daly EJ et al. Presented at the 54th Annual Meeting of the ACNP; Dec. 2015; Hollywood, FL.4. Loo CK et al. Acta Psychiatr Scand. 2016;134(1):48-56.
MADRS: Montgomery-AsbergDepression Rating Scale
A Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders
Recommendations from the American Psychiatric Association Council of Research Task Force on Novel Biomarkers and Treatment Recommendations for Clinical Use of Ketamine
Patient Selection • Strongest evidence for major depressive disorder• Less evidence in other mood disorders• Baseline symptom assessment• Antidepressant treatment history• Physical and laboratory • Informed consent including discussion of potential risks and benefits
Clinical Experience and Training
• Currently no recommendations or guidelines• Clinicians should be prepared to manage potential cardiovascular events and behavioral effects of ketamine
Treatment Setting • Setup for monitoring of cardiovascular and respiratory function
Medication Delivery • Most studies use 0.5 mg/kg of IV ketamine delivered over 40 minutes• Dose may need to be adjusted for patients with BMI>30
Follow-up and Assessments • Use rating instruments to assess clinical response and evaluate risk:benefit ratio of continued treatment
Efficacy of Longer-term Repeated Administration
• Studies suggest that repeated dosing may extend the duration of ketamine effects• Ketamine administration 2X/week over 2-3 weeks seems as effective as 3X/week over 2-3 weeks• Taper or discontinue treatment based on an individual patient basis
Safety Measures and Continuation of Treatment
• Risk of cognitive impairment and cystitis are associated with chronic ketamine use• Substance abuse liability• Frequent ketamine administration is not recommended
Future Directions • Major knowledge gaps remain regarding long-term efficacy and safety • Further, large-scale studies are needed • Clinicians providing ketamine treatment are encouraged to participate in coordinated systems of data collection
Sanacora G et al. JAMA Psychiatry. 2017;74(4):399-405.
Other Glutamatergic ModulatorsFailed to Show Efficacy or No Longer in Development
1. Mathew SJ et al. Neuropsychopharmacology. 2017; 2. Zarate CA et al. Am J Psychiatry. 2006;163(1):153-5; 3. Smith EG et al. J Clin Psychiatry 2013; 74: 966–973; 4. Sanacora G et al. Neuropsychopharmacology. 2017;42(4):844-853; 5. Preskorn SH et al. J
Clin Psychopharmacol. 2008;28(6):631-7; 6. Heresco-levy U. et al. Int J Neuropsychopharmacol. 2013;16(3):501-6; 7. Liu RJ et al. Neuropsychopharmacology. 2017;42(6):1231-1242; 8. Nagele P et al. Biol Psychiatry. 2015;78(1):10-8.
Agent TargetRiluzole Voltage-gated
sodium channels
Did not out-preform placebo on mean MADRS10.05
Memantine NMDA receptor Trials for depression unsuccessful2,3
Lanicemine NMDA receptor Failed to show superior efficacy4
CP-101,606 NMDA-NR2B subunit
Ceased due to association with cardiac conduction abnormalities5
EVT-101 NR2B selective antagonist
Clinical hold issued by the FDA
MK-0657 NMDA-NR2B subunit
Weak evidence of efficacy
AZD-6423 NMDA receptor Weak evidence of efficacy
Agent Target
d-Cycloserine NMDA receptor Moderate evidence6
GLYX-13 (rapastinel)
NMDA receptor Currently in Phase III; Moderate evidence7
AVP-786 NMDA receptor, Sigma-1 receptor,
SERT, NET
Phase II clinical trial in MDD) as adjunct
AVP-923 NMDA receptor, Sigma-1 receptor,
SERT, NET
Phase II clinical trial in MDD
Nitrous oxide NMDA receptor Preliminary evidence of efficacy for MDD8
Still in Early Development
Rapastinel: An NMDA Receptor Glycine-Site Functional Partial Agonist vs Postive Allosteric Modulator
•Produces rapid antidepressant effects− Single Dose Study Phase IIA (n=116): Single IV dose of rapastinel dose of 1,
5, 10, or 30 mg, or placebo1
• At 1-week post-infusion, 5 and 10 mg of rapastinel showed significant antidepressant response
− Repeated Dose Study Phase IIB (n=116): Weekly infusions of IV rapastinel(at doses of 1, 5, or 10 mg) or placebo, with follow-up on days 3, 7, and 142
• IV rapastinel 5 or 10 mg showed a reduction in HAM-D scores on days 1 through 7, but no effects were observed thereafter
•No ketamine-like side effects
•Currently in large phase III trials for MDD1. Moskal JR et al. Expert Opin Investig Drugs. 2014;23(2):243-54; 2. Preskorn S et al. J Psychiatr Pract.
2015;21(2):140-9; Liu RJ et al. Neuropsychopharmacology. 2017;42(6):1231-1242.
Endogenous Opioid Receptors
Stahl SM. Stahl's Essential Psychopharmacology. 4th ed. 2013; Benarroch EE. Neurology. 2012;79(8):807-14.
δ κμ
receptorreceptor
receptor
Opioid Peptides𝛽-endorphinenkephalindynorphin
Opioid ReceptorsMu (μ)Delta (δ)Kappa (κ)
Endogenous Opioid Receptors
• δ-opioid receptor agonists and κ-opioid receptor antagonists have antidepressant potential
• Likely to be implicated in mood regulation
• All 3 opioid receptors modulate BDNF activity and neurogenesis in the hippocampus
Opioid Receptor
Main Endogenous
Agonists
Reward Mechanisms
Effect on Pain AgonismEffects on Behavior
Mu (μ) 𝛽-EndorphinMet-enkephalin
Facilitates Analgesia (spinal)
Improved mood, reward and dependence, euphoria, antidepressant-like behavior,
sedation
Delta (δ) Enkephalins Facilitates Analgesia (supraspinal & spinal
analgesia)
Improved mood; antidepressant and antianxiety-like behavior, sedation
Kappa (κ) Dynorphin A Inhibits Analgesia (spinal) Worsened mood; dysphoria, anti-reward, sedation
Benarroch EE. Neurology. 2012;79(8):807-14; Lutz PE, Kieffer BL. Trends Neurosci. 2013;36(3):195-206.
Buprenorphine• Partial mu opioid agonist
• Kappa antagonist
• Currently used in addiction treatment
• Open label, positive data in refractory depression
• Low Dose Buprenorphine Reduces Suicidal Ideation
−Double-blind, placebo-controlled trial 88 patients received either 0.1-0.8 mg/day (mean dose 0.44 mg/day) or placebo for 4 weeks
−Very low dosages of buprenorphine were associated with decreased suicidal ideation in a group of severely suicidal patients without substance abuse
Yovell Y et al. Am J Psychiatry. 2016;173(5):491-8.
ALKS 5461: Buprenorphine & Samidorphan
• Combination of buprenorphine (partial μ-opioid agonist, kappa antagonist) and samidorphan (μ antagonist)
• Samidorphan added to counteract the μ-opioid agonist activity of buprenorphine & reduce its addictive potential
• Kappa antagonism has shown antidepressant activity in animal models
Fava M et al. Am J Psychiatry. 2016;173(5):499-508.
Study 205• Ph III Double-blind, placebo controlled • 11 week trial in AD non-responders
(n=814)• Doses of buprenorphine/ samidorphan−0.5/0.5 mg−2/2 mg
• Both doses not statistically superior to placebo on primary endpoint (MADRS at week 5)−Post hoc analysis showed significance
for the 2/2 mg dose at other time points
ALKS 5461: Buprenorphine & Samidorphan
Ehrich E et al. Biol Psychiatry. 2017;81(10):S23
• Ph III Multicenter, randomized, double-blind, pbo-controlled (n=407)
• Doses of buprenorphine/samidorphan− 1/1 mg− 2/2 mg
• Evidence of antidepressant activity in both groups
• Statistically significant for the 2/2mg group only
Study 207
The most common AEs:− Nausea− Dizziness− Fatigue
2/2mg Superior to Placebo− Improving core symptoms of
depression (MADRS-6, p=0.018)− Overall symptoms of depression
(MADRS-10, p=0.026)
No pattern of AEs indicative of abuse potential
ALKS 5461 as Adjunct in MDD
•Study 208: ongoing long-term phase 3b will evaluate the efficacy, safety, and tolerability of ALKS 5461 as adjunctive treatment in patients with MDD
•Agonist-antagonist opioid modulation represents a novel approach to the treatment of MDD
•May be an alternative to adjunct treatment with antipsychotics
Ehrich E et al. Neuropsychopharmacology. 2015;40(6):1448-55; Fava M et al. Am J Psychiatry. 2016;173(5):499-508.
Onabotulinumtoxin A•Acetylcholine (Ach) release inhibitor and neuromuscular blocking agent
•2 positive randomized-controlled trials in MDD
•Effects of one injection last up to 16 weeks
•Treatment in the glabellar (forehead) region can treat MDD
•3 groups (n=101)−Statistically significant reduction in depressive symptoms in those
who received botulinum toxin A versus placebo injections in the frown muscles.
Cohen IV et al. Sci Rep. 2017;7(1):1450; Magid M et al. J Clin Psychiatry. 2014;75(8):837-44; Parsaik AK et al. J Psychiatr Pract. 2016;22(2):99-110.
Increased Cholinergic Activity Associated with Depression
•Depression may be associated with hyperactivation of the cholinergic system and, as a consequence, decreased activity in the noradrenergic system
•Anticholinergic agents have been associated with antidepressant effects−These antidepressant effects are thought to be mediated through
downstream increase in neuroplasticity
•Typical anticholinergic adverse side effects, such as dry mouth, blurred vision, and drowsiness may imply limitation to its broad clinical use
Dale E et al. Biochem Pharmacol. 2015;95(2):81-97; Scarr E et al. Front Cell Neurosci. 2013;7:55.
Rapid Antidepressant Actions of Scopolamine
•Acetylcholine muscarinic (AChM) receptor antagonist
•Double-blind, placebo-controlled, crossover clinical trial (n=18)−Scopolamine infused at 4.0 μg/kg intravenously produced robust antidepressant effects versus placebo, which were evident within 3 days after the initial infusion1
•Scopolamine may exert antidepressant effects by acting on the MTORC1 complex via the mTOR pathway and thereby inducing synaptogenesis
1. Drevets WC et al. Biol Psychiatry. 2013;73(12):1156-63; Navarria A et al. Neurobiol Dis. 2015;82:254-61; Khajavi D et al. J Clin Psychiatry. 2012;73(11):1428-33.
Emerging Somatic Treatments
•Deep Transcranial Magnetic Stimulation (DTMS)
•Repetitive Transcranial Magnetic Stimulation (rTMS)
•Synchronized Transcranial Magnetic Stimulation (sTMS)
•Low Field Magnetic Stimulation (LFMS)
Bewernick B et al. F1000Res. 2015;4
Summary
•Neurobiological substrates of depression may go beyond monoaminergic circuits
•Glutamatergic targets like ketamine, esketamine, and rapastinel have shown promise in treatment of MDD
•Opioid agents like buprenorphine and ALKS 5461 have shown efficacy in treatment of MDD
•Additional research is needed to validate these targets
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