Presented by Dr. Adam J. Prus, this one-hour long webinar offered an overview of the monoamine hypothesis of antidepressant drug actions. Participants learned about general research and development approaches for developing novel antidepressant drugs. The presentation focused on a new class of antidepressant drugs called Triple Reuptake Inhibitors, which are currently being tested in clinical trials.
2. Historical and modern developments in antidepressant
drug research
Topics covered
Classes of antidepressant drugs
Biological actions
Therapeutic effects
Adverse effects
Triple reuptake inhibitors
Is ketamine an antidepressant drug?
3. Depression
Lifetime prevalence of major depressive disorder among
U.S. individuals is 16% (Kessler et al. 2005)
Occurs across age groups
About 1 in 6 commit suicide
CDC finds antidepressants drugs third most prescribed
among those 18 and older
Lifetime prevalence of major
depressive disorder across age
Most prescribed among 18 to 44 year olds groups (Kessler et al. 2005)
Women twice as likely as men to take
antidepressant drug
4. The Dawn of Psychopharmacology
Major psychoactive medications discovered in 1950s
Henri Laborit discovers reduction in psychosis by chlorpromazine (Thorazine)
in 1952 (first antipsychotic drug)
The antipsychotic haloperidol (Haldol) discovered in 1958
The first antidepressant drug, iproniazid (Marsilid), synthesized in 1953
Other related 1950’s discoveries
In 1954, James Olds and Peter Milner report on a reward system in the brain
In 1957, Kathleen Montagu discovers dopamine in the brain. Arvid Carlsson,
in 1958, determines that central nervous system dopamine has functional
significance as it mediates effects of the drug reserpine
5. Iproniazid
First developed for treatment of tuberculosis in 1953 (Fox & Gibas, 1953)
Found to reverse sedation and pupil constriction caused by reserpine
Reserpine later found to deplete monoamine neurotransmitter levels
In 1959, Saunders and colleagues report first clinical data revealing reduced
depressive mood
Later discovered to inhibit monoamine oxidase, an enzyme that breaks down
monoamine neurotransmitters (dopamine, norepinephrine, and serotonin).
Monoamine hypothesis for depression: Monoamine neurotransmitter deficiency
causes depressed mood.
6. MAO Inhibitors
Antidepressant drugs that inhibit monoamine oxidase (MAO)
MAO Inhibitors prevent break down of serotonin, dopamine, and norepinephrine
Other monoamine chemicals, such as tyramine
MAO types
MAOA: Brain, PNS, and intestinal tract
MAOB: Brain and lesser extent in PNS
7. MAO Inhibitors
Cheese reaction
Increased heart rate, hypertension, sweating, inhibited digestion, and other
symptoms caused by activated sympathetic nervous system
Occurs when peripheral norepinephrine and tyramine levels elevate
Patients advised to avoid dairy products, meats, and grains when taking MAO
inhibitors
Response time
May require several weeks for antidepressant effects
8. MAO Inhibitors
Irreversible MAO inhibitor
Drug never releases from MAO
Neurons must synthesize more MAO
Iproniazid
Reversible MAO inhibitor
Drug either temporarily binds to MAO or other compounds such as tyramine
displace the drug from MAO
9. MAO Inhibitors
Modern MAO inhibitors
Selective MAOB inhibitors
Act mainly in brain
Reduced risk of cheese reaction
Selegiline (Emsam)
Reversible inhibitor of MAOA
Selectively inhibits MAOA
Can be displaced by tyramine
Reduced risk of cheese reaction
Moclobemide (Aurorix, Manerix)
10. Imipramine
Developed from attempt to make chlorpromazine-like drugs for treating
schizophrenia
First tricyclic antidepressant drug
Failed to cause cheese reaction
Imipramine Chlorpromazine
11. Tricylic antidepressant drugs
Block reuptake of norepinephrine and serotonin
Led to notion that increasing norepinephrine and serotonin concentrations
may be sufficient for antidepressant effects
Antagonist for various receptors
Often muscarinic receptors
Can cause dry mouth, dry eyes, constipation, and other effects from
blocking peripheral receptors
Often histamine receptors
Sedation
Several weeks for efficacy
12. Further antidepressant drug development
Success of tricyclic antidepressant drugs sparked efforts into developing new
antidepressant drugs
Studies conducted to specifically evaluate serotonin’s role in depressed mood
In 1960’s, Arvid Carlsson worked with Astra Pharmaceuticals to develop
zimelidine (Zelmid), the first selective serotonin reuptake inhibitor
Marketed in Europe beginning in 1981
Withdrawn because it was found to damage myelin sheathing around
central and peripheral axons
13. Fluoxetine (Prozac)
Ray Fuller, a senior pharmacologist at Lilly, began pushing to develop serotonin
drugs for treating depression
Fuller, biochemist David Wong, and chemist Bryan Molloy worked to develop
compounds, discovering drugs that inhibited reuptake of serotonin
In 1974, this team develops Lilly 110140, also known as fluoxetine
In 1983, John Feighner publishes clinical study showing fluoxetine equivalent to
tricyclic antidepressants, but without most adverse effects
Fluoxetine met FDA approval in 1987
14. Selective Serotonin Reuptake Inhibitors
Inhibit serotonin transporters
Increased activation of serotonin receptors, such as 5-HT2A and 5-HT1A
May require several weeks for efficacy
Serotonin Syndrome: agitation, restlessness, disturbances in cognitive
functioning, and possibly hallucinations
Serotonin discontinuation syndrome: sensory disturbances, sleeping
disturbances, disequilibrium, flulike symptoms, and gastrointestinal effects
Sexual side effects: erectile dysfunction, inability to achieve orgasm, and loss of
sexual drive
Approximately 1/3rd of patients (Clayton et al., 2001)
16. SSRI vs. SNRI
According to a review of antidepressant clinical trials, SNRIs consistently reveal greater
improvements in depressive symptoms than SSRIs. However, these differences were seldom
robust. (Papakostas et al., 2007).
17. Atypical Antidepressant Drugs
Also referred to as “multi-modal antidepressant drugs”
Do not fall into previously described categories
Bupropion (Wellbutrin): Dopamine and norepinephrine reuptake inhibitor
Comparable in efficacy to SSRIs for depression
Might be less effective when anxiety associated with depression (Papakostas
et al. 2008)
Reduced risk of sexual dysfunction (Clayton et al., 2002)
Requires several weeks for significant clinical response (e.g., Weihs et al.,
2002)
18. Where We Are
Serotonin-
Tricyclic Selective Serotonin Norepinephrine
MAO Inhibitors Antidepressants Reuptake Inhibitors Reuptake Inhibitors
Dopamine Norepinephrine Serotonin Serotonin
Norepinephrine Serotonin Norepinephrine
Serotonin Antagonism of
muscarinic and
Atypical
histamine receptors
Antidepressants
Dopamine
Norepinephrine
19. Where We Are Going
New antidepressants drugs will focus on
Lengthy response time
Changes in dopamine receptors
Role in anhedonia, goal-directed behavior, etc.
Proliferation in hippocampus
Sexual dysfunction
Might be due to serotonin
20. A Triple Reuptake Inhibitor?
Triple reuptake inhibitors
A drug that can block reuptake of serotonin, dopamine, and norepinephrine
Reduced selectivity of serotonin reuptake may reduce risk of sexual
dysfunction
Increased concentrations of dopamine may reduce response time
Proof of concept: Studies combining SSRI with bupropion (a dopamine-
norepinephrine reuptake inhibitor)
21. A Triple Reuptake Inhibitor?
Augmentation with bupropion for SSRI or SNRI
Improves response in patients resistant to SSRI or SNRI (DeBattista et al.
2003)
“Antidote” for SSRI- or SNRI-induced sexual dysfunction (review by Zisook et
al., 2006)
22. A Triple Reuptake Inhibitor?
Development status
In 2007, at least 4 companies working on TRI’s (Skolnick & Basile, 2006)
Neurosearch partnering with Glaxo Smith & Kline
DOV Pharmaceuticals
Sepracor
Albany Molecular partnering with Bristol Meyers Squibb
DOV 216,303
Effective in 2-week clinical study w/ no placebo control
Clinical development ceased
23. A Triple Reuptake Inhibitor?
Development status
Euthymics Biosciences Inc.
Purchased TRI’s from DOV Pharmaceuticals
Currently pursuing the serotonin-preferring TRI amitifadine,
formerly DOV 21947 (or EB-1010)
25. Amitifadine
Tran et al. (2012) tested amitifadine in MDD patients
Placebo control, 6 weeks, randomized, double-blind
26. Amitifadine
Current status
Phase II and III testing scheduled to end in Feb. 2013
Placebo and SSRI comparators
27. Is Ketamine an Antidepressant Drug?
Ketamine for treating depression?
Berman et al. 2000
Single administration of low dose (0.5
mg/kg, i.v.) ketamine in MDD patients
Reduced depressive symptoms lasting
up to 3 days
Zarate et al. (2006) reported symptom
reductions lasting up to a week
Berman et al. 2000
Immediate response with long-lasting effects HDRS = Hamilton Depression Rating
Scale
28. Is Ketamine an Antidepressant Drug?
Ketamine for treating depression?
Changes in prefrontal cortical
neurotransmission
Increased dopamine and glutamate
concentrations in prefrontal cortex (Li et
al. 2010)
Increased dopamine concentrations in
nucleus accumbens by NMDA* receptor Del Arco et al. 2008
antagonist CPP (Del Arco et al. 2008) CPP = 3-[(R)-2-carboxypiperazin-4-yl]-
propyl-1- phophonic acid; noncompetitive
NMDA receptor antagonist
*N-Methyl-D-aspartate
29. Is Ketamine an Antidepressant Drug?
Ketamine for treating depression?
Sometimes referred to as “academia’s antidepressant drug”
Liability insurance companies may not provide coverage
Requires treatment in hospital setting
Safe if other disorders present?
Mainly pilot-type clinical trials conducted so far
Few randomized controlled trials
Few placebo controlled trials
Clinicaltrials.gov: 21 trials recruiting or planning for recruiting
30. Summary
All approved antidepressant drugs enhance monoamine neurotransmission
Limitations include delayed response time and sexual dysfunction risk
TRI’s likely to be evaluated by FDA
Ketamine research suggests new research directions for improving
antidepressant efficacy
31. References
Berman, R. M., Cappiello, A., Anand, A., Oren, D. A., Heninger, G. R., Charney, D. S., & Krystal, J. H. (2000). Antidepressant effects of ketamine in depressed patients. Biological Psychiatry, 47(4),
351–354.
Carlsson, A., Lindqvist, M., Magnusson, T., & Waldeck, B. (1958). On the presence of 3-hydroxytyramine in brain. Science, 127(3296), 471.
Clayton AH, McGarvey EL, Abouesh AI, Pinkerton RC. (2001) Substitution of an SSRI with bupropion sustained release following SSRI-induced sexual dysfunction. J Clin Psychiatry. 62(3):185-90.
DeBattista C, Solvason HB, Poirier J, Kendrick E, Schatzberg AF (2003): A prospective trial of bupropion SR augmentation of partial and nonresponders to serotonergic antidepressants. J Clin
Psychopharmacol 23: 27–30.
Covington, HE, Vialou, V, Nestler, EJ. (2010) From synapse to nucleus: novel targets for treating depression. Neuropharmacology, 58(4-5):683-93
Clayton, A.H., Pradko, J.F., Croft, H.A, Montano, C.B., Leadbetter, R.A., Bolden-Watson, C., Bass, K.I., Donahue, R.M., Jamerson, B.D., and Metz, A. (2002) Prevalence of sexual dysfunction
among new antidepressants. J Clin Psychiatry, 63, 357-366
Feighner, J.P. (1983) The new generation of antidepressants. Journal of Clinical Psychiatry, 44, 49-55.
Fox, H. H., & Gibas, J. T. (1953). Synthetic tuberculostats. VII Monoalkyl derivatives of isonico- tinylhydrazine. Journal of Organic Chemistry, 18, 994–1002.
Li, N., Lee, B., Liu, R. J., Banasr, M., Dwyer, J. M., Iwata, M., . .. Duman, R. S. (2010). mTOR- dependent synapse formation un- derlies the rapid antidepressant effects of NMDA antagonists.
Science, 329(5994), 959–964.
Montagu, K. A. (1957). Catechol com- pounds in rat tissues and in brains of different animals. Nature, 180(4579), 244–245.
Olds, J., & Milner, P. (1954). Positive reinforcement produced by electri- cal stimulation of septal area and other regions of rat brain. Journal of Comparative and Physiological Psychology, 47(6),
419–427.
Papakostas, G. I., Thase, M. E., Fava, M., Nelson, J. C., & Shelton, R. C. (2007). Are Antidepressant Drugs That Combine Serotonergic and Noradrenergic Mechanisms of Action More Effective
Than the Selective Serotonin Reuptake Inhibitors in Treating Major Depressive Disorder? A Meta-analysis of Studies of Newer Agents. Biological Psychiatry, 62(11), 1217-1227.
Papakostas, G.I., Stahl, S.M., Krishen, A., Seifert, C.A., Tucker, V.L., Goodale, E.P., Fava, M. (2008) Reuptake inhibitors in the treatment of major depressive disorder with high levels of anxiety
(anxious depression): a pooled analysis of 10 studies. J Clin Psychiatry, 69, 1287-1292.
Saunders, J. C., Radinger, N., Rochlin, D., & Kline, N. S. (1959). Treat- ment of depressed and regressed patients with iproniazid and reser- pine. Diseases of the Nervous Sys- tem, 20, 31–39.
Skolnick, P., and Basile, A.S. (2006) Triple reuptake inhibitors as antidepressants. Drug Discovery Today: Therapeutic Strategies.3, 489-494.
32. References
Tran, P., Skolnick, P., Czobor, P., Huang, N.Y., Bradshaw, M., McKinney, A., Fava, M. (2012) Efficacy and tolerability of the novel triple reuptake inhibitor amitifadine in the treatment of patients with
major depressive disorder: a randomized, double-blind, placebo-controlled trial. J Psychiatr Res. 46(1):64-71
Weihs, K.L, Houser, T.L, Batey, S.R., Ascher, J.A., Bolden-Watson, C., Donahue, M.J., and Metz, A. (2002) Continuation phase treatment with bupropion SR effectively decreases the risk for
relapse of depression. Biol Psychiatry, 51, 753-761.
33. Other Novel Directions
Review by Covington, Vialou, & Nestler, 2010
Neurotrophins
Possible hippocampal neuronal loss in depression
Antidepressants increase neurogenesis
BDNF studied for antidepressant effects
Intracellular cascades for TrkB signalling
Peptides involved in feeding behavior
Orexin, melanin, and neuropeptide Y elicit antidepressant effects in animals
34. Other Novel Directions
Review by Covington, Vialou, & Nestler, 2010
Estrogen receptors
Women more likely to be diagnosed with depression than men
Appears to be reduced activation of estrogen beta receptors during
depression
Estrogen beta receptor KO mice exhibit depressive and anxiety-like behavior
35. Another Consideration - Enzymes
Polymorphisms may alter metabolism rate of antidepressant drug
Fast metabolizer: Shorter acting drug effects
Poor metabolizer: Longer acting drug effects; Possible greater adverse
effects
For example
Fluoxetine: CYP450- 2C9, 2D6, 3A4
Fluvoxamine: 1A2, 2D6, 3A4
Caffeine: 1A2
Notes de l'éditeur
Tyramine can also displace norepinephrine from vesicles, therefore leading to increased norepinephrine levels
Considered much safer than drugs from other categories
Trying to figure out how to show that industry likely won’t pursue reduced response time or treatment resistant since there are no leads to go on. Also, might consider proliferation in hippocampus. Ultimately want to show how sexual dysfuction might be driving antidepressant drug development. Also, could bring in Wellbutrin story – maybe before this slide.