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Historical and ModernDevelopments in AntidepressantDrug ResearchDr. Adam J. PrusNorthern Michigan University
Historical and modern developments in antidepressantdrug researchTopics coveredClasses of antidepressant drugs   Biologica...
DepressionLifetime prevalence of major depressive disorder among    U.S. individuals is 16% (Kessler et al. 2005)        O...
The Dawn of PsychopharmacologyMajor psychoactive medications discovered in 1950s   Henri Laborit discovers reduction in ps...
IproniazidFirst developed for treatment of tuberculosis in 1953 (Fox & Gibas, 1953)Found to reverse sedation and pupil con...
MAO InhibitorsAntidepressant drugs that inhibit monoamine oxidase (MAO)MAO Inhibitors prevent break down of serotonin, dop...
MAO InhibitorsCheese reaction   Increased heart rate, hypertension, sweating, inhibited digestion, and other   symptoms ca...
MAO InhibitorsIrreversible MAO inhibitor   Drug never releases from MAO   Neurons must synthesize more MAO   IproniazidRev...
MAO InhibitorsModern MAO inhibitors  Selective MAOB inhibitors     Act mainly in brain     Reduced risk of cheese reaction...
ImipramineDeveloped from attempt to make chlorpromazine-like drugs for treating  schizophreniaFirst tricyclic antidepressa...
Tricylic antidepressant drugsBlock reuptake of norepinephrine and serotonin   Led to notion that increasing norepinephrine...
Further antidepressant drug developmentSuccess of tricyclic antidepressant drugs sparked efforts into developing new   ant...
Fluoxetine (Prozac)Ray Fuller, a senior pharmacologist at Lilly, began pushing to develop serotonin  drugs for treating de...
Selective Serotonin Reuptake InhibitorsInhibit serotonin transportersIncreased activation of serotonin receptors, such as ...
Serotonin-Norepinephrine Reuptake InhibitorsFirst SNRI was venlafaxine (Effexor)   FDA approval in 1993Generally considere...
SSRI vs. SNRI  According to a review of antidepressant clinical trials, SNRIs consistently reveal greater  improvements in...
Atypical Antidepressant DrugsAlso referred to as “multi-modal antidepressant drugs”Do not fall into previously described c...
Where We Are                                                       Serotonin-                 Tricyclic       Selective Se...
Where We Are GoingNew antidepressants drugs will focus on   Lengthy response time        Changes in dopamine receptors    ...
A Triple Reuptake Inhibitor?Triple reuptake inhibitors   A drug that can block reuptake of serotonin, dopamine, and norepi...
A Triple Reuptake Inhibitor?Augmentation with bupropion for SSRI or SNRI   Improves response in patients resistant to SSRI...
A Triple Reuptake Inhibitor?Development status   In 2007, at least 4 companies working on TRI’s (Skolnick & Basile, 2006) ...
A Triple Reuptake Inhibitor?Development status        Euthymics Biosciences Inc.        Purchased TRI’s from DOV Pharmaceu...
Amitifadine   Tran et al. (2012) tested amitifadine in MDD patients       Placebo control, 6 weeks, randomized, double-bli...
AmitifadineTran et al. (2012) tested amitifadine in MDD patients   Placebo control, 6 weeks, randomized, double-blind
AmitifadineCurrent status   Phase II and III testing scheduled to end in Feb. 2013                 Placebo and SSRI compar...
Is Ketamine an Antidepressant Drug?Ketamine for treating depression?   Berman et al. 2000        Single administration of ...
Is Ketamine an Antidepressant Drug?   Ketamine for treating depression?       Changes in prefrontal cortical       neurotr...
Is Ketamine an Antidepressant Drug?Ketamine for treating depression?   Sometimes referred to as “academia’s antidepressant...
SummaryAll approved antidepressant drugs enhance monoamine neurotransmissionLimitations include delayed response time and ...
ReferencesBerman, R. M., Cappiello, A., Anand, A., Oren, D. A., Heninger, G. R., Charney, D. S., & Krystal, J. H. (2000). ...
ReferencesTran, P., Skolnick, P., Czobor, P., Huang, N.Y., Bradshaw, M., McKinney, A., Fava, M. (2012) Efficacy and tolera...
Other Novel DirectionsReview by Covington, Vialou, & Nestler, 2010Neurotrophins   Possible hippocampal neuronal loss in de...
Other Novel DirectionsReview by Covington, Vialou, & Nestler, 2010Estrogen receptors   Women more likely to be diagnosed w...
Another Consideration - EnzymesPolymorphisms may alter metabolism rate of antidepressant drug   Fast metabolizer: Shorter ...
Cengage Learning Webinar, Psychology, Historical & Modern Developments in Antidepressant Drug Research
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Cengage Learning Webinar, Psychology, Historical & Modern Developments in Antidepressant Drug Research

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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.

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  • 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.
  • Transcript of "Cengage Learning Webinar, Psychology, Historical & Modern Developments in Antidepressant Drug Research"

    1. 1. Historical and ModernDevelopments in AntidepressantDrug ResearchDr. Adam J. PrusNorthern Michigan University
    2. 2. Historical and modern developments in antidepressantdrug researchTopics coveredClasses of antidepressant drugs Biological actions Therapeutic effects Adverse effectsTriple reuptake inhibitorsIs ketamine an antidepressant drug?
    3. 3. DepressionLifetime prevalence of major depressive disorder among U.S. individuals is 16% (Kessler et al. 2005) Occurs across age groups About 1 in 6 commit suicideCDC 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. 4. The Dawn of PsychopharmacologyMajor 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 1953Other 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. 5. IproniazidFirst 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 levelsIn 1959, Saunders and colleagues report first clinical data revealing reduced depressive moodLater 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. 6. MAO InhibitorsAntidepressant drugs that inhibit monoamine oxidase (MAO)MAO Inhibitors prevent break down of serotonin, dopamine, and norepinephrine Other monoamine chemicals, such as tyramineMAO types MAOA: Brain, PNS, and intestinal tract MAOB: Brain and lesser extent in PNS
    7. 7. MAO InhibitorsCheese 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 inhibitorsResponse time May require several weeks for antidepressant effects
    8. 8. MAO InhibitorsIrreversible MAO inhibitor Drug never releases from MAO Neurons must synthesize more MAO IproniazidReversible MAO inhibitor Drug either temporarily binds to MAO or other compounds such as tyramine displace the drug from MAO
    9. 9. MAO InhibitorsModern 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. 10. ImipramineDeveloped from attempt to make chlorpromazine-like drugs for treating schizophreniaFirst tricyclic antidepressant drugFailed to cause cheese reaction Imipramine Chlorpromazine
    11. 11. Tricylic antidepressant drugsBlock reuptake of norepinephrine and serotonin Led to notion that increasing norepinephrine and serotonin concentrations may be sufficient for antidepressant effectsAntagonist for various receptors Often muscarinic receptors Can cause dry mouth, dry eyes, constipation, and other effects from blocking peripheral receptors Often histamine receptors SedationSeveral weeks for efficacy
    12. 12. Further antidepressant drug developmentSuccess of tricyclic antidepressant drugs sparked efforts into developing new antidepressant drugsStudies 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. 13. Fluoxetine (Prozac)Ray Fuller, a senior pharmacologist at Lilly, began pushing to develop serotonin drugs for treating depressionFuller, biochemist David Wong, and chemist Bryan Molloy worked to develop compounds, discovering drugs that inhibited reuptake of serotoninIn 1974, this team develops Lilly 110140, also known as fluoxetineIn 1983, John Feighner publishes clinical study showing fluoxetine equivalent to tricyclic antidepressants, but without most adverse effects Fluoxetine met FDA approval in 1987
    14. 14. Selective Serotonin Reuptake InhibitorsInhibit serotonin transportersIncreased activation of serotonin receptors, such as 5-HT2A and 5-HT1AMay require several weeks for efficacySerotonin Syndrome: agitation, restlessness, disturbances in cognitive functioning, and possibly hallucinationsSerotonin discontinuation syndrome: sensory disturbances, sleeping disturbances, disequilibrium, flulike symptoms, and gastrointestinal effectsSexual side effects: erectile dysfunction, inability to achieve orgasm, and loss of sexual drive Approximately 1/3rd of patients (Clayton et al., 2001)
    15. 15. Serotonin-Norepinephrine Reuptake InhibitorsFirst SNRI was venlafaxine (Effexor) FDA approval in 1993Generally considered at least as effective as SSRIs
    16. 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. 17. Atypical Antidepressant DrugsAlso referred to as “multi-modal antidepressant drugs”Do not fall into previously described categoriesBupropion (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. 18. Where We Are Serotonin- Tricyclic Selective Serotonin NorepinephrineMAO Inhibitors Antidepressants Reuptake Inhibitors Reuptake InhibitorsDopamine Norepinephrine Serotonin SerotoninNorepinephrine Serotonin NorepinephrineSerotonin Antagonism of muscarinic and Atypical histamine receptors Antidepressants Dopamine Norepinephrine
    19. 19. Where We Are GoingNew 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. 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. 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. 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. 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)
    24. 24. Amitifadine Tran et al. (2012) tested amitifadine in MDD patients Placebo control, 6 weeks, randomized, double-blindMADRS = Montgomery Asberg Depression Rating Scale
    25. 25. AmitifadineTran et al. (2012) tested amitifadine in MDD patients Placebo control, 6 weeks, randomized, double-blind
    26. 26. AmitifadineCurrent status Phase II and III testing scheduled to end in Feb. 2013 Placebo and SSRI comparators
    27. 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. 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. 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 trialsClinicaltrials.gov: 21 trials recruiting or planning for recruiting
    30. 30. SummaryAll approved antidepressant drugs enhance monoamine neurotransmissionLimitations include delayed response time and sexual dysfunction riskTRI’s likely to be evaluated by FDAKetamine research suggests new research directions for improving antidepressant efficacy
    31. 31. ReferencesBerman, 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):683-93Clayton, 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, 357-366Feighner, 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. 32. ReferencesTran, 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):64-71Weihs, 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. 33. Other Novel DirectionsReview by Covington, Vialou, & Nestler, 2010Neurotrophins Possible hippocampal neuronal loss in depression Antidepressants increase neurogenesis BDNF studied for antidepressant effects Intracellular cascades for TrkB signallingPeptides involved in feeding behavior Orexin, melanin, and neuropeptide Y elicit antidepressant effects in animals
    34. 34. Other Novel DirectionsReview by Covington, Vialou, & Nestler, 2010Estrogen 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. 35. Another Consideration - EnzymesPolymorphisms 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
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