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Historical and Modern
Developments in Antidepressant
Drug Research


Dr. Adam J. Prus
Northern Michigan University
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?
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
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
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.
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
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
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
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)
Imipramine



Developed from attempt to make chlorpromazine-like drugs for treating
  schizophrenia
First tricyclic antidepressant drug
Failed to cause cheese reaction




                                          Imipramine              Chlorpromazine
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
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
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
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)
Serotonin-Norepinephrine Reuptake Inhibitors



First SNRI was venlafaxine (Effexor)
   FDA approval in 1993
Generally considered at least as effective as SSRIs
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).
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)
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
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
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)
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)
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
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)
Amitifadine



   Tran et al. (2012) tested amitifadine in MDD patients
       Placebo control, 6 weeks, randomized, double-blind




MADRS = Montgomery Asberg Depression Rating Scale
Amitifadine



Tran et al. (2012) tested amitifadine in MDD patients
   Placebo control, 6 weeks, randomized, double-blind
Amitifadine



Current status
   Phase II and III testing scheduled to end in Feb. 2013
                 Placebo and SSRI comparators
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
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
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
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
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.
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.
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
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
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
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

  • 1. Historical and Modern Developments in Antidepressant Drug Research Dr. Adam J. Prus Northern Michigan University
  • 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)
  • 15. Serotonin-Norepinephrine Reuptake Inhibitors First SNRI was venlafaxine (Effexor) FDA approval in 1993 Generally considered at least as effective as SSRIs
  • 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)
  • 24. Amitifadine Tran et al. (2012) tested amitifadine in MDD patients Placebo control, 6 weeks, randomized, double-blind MADRS = Montgomery Asberg Depression Rating Scale
  • 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

Notas do Editor

  1. Tyramine can also displace norepinephrine from vesicles, therefore leading to increased norepinephrine levels
  2. Considered much safer than drugs from other categories
  3. 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.