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

Most prescribed among 18 to 44 year olds

Women twice as likely as men to take antidepressant drug

Lifetime prevalence of major depressive disorder across age groups (Kessler et al. 2005)

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

MAO Inhibitors

DopamineNorepinephrineSerotonin

Tricyclic Antidepressants

NorepinephrineSerotoninAntagonism of muscarinic and histamine receptors

Selective Serotonin Reuptake Inhibitors

Serotonin

Serotonin-Norepinephrine Reuptake Inhibitors

SerotoninNorepinephrine

Atypical Antidepressants

DopamineNorepinephrine

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

Immediate response with long-lasting effects

Berman et al. 2000HDRS = 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 antagonist CPP (Del Arco et al. 2008)

Del Arco et al. 2008CPP = 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, 3A4Fluvoxamine: 1A2, 2D6, 3A4Caffeine: 1A2