here is that there is a breif discussion about depression topic

1. ANTIDEPRESSANTS
Phani.karnati

2. DEPRESSION
 Types
 Symptoms
 Diagnosis
 Causes
 Treatment

3. TYPES OF DEPRESSION
 Major depression
 Chronic depression (Dysthymia)
 Atypical depression
 Bipolar disorder/Manic depression
 Seasonal depression (SAD)

4. SYMPTOMS
 persistently sad, anxious, or empty moods
 loss of pleasure in usual activities (anhedonia)
 feelings of helplessness, guilt, or worthlessness
 crying, hopelessness, or persistent pessimism
 fatigue or decreased energy
 loss of memory, concentration, or decision-making capability
 restlessness, irritability
 sleep disturbances
 change in appetite or weight
 physical symptoms that defy diagnosis and do not respond to
treatment (especially pain and gastrointestinal complaints)
 thoughts of suicide or death, or suicide attempts
 poor self-image or self-esteem (as illustrated, for example, by
verbal self-reproach)

5. DIAGNOSIS
 Extensive patient and family history
 Blood test for hypothyroidism
 Current medication
 DSM-IV
 One of the first two symptoms
 Five other symptoms

6. CAUSES OF DEPRESSION
 Genetics
 Death/Abuse
 Medications

7. TREATMENT FOR DEPRESSION
 Psychotherapy
 Electroconvulsive therapy
 Natural alternatives
 Medication
 SSRIs
 MAOIs
 TCAs
 SNRIs
 NDRIs
 TeCAs

8. NEUROTRANSMITTERS AND THE
CATECHOLAMINE HYPOTHESIS
 Neurotransmitters pass along signal
 Smaller amount of neurotransmitters causes
depression

9. MONOAMINE OXIDASE (MAO) AND
DEPRESSION
 MAO catalyze deamination of intracellular
monoamines
 MAO-A oxidizes epinephrine, norepinephrine,
serotonin
 MAO-B oxidizes phenylethylamine
 Both oxidize dopamine nonpreferentially
 MAO transporters reuptake extracellular
monoamine

10. MONOAMINE OXIDASE INHIBITORS
(MAOIS)
 History
 Isoniazid
 Iproniazid
 Current Drugs
 Mechanism of Action
 Side Effects Isoniazid
Iproniazid

11. MAOIS ON THE MARKET
 MAO Inhibitors (nonselective)
 Phenelzine (Nardil)
 Tranylcypromine (Parnate)
 Isocarboxazid (Marplan)
 MAO-B Inhibitors (selective for MAO-B)
 Selegiline (Emsam)

12. MAOIS MECHANISM OF ACTION
 MAO contains a
cysteinyl-linked
flavin
 MAOIs covalently
bind to N-5 of the
flavin residue of
the enzyme

14. MAOIS SIDE EFFECTS

15. MAOIS SIDE EFFECTS
 Side effects have put MAOIs in the second or
third line of defense despite superior efficacy
 MAO-A inhibitors interfere with breakdown of
tyramine
 High tyramine levels cause hypertensive crisis (the
“cheese effect”)
 Can be controlled with restricted diet
 MAOIs interact with certain drugs
 Serotoninsyndrome (muscle rigidity, fever, seizures)
 Pain medications and SSRIs must be avoided

16. THE RECEPTOR SENSITIVITY
HYPOTHESIS
 Supersensitivity and up-regulation of post-
synaptic receptors leads to depression
 Suicidal and depressed patients have increased
5HT-α2 receptors

17. TRICYCLIC ANTIDEPRESSANTS
(TCAS)
 History
 Imipramine
 Current Drugs
 Mechanism of Action
 Side Effects
Imipramine

18. TCAS ON THE MARKET
 Amitriptyline
 Desipramine (Norpramin)
 Doxepin (Sinequan)
 Imipramine (Tofranil, Tofranil-PM)
 Nortriptyline (Pamelor)
 Protriptyline (Vivactil)
 Trimipramine (Surmontil)

19. TCAS MECHANISM OF ACTION
 TCAs inhibit serotonin,
norepinephrine, and dopamine
transporters, slowing reuptake
 TCAs also allow for the
downregulation of post-
synaptic receptors
 All TCAs and SSRIs contain
an essential amino group that
appears to interact with Asp-
98 in hSERT

20. TCAS SIDE EFFECTS
 Muscarinic M1 receptor antagonism - anticholinergic
effects including dry mouth, blurred vision,
constipation, urinary retention and impotence
 Histamine H1 receptor antagonism - sedation and
weight gain
 Adrenergic α receptor antagonism - postural
hypotension
 Direct membrane effects - reduced seizure threshold,
arrhythmia
 Serotonin 5-HT2 receptor antagonism - weight gain
(and reduced anxiety)

21. TCAS SIDE EFFECTS
 Nonselectivity results in
greater side effects
 TCAs can also lead to
cardiotoxicity
 Increased LDH leakage
 Slow cardiac conduction
 High potency can lead to
mania
 Contraindicated with
persons with bipolar
disorder or manic depression

22. TETRACYCLIC ANTIDEPRESSANTS
(TECAS)
 Current Drugs
 Mirtazapine (Remeron)
 Mechanism of Action
 Same as TCAs
 Side Effects

23. SELECTIVE SEROTONIN REUPTAKE
INHIBITORS
 Most commonly prescribed class
 Current drugs
 Mechanism of action
 Side effects
Serotonin

24. SSRIS ON THE MARKET
 citalopram (Celexa)
 dapoxetine (Priligy)
 escitalopram (Lexapro)
 fluoxetine (Prozac)
 fluvoxamine (Luvox) Fluoxetine 1:1
 paroxetine (Paxil)
 sertraline (Zoloft)
 zimelidine (Zelmid) (discontinued)
 indalpine (Upstene) (discontinued)
Sertraline

25. SSRIS MECHANISM OF ACTION
 Exact mechanism remains uncertain
 Ser-438 residue in the human serotonin
transporter (hSERT) appears to be a determining
factor in SSRI potency
 Antidepressants interact directly with hSERT
 http://www.mayoclinic.com/health/antidepressants/MM0066

26. SSRIS SIDE EFFECTS

27. SSRIS SIDE EFFECTS
 Many disappear within 4 weeks (adaption phase)
 Side effects more manageable compared to
MAOIs and TCAs
 Sexual side effects are common
 SSRI cessation syndrome
 Brainzaps
 Sexual dysfunction

28. SEROTONIN-NOREPINEPHRINE
REUPTAKE INHIBITORS (SNRIS)
 Slightly greater efficacy than SSRIs
 Slightly fewer adverse effects than SSRIs
 Current drugs
 Venlafaxine (Effexor)
 Duloxetine (Cymbalta)
 Mechanism of Action
 Verysimilar to SSRIs
 Works on both neurotransmitters
Venlafaxine 1:1
 Side effects Duloxetine
 Similar to SSRIs
 Suicide

30. NOREPINEPHRINE-DOPAMINE
REUPTAKE INHIBITORS (NDRIS)
 Current drugs
 Bupropion (Wellbutrin)
 Mechanims of Action
 Similar to SSRIs and SNRIs
 More potent in inhibiting dopamine
 Also anα3-β4 nicotinic antagonist
Bupropion 1:1
 Adverse effects
 Lowers seizure threshold
 Suicide
 Does not cause weight gain or sexual dysfunction
(even used to treat the two)

31. ASSIGNED READING
 An Introduction to Medicinal Chemistry, by
Graham L. Patrick, Chapter 20, pp. 593-8.
 Kelly, John. Novel therapeutic targets for the
treatment of depression. Current Medicinal
Chemistry: Central Nervous System Agents
(2003), 3(4), 311-322.
Optional Reading:
Wong, David T.; Perry, Kenneth W.; Bymaster, Frank P. Case
History: The Discovery of Fluoxetine Hydrochloride (Prozac).
Nature Reviews Drug Discovery (2005), 4(9), 764-774.
Krishnan, K. Ranga. Revisiting monoamine oxidase inhibitors.
Journal of Clinical Psychiatry (Memphis, TN, United States)
(2007), 68(Suppl. 8), 35-41.

32. HOMEWORK QUESTIONS
1. Many of the medications to treat depression are thought to involve
systems utilizing the monoamine neurotransmitters, noradrenaline,
dopamine, and serotonin (5-HT). Draw the structures of these
neurotransmitters. Why are they called monoamines? Illustrate their
structural resemblance to one another.
2. Monoamine oxidase inhibitors (MAOIs) increase CNS synaptic
concentrations of these monoamines by inhibiting an enzyme responsible
for their degradation. Draw the reaction scheme for the biological
degradation of noradrenaline by monoamine oxidase.
3. Illustrate how the TCAs and SSRIs might resemble the monoamine
neurotransmitters, providing one example of each class of antidepressant.

33. REFERENCES
 http://ajp.psychiatryonline.org/cgi/reprint/157/11/1901
 http://www.webmd.com/depression/
 http://pn.psychiatryonline.org/content/41/24/21.full
 http://www.mayoclinic.com/health/maois/MH00072
 http://www.springerlink.com/content/b9b8668ff59f89d7/fulltext.pdf
 http://www.emsam.com/pi_emsam.pdf
 http://www.nevdgp.org.au/info/topics/depression_theory.htm
 http://www.uspharmacist.com/content/t/psychotropic_disorders/c/11467/
 http://www.jbc.org/content/284/15/10276.full.pdf+html
 http://www.aafp.org/afp/981200ap/cadieux.html
 http://www.mayoclinic.com/health/antidepressants/MH00071
 http://books.google.com/books?
id=R0W1ErpsQpkC&pg=PA565&lpg=PA565&dq=tcas+mechanism+of+action&source=bl&ots=oAS
le2Z-
pr&sig=36CB_3JY4uD3LIYvqXWmAb3nliY&hl=en&ei=HzfFS9OrB4Tu9gTD6_ixDg&sa=X&oi=bo
ok_result&ct=result&resnum=8&ved=0CCoQ6AEwBw#v=onepage&q=tcas%20mechanism%20of
%20action&f=false
 http://www.informaworld.com/smpp/content~content=a916036122&db=all