ANTIDEPRESSANTS
Samaiya Mushtaq
CHEM 5398
DEPRESSION
Types
 Symptoms
 Diagnosis
 Causes
 Treatment

TYPES OF DEPRESSION
Major depression
 Chronic depression (Dysthymia)
 Atypical depression
 Bipolar disorder/Manic depression
 Seasonal depression (SAD)

SYMPTOMS











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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)
DIAGNOSIS
Extensive patient and family history
 Blood test for hypothyroidism
 Current medication
 DSM-IV



One of the first two symptoms
Five other symptoms
CAUSES OF DEPRESSION
Genetics
 Death/Abuse
 Medications

TREATMENT FOR DEPRESSION
Psychotherapy
 Electroconvulsive therapy
 Natural alternatives
 Medication

SSRIs
 MAOIs
 TCAs
 SNRIs
 NDRIs
 TeCAs

NEUROTRANSMITTERS AND THE
CATECHOLAMINE HYPOTHESIS
Neurotransmitters pass along signal
 Smaller amount of neurotransmitters causes
depression

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
MONOAMINE OXIDASE INHIBITORS
(MAOIS)

History
Isoniazid
 Iproniazid

Current Drugs
 Mechanism of Action
 Side Effects

Isoniazid
Iproniazid
MAOIS ON THE MARKET

MAO Inhibitors (nonselective)
Phenelzine (Nardil)
 Tranylcypromine (Parnate)
 Isocarboxazid (Marplan)


MAO-B Inhibitors (selective for MAO-B)

Selegiline (Emsam)
MAOIS MECHANISM OF ACTION
MAO contains a
cysteinyl-linked
flavin
 MAOIs covalently
bind to N-5 of the
flavin residue of
the enzyme

MAOIS SIDE EFFECTS
Drowsiness/Fatigue  Muscle twitching
 Weight gain
 Constipation
 Nausea
 Blurred vision
 Diarrhea
 Headache
 Dizziness
 Increased appetite
 Low blood pressure  Restlessness
 Lightheadedness,
 Shakiness
 Decreased urine output  Weakness
 Decreased sexual
 Increased sweating
function
 Sleep disturbances

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
Serotonin syndrome (muscle rigidity, fever, seizures)
 Pain medications and SSRIs must be avoided

THE RECEPTOR SENSITIVITY
HYPOTHESIS
Supersensitivity and up-regulation of postsynaptic receptors leads to depression
 Suicidal and depressed patients have increased
5HT-α2 receptors

TRICYCLIC ANTIDEPRESSANTS
(TCAS)

History

Imipramine
Current Drugs
 Mechanism of Action
 Side Effects

Imipramine
TCAS ON THE MARKET
Amitriptyline
 Desipramine (Norpramin)
 Doxepin (Sinequan)
 Imipramine (Tofranil, Tofranil-PM)
 Nortriptyline (Pamelor)
 Protriptyline (Vivactil)
 Trimipramine (Surmontil)

TCAS MECHANISM OF ACTION
TCAs inhibit serotonin,
norepinephrine, and dopamine
transporters, slowing reuptake
 TCAs also allow for the
downregulation of postsynaptic receptors
 All TCAs and SSRIs contain
an essential amino group that
appears to interact with Asp98 in hSERT

TCAS SIDE EFFECTS
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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)
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
TETRACYCLIC ANTIDEPRESSANTS
(TECAS)

Current Drugs


Mechanism of Action


Mirtazapine (Remeron)
Same as TCAs
Side Effects
SELECTIVE SEROTONIN REUPTAKE
INHIBITORS
Most commonly prescribed class
 Current drugs
 Mechanism of action
 Side effects

Serotonin
SSRIS ON THE MARKET
citalopram (Celexa)
 dapoxetine (Priligy)
 escitalopram (Lexapro)
 fluoxetine (Prozac)
 fluvoxamine (Luvox)
 paroxetine (Paxil)
 sertraline (Zoloft)
 zimelidine (Zelmid) (discontinued)
 indalpine (Upstene) (discontinued)

Fluoxetine 1:1
Sertraline
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/antidepressant
s/MM00660

SSRIS SIDE EFFECTS
Anhedonia
 Apathy
 Nausea/vomiting
 Drowsiness or
somnolence
 Headache
 Bruxism (involuntarily
grinding of the teeth)
 Extremely vivid and
strange dreams
 Dizziness

Fatigue
 Changes in sexual
behavior
 Suicidal thoughts

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

Brain zaps
 Sexual dysfunction

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
Very similar to SSRIs
 Works on both neurotransmitters


Side effects
Similar to SSRIs
 Suicide

Venlafaxine 1:1
Duloxetine
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


Adverse effects
Bupropion 1:1
Lowers seizure threshold
 Suicide
 Does not cause weight gain or sexual dysfunction
(even used to treat the two)

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.
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.
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=oASle2Zpr&sig=36CB_3JY4uD3LIYvqXWmAb3nliY&hl=en&ei=HzfFS9OrB4Tu9gTD6_ixDg&sa=X&oi=boo
k_result&ct=result&resnum=8&ved=0CCoQ6AEwBw#v=onepage&q=tcas%20mechanism%20of%2
0action&f=false
http://www.informaworld.com/smpp/content~content=a916036122&db=all