ANTIDEPRESSANTS

DEPRESSION
Types
Symptoms
Diagnosis
Causes
Treatment

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

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)

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

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-2 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

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 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
Mirtazapine

Mechanism of Action
Same

(Remeron)

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/antidepressa
nts/MM00660

SSRIS SIDE EFFECTS

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
Suicide

to SSRIs

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 an3-4 nicotinic antagonist

Adverse effects
Lowers

Suicide
Does

Bupropion 1:1

seizure threshold

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=oASl
e2Zpr&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