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 post-
synaptic 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 post-
synaptic receptors
 All TCAs and SSRIs contain
an essential amino group
that appears to interact
with Asp-98 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 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
 Mirtazapine (Remeron)
 Mechanism of Action
 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) Fluoxetine 1:1

 paroxetine (Paxil)

 sertraline (Zoloft)

 zimelidine (Zelmid) (discontinued)

 indalpine (Upstene) (discontinued)

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/antidepres
sants/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

 Brainzaps
 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
 Verysimilar to SSRIs
 Works on both neurotransmitters
Venlafaxine 1:1
 Side effects Duloxetine
 Similar to SSRIs
 Suicide
NOREPINEPHRINE-DOPAMINE
REUPTAKE INHIBITORS (NDRIS)
 Current drugs
 Bupropion (Wellbutrin)
 Mechanims of Action
 Similarto 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)
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=oASle2Z-
pr&sig=36CB_3JY4uD3LIYvqXWmAb3nliY&hl=en&ei=HzfFS9OrB4Tu9gTD6_ixDg&sa=X&oi=
book_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