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
Drowsiness/Fatigue Muscle twitching
Constipation Weight gain

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 post-
synaptic 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 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 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/antidepressant
s/MM00660
SSRIS SIDE EFFECTS
Anhedonia Fatigue
Apathy Changes in sexual

Nausea/vomiting behavior
Drowsiness or Suicidal thoughts

somnolence
Headache

Bruxism (involuntarily
grinding of the teeth)
Extremely vivid and
strange dreams
Dizziness
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
Venlafaxine 1:1
Side effects Duloxetine
Similar to SSRIs
Suicide
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
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+
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http://www.informaworld.com/smpp/content~content=a916036122&db=all