2. Introduction
• Major depressive disorder is state when an
individual experiences one or more major
depressive episodes (decreased mood)
without a history of manic, mixed, or
hypomanic episodes
3. Forms of Primary Depression
• Major Depression
–Unipolar
–Bipolar
• Dysthymia
• Adjustment Disorder
6. 6 - 24 months
2+ years
DEPRESSION
NORMAL
MOOD
DYSTHYMIA PARTIAL RECOVERY
DOUBLE DEPRESSION
5-8 Stahl S M, Essential
Psychopharmacology (2000)
7. Epidemiology
• The estimated lifetime prevalence was reported
to be 20.4% in women and 9.6% in men
• Depression occurs in all age, racial, ethnic, and
socioeconomic groups.
• Prevalence of depression is more in medically ill
patient than the general population.
8. Etiology
• Neurobiological factors:
– Family, twin &adoption studies
• Psychosocial factors
– Social stressors as precipitators
• Developmental factors:
– Early stressful life events
9. Organic causes of Depression
Pharmacologic: corticosteroids, reserpine, methyldopa,
cimetidine, indomethacin, phenothiazines, cycloserine, vincrstine,
vinblastine, insecticides, contraceptives
Infectious: tertiary syphilis, influenza, AIDS, viral pneumonia,
viral hepatitis, infectious mononucleosis, tuberculosis
Endocrine: hypo & hyperthyroidism, hyperparathyroidism,
post-partum, menses-related, Cushing’s disease (hyperadrenalism),
Addison’s disease (adrenal insufficiency)
Immunologic: SLE, Rheumatoid Arthritis
Neurologic: MS, Parkinson’s disease, head trauma, complex
partial seizure, cerebral tumors, stroke, early dementia, sleep apnea
Nutritional: Vitamin deficiencies (B12, C, Folate, niacin)
Neoplastic: Cancer of the head of the pancreas,
13. Tricyclic Antidepressant (TCA)
• The TCAs were discovered during the search for new
and safer antipsychotic agents. The first among
these was imipramine.
• The TCAs have a high affinity for many CNS receptors
including muscarinic cholinergic, histaminergic,
alpha-adrenergic, as well as serotonin &
norepinephrine transporters
• The antidepressant effect of the TCAs is attributed to
their inhibition of NE & 5-HT transporters.
15. TCA
• Side Effects:
– Dry mouth, urinary retention, constipation,
tachycardia, & blurred vision (anticholinergic)
– Sedation & weight gain (antihistaminic)
– Can cause cardiac conduction delays, particularly
first-degree atrioventicular and bundle branch block.
– Orthostatic hypotension attributed to blockade of
alpha adrenergic receptors
– Less common side effects are sexual dysfunction
18. Monoamine Oxidase Inhibitors
• The action of MAOI is to increase the availability of the monoamine
neurotransmitter NE, DA, and 5-HT by blocking their metabolism.
• The classical MAOI are non-selective & irreversible ( Phenelzine,
Tranylcypromine, & Isocarboxazid)
• The newer ones are selective and reversible
– Reversible inhibitor of MAO-A (Moclobemide)
– Selective inhibitor of MAO-B (Deprenyl)
• Despite their efficacy, their clinical use has been limited due to the
life threatening “hypertensive crisis” when they are ingested with
certain food or medications (tyramine, sympathomimetics etc.
19. The tyramine, as in cheese, increases the release of NE
(1) and the irreversible MAO-inhibitor causes MAO
enzyme to stop destroying NE (2). This increase in NE
can lead to dangerous elevations of blood pressure (3).
1 2
3
MAO inhibitor tells
the enzyme to stop
destroying NE
20. In the case of a reversible inhibitor of MAO (1), the NE
released by tyramine can displace the RIMA (2), allowing
for normal destruction of the extra NE (3).
1
3
2
21. MAOI…….
• Another untoward drug-drug interaction is
the so called Serotonin syndrome if it is co-
administered with SSRIs, TCAs & some of
the newer antidepressant.
Agitation or restlessness, Diarrhea, Fast heart beat, Hallucinations,
Increased body temperature, Loss of coordination, Nausea, Overactive
reflexes, Rapid changes in blood pressure, Vomiting
• Other side effects of MAOI include dizziness,
orthostatic hypotension, suppression of
REM sleep, weight gain & sexual
dysfunction.
23. Selective Serotonin Reuptake Inhibitors
(SSRI)
• First introduced in 1988 fluoxetine (Prozac)
• 6 SSRIs are currently marketed in USA ( in order of release:
fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram, &
escitalopram )
• Efficacious like other antidepressants (TCAs etc.)
• Disinhibition of serotonergic neurotransmission in the
pathway from midbrain raphe to prefrontal cortex could
hypothetically help mediate the antidepressant effects of
SSRIs.
• Disinhibition of the pathway from midbrain raphe to Basal
ganglia mediate the therapeutic actions of SSRIs in OCD.
24. SSRIs …………………
Disinhibition of the pathway to limbic cortex &
hippocampus, mediate the therapeutic actions in
panic disorders, Social Anxiety Disorder & possibly
GAD.
Disinhibition of the pathway to the hypothalamus
mediate the therapeutic actions in Bulimia & Binge
eating disorder.
Stimulation of 5HT-2 receptors hypothetically
mediates several side effects of SSRIs ie anxiety,
insomnia, sexual dysfunction, akathisia, &agitation.
Stimulation of the 5HT-3 receptor appears to be
responsible for various GI side effects of SSRIs.
25. SSRI….
SSRIs differ in their pharmacokinetic profiles in:
◦ Half-life, presence or absence of metabolites, capacity to
inhibit one or another of the cytochrome P450
isoenzymes & protein binding.
◦ Fluoxetine has the longest half-life at 4-6 days for the
parent compound & 7 to 9 days for its active metabolite.
◦ Fluoxetine, & paroxetine are strong inhibitors of CYP2D6
isoenzyme ( substrates include TCAs, phenytoin, B-
blockers, & diazepam
◦ Fluvoxamine, fluoxetine & sertraline inhibit the CYP3A4
(substrates include terfenadine, astemizole,
carbamazepine, & several benzodiazepines)
26. Norepinephrine & Dopamine Reuptake
inhibitor
Bupropion is the prototypical agent of the NE &
dopamine reuptake inhibitors.
Boosts norepinephrine & dopamine in the
synapse
It is used also as augmenting agent
Most common side effects include anxiety,
agitation, decreased appetite& insomnia.
The most dangerous side effect of bupropion is its
increase in seizure risk
Other applications of bupropion are for ADHD &
treatment of smoking cessation.
28. SNRI….
Venlafaxine and Duloxetine
Do not have affinity for muscarinic,
cholinergic, histaminic or alpha-adrenergic
receptors.
It has lower protein binding capacity
At higher dosage, also act as a dopamine
reuptake inhibitors.
The most common side effects are nausea,
anorexia, insomnia, and nervousness.
29. Mirtazapine (Remeron)
• It is an alpha-2 antagonist presynaptically
• Alpha-2 antagonism disinhibits both NE & 5HT
neurotransmission.
• Very efficacious in the treatment of depression
• Side effect-increased appetite
35. a=Doses listed are total daily
doses; elderly patients are
usually treated with
approximately one-half of
the dose listed.
b=Parent drug plus
metabolite.
c=It has been suggested that
combined imipramine +
desipramine concentrations
should fall between 150–240
ng/mL.
d=Transdermal delivery
system designed to deliver
stated dose continuously
over a 24-hour period.
36. 1st line agent
Li (?valproate, mood
stabilizers)
1st line agent T3 / T4
1st line agent
buspirone
(?pindolol)
TCA MAOI
1st line agent
1st line agent
estrogen
zaleplon /
zolpidem /
benzo
classic combo
thyroid combo
serotonin 1A combo
cautious combo
E2 estrogen combo
insomnia / anxiety
combo
+
+
+
+
+
+
Antidepressant
combos
37.
38.
39.
40. Special population
• Elderly-
– SSRI-first choice
– Bupropion and venlafaxine
• Because of less anticholnergic and cvs side effects
41. • Children and Adolescents
– Fluoxetine is the only for <18 years of age
• Pregnancy
– Nonpharmacologic-in general
– No major teratogenic effects have been
identified with the SSRIs or TCAs
