Pharmacologic

Treatment of
Depression

Ten Leading Causes of

Disability in the World
Cost (in
DALYs)

Cumulativ
e%
of Cost

Unipolar major depression

42,972

10.3

Tuberculosis

19,673

14.9

Road traffic accidents

19,625

19.6

Alcohol use

14,848

23.2

Self-inflicted injuries

14,645

26.7

Bipolar Disorder

13,189

29.8

War

13,134

32.9

Violence

12,955

36.0

Schizophrenia

12,542

39.0

Iron deficiency anemia

12,511

42.0

Type of Disability

Antidepressants History

1958
1958
1982
1988
1989
1994
1994
1996

Monoamine oxidase inhibitors (MAOIs)

Tricyclics (TCAs)
Trazodone (Deseryl)
Fluoxetine (Prozac)
Bupropion (Wellbutrin)
Nefazodone (Serzone)
Venlafaxine (Effexor)
Mirtazapine (Remeron)

Treatment Response
Categories
PREVALENC
E IN RCTS

STATE

OBJECTIVE
CRITERION

CLINICAL
STATUS

Remissio
n

HAM-D 7

No residual
psychopathology

~ 40%

Response

50%
decrease in
HAM-D without
remission

Substantially
improved, but with
residual sxs

~ 25%

Partial
response

25%-50%
decrease in
HAM-D

Mild-moderate
improvement

~ 10%

No clinically
meaningful
response

~ 25%

Nonrespons < 25%

decrease
e

in HAM-D

Efficacy vs
Effectiveness

Fig. 1. Survival analysis of weeks to major depressive episode relapse (MDE):

comparing patients with unipolar major depressive disorder who recovered
from intake MDE with residual subsyndromal depressive symptoms vs.
asymptomatic status. Wilcoxon Chi Square Test of Difference=47.96;
P<0.0001.

Why Is Achieving
Remission Important?

Residual symptoms put patients at high risk

of relapse and recurrence
Patients with residual symptoms after
medication treatment are 3.5 times more
likely to relapse compared to those fully
recovered (Judd et al, 1998)
This risk is greater than the risk associated
with having 3 prior depressive episodes
Similar finding exists after response to
cognitive therapy

Major Depression
Syndromal classification with

disturbances of mood,
neurovegetative and cognitive
functioning

Major Depression
At least 5 of the following symptoms
present for at least 2 weeks (either
#1 or #2 must be present):
1) depressed mood
2) anhedonia loss of interest or
pleasure
3) change in appetite
4) sleep disturbance

Major Depression
5) psychomotor retardation or agitation
6) decreased energy
7) feeling of worthlessness or
inappropriate guilt
8) diminished ability to think or
concentrate
9) recurrent thoughts of death or
suicidal
ideation

Major Depression
Symptoms cause marked distress and/or
impairment in social or occupational
functioning.

No evidence of medical or substanceinduced etiology for the patients

symptoms.

Symptoms are not due to a normal

reaction to the death of a loved one.

Special Diagnostic
Considerations

Bereavement
Late life onset
Subtypes
Cluster B personality disorders

Bereavement and
Late Life Depression
25 35% of widows/widowers meet
diagnostic criteria for major
depressive disorder at 2 months.

~15% of widows/widowers meet

diagnostic criteria for major
depressive disorder at one year.

This figure remains stable throughout

the second year.

Subtypes of Depression
Atypical
Reverse

neurovegetative
symptoms
Mood reactivity
Hypersensitivity to rejection
MAO-Is and SSRIs are more
effective treatments

Subtypes of Depression
Psychotic

(~10% of all MDD)

Delusions common, may have
hallucinations
Delusions usually mood
congruent
Combined antidepressant
and antipsychotic therapy or
ECT is necessary

Subtypes of Depression
Melancholic

No mood reactivity
Anhedonia
Prominent neurovegetative
disturbance
More likely to respond to
biological treatments

Subtypes of Depression
Catatonic

Motoric immobility
(catalepsy)
Mutism
Ecolalia or echopraxia

What is the course

of antidepressant
response?

Why a temporal delay

for maximal
therapeutic benefit

-adrenergic

regulation

5-HT2

receptor down-

receptor down-regulation

Tricyclic
Antidepressants
Characteristic three-ring nucleus
(TCAs)
Clinical
effects

Normalization of mood and resolution of

neurovegetative symptoms
Biochemical effects
Inhibit monoamine uptake at nerve
terminals
May potentiate action of drugs that cause
neurotransmitter release
Temporal delay of weeks for clinical effects,
although biochemical effects are immediate

Mechanism of action of
TCAs
Tertiary TCAs
imipramine
amitriptyline
clomipramine
Secondary TCAs
desipramine
nortriptyline

Inhibit 5-HT uptake

(weaker inhibition of NE uptake)

Inhibit NE uptake
(weaker inhibition of 5-HT uptake)

TCA Metabolism
imipramine

desipramine
N

N
H3C

CH3

N
CH3

amitriptyline

nortriptyline

N
H3C

CH3

tertiary amines

N
CH3

secondary amines

In vivo action of TCAs

If one administers a tertiary TCA

If one administers a secondary TCA

there is always both the tertiary

and the secondary amine in the
circulation
there is only the secondary
amine in the circulation.

Neuropharmacology of
TCAs

Inhibit monoamine uptake (NE and 5HT)

Muscarinic cholinergic antagonism

H1 histamine antagonism

1-adrenergic antagonism

TricyclicsContraindications

QTc greater than 450 msec

Conditions worsened by
muscarinic blockade (eg
myasthenia gravis, BPH)
pre-existing orthostatic
hypotension
Seizure disorder

Side effect profile of

TCAs
Dry

mouth
Constipation
Dizziness
Tachycardia
Urinary retention
Impaired sexual funtion
Orthostatic hypotension

Low therapeutic index

of TCAs

Cardiotoxicity: resulting from combination of:

Conduction defects, arrhythmias
Delirium
Potentiation of effects of other sedating drugs
Consequences
suicide
requires care in prescribing
monitoring drugs that might have
synergistic effects on monoamine function

Monoamine Oxidase
Inhibitors (MAOIs)
Irreversibly

inhibit monoamine
oxidase enzymes
Effective for major depression,
panic disorder, social phobia
Drug interactions and dietary
restrictions limit use

Biochemistry of MAO

Occurs as two isoenzymes

MAO-A
Oxidizes norepinephrine,
serotonin, tyramine
MAO-B
selective

for dopamine
metabolism

Dietary and Drug

Interactions

Increased stores of catecholamines sensitize patients

to effects of sympathomimetics
Accumulation of tyramine (sympathomimetic) = high
risk of hypertensive reactions to dietary tyramine
requires dietary restrictions
Interactions with other sympathomimetic drugs
Antidepressants
OTC cold remedies
phenylpropanolamine
Meperidine
L-dopa

Examples of MAOIs

Irreversible, non-selective MAOIs

phenelzine
isocarboxazid
tranylcypromine

Selective MAO-B inhibitors

deprenyl (selegiline)
loses its specificity for MAO-B in antidepressant doses

Reversible monoamine oxidase inhibitors

(RIMAs)

Moclobemide not approved

Appears to be relatively free of food/drug interactions

Serotonin syndrome

Evoked by interaction between serotonergic

agents
e.g., SSRIs and MAOIs
Combination of increased stores plus
inhibition of reuptake after release
Symptoms
Hyperthermia
Muscle rigidity
Myoclonus
Rapid changes in mental status and vital signs
Can be lethal

Selective Serotonin
Uptake Inhibitors
(SSRIs)

Currently marketed medications

fluoxetine (Prozac).
sertraline (Zoloft).
paroxetine (Paxil)
fluvoxamine (Luvox)
citalopram (Celexa)
escitalopram (Lexapro)
Selectively inhibit 5-HT (not NE) uptake
Differ from TCAs by having little affinity for
muscarinic, as well as many other neuroreceptors

Selective Serotonin
Uptake Inhibitors
(SSRIs)

Much higher therapeutic index than

TCAs or MAO-Is

Much better tolerated in early therapy

Equal or almost equal in efficacy to

TCAs

Side effects associated

with SSRIs
Nausea
Sexual

dysfunction

Delayed
ejaculation/anorgasmia
Anxiety
Insomnia

Selective NorepinephrineSerotonin Reuptake

Inhibitors

Venlafaxine (Effexor) Duloxetine

(Cymbalta):
relatively devoid of antihistaminergic,
anticholinergic, and antiadrenergic
properties
nonselective inhibitor of both NE and
5-HT uptake.
Adverse effects: GI , Sexual
dysfunction, hypertension (venlafaxine)

Other antidepressants

Trazodone
mixed 5-HT agonist/antagonist
1 antagonist
H1 antagonist
Nefazodone (Serzone)
5 HT2 antagonist
Bupropion (Wellbutrin; Zyban)
Inhibits uptake of DA and NE
antismoking properties probably involves parent
molecule
Lacks sexual side effects
Seizure risk

Mirtazapine (Remeron)
2 antagonist
5H2 and 5HT3 antagonist
Net effect selective increase in 5HT 1A
function
H1 antagonist
advantages: sedation, no adverse sexual
effects

Antidepressants and
drug interactions

Pharmacodynamic
Additive effects with alcohol and other sedating
drugs
MAOI interactions
Pharmakokinetic
Cytochrome P450-2D6 inhibition
Fluoxetine and paroxetine
Increased levels of TCAs, antipsychotics, warfarin
Cytochrome P450-3A4 inhibition
Nefazodone and fluvoxamine
Increased levels of terfenadine, astemizole,
cisapride can cause fatal arrhythmias

Other uses for antidepressants

Panic

Disorder
Obsessive Compulsive Disorder
Only the ADs that inhibit serotonin
reuptake

Social Phobia
Post Traumatic Stress Disorder
Premenstrual Dysphoric Disorder
Chronic pain syndromes

Treatment
Course
One episode 50% chance of
reoccurence
Two episodes 70% chance of
reoccurence
Three or more episodes - >90%
chance of reoccurence

When Do You
Characterize a Response
As Treatment
After a patient has been onResistant?
an antidepressant at for

a reasonable amount of time at an adequate dose

No commonly accepted time point
Most drug trial data comes from 8 week long
studies
If no onset of response by weeks 4 or 6, there is
a 73-88% chance of not having onset of response
by end of 8 wk trial (Nierenberg et al, 2000), so 4
weeks is a reasonable point to increase dose
An 8-12 week course is consistent with acute
treatment framework and allows patients 8
weeks at a dose expected to produce response