Kiung Hsia Ling

2/09/09
Depression is a common, chronic, and
potentially debilitating illness that has
tempered the human condition since the
beginning of recorded history.
Although many people experince “the blues”
from time to time, the term depression is
reserved in psychiatry to define a specific
medical condition with distinctive biologic and
pharmacologic implications
Onset occurs most commonly in the late 20s,
but there is a wide range and the first episode
may actually present at any age.
The observed peak onset in females is
between 35 and 45 years of age and in males
it occurs most commonly after age 55.
Genetic factors may play a major role in the
cause of depression. First degree relatives off
depressed individuals are 2.7 times more
likely to have depression if one parent is
afflicted, and 3.0 times more likely if both
parents suffer from depression.
1. At least five of the following symptoms have been present during
the same 2-week period and represent a change from previous
functioning. One of the symptoms must be either depressed mood
or loss of interest/pleasure
 Depressed mood most of the day, nearly every day
 Loss of interest in pleasurable activities most of the day, nearly
every day
 Change in weight or appetite when not dieting
 Insomnia or hypersomnia nearly every day
 Fatigue or loss of energy nearly every day
 Diminished ability to think or concentrate, or indecisiveness
 Feelings of worthlessness or excessive or inappropriate guilt nearly
every day
 Psychomotor agitation or retardation nearly every day
 Recurrent thoughts of death or suicidal ideation
1. Symptoms cause clinically significant distress or impairment in
social, occupational, or other important areas of functioning
2. Symptoms are not caused by an underlying medical condition or
substance (e.g. medicationsor recreational drugs)
1. Cardiovascular agents
 Beta-blockers
 Methyldopa
 Procainamide
 Reserpine
1. Central nervous system agents
 Barbiturates
 Chloral hydrate
 Phenytoin
1. Hormonal agents
 Corticosteroids
 Progestins
 Tamoxifen
1. Others
 Indomethacin
 Interferon
 Isotretinoin
 Mefloquine
Although pharmacologic intervention has
becomes the primary treatment modality for
relieving depression symptoms, the efficacy
and suitability of other therapeutic options
should not be overlooked.
A wider variety of other therapeutic
interventions exist, including psychotherapy,
ECT, light therapy, sleep deprivation, etc.
.
 Is a safe, rapid-acting, and highly effective therapeutic intervention that
continues to suffer, ostensibly, from a poor public image.
 Adjunctive medications are now routinely administered to prevent adverse
effects and reduce morbidity (e.g. a short-acting barbiturate for general
anesthesia, an anticholinergic agent to prevent bradycardia and dry
excesssive airway secretions, and succinylcholine to prevent fractures from
tonic-clonic contractions)
 ECT features the induction of generalized seizures through an electric
current delivered by bilateral or unilateral electrode placement.
 Certain medications may raise seizure thresholds (benzodiazepines) or
promote cognitive impairment (lithium) and should be discontinued before
the procedure
 ADR: are generally minimal and consist mainly of transient anterograde
amnesia (difficulty remembering events around the time of the procedure),
retrograde amnesia, confusion, headaches, and muscle aches.
Cardiovascular effects (e.g. ventricular arrhythmias, MI are the most
ominous sequelae, but these events are actuallyl quite rare)
 Recommended for patients with treatment-resistant depression, severe
vegetative depression, psychotic depression, and depression in pregnancy.
 Overall response rates are rather impressive, ranging from 70% to 90%,
and ECT has the distinct advantage of inducing a therapeutic response
within the first week or two of treatments.
Reduce the symptoms of acute depression,
facilitate the patient’s return to a premorbid
level of functioning, and prevent further
episodes of depression.
Whether or not to hospitalize the patient is
often the first decision that is made in
consideration of the patient’s risk of suicide,
physical state of health, social support
system, and presence of a psychotic and/ or
catatonic depression
 Studies have found that antidepressants are of equivalent
efficacy when administered in comparable doses.
 Because one cannot predict which antidepressant will be the
most effective in an individual patient, the initial choice is made
empirically.
 Factors: patient’s history of response, pharmacogenetics
(history of familial antidepressant response), subtype of
depression, patient’s concurrent medical history, potential for
drug-drug interactions, adverse events profile, and drug cost.
 Although the pathophysiology of major depression remains
elusive, can select from multiple drug therapies with different
mechanisms of action.
 Failure to respond to one antidepressant class or one
antidepressant drug within a class does not predict a failed
response to another drug class or another drug within the class.
 At present, 22 medications have received FDA approval
for the treatment of depression. They can be grouped
together into four catogories
- SSRIs (selective serotonin reuptake inhibitors)
 Fluoxetine (Prozac)
 Sertraline (Zoloft)
 Escitalopram (Lexapro)
- TCAs (tricyclic antidepressants)
 Amitriptyline (Elavil)
 Imipramine (Tofranil0
- Monoamine oxidase (MAO) inhibitors
 Phenelzine (Nardil)
 Tranylcypromine(Parnate)
- Miscellaneous
 Venlafaxine (Effexor)
 Mirtazapine (Remeron)
 A similar delayed pattern of therapeutics response has been
observed with all antidepressant medications
 Traditionally, patients have been informed that approximately
4 to 6 weeks must elapse before they will experience any
therapeutic benefit from medication.
 The pattern of patient response can be genralized, with
neurovegetative symptoms (e.g. altered sleep or appetite,
decreased energy, excessive worrying and irritability often the
first to subside.
 The cognitive symptoms are slower to response, and 3 to 4
weeks or more may elapse before improvements are evident.
These symptoms include excessive guilt or pessimism, poor
concentration, hopelessness or sadness, and decreased libido
 Thus, patient should be counseled concerning this anticipated
delay in therapeutic response and advised that optimal
improvement may take ≥4 weeks in order to prevent patient
may stop the medication prematurely.
 According to the guidelines released by the Agency for Health Care
Policy Research (AHCPR), antidepressant treatment can be broken
down into three stages
 Acute treatment phase: 3 months
 Continuation treatment phase: 4-9 months
 Maintenance treatment phase: variable
 Acute and continuation treatment recommended for all patients
with major depressive disorder (i.e., minimal duration of treatment
= 7 months)
 Decision to prescribe maintenance treatment is based on the
following:
- number of previous episodes, severity of previous episodes,
family history of depression, patient age (worse prognosis if
elderly),
response to antidepressant, persistence of environmental
stressors
 Indefinite maintenance treatment is recommended if any one of the
following criteria are met.
- 3 or more previous episodes (regardless of age)
- 2 or more previous episodes and age older than 50 yr
- 1 or m0re and age older than 60 yr
 Were the most popular class of medications used to treat
depression
 The acquisition cost for TCAs is quite low, and there are some
providers who continue to prefer this class of medication for the
treatment of severe or melancholic depression
 Also for other indication as well e.g. migraine prophylaxis and
chronic pain
 Unfortunately, TCAs possess a variety of ADRs, ranging from
bothersome (dry mouth, sedation, constipation) to serious
(cardiovascular effects), which often prevent patients from
receiving therapeutic doses of medication
 This relatively high side-effects burden can also discourage
clinicians from prescribing TCAs for elderly patients or those
with certain medical conditions (e.g. BPH, cardiac arrthymias,
narrow-angle glaucoma, dementia)
 Anticholinergic effects: dry mouth, blurred vision, constipation,
and urinary retention. Although pt may develop tolerance to
these effects, they may never disappear completely
 Counseling: pts with dry mouth, may tend to drink excessive
fluids to relieve discomfort. To minimize the inherent potential
for weight gain, pts should be advised to avoid caloric
beverages and drink water or dietetic fluids instead. Sugarless
gum or hard candy is often recommended as well
 Can be very sedating and are usually administered at bedtime
to minimize functional impairment
 Confusion or memory deficits also may occur and can be
onerous in elderly pts. The secondary amines may be more
tolerable in this regard
 Cardiovascular function: is a legitimate and serious concern.
Due to their quinidine-like properties on prolonging cardiac
conduction through His-Purkinje system. This, in conjunction
with positive chronotropic and adrenergic-blocking properties,
can lead to re-entry arrhythmias
 Orthostatic hypotension: most common, will lead to bone
fractures, lacerations and even MI. Tertiary amines (imipramine)
may cause more severe orthostatic hypotension than secondary
Numerous advantage over older compounds,
including a lower side-effect burden, safety in
overddose, less dosage titration, once-daily
administration, and patient adherence.
Results of a meta-analysis concluded that, although
the overall efficacy of the two antidepressants classes
was comparable, primary care patients receiving an
SSRI were much less likely to discontinue therapy
prematurely because of to side effects
Although SSRIs are more expensive than TCAs, this
additional cost may be offset by enhanced medication
adherence rates and decreased relapse rates
 GI complaints: nausea, but this tends to be a transient
effect that diminishes after the first weeks or so of
treatment. Typically, can cause some local GI irritation
1 or 2 hours after oral administration. Thus, pts should
be advised to take the medication after a meal or
snack
 Diarrhea: 15-20%. Fortunately, often remits after 1
weeks of so of continued therapy and rarely requires
an interruption of treatment.
 Myriad effects on CNS: disturbances in sleep of
disposition being a primary concern, have significant
effects on sleep architecture and may prolong the REM
stage, resulting in less fitful sleep. It should be
emphasized that this is usually a transient
phenomenon that occurs during the first week or two
of treatment; sleep may actually improve from
baseline once the antidepressants properties of the
medication emerge.
Studies in melancholic depression and treatment-
resistant depression
Common ADRs: nausea, constipation,
somnolence, dry mouth, dizziness, nervousness,
sweating, asthenia, abnormal ejaculation, and
anorexia. Dose related
May cause a dose-related increase in diastolic
blood pressure, and baseline blood pressure is not
a useful predictor of the occurrence of this
phenomenon. BP should be monitored regularly
during therapy, and dosage reduction or
discontinuation may be necessary if sustained
hypertension occurs
Modulating serotonin and norepinephrine
activity through a complex MOA
In a comparative randomized trial with
fluoxetine for moderate to severe depression,
mirtazapine appeared to be much effective
than the SSRI after 4 weeks of treatment, but
the differences were no longer significant at 6
weeks.
Common ADRs: sedation and weight gain
 Drug Brand Name Starting Dose Maximum Usual Dosage
(mg/day) Dosage (mg/day)
(mg/day)
Fluoxetine Prozac 10 80 10-20mg OD
Sertraline Zoloft 25 200 50mg OD
Escitalopram Lexapro 5 20 10mg OD
Amitriptyline Elavil 50 300 100-300mg OD

Imipramine Tofranil 50 300 100-300mg OD

Venlafaxine XR Effexor XR 37.5 225 150mg OD

Mirtazapine Remeron 15 45 15-30mg ON

 Depression is NOT a personality flaw or a weakness of
character
 All antidepressants are equally effective (approximately
65% of pts receiving a therapeutic trial of any
antidepressant medication will have a beneficial response)
 Most pts receiving antidepressants will experience some
side effects initially
 Antidepressants should be taken at the same time daily
 The response to antidepressants is delayed (several weeks
may pass before begin to feel better and it may take 4 to 6
weeks before maximal benefits are evident)
 Antidepressants must be taken for at least 6 to 9 months
(even if feeling completely better, studies have shown that
people who stop their medication during the first 6 months
are much more likely to become depressed again)
 Antidepressants are NOT addictive substances
(antidepressants may elevate the moods of depressed
individuals but do not acts as stimulants and are not
associated with craving or other abuse patterns)
Remains one of the most commonly occurring
mental illnesses in adults, and it is often
undiagnosed and untreated.
Pharmacologic intervention is the cornerstone
of antidepressant treatment.
Antidepressant medications have a broad
spectrum of neurochemical effects and
influence a variety of receptors peripherally
and centrally.
 American Psychiatric Association. Diagnostic and Statistical Manual of
Mental Disorders, 4th ed. American Psychiatric Association, 2000:356
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 Delgado PL, Moreno FA, Potter R, et al. Norepinephrine and serotonin in
antidepressant action: Evidence from neurotransmitter depletion
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 Bryant SG, Brown CS. Current concepts in clinical therapeutics: Major
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 Katon W, Sullivan MD. Depression and chronic medical illness. J Clin
Psychiatry 1990;51:3-11
 American Psychiatric Association. Practice guideline for the treatment
of patients with major depressive disorder. Am J Psychiatry 2000;157:1-
45
 Rothschild AJ. Management of psychotic treatment-resistant
depression. Psychiatr Clin North Am 1996;59:5-9
 Ballenger JC. Clinical evaluation of venlafaxine. J Clin Psychopharmacol
1996;16:29-35
 Gormon JM. Mirtazapine: Clinical overview. J Clin Psychiatry 1999;60:9-
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