Anti Depressants

1
 Prevalence and Consequence of
untreated depression
• According to the World Health Organization
(WHO, 2002)…
– Depression is the leading cause of disability
• One in 10 Americans ………..take
antidepressants
• Zoloft®, Prozac® and Effexor® are ………..
– currently the most commonly prescribed class of
drugs in the United States,
– just ahead of high-blood pressure medicine, according
to the Centers for Disease Control.

2
 Prevalence and Consequence of untreated
depression
• SSRIs and SNRIs ………
– have become by far the most common types of
antidepressant dispensed by pharmacies, driving a
tripling of prescriptions since 1988.
• About 33% of all depressed patients attempt…
– suicide - About half of them succeed
• 31,000 death per year in the US

3
 Prevalence of Depression in Specific
Medically Ill Population
45
40
35
30
25
20
15
10
5
0
DM MI CRF EPILEPSY STROKE CANCER CHRONIC
PAIN

4
5
 Diagnostic Criteria
• I. Five or more of the following symptoms for at least two-
week period. One of the symptoms is either:
– Depressed mood
– Loss of interest in pleasurable activities

• II. The symptoms cause clinically significant distress or

impairment in social, occupational, or other important
areas of functioning.

• III. Cannot be established that an organic factor initiated or

maintained the disturbance

6
 Diagnostic Criteria
A SAD FACE
A – Appetite (Poor; 5-10 lb gain if atypical)
S – Sleep (insomnia)
A – Anhedonia (loss of interest in life)
D - Depressed Mood
F - Fatigue
A - Agitation
C – Concentration (Lack of)
E – Esteem (low self-esteem)
S - Suicide thought (still remains high)

7
8
 Risk Factors
• Genetic predisposition
– 2.5x greater: 1st degree relative
– twins: 65% increases incidence
• Gender difference……….. F 25%; M 15%
• Age…………Elderly higher incidence
• Race…Whites >Native Americans >African Americans
• Co morbidity…….
• Marital status……….Single>Divorced>Widow
• Substance abuse
• Family History

9
 Risk Factors
• SINGLE
• ELDERLY
• FEMALE
• WHITE
• FAMILY Hx
• CO-MORBIDITY

10
 Pathophysiology

1. Depressed patient reported to have a specific gene

called “5HTT” regulates the movement of 5HT
2. Dysregulation of Serotonin (5HT) and Norepinephrine
(NE) in the brain are strongly associated with
depression
3. Biogenic Amines hypothesis
Depletion of NE, 5HT, and DA – depression
E.g. Reserpine
4. Permissive Hypothesis
Increased NE = Mania…………..Decreased NE = Depression
5. Change in receptor sensitivity – altered response
11
12
 Factors to consider in choosing a
specific antidepressant
• Prior response to agent
– Use it if it works in the past
• Anticipated S.E
– E.g. Drugs that are associated with wt gain (young vs. old)
• Concomitant illness
– Mood stablizers – Mania
– Avoid Bupropione/TCA – Seizure d/o
– Bupropirone – Parkinsons’ Disease
– TCA – Migraine
• Drug interactions
• Cost

13
 General Treatment Rules
• Often takes………. 4-6 weeks for response
• Monitor for ……response versus remission
• SSRI’s are ………….
– the first line of treatment for most MDD’s
• Address biopsychosocial needs and maintain
meds for 6-12 months

14
 Lag-Time
Side Effects Efficacy
60

50

40

30

20

10

0 3-D Line 1
1 2 3 4 5 6

15
16
 SSRI
• Citalopram (Celexa):
– 20 mg initially; maintenance 40 mg per day; maximum dose 60
mg per day.
• Escitalopram (Lexapro, Cipralex):
– 10 mg and shown to be as effective as 20 mg in most cases.
Maximum dose 20 mg. Also helps with anxiety.
• Paroxetine (Paxil, Seroxat): Also used to treat panic
disorder, OCD, social anxiety disorder, generalized anxiety
disorder and PTSD.
– Usual dose 25 mg per day; may be increased to 40 mg per day.
Available in controlled release 12.5 to 37.5 mg per day; controlled
release dose maximum 50 mg per day.
– Less cycling in patients who are bipolar. 17
 SSRI
• Fluoxetine (Prozac): Also used to treat OCD, bulimia, and
panic disorder.
– Long half-life; less withdrawal when medication is stopped.
– Dosing is 20 mg to a maximum of 80 mg.
• Fluvoxamine (Luvox): Although primarily used in the
treatment of OCD, it can be used for depression.
– Initial dose is 50 mg,
– If daily dose is greater than 100 mg give in equally divided doses
or give larger dose at bedtime not to exceed 300 mg per day.
• Sertraline (Zoloft, Lustral): Also used to treat panic
disorder, OCD, PTSD, social anxiety disorder, premenstrual
dysphoric disorder.
– Dosing is 50-200 mg per day and should be titrated upward 18
 SSRIs Dosage
• Fluoxetine [Prozac] 20-80 mg/d
• Paroxetine [Paxil] 10-50 mg/d
• Sertraline [Zoloft] 25-200 mg/d
• Fluvoxamine [Luvox] 50-300 mg/d
• Citalopram [Celexa] 20-50 mg/d

• Initial response 2-4 wks

• If there is a response but not adequate response
after 3-4 wks dose.
• If no response at all, switch.
19
 SSRI’s Side Effects
• GI: N/V/diarrhea
– Fluoxetine/sertraline
– Constipation (paroxetine)
• Central nervous system:
– Nervousness, insomnia………fluoxetine
– Somnolence ………..paroxetine
– tremor, dry mouth …………..paroxetine
• Sexual dysfunction
– All, except fluoxetine

20
 SSRIs and Sexual Dysfunction
• Common………..class effect
• Affects both……….men and women
• Reduced libido
• Orgasmic dysfunction
– delayed ejaculation
– anorgasmia
• Erection difficulties ……..minimal

Keller Ashton A et al. J Sex Marital Ther. 1997;23:165-175.

Segraves RT. J Clin Psychiatry. 1998;59(suppl 4):48-54.

21
22
 SSRI – Serotonin Syndrome
• A "serotonin syndrome" may occur, where
mental status changes along with ………
– Agitation sweating
– Shivering tremors
– Diarrhea incoordination
– fever may develop

• This syndrome may be life-threatening.

23
 SSRI – Serotonin Syndrome
• SSRIs should not be used with any drug that
increases serotonin concentrations, including….
– MAO inhibitors
– Tramadol
– Meperidine
– Sumatriptan
– Lithium

24
25
 Tricyclic Antidepressants (TCAs)

• Chemical structure with characteristic three-ring nucleus

• Originally developed as antipsychotics (1949), but were
found to have no effect in this indication.
imipramine
• Principal mechanism of action:
– blockade of re-uptake of noradrenaline (NA) and
serotonin (5-HT) by competition for binding site of the
carrier protein.
– in most TCA, other receptors (incl. those outside the
CNS) are also affected: blockade of H1-receptor, -
receptors
26
 TCA’s
• Tertiary amines
– amitriptyline (Elavil) = 50-300 mg
– imipramine (Tofranil) = 50-300 mg
– doxepine (Sinequan) = 50-300 mg

• Secondary amines
– nortriptyline (Aventyl) = 50-150 mg
– desipramine (Norpramine) = 50-300 mg
– protryptline (Vivactil) = 15-60 mg
27
 Most Common Side effects Reported
Percentage of people taking TCAs
– Dry mouth - 74%
– Drowsiness - 52%
– Dizziness - 38%
– Constipation - 29%
– Confusion - 14%
• Drowsiness may wear off over time.
• The other side effects probably won't, however.

28
 TCA Overdose & Acute Intoxication
• Unfortunately TCA have…… a low therapeutic index:
• Target systems (toxicity) – the CNS and heart
– Initially excitement, hallucinations and delirium is observed,
may be accompanied with convulsions.
– Coma and respiratory depression may follow.
• Cardiac dysrrhythmias are very common – tachycardia
– QRS complex widening, QT interval elongation.
– Ventricular fibrillation and sudden death may occur.
• Hypotension
• Treatment- diazepam (seizures),
– No effect of haemodialysis and hemoperfusion is practically
ineffective

29
 Serotonin-norepinephrine reuptake
inhibitors (SNRIs)
• Venlafaxine (Effexor): Also used to treat generalized
anxiety disorder and social anxiety disorder.
– Dose 37.5 mg …..Maximum dose 375 mg in XL form.
– Blood pressure should be monitored as this medication can
increase it.
• Desvenlafaxine (Pristiq)……Similar to Venlafaxine.
• Duloxetine (Cymbalta)………….
– Dosing 40 mg two X daily or 60 mg once daily.
• Milnacipran

30
SNRI antidepressants (Venlafaxine, Duloxetine, etc.)
and Worsening of Heart Failure
• There are reports of ………
– heart failure exacerbations in patients shortly after starting
venlafaxine (Effexor®) or duloxetine.
• Not well proven – Depression itself can also worsen
heart failure.
• To be safe ……….
– suggest using an SSRI (sertraline, etc) for initial treatment of
depression in heart failure patients.
• Counsel heart failure patients to report …………
– right away any fatigue, edema, trouble breathing, etc after
starting an SNRI.
31
 SNRI antidepressants and Worsening of
Heart Failure
• All serotonin norepinephrine reuptake inhibitors can increase
heart rate and blood pressure...
– which can cause problems for patients with advanced or unstable heart
failure.
• Heart failure patients have ……..
– high circulating levels of NE to compensate for poor cardiac output.
– NE helps to make the heart pump faster and more forcefully.
• However, this sustained response increases demand on an
already damaged heart...
– eventually leading to further deterioration of heart function.
• It makes sense that drugs that increase norepinephrine might
lead to worsening heart failure.
32
 Norepinephrine-dopamine reuptake
inhibitors (NDRIs)……Bupropion
• Brand names: Wellbutrin SR
• Half-life : 10-21 hours
• Dosage: Initiate with 100 mg bid
• Maintenance dose: 300-450 mg/day (divided doses)
• Notes: max dose 150 mg/dose
• Contraindication: seizure, anorexia

33
 MonoAmine Oxidase Inhibitors (MAOI)
The first compounds (iproniazid derivatives) were
originally developed as antimycobacterial drugs by
chemical modification of isoniazid molecule (1950s).

Agents Initial MD
Dose (mg/day)
• Selegiline (Eldepryl) 5 mg 10-30
• Isocarboxazide (Marplan) 10 mg 30-60
• Phenelzine (Nardil) 15 mg 45-90
• Tranylcypromine (Parnate) 10 mg 20-40

ADR……hypertensive crisis, hepatotoxicity, insomnia

34
 MOA….Interaction with foods
• The most serious problem of this class of drugs
• Tyramine „cheese and wine“ reaction
– some kind of foods contain high amounts of tyramine (natural
indirect sympathomimetic produced during fermentation), which
is however normally metabolized by MAO in the gut and liver.
– In depressed patients treated with MAOI, these enzymes are also
inhibited  bioavailability of tyramine is significantly higher
which together with pharmacodynamic synergism  strikingly
increased noradrenaline transmission results in hypertensive
crisis, severe headache and potentially fatal intracranial
hemorrhage or other organ damage.
• Dietary precautions: restriction in the consumption of
some maturing cheeses, wine, beer, yogurts, bananas etc.
35
 Difficult-to-Treat Depression
(Treatment Resistant Depression)
• Approximately 29% to 46% of patients with depression do
not have good response to antidepressants.
• Intolerance is frequently a cause of treatment failure or
inadequate response
• Antidepressant treatment at an adequate dose for at least
four to eight weeks is necessary before deeming a patient
nonresponsive or only partially response to a medication.
• Higher doses may be an option, but this risks more frequent
and severe adverse effects.

36
 Sexual Side Effects
Management

• First: “wait and see” approach - Some problems

diminish or fade over time.
• lower the dose of the medication
• allow a one- or two-day drug holiday each week
• switch to wellbutrin (buproprion) – not recommended
for persons with seizure disorders, or with a diagnosis
of anorexia

37
 Sexual Side Effects
Management
Use other drugs:
◦ For men, PDE5 inhibitor such as
Viagra, Cialis or Levitra (up to 55
percent response rate).

38
 Antidepressants and
Increased Suicidal Risk
 In 2004, the FDA issued a health advisory recommending
close observation for worsening depression in both
adults and children treated with antidepressants.
• The risk of committing suicide is found to be more in the
patients undergoing antidepressant treatment.
• If the person is taking the antidepressants for the first
time or if the dose has changed abruptly, then monitoring
of the person is essential as they might commit suicide.
• Antidepressants will not provide benefits to all the
depression patients
39