Transcript Introduction  Treatment of depression  Drug treatment  1. Tricyclic Antidepressants (TCA) 2. Serotonin - Specific Reuptake Inhibitors (SSRI) 3.

Introduction
 Treatment of depression
 Drug treatment

1. Tricyclic Antidepressants (TCA)
2. Serotonin - Specific Reuptake Inhibitors (SSRI)
3. Monamine Oxidase Inhibitors (MAOI)
4. Heterocyclic Antidepressants
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“An affective disorder characterized by loss of
interest or pleasure in almost all a person’s usual
activities or pastimes.”
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Sadness, Despair, Guilt, Pessimism
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Decrease in energy
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Decrease in sex drive
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Insomnia and fatigue
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Thoughts of death and suicide
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Mental slowing, lack of conc
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Non pharmacologic treatment
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Reactive or Secondary (~60%)
 Related to some “loss”, physical illness (MI, Cancer),
 Drugs, (alcohol, beta blockers, prednisone, reserpine, cocaine)
 Other psychiatric disorders (senility)
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Melancholic (~25%)
 Major or Endogenous
 No clear/adequate precipitating event
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Pharmacologic treatment
Mood stabilizer (lithium)
Bipolar affective(Manic-depressive)
 Episodes of mania associated with depression
 Depression alone - occasional; Mania alone – rare
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Chronic or Dysthymia (~3-6%)
 Less severe, but long lasting (>2 yrs)
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Atypical
 Patients overeat, oversleep, react strongly to rejection
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Seasonal affective disorder
 Annual episodes of depression during fall or winter
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Amine hypothesis: Depression is associated with
decreased amine-dependent synaptic transmission.
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Almost all antidepressants affect metabolism or
reuptake of serotonin, NE, or both.
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Several brain circuits have also become dysfunctional.
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Some are also selective antagonists of serotonin or
norepinephrine.
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The full clinical effects of drugs requires 4-8 weeks.
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Psychotherapy
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Electroconvulsive therapy
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Natural alternatives
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Medication
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Drugs first introduced 50 years ago that were
were used for treatment of other disorders
including:
 Anxiety disorders, dysthymia, chronic pain and
behavioral problems
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Antidepressants discovered accidentally while
investigating antipsychotic phenothiazines
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Imipramine - first antidepressant discovered
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Drugs & structure
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Mechanism of Action
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Side effects
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Overdose
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)Imipramine( ‫ ایمی پرامین‬
)Desipramine( ‫ دس ی پرامین‬
)Amitriptyline( ‫ آمی تریپتیلین‬
)Protryptyline( ‫پروتریپتیلین‬
)Clomipramine( ‫کلومیپرامین‬
)Trimipramine( ‫ترمیپرامین‬
)Nortriptyline(‫نورتریپتیلین‬
)Doxepin( ‫دوکسپین‬
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TCA inhibit the reuptake of the biogenic amines,
mostly norepinephrine (NE), as well as serotonin
(5HT).
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 Phenothiazine like “side effects”:
 Antimuscarinic (M1): dry mouth, constipation,
urinary retention, aggravation of glaucoma
 Antihistamine (H1): sedation (tolerance can
develop)
 Na channel block: QRS, arrhythmias*
 alpha blockade (α1) : orthostatic hypotension,
tachycardia** erectile dysfunction
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
Are extremely dangerous in overdose
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More than 1 g of a tricyclic is potentially lethal
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TCAs increase suicidal risks.
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Manifestations are: mydriasis, respiratory
depression, seizure, cardiac arrhythmia and
coma
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Drugs & structures
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MOA & Uses
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Side effects
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Properties of individual drugs
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 Fluoxetine
 Paroxetine
Its active metabolite has a
half-life of 7-9 days.
 Sertraline
 Fluvoxamine
 Citalopram
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SSRI
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Available for the past 15 years
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MOA: Allows for more serotonin to be available
to stimulate postsynaptic receptors
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Available to treat depression, anxiety disorders,
ADHD, obesity, alcohol abuse, childhood
anxiety, etc.
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Serotonin syndrome:
 When a SSRI is used with a MAOI causes marked increases
of serotonin in the synapses.
 Characterized by: muscle rigidity, myoclonus,
hyperthermia & rapid changes in mental status and vital
signs. It may be fatal.
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Serotonin withdrawal syndrome: within a few days and
can persist 3-4 weeks. Symptoms: disequilibrium,
gastrointestinal problems, flu-like symptoms,
sensory disturbances, sleep disturbances
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Fluoxetine (Prozac) – first SSRI available, long half life,
slow onset of action, can cause sexual dysfunction,
anxiety, insomnia and agitation, Nausea, Headache,
Insomnia, Weight gain
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Sertraline (Zoloft) – second SSRI approved, low risk of
toxicity, few interactions, more selective and potent
than Prozac
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Paroxetine (Paxil) – third SSRI available, more selective
than Prozac, highly effective in reducing anxiety and
posttraumatic stress disorder (PTSD) as well as OCD,
panic disorder, social phobia, and chronic headache. 30
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Fluvoxamine (Luvox) – structural derivative of Prozac,
became available for OCD, also treats PTSD, dysphoria,
panic disorder, and social phobia
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Citalopram (Celexa) – well absorbed orally, few drug
interactions, treats major depression, social phobia,
panic disorder and OCD
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SSRIs are more selective for 5-HT transporter
than NE transporter (300 to 7000).
Trazodone, nefazodone, & mirtazapine
antagonize serotonin receptors.
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History, Isoniazid,Iproniazid
MAO and depression
Current Drugs
Mechanism of Action
Side Effects
Isoniazid
Iproniazid
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MAO catalyze deamination of intracellular
monoamines (NEP, EP, Serotonin, DA …).
 MAO-A oxidizes NEP, EP, Serotonin and DA
 MAO-B oxidizes phenylethylamine
 Both oxidize dopamine nonpreferentially
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MAO transporters reuptake extracellular
monoamine
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Tranylcypromine (non-selective, reversible)
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Phenelzine (non-selective, irreversible)
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Selegiline (selective MAO-B, irreverisible)
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Moclobemide (selective MAO-A, reversible)
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MAOI
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Monoamine oxidase, located on outer membrane
of mitochondria; deaminates catecholamines free in
nerve terminal that are not protected by vesicles
Cocaine blocks the NET
Reuptake of NE
Stimulant
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MAO-A metabolizes norepinephrine, serotonin
& tyramine.
MAO-B is more selective for dopamine.
Nonselective MAO inhibitors can lead to
hypertensive reactions due to tyramine in
ingested food.
Tyramine is found in banana, fermented food
(cheese) & fermented beverages.
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Drug classification:
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Serot and NEP Reuptake Inhibitors (SNRIs):
 Venlafaxine
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NEP and Dopamine Reuptake Inhibitor (NDRI):
 Bupropion
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Mechanism of Action
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Side Effe
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Second generation
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Third generation
 Amoxapine
 Venlafaxine
 Maprotiline
 Mirtazapine
 Trazodone
 Nefazodone
 Bupropion
 Duloxetin
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Second generation
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Third generation
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‫‪‬‬
‫مکانیسم‪ :‬مکانیسم مشترکی ندارند‬
‫‪‬‬
‫آثارشان دیر ظاهر می شود‬
‫عوارض متفاوت و کمتر از ‪TCA‬‬
‫‪‬‬
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SNRIs act upon two neurotransmitters in the brain that are
known to play an important part in mood.
SNRIs were developed more recently than SSRIs, and there are
relatively few of them.
Their efficacy as well as their tolerability appears to be
somewhat better than the SSRIs, owing to their compound
effect.
Because of their specificity for the serotonin and norepinephrine
reuptake proteins, lack most of the adverse side effects of TCA
and MAOI.
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Venlafaxine hydrochloride first introduced by Wyeth in 1993.
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It is used primarily for the treatment of depression, generalized
anxiety disorder, and social anxiety disorder in adults.
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Venlafaxine is the first and most commonly used SNRI.
Venlafaxine has a single chiral centre and exists as a racemic
mixture of R-(–)- and S-(+)-enantiomers. The R-enantiomer
exhibits dual presynaptic inhibition of serotonin and
noradrenaline reuptake, while the S-enantiomer is
predominantly a serotonin reuptake inhibitor.
 In vitro, venlafaxine is approximately 3- to 5-fold more potent at
inhibiting serotonin than noradrenaline reuptake. It has low
affinity for muscarinic cholinergic, histamine H1 and adrenergic
receptors.

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Because of its relatively short half-life of 4 hours,
Effexor should be administered in divided dosages
throughout the day.
 Side effects may include nausea, dizziness, sleepiness,
abnormal ejaculation, sweating, dry mouth, gas or
stomach pain, abnormal vision, nervousness, insomnia,
loss of appetite, constipation, confusion/agitation,
tremors, and drowsiness.

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Norepinephrine and Dopamine
Reuptake Inhibitor (NDRI)
Bupropion
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
These are a class of antidepressants that are not really
categorized as a special group of antidepressants.
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The only antidepressant in this group is Bupropion,
which is an antidepressant chemically unrelated to
tricyclics or SSRIs. It is similar in structure to the
stimulant cathinone, and to phenethylamines in general.
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Bupropion was first synthesized in 1966
It was approved by the FDA in 1985 and
marketed under the name Wellbutrin as an
antidepressant.
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Bupropion is a
selective
catecholamine
(norepinephrine
and dopamine)
reuptake
inhibitor.
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Bupropion is metabolised in the liver. It has at least
three active metabolites; hydroxybupropion,
threohydrobupropion and erythrohydrobupropion.
 These active metabolites are further metabolised
to inactive metabolites and eliminated through
excretion into the urine. The half-life of bupropion
is 20 hours as is hydroxybupropion's.
 Threohydrobupropion's half-life is 37 hours and
erythrohydrobupropion's 33 hours.
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Common side effects include dry mouth, tremors,
anxiety, loss of appetite, agitation, dizziness, headache,
excessive sweating, increased risk of seizure, and
insomnia. Bupropion causes less insomnia if it is taken
just before going to bed.
 Sexual side effects normally accompanying SSRI's do not
accompany bupropion. Interestingly, patients commonly
report increased libido, perhaps evidence of its
dopaminergic properties.
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Comparisons of the antidepressants showed
that they are roughly equivalent in efficacy.
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Individual patients may respond better to one
drug than to another.
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Patients depressed enough to be hospitalized
respond better to classic TCAs than to SSRIs.
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Outpatient studies also show a greater
efficacy of TCAs over SSRIs.
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SSRIs are not sedative, safe in overdose and have mild
adverse effects so they are widely prescribed.
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Finding the right drug and the right dose must be
accomplished empirically.
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If it is the first depressive episode and if the treatment was
satisfactory, withdraw treatment after 6-9 months.
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A patient who has had previous episodes of depression is a
candidate for maintenance therapy.
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The duration of maintenance treatment varies and may
continue indefinitely.
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Depression
Definitely requires pharmacologic treatment
Panic disorder given the high rate of suicide in patients
1. Are acute episodes of anxiety
2. disorders
Benzodiazepines are preferred drugs
Obsessive-compulsive
Fluoxetine and clomipramine
Enuresis
1. Effect of drug lasts as long as treatment is continued
Chronic pain
2. Used for elderly institutionalized patients
3. Drug therapy is NOT the choice treatment
TCAs are useful, SSRIs
have no effect
Attention deficit hyperkinetic
disorder
(ADHD)
Atomoxetin (NET inhibitor)
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He’s
MANIC!!!!!
Take Home Message:
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
Effective in treating bipolar (manic - depressive)
disorder.
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A “mood stabilizer”
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Has multiple effects including inhibiting enzymes
involved in PI recycling
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
In mania, there is increased activity of NTs
utilizing DAG/IP3 2nd messengers
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Li “reduces” the response produced by these
overactive NTs
 Selective depression of “overactive circuits”
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Side Effects: polydypsia, polyuria*, edema, weight
gain, thyroid enlargement, hypothyroidism (5%)
 Toxicity:
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 Low dose: nausea & vomiting
 High dose: seizures, circulatory collapse, coma
Avoid dehydration, diarrhea, vomiting, diuretics
 Alternative drugs for bipolar disorder
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 Valproic acid & carbamezepine
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SSRIs can unmask mania in patients with a bipolar disorder
*Li causes the renal collecting duct to become resistant to ADH
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1) Tricyclics and Tetracyclics (TCA)
Imipramine
Doxepin
Desipramine
Maprotiline
Clomipramine Amitriptyline
Amoxepine
Nortriptyline
Trimipramine
Protriptyline
2) Monoamine Oxidase Inhibitors (MAOIs)
Tranylcypramine Phenelzine
Moclobemide
3) Serotonin Selective Reuptake Inhibitors (SSRIs)
Fluoxetine
Fluvoxamine
Sertraline
Paroxetine
Citalopram
4) Dual Serotonin and Norepinephrine Reuptake Inhibitor (SNRI)
Venlafaxine
Duloxetine
5) Serotonin-2 Antogonist and Reuptake Inhibitors (SARIs)
Nefazodone
Trazodone
6) Norepinephrine and Dopamine Reuptake Inhibitor (NDRI)
Bupropion
7) Noradrenergic and Specific Serotonergic Antidepressant (NaSSAs)
Mirtazapine
8) Noradrenalin Specific Reuptake Inhibitor (NRI)
Reboxetine
9) Serotonin Reuptake Enhancer
Tianeptine
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•
TCA’s
–
–
–
•
Less well tolerated in elderly
Less expensive
Higher overdose potential
SSRIs & Heterocyclics
–
–
Empirical selection
Bupropion has less sexual side effects* &
may help smokers “quit” the habit
• (contraindicated in pts. w/ seizure history)
– Escitalopram (Lexapro ®) - no weight gain
•
Atypical Depression
–
•
MAOI (phenelzine)
Manic-Depressive
–
Li, carbamazepine, valproic acid
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