Antidepression Agents

1
Anti-depression Agents

• Depression a reduction in mood leading to
  behavioral changes can include extreme
  pessimism, loss of self-esteem, unhappiness
  self-destructive thoughts or behavior,
  withdrawal, loss of all interests, agitation,
  lack of energy, insomnia decrease in social
  interaction, appetite and libido
• Two types of clinical depression
• Exogenous or reactive or secondary most
  frequently encountered and caused by external
  stress or misfortune - may or may not resolve
  itself spontaneously
• Endogenous or primary occurs due to unknown
  causes and appears due to biochemical imbalances
  - treatment usually involves anti-depressant
  medications and in delusional or life-threatening
  cases use of electroconvulsive therapy (ECT).

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Anti-depression Agents

• Mechanisms of depression
• Imbalances of catecholamines especially
  norepinephrine in the limbic area of the brain
• Simple low levels - depression
• Excessive levels of NE - manic or excessive mood
  changes
• Serotonin imbalance low levels of 5-HT
• Both of these mechanisms are known as the
  monoamine hypothesis of depression
• Two situations can arise when taking
  anti-depressant medications that can affect the
  success or failure of therapy
• Receptor down-regulation occurs with all drugs
  except with SSRIs
• b-adrenergic receptor numbers decrease with a
  loss of sensitivity
• An increase in 5-HT1A receptor sensitivity occurs
  with all antidepressants
• Categories of antidepressant medications
• TCA Tricyclic antidepressants First
  generation agents Metabolism Demethylation,
  hydroxylation and glucuronidation
• Second and third generation heterocyclic
  compounds
• SSRI Selective serotonin reuptake inhibitors
• MAOI Monoamine oxidase inhibitors

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Norepinephrine
amine
Catechol

• a.a. tyrosine is converted to L-dopa which is
  then hydroxylated to Dopamine
• B-hydroxylase converts dopamine to norepi
• Norepi release Ca2
• Receptor binding (Also see 5?7)

• Catechol O-methyl transferase degrades
  catecholamines
• Reuptake into presynaptic neuron
• Repackaging
• Degraded by mitochondrial MAO
• Path for indirect sympathomimetics

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TCAs - 3º Amines

• Inhibit NE and 5-HT reuptake
• 5-HT Selective amitriptyline, clomipramine,
  imipramine, trimipramine
• NE Selective Doxepin
• MANY side-effects (scale of 1-4)
• Seizures 2
• Sedation 3
• Hypotension 2
• Weight gain 2
• Sexual effects 2

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TCAs - 3º Amines
See Table 19-1, p452 In Goodman Gilman
Depression Tablets and injection Not
recommended for children lt12 years old Dosage
50-300 mg/day Half-life 31-46 hours Very high
serotonin uptake blocking activity and
anticholinergic and sedation side effects
Obsessive-compulsive disorder Capsules Dosage
25-250 mg/day High incidence of male sexual
dysfunction Half-life 19-37 hours High
serotonin uptake blocking activity and
anticholinergic and sedation side effects
Depression Capsules and oral concentrate Not
recommended for children lt12 years old Dosage
25-300 mg/day Half-life 8-24 hours Moderate
serotonin uptake blocking activity and
anticholinergic effects Moderate sedation side
effects
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TCAs - 3º Amines
Depression and childhood enuresis (lt6 years)
Tablets Dosage 30-300 mg/day Half-life 11-25
hours High serotonin uptake blocking activity
Moderate anticholinergic and sedation side
effects High orthostatic hypotension compared to
other TCAs Depression Capsules Dosage 50-300
mg/day Half-life 7-30 hours Slight serotonin
and norepinephrine uptake blocking activity
Moderate anticholinergic and sedation side
effects
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TCAs - 2º Amines

• All inhibit selective reuptake of NE
• Dopamine blocking agent Amoxapine
• MANY side-effects, reduced relative to 3º TCAs
  with the exceptions
• Sexual effects 2
• Cardiac effects 2

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TCAs - 2º Amines
Depression Tablets Not recommended for
children Dosage 15-60 mg/day Half-life 67-89
hours High norepinephrine uptake blocking
activity and anticholinergic effects Less
orthostatic hypotension and slight sedation side
effects Depression Tablets Not recommended for
lt 16 years of age Dosage 50-600 mg/day Half-life
8 hours Moderate to high serotonin and
norepinephrine uptake blocking activity, also
blocks dopamine receptors High anticholinergic
and moderate sedation side effects
Second Generation
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TCAs - 2º Amines
Depression Capsules and solution Not
recommended for children Dosage 30-100
mg/day Half-life 18-44 hours Moderate
norepinephrine and high serotonin uptake
blocking activity and moderate anticholinergic
effects Slight orthostatic hypotension
Depression (also cocaine withdrawal)
Tablets Not recommended for lt 16 years of
age Dosage 25-300 mg/day Half-life 12-24
hours High serotonin and moderate norepinephrine
uptake blocking activity Least anticholinergic,
sedation and orthostatic hypotension of the
activity of the secondary amines
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TCAs - 2º Amines
Second Generation
Depression and anxiety associated with depression
Tablets MOA blocks reuptake of norepinephrine
5-HT Metabolism Hepatic 88 protein bound,
excreted in urine and via the bile Contraindicated
in patients with known or suspected seizure
disorders
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Anti-depression Agents - Other
Depression, alcoholism aggressive behavior,
cocaine withdrawl Tablets MOA selectively
inhibits serotonin reuptake and potentiates
5-hydroxytryptamine actions Metabolism
CYP3A4 Onset of action often takes 2-4 weeks Take
with food to avoid lightheadedness, males - if
prolonged, inappropriate or painful erections
occurs immediately discontinue the drug and
contact MD Depression tablets including a
sustained release tablet Associated with seizures
frequency increase w/dosage MOA related to
phenethylamines and mechanism is unknown -
believed to prevent reuptake of dopamine. No
prevention of NE or serotonin reuptake.
Metabolism primarily excreted in the urine
unchanged although several hepatic metabolites
are active Photosensitivity possible
Triazolopyridine
Aminoketone
Budeprion Wellbutrin SR
Smoking cessation
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Anti-depression Agents - Other
Depression and generalized anxiety disorder
tablets and extended release capsules MOA
potent inhibitors of serotonin and norepinephrine
reuptake Metabolism hepatic primarily by
demethylation and glucuronidation Photosensitivity
possible, notify MD if a rash or hives or other
allergic reactions occur
Phenethylamine
Depression Tablets MOA inhibits neuronal
serotonin and norepinephrine uptake 5-HT2
antagonist Metabolism hepatic N-dealkylation
and hydroxylation via CYP 3A4 and 2D6 Warning
May cause liver damage---watch for signs and
symptoms Photosensitivity possible
Phenylpiperidine
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Anti-depression Agents - Other
Third Generation
Depression Tablets MOA potent antagonist of
5-HT2 and 5-HT3 receptors, also a2-NE
Metabolism CYP2D6 and 1A2 involving
demethylation, hydroxylation and glucoronide
formation Potent antagonist of H1 histamine
receptors - prominent sedative effects Agranulocyt
osisis possible side effect - contact MD for
infection
This is a good drug for people that dont respond
well to SSRIs and can tolerate the sedative
effects
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Benzodiazepines
Indications anxiety, PMS, panic disorder with or
without agoraphobia, depression 0.25,0.5,1 and 2
mg tablets oral solution Withdrawal may be
severe Generics also
Indications anxiety, acute alcohol withdrawl,
adjunct in partial seizures 3.75, 7.5, 15
tablets 11.25, 22.5 single dose tablets Prodrug
? Nordazepam Generics also
Indications anxiety, acute alcohol withdrawl,
preoperative apprehension and anxiety 10 and 25
tablets 5,10 and 25 mg capsules,
injection Long-acting, self-tapering Generics
also
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SSRIs

• Highly selective 5-HT reuptake inhibition
• Antagonism of muscarinic, histaminergic, and
  a1-adrenergic receptors has been hypothesized to
  be associated with various anticholinergic,
  sedative, and cardiovascular effects of tricyclic
  antidepressants.
• SSRIs bind to these and other membrane receptors
  from brain tissue much less potently in vitro
  than do the tricyclic drugs.
• Many indications
• School phobias, bed wetting, eating disorders,
  sleep disturbances (insomnia), nail biting, hair
  pulling, headache, Addictions (alcohol, gamblng),
  back pain, stomach upset, premenstrual syndrome.
• Never stop cold turkey taper dosage!
• "antidepressant discontinuation syndrome"

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SSRIs
Obsessive-compulsive disorder, depression,
bulimia nervosa and other uses Tablets,
pulvules, oral solution 7 of patients will
develop a rash or uticaria, may alter glycemic
control in diabetics Half-life of 1 to 348 hours,
95 protein bound, takes 28 days to reach steady
state Hepatic metabolism and elimination - use
caution in hepatic impairment Obsessive-compulsiv
e disorder and other unlabeled uses
Tablets Half-life of 14-16 hours, 80 protein
bound, takes 7 days to reach steady state Hepatic
metabolism - use caution in hepatic impairment,
94 of hepatic metabolites are excreted
renallyuse caution in renal impairment
Fluvoxamine - Luvox
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SSRIs
Obsessive-compulsive disorder, depression, panic
disorders, social anxiety disorders and other
unlabeled uses Tablets, oral suspension Half-lif
e of 21 hours, 93-95 protein bound, takes 10-14
days to reach steady state Elderly or debilitated
patients with severe renal or hepatic impairment
- start as 10 mg/day but do NOT exceed 40 mg/day
64 renal excretion and 36 fecal excretion Use
caution on withdrawalmay cause development of
psychiatric problems such as severe behavioral
symptoms Obsessive-compulsive disorder,
depression, panic disorder, post-traumatic stress
disorder and unlabeled uses Tablets, oral
concentrate Half-life of 26-104 hours, 98
protein bound, takes 7 days to reach steady
state Hepatic metabolism 45 renal excretion
and 45 fecal excretion
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SSRIs
S-enantiomer - Lexapro
Depression, panic disorders, social anxiety
disorders and other unlabeled uses Tablets,
oral suspension Half-life of 35 hours, 80
protein bound, takes 7 days to reach steady
state Hepatic impairment - 20 mg/day 35 renal
excretion and 65 fecal excretion. Use caution
in severe renal impairment Favorable side effect
profile no associated weight gain lower
potential for CYP450-induced drug interactions,
insomnia, anxiety, agitation, nervousness and
fatigue All SSRIs have MANY drug interactions
only contraindications are concurrent use or
within 14 days of discontinuation of a MAOI or
cisapride - Propulsid (GERDs)
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MAOIs

• MOA Monoamine oxidase is a complex enzyme
  system distributed widely throughout the body and
  its is responsible for metabolic decomposition of
  biogenic amines such as norepinephrine,
  epinephrine, dopamine, serotonin
• Two enzyme types
• Different substrate preferences and inihibition
  sensitivity
• Locations neural tissue and hepatic tissue
• MAO-A de-amination of endogenous amines
• MAO-B de-amination of exogenous benzylamines and
  phenethylamines Selegiline (Parkinsons)
• Currently used MAOI drugs are non-selective
• Exception selegiline used in Parkinsons
  treatment (MAO-B)
• All drugs are IRREVERSIBLE inhibitors
• Metabolism hydrazine based agents form active
  metabolites, inactivation of these drugs occurs
  via acetylation - remember the slow/fast
  acetylation populations?
• Many drug interactions including OTC agents -
  warn patient to inform MD and dentist that they
  are using taking these agents
• Do NOT discontinue abruptly ? hypertensive
  emergency

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MAOIs

• Indications Depression and some unlabeled uses
  These drugs are NOT first line agents for use
  in treating depression used only in patients
  unresponsive to other agents
• Some use in bulimia, cocaine addiction, night
  terrors, post-traumatic stress disorder,
  resistant migraines, panic disorders
• Warning to the patient Patients must be warned
  against eating foods that are high in tyramine,
  dopamine or tryptophan during treatment and for
  two weeks following discontinuation - only the
  highest containing products are listed below
• Cheese/dairy products blue, boursault,
  camembert, cheddar, emmenthaler, stilton and
  swiss cheeses yogurt
• Meat/Fish products beef or chicken liver,
  fermented sausages (bologna, pepperoni, salami,
  summer sausage, game meat, spoiled or pickled
  herring
• Alcoholic beverages (undistilled) beer, red
  wine, sherry, liqueurs
• Fruit/vegetables sauerkraut, yeast extracts -
  but can include bananas, bean curd, dried fruits
  such as raisins and prunes, avocados, figs,
  raspberries, soy sauce
• Foods containing other vasopressors broad
  beansoverripe fava beans, caffeine containing
  products, chocolate, ginseng

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MAOIs
15 mg tablets Initial dose should not be more
than 15 mg TID with titration up to 90 mg/day if
necessary 10 mg tablets Initial dose should not
be more than 10 mg TID with eventual titration up
to no more than 60 mg/day if necessary 10 mg
tablets Initial dose should not be more than 10
mg BID with eventual titration up to no more than
60 mg/day if necessary
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Summary

• Common Depression SSRI
• Depression anxiety Benzo or Lexapro
• Atypical Depression Imipramine or Phenylzine