Pharmacology of Antidepressants

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Pharmacology of Antidepressants

• Dr Andrew P Mallon

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Classes of AntidepressantsTricyclic-tertiary
amines

• amitriptyline (Elavil)
• imipramine (Tofranil)
• doxepin (Sinequan)
• clomipramine (Anafranil)
• trimipramine (Surmontil)

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Classes of AntidepressantsTricyclic-secondary
amines

• desipramine (Norpramin)
• nortriptyline (Pamelor)
• protriptyline (Vivactyl)
• amoxapine (Ascendin)

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Classes of AntidepressantsAtypical
(non-tricyclic)

• maprotiline (Ludiomil)
• trazodone (Desyrel)
• bupropion (Wellbutrin)
• venlafaxine (Effexor)
• nefazodone (Serzone)
• mirtazapine (Remeron)

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Classes of AntidepressantsSpecific serotonin
reuptake inhibitors (SSRIs)

• fluoxetine (Prozac)
• sertraline (Zoloft)
• paroxetine (Paxil)
• fluvoxamine (Luvox)
• citalopram (Celexa)

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Classes of AntidepressantsMonoamine oxidase
inhibitors (MAOIs)

• phenelzine (Nardil)
• isocarboxazid (Marplan)
• tranylcypromine (Parnate)
• selegiline (Deprenyl)

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Classes of AntidepressantsPsychostimulants

• methylphenidate (Ritalin)
• dextro-amphetamine (Dexedrine)
• magnesium pemoline (Cylert)
• dex amphetamine (Adderall)
• methamphetamine (Desoxyn)
• modafinil (Provigil)

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Evaluation of the depressed patientGoals of the
evaluation

• Establish a diagnosis
• Identify specific target symptoms
• Consider comorbidity
• Quantify depression and/or specific symptoms

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Evaluation of the depressed patient

• Obtain psychiatric history and perform mental
  status exam
• Identify and r/o underlying medical problems
• Physical exam in the past year

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Evaluation of the depressed patient

• Optional exams
• Laboratory
• Neurological exam
• Dexamethasone suppression test
• TRH test

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Is an antidepressant indicated?

• The decision to treat a patient with
  antidepressants should be based on the following
• Severity of symptoms and ability to identify
  target symptoms
• Impairment of functioning
• Patients view of medication
• Not necessarily the specific diagnosis

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Predictors of antidepressant response.

• Acute onset
• Severe depressive symptoms
• Positive previous response to medication
• Patients willingness to accept medication as an
  aid to successful treatment

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How to start antidepressants?

• Start low to assess tolerance of side effects
• Increase dosage rapidly as tolerated
• Maintain typical dose for at least 4 to 8 weeks

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Most common reasons antidepressants fail

• Dosage too low
• Duration of trial to short
• Poor compliance
• Intolerable side effects

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What is an adequate trial?

• Adequate dose
• 5 mg/kg/d
• Nortriptyline 100 to 150/d (therapeutic window)
• Fluoxetine 20 mg/d
• Adequate duration
• 4 8 weeks

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Indications for serum levels

• Unequivocally useful for
• Patients who are not responding to usual doses
• Patients who are at increased risk for toxicity,
  e.g. cardiac patients
• May be useful for
• Patients where prompt response is critical
• Determining compliance and metabolic availability

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Therapeutic Blood Levelsfor antidepressants

• Known
• imipramine
• desipramine
• nortriptyline
• Possibly known
• amitriptyline
• Under assessment
• All other antidepressants

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How Antidepressants Work

• Most of the important clinical actions of
  antidepressant drugs cannot be fully accounted
  for on the basis of synaptic pharmacology.
• There are two important observations that
  contribute to this rationale.

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How Antidepressants Work

• Many drugs require long term administration to be
  effective.
• Drugs of abuse require repeated administration to
  produce tolerance and physical dependence.

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How Antidepressants Work

• Clinical effects would appear to result from the
  slow onset adaptive changes that occur within
  neurons, not within the synapse.
• That is, activation of intraneuronal messenger
  pathway and regulation of neural gene expression
  play a central role. (drug-induced neural
  plasticity).

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Synaptic Pharmacologyof antidepressants

• Acute
• Block reuptake or degradation of monoamines and
  post-synaptic alpha-1 receptor.
• Chronic
• Down regulation of the post-synaptic receptors
• Alteration of second messenger systems
• Alteration of protein synthesis.

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After Dosing Antidepressants(days)
Synaptic effects hours to days
Side effects hours to days
Therapeutic effect 1 to 6 weeks
Series 1
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Pharmacokinetics of Antidepressants

• Absorption is rapid
• Metabolism extensive 1st pass
• Oxidation, hydroxylation, demethylation
• 5 slow acetylators
• Protein bound 90 95

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Antidepressant half-lives (hrs)
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Cardiac Side-effectsof tricyclic antidepressants

• Cardiac conduction delay
• Anti-arrhythmic at therapeutic doses
• Arrhythmigenic at toxic doses
• Minimal effects on cardiac output

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Cardiac Side-effectsof tricyclic antidepressants

• Monitoring EKG parameters
• QTc 450 msec
• PR 210 msec
• QRS - gt30 above baseline

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How to choose an antidepressant

• Rationale should be based on side effects, not
  efficacy
• The SSRIs, secondary amines, and atypical
  antidepressants, are generally better choices.
• Why?

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Norepinephrine uptake blockadePossible clinical
consequences

• Tremors
• Tachycardia

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Norepinephrine uptake blockade (potency)
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Serotonin reuptake blockadePossible clinical
consequences

• Gastrointestinal disturbances
• Anxiety (dose dependent)
• Sexual dysfunction

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Serotonin uptake blockade(potency)
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Blocking selectivity5-HT vs. NE
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Dopaminergic uptake blockadePossible clinical
consequences

• Psychomotor activation
• Antiparkinsonian effects
• Psychoses
• Increased attention/concentration

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Dopamine uptake blockade (potency)
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Histamine H1 blockadePossible clinical
consequences

• Sedation, drowsiness
• Weight gain
• hypotension

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Histamine H1 receptor blockade (affinity)
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Muscarinic receptor blockadepossible clinical
consequences

• Blurred vision
• Dry mouth
• Sinus tachycardia
• Constipation
• Urinary retention
• Memory dysfunction

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Muscarinic receptor blockade (affinity)
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alpha 1 receptor blockadepossible clinical
consequences

• Postural hypotension
• Reflex tachycardia
• Dizziness

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alpha-1 receptor blockade (affinity)
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imipramine (Tofranil)receptor affinities
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fluoxetine (Prozac)receptor affinities
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