Mar 29

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Mar 29 Depression and the Older Antidepressants
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• Major Depressive Disorder
• Symptoms
• depressed mood or loss of interest for at least 2
  weeks
• slowing down of behavior - slowed speech
• feelings of worthlessness or extreme guilt
• difficulty concentrating
• sleep disturbances
• recurrent thoughts of death or suicide

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• Major Depressive Disorder
• difficulty concentrating
• sleep disturbances
• recurrent thoughts of death or suicide not due to
  illness or acute grief
• must be of degree to interfere with social,
  occupational, and other important functioning

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• Major Depressive Disorder
• Facts
• at some point in life, depression effects 5-12
  of males and 10-25 of females
• (twice as common in women)
• prevalence is not related to educational level,
  income level, ethnicity
• among people who experience depression at some
  point in life, 50 have more than one episode

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• Biological Causes
• 1. Genetic influences
• Monozygotic twins - 40-65 concordance (chance
  that if one twin has it, the other does too)
• Dizygotic twins - 10-20 concordance
• 2. Neurochemical characteristics
• a. reduced levels of metabolites of
  norepinephrine in cerebrospinal fluid and urine

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• Biological Causes
• 2. Neurochemical characteristics
• b. abnormal endocrine functions controlled by
  norepinephrine
• High cortisol levels due to dysfunction in
  hypothalamic-pituitary-adrenal axis control
  system
• Neurons in hypothalamus use norepinephrine
  as the neurotransmitter that tells other
  hypothalamic neurons to stop releasing
  Corticotropin Releasing Factor (CRF).

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The hypothalamic-pituitary-adrenal axis Stress
stimulates neurons in the hypothalamus to release
corticotropin-releasing factor (CRF) CRF
stimulates limbic system- emotional response
(how?) CRF stimulates anterior pituitary to
release adrenocorticotrophic hormone (ACTH).
(How?) ACTH stimulates release of
glucocorticoids from the adrenal cortex.
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• 2. Neurochemical characteristics
• b. abnormal endocrine functions controlled by
  norepinephrine - high cortisol levels
• c. abnormal response on dexamethasone suppression
  test
• Dexamethasone - synthetic cortisol.
• Measure cortisol levels at 1100 PM
• Then give dexamethasone.
• In AM, should have lower cortisol.
• Not so in many depressed people.
• Improved by antidepressant meds

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CRH receptor antagonists under development
for use as antidepressants
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• 2. Neurochemical characteristics
• d. reduced levels of metabolites of serotonin
  (respond to drugs that increase serotonin)
• e. Increased density of NE and 5HT2 receptors
  (suggest adaptation to reduced levels of
  neurotransmitters)
• f. Serotonin plays an important role in blood
  platelets which helps protect them from excess
  clumping. Among depressed, more platelet
  aggregation is seen, along with increased risk
  for heart attack and stroke.
• g. drugs that block or deplete NE or SE can cause
  depression (Reserpine and certain drugs used to
  treat high blood pressure)

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• 2. Neurochemical characteristics
• g. drugs that block or deplete NE or SE can cause
  depression
• h. animals showing learned helplessness have
  reduced levels of NE and SE (and elevated
  cortisol)

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• 3. Illnesses that may produce depression
• Cushings Syndrome (85)
• Pituitary tumors produce too much ACTH --gt then
  adrenals release too much cortisol
• or
• Adrenal tumors may produce too much cortisol.
• Excessive treatment with corticosteroids may
  mimic syndrome.
• All causes lead to obesity and unusual body hair
  growth

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• 3. Illnesses that may produce depression
• Cushings Syndrome (85)
• Thyroid disorders (underactive - depression
  overactive - excessive energy reduced sleep
  needs possible mania)
• Parkinsons Disease (50)
• Substance abuse disorders
• Long term use of certain drugs at high levels
  alters relevant neurochemical systems (NE, DA,
  SE) - Cocaine, Methamphetamine Ecstasy.

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• Suicide
• 80 of those who commit suicide suffer from
  depression or bipolar disorder
• among the depressed, 15 commit suicide each year
• suicide victims have lower concentrations of
  serotonin in their brain
• suicide victims show high levels of cortisol

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• General Health
• Depression increases the risk of dying after
  heart attack or stroke (mood? blood?)
• Chronic overactivation of the stress circuit
  increases risk for heart disease and stroke

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• Drugs Used to Treat Depressive Disorders
• MAO inhibitors
• 2. Tricyclic antidepressants
• 3. Selective Serotonin Reuptake Inhibitors

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• II. Antidepressants
• A. Monoamine Oxidase Inhibitors
• in early 1950s, iproniazid, used to treat
  tuberculosis, was noted to elevate mood
• use as antidepressant began in late 1950s, but
  caused liver toxicity
• other drugs then developed, but use has always
  been limited by severe side effects
• used for those who do not respond to tricyclic
  antidepressants or SSRIs
• Phenylzine (Nardil)
• Isocarboxazid (Marplan)
• Tranylcypromine (Parnate)
• Selegiline (Eldepryl)
• Moclobemide (Manorix Aurorix)
• Brofaromine (Consonar)

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• Pharmacodynamics
• inhibition of monoamine oxidase(s) the enzyme
  family that breaks down monoamine transmitters,
  NE, E, DA, SE following reuptake
• there are 2 MAO types A and B
• MAO A breaks down E, NE, DA, and SE within
  neurons and some glial cells
• MAO B breaks down DA in nigrostriatal regions
  also breaks down tyramine and other substances in
  neurons and some glial cells (protects the
  neuron)
• does not break down the neurotransmitters inside
  vesicles only the ones found or reuptaken into
  cytoplasm
• in gut, MAOs, especially MAO B break down
  several food stuffs importantly tyramine

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• Unpleasant, possibly Life-Threatening Drug-Food
  Interaction
• in gut, MAOs, especially MAO B break down
  several food stuffs importantly tyramine
• inhibition of breakdown by MAO due to these
  drugs leads to buildup of tyramine which causes
  toxic sympathomimetic effects
• these coupled with elevated actions of NE lead
  to dangerous hypertensive crisis elevated blood
  pressure heart rate increase, severe occipital
  headache motor agitation, sweating -gt if
  untreated, stroke, loss of consciousness, death
• effects occur in 20 min- 1 hour after ingestion
  of the food containing tyramine
• must avoid aged foods cheese, sausages,
  alcohols, sauerkraut, pickled or fermented foods,
  and others

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Foods to Avoid on MAOI Diet aged cheese aged
or cured meats (e.g., air-dried sausage) any
potentially spoiled meat, poultry, or fish broad
(fava) bean pods Marmite concentrated yeast
extract sauerkraut soy sauce and soy bean
condiments tap beer Wine domestic
bottled/canned beer in moderation
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Other Side Effects Dizziness Fatigue Headache
Jaundice Dry mouth Anorgasmia Insomnia
Erectile dysfunction Postural hypotension
Blurred vision Urinary retention/hesitancy
Nausea Peripheral edema Constipation Muscle
weakness/jerking Multiple reasons beyond just
brain-based actions.
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A. Monoamine Oxidase Inhibitors Phenylzine
(Nardil) - non-selective and irreversible Isocarbo
xazid (Marplan) - non-selective and
irreversible Tranylcypromine (Parnate) -
non-selective and irreversible Selegiline
(Eldepryl) selective B, irreversible Moclobemide
(Manorix Aurorix)- selective A and reversible
Brofaromine (Consonar) - selective A and
reversible Taken orally Delayed action Efficacy
of 70-80 for reduction of depressive symptoms.
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• B. Tricyclic Antidepressants (and tetracyclic)
• main treatment for depression from 1960-1980
• still among best treatments for the moderately
  to severely depressed (non-delusional) person
  80 response
• many side effects and poor safety margin
• oldest is Imipramine (Tofranil)
• 10 are on US market

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B. Tricyclic Antidepressants (and
tetracyclic) Imipramine (Tofranil) Desipramine
(Norpramin) Amitriptyline (Elavil) Nortriptyline
(Aventyl Pamelor) Clomipramine
(Anafranil) Trimipramine (Surmontil) Doxepin
(Sinequan Adapin) Protriptyline
(Vivactil) Amoxapine (Asendin) Maprotiline
(Ludiomil)
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• Pharmacokinetics
• Well absorbed orally
• Peak in 2-6 hours
• Individual differences in metabolism slow
  metabolizers and fast metabolizers
• Liver metabolism by CYP2D6
• Renal clearance
• Most TCAs have half-life around 24 hours
• Allows once/day dosing for all
• Elderly may need lower doses
• Very narrow therapeutic index 6-10 with fatal
  cardiac arrhythmias as cause of death (can
  overdose on a 1 week supply)
• Plasma concentrations are monitored

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• Pharmacodynamics
• vary in ratio of blocking NE and SE reuptake
  all block NE
• also block muscarinic cholinergic receptors,
  alpha receptors for NE in PNS, and histamine
  receptors
• Actions on NE (and SE) occur within hours, but
  depression reduction takes 1-2 weeks Why?
• 1. Receptor Sensitivity Hypothesis correlates
  of depressive symptom reduction
• With repeated increase in the NE supply due to
  tricyclic action, beta adrenergic receptors for
  NE in brain down regulate by reducing in number
• Also enhanced serotonergic transmission at 5HT1A
  receptors alongside down regulation of 5HT2
  receptors

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1. Receptor Sensitivity Hypothesis correlates
of depressive symptom reduction With repeated
increase in the NE supply due to tricyclic
action, beta adrenergic receptors for NE in brain
down regulate by reducing in number Also enhanced
serotonergic transmission at 5HT1A receptors 2.
May stimulate neuronal proliferation and increase
number of neurons in limbic areas (fits with idea
that stress ultimately destroys hippocampal
neurons as part of how chronic stress may cause
depression)
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Tricyclic Action Side effects

• Reuptake blockade of NE heart arrhythmias
• Blockade of Muscarinic Receptors Dry mouth and
  eyes
• (anticholinergic effects) Urinary retention
• Constipation
• Blurred vision
• Confusion-gt Delirium
• Blockade of alpha-NE Postural hypotension
• receptors in the PNS Dizziness
• (anti-adrenergic effects) Drowsiness
• Blockade of histamine receptors Sedation
• Weight gain
• (15 lbs in 6mo)

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• Tricyclic Antidepressants Drug Interactions
• based on liver enzyme competition or induction
• Prozac and TCAs TCA levels build up to
  dangerous level
• MAOIs also dangerous stroke seizures
• Haloperidol and Phenothiazines (antipsychotics)
  can block metabolism of TCAs they build up
• Barbiturates induce metabolism - need higher
  dose of TCAs
• Phenytoin (Dilantin) Phenytoin may be elevated
  into toxic range