Psychopharmacology of Depression
History of Antidepressants
From:< http://web.grinnell.edu/courses/sst/f01/SST395-01/PublicPages/PerfectDrugs/Chris/history/index2.html>
Prior to the 1950s, psychotherapy was the treatment of choice for depression and anxiety.
All mental disorders, psychiatrists believed, are caused by anxiety -- resulting from internal conflicts. Other common treatments included: fresh air, electric shock, and lobotomy.
History of Antidepressants
From: http://web.grinnell.edu/courses/sst/f01/SST395-01/PublicPages/PerfectDrugs/Chris/history/index2.html
1949, serendipity, John Cade, an Australian psychiatrist, observed the sedating effects of lithium in guinea pigs. He determined lithium to be safe for human consumption by trying it himself. Then administered it to manic patients, who were subsequently relieved of their manic symptoms.
1960s, widespread use of lithium.
History of Antidepressants
From: http://www.coolnurse.com/lsd.htm
1938, LSD synthesized by Dr. Albert Hofmann of Swiss Sandoz, as a circulatory and respiratory stimulant; no real benefits identified.
1948, Sandoz Laboratories began marketing LSD in USA, trade name “Delysid,” as a psychiatric cure-all --for everything from schizophrenia to criminal behavior, sexual perversions and alcoholism. Sandoz, suggested that psychiatrists take the drug themselves in order to “gain an understanding of the subjective experiences of the schizophrenic.” LSD was prescribed as treatment to over 40,000 patients. Although initial observations on the benefits of LSD were highly optimistic, empirical data developed subsequently proved much less promising.
History of Antidepressants
From: http://web.grinnell.edu/courses/sst/f01/SST395-01/PublicPages/PerfectDrugs/Chris/history/index2.html
1952, Robert Kuhn thus discovered, imipramine for tx of depression.
inspired by the introduction of chlorpromazine for treating schizophrenia, he searched for antidepressant agents among similar compounds, antihistamines -- a class of drugs found in cough syrups.
History of Antidepressants
From: http://web.grinnell.edu/courses/sst/f01/SST395-01/PublicPages/PerfectDrugs/Chris/history/index2.html
1953, pharmaceutical treatment of unipolar depression began; observation (serendipity, again) iproniazid, a tuberculosis drug, had side-effect of boundless energy. Termed "psychic energizer" by Nathan Kline, first investigated its psychological effects, proposed that might prove useful in treating depression.
1957, following initial clinical success in depression trials, >400,000 prescriptions in a year. Many people treated with iproniazid developed jaundice > withdrawn from the market.
History of Antidepressants
From: http://web.grinnell.edu/courses/sst/f01/SST395-01/PublicPages/PerfectDrugs/Chris/history/index2.html
1971, David Wong, at Eli Lilly, began, like other researchers at the time, testing anithistamines for blockage of norepinephrine reuptake. After realizing through his antihistamine studies that similar compounds can have dramatically differing effects on neurotransmitter systems, Wong began testing compounds that failed to block norepinephrine reuptake. One of these nearly forgotton compounds, fluoxetine hydrochloride, he discovered, blocked reuptake of serotonin but not of other neurotransmitters. Over a decade later, after countless animal and clinical studies, fluoxetine hyrdrochloride was released to the world as Prozac. This changed the landscape of psychiatry, expanding the pharmaceutical treatment of depression to epidemic proportions.
Theory: Mechanism of Drug Action
“It is difficult to state with certainty that reuptake inhibition is the essential feature needed for antidepressant efficacy.”
c1965, the biological amine theory of mania & depression: drug induced increases in norepinephrine (a catecholamine) & serotonin > relief from depression; therefore, deficiencies in those neurotransmitters causes major depressive episodes.
BUT, the time course of action is great between the quick increase in those neurotransmitters soon after the drug is taken & the 3-6 weeks before the depression lifts.
Tricyclic Antidepressants (TCA)
• Oral
• amitriptyline (Elavil)
• Syrup (Canada)
• Tablets (U.S. and Canada)
• amoxapine (Asendin)
• Tablets (U.S. and Canada)
• clomipramine (Anafranil)
• Capsules (U.S.)
• Tablets (Canada)
• desipramine (Norpramin)
• Tablets (U.S. and Canada)
• doxepin (Adapin, Sinequan)
• Capsules (U.S. and Canada)
• Oral solution (U.S.)
• imipramine (Tofranil)
• Capsules (U.S.)
• Tablets (U.S. and Canada)
• nortriptyline (Pamelor, Aventyl)
• Capsules (U.S. and Canada)
• Oral solution (U.S.)
• protriptyline
• Tablets (U.S. and Canada)
• trimipramine
• Capsules (U.S. and Canada)
• Tablets (Canada)
• Parenteral
• amitriptyline (Elavil)
• Injection (U.S.)
• imipramine (Tofranil)
• Injection (U.S.)
Tricyclic Antidepressants (TCA)
Pharmacologic Actions of TCAs (now mostly available as generics, so not researched)
1. Block presynaptic norepinephrine reuptake transporter.
2. Block the presynaptic serotonin reuptake transporter.
3. Block postsynaptiac histamine receptors.
4. Block postsynaptic acetycholine receptors.
Tricyclic Antidepressants (TCA)
Equally effective on HAM-D* as SSRIs (for anxiety too). *see pdf
As effective as St. Johns Wort.
No recreational value (not euphoric).
Withdrawal is not dangerous (as it can be with SSRIs).
Tricyclic Antidepressants (TCA)
Exert a wide variety of CNS effect, so have more toxic (side) effects than SSRIs. (esp.with children & elderly).
Potentially fatal if taken in overdose, because of cardiotoxic effects.
Not used much for children; not shown to work & high potential for toxicity w/ cases of sudden death.
Can impair: attention, memory, motor speed, dexterity.
2nd-Generation (Atypical) Antidepressants
bupropion (Wellbutrin)
venlafaxine (Effexor)
mirtazapine (Remeron)
trazadone (Desyrel)
nefazadone (Serzone)
2nd-Generation (Atypical) Antidepressants
c1978-c1985, effort to overcome disadvantages of TCAs:
slow onset
limited efficacy
significant side effects
2nd-Generation (Atypical) Antidepressants
Ludiomil, (rarely) cause seizures, so not used much.
Asendin, has parkinsonian-like side (toxic) effecct.
Desyrel, short onset of action (1 week) with c 1 month for optimal effect. Drowsiness is a side effect, used hs.
Welbutrin or Zyban, antidepressant & anticraving (nicotine & other drugs); side (toxic) effects: psychosis, seizures, panic, >libido, weight loss.
Effexor, > cognitive & psychomotor function, not anticholinergic, takes 1-2 weeks, modest toxic effects, may be superior tx for major depression.
SSRIs (Serotonin-Specific Reuptake Inhibitors)
• fluoxetine (trade name: Prozac, Fontex, Seromex, Seronil, Sarafem)
• sertraline (trade name: Zoloft, Lustral)
• escitalopram oxalate (trade name: Lexapro, Cipralex)
• citalopram (trade name: Celexa, Cipramil, Emocal, Sepram)
• fluvoxamine maleate (trade name: Luvox, Faverin)
• Paroxetine (trade name: Paxil, Seroxat, Aropax)
SSRIs (Serotonin-Specific Reuptake Inhibitors)
The connection between serotonin and depression remains unclear.
All SSRIs appear equally effective.
Indications include: major depression, anxiety disorders, childhood anxiety, ADHD, morbid obesity, alcohol abuse.
SSRIs (Serotonin-Specific Reuptake Inhibitors)
Serotonin Syndrome (from hi dose or drug interaction)
Potentially lethal: confusion, hypomania, agitation, fever, chills, sweating, diarrhea, tachycardia, movement disorders.
Resolves 23-48 hrs after dc.
SSRIs (Serotonin-Specific Reuptake Inhibitors)
Serotonin Withdrawal Syndrome:
c60% people become dependent
onset a few days after dc, lasts 3-4 weeks
Dizziness, vertigo, ataxia
Nausea, vomiting, diarrhea
Fatigue, lethargy, chills
Sensory disturbances
Insomnia, vivid dreams
Anxiety, crying spells
SSRIs (Serotonin-Specific Reuptake Inhibitors)
Children & SSRIs
1991-1995, antidepressant use increased greatly in children and even preschoolers. They are only marginally more effective than placebo, and psychological interventions have similar efficacy.
No empirical evidence to support psychotropic drug treatment in very young children.
“It appears that behaviorally disturbed children are now increasingly subjected to quick and inexpensive pharmacological fixes as opposed to informed, multimodal therapy associated with optimal outcomes.”Coyle, Journal of American Medical Association, 2000.
.
SSRIs (Serotonin-Specific Reuptake Inhibitors)
Antidepressants
What antidepressants should you and your health care practitioner monitor closely?
According to the FDA, drugs that require close monitoring are citalopram (Celexa), duloxetine (Cymbalta), venlafaxine (Effexor), escitalopram (Lexapro), fluvoxamine (Luvox), paroxetine (Paxil), fluoxetine (Prozac), mirtazapine (Remeron), nefazodone (Serzone), bupropion (Wellbutrin), and sertaline (Zoloft).
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