Antidepressants

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Antidepressants

• speaker Jain-Fang Chen
• date 2005/09/15

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What is depression?

• To feel depressed occasionally is normal.
  Everyone has
• bad days.
• When doctors talk about depression though, they
  are
• referring to more than a mood or feeling that
  may last a
• few days and disappear.
• Clinical depression is more than feeling sad or
  blue. It
• can make people feel worthless, hopeless or
  even like
• giving up.

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What are the symptoms of depression?

• Sadness
• Sleep Disturbance
• Appetite and Weight Change
• Lack Pep and Engergy
• Lose Interest and Motivation
• Slowed Pace
• Poor Concentration and Memory
• Lose Self Confidence /
• Experience Feelings of Guilt
• Thoughts of Suicide

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Is Depression a Serious Illness?

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What can cause depression?
Emotional TraumaRape, Assault, etc.
We Can Inherit It In Our Genes
Other IllnessesPrescription Drugs
depression
Poor Nutritionas a Child
Hormonal Imbalances
Stress Aging Deplete Nutrients
Loss - Job, Home, Divorce, Death
Endogenous No External Cause
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(Laird and Benefield, 1995 Wells et al., 1997
Saklad, 1995 Scott et al., 1996)
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(Laird and Benefield, 1995 Wells et al., 1997
Saklad, 1995 Scott et al., 1996)
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(Franco-Bronson, 1996 Wells et al., 1997
Saklad , 1995 Katon and Sullivan, 1990)
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(Franco-Bronson, 1996 Wells et al., 1997
Saklad , 1995 Katon and Sullivan, 1990)
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DSM-IV criteria for major depression

• At least five of the following symptoms for at
• least two weeks (symptom 1 or 2 must be present)
• Depressed mood
• Loss of interest or pleasure
• Significant appetite or weight loss or gain
• Insomnia or hypersomnia
• Psychomotor agitation or retardation
• Fatigue or loss of energy
• Feelings of worthlessness or excessive guilt
• Impaired thinking or concentration,
  indecisiveness
• Suicidal thoughts/thoughts of death

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Is there more than one type of depression?

• Mild depression
• Severe depression
• Bipolar depression
• Dysthymia
• Postnatal depression

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How is depression treated?
There are a number of options which are available
Antidepressant drugs
Psychological therapy
cognitive therapy or behaviour therapy
Support groups
Meeting people who have shared similar
experiences can sometimes help.
Stress management
relaxation exercises, massage and aromatherapy
Complementary medicine
acupuncture and homeopathy
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• The serotoninergic system is known to modulate
  mood,
• emotion, sleep and appetite and thus is
  implicated in the
• control of numerous behavioural and
  physiological
• functions.
  (Schloss and Williams,
  1998 )
• Decreased serotoninergic neurotransmission has
  been
• proposed to play a key role in the aetiology
  of depression.
• 
  
  (Schloss and Williams, 1998 )
• Neither 5-HT nor NE depletion induced clinical
  depression
• in healthy subjects or worsened depression in
  unmedicated symptomatic patients with major
  depression.
• 
  
  (Delgado and Moreno, 2000)

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Summary of characterised 5-HT receptors
(http//www.masterliness.com/a/5.HT.receptor.htm)
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Antidepressants
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Classification of Antidepressants

• Antidepressants are classified by their chemical
  structure and mechanism of action.
• Antidepressants are thought to increase levels
  of norepinephrine, serotonin, or
• dopamine at the synapse to restore equilibrium
  to neurotransmitter activity.

(Cohen, 1997 Preskorn, 1994)
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Tricyclic antidepressants (TCAs)
Inhibit the reuptake of norepinephrine in the
CNS Inhibit the reuptake of serotonin Act on
histamine muscarinic receptors
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Tricyclic antidepressants (TCAs)
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Tricyclic antidepressants (TCAs)

• Adverse Reactions
• Side effects are mostly due to antimuscarinic
  actions.
• Dry mouth, constipation, blurred vision,
  increased intraocular pressure,
• urinary retention, hyperthermia, drowsiness
  can occur, nervousness,
• insomia, headache, ataxia, tremor,
  confusion/delirium can occur esp
• in older patients, N/V, gastric irritation,
  hypotension, tachtcardia,
• sweating, wt gain.

• urinary retention
• prostatic hyperplasia
• chronic constipation
• CV disease
• untreated angle-closure glaucoma
• history of epilepsy
• impaired hapatic function

Start w/ low dose to minimize side effects
Elderly patient may be sensitive to side effects
Do not stop medication abruptly
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Monoamine Oxidase Inhibitor (MAOI)

• Two isozymes - MAOA and MAOB exist
• MAOA inhibitors more effective in
• depression (MAOB is high in the
• striatum and primarily catabolizes
• dopamine).

Inhibits action of monoamine oxidase
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Monoamine oxidase inhibitor
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Monoamine oxidase inhibitor

• Adverse Reactions
• Orthostatic hypotension, dizziness, headache,
  dry mouth, constipation,
• N/V, edema, drowsiness, weakness, fatigue,
  nervousness,
• muscle tremors, sweating, sexual
  dysfunctions.
• Side effects are frequent more severe than
  other antidepressants.

• liver disease
• cerebrovascular disease
• pheochromocytoma
• CV disease or blood disorders
• elderly patients, agitated patients
• hyperthyrodism

Start w/ low dose to minimize side effects
Potentially fatal hypertensive crises combined
w/ food containing tyramine (ex. cheeses, smoked
foods)
Potentially fatal drug interaction
Sympathomimetics, TCAs, SSRI, SNRIs, Nefazodone,
Trazodone

• Monitor BP in all patients
• Taper dose slowly
• (4wk recommended)

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Selective Serotonin Reuptake Inhibitors (SSRIs)
Inhibit the reuptake of serotonin Normalize
serotonergic imbalance
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Selective Serotonin Reuptake Inhibitors (SSRIs)
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Bupropion(Dopamine-Norepinephrine Reuptake
Inhibitor)
Dosage Initial dose100 mg bid Max dose150 mg
tid

• Adverse Reactions
• nausea, agitation, insomnia, constipation,
• tremor, chest pain, tachycardia, flushing,
• dizziness, dry mouth
• Sexual dysfunction is generally less than
• w/ SSRIs.

• Special Instruction
• Start w/ low dose to minimize side effects
• Contraindication in patient w/ history of
  seizure,
• Use w/ caution in patient w/ head trauma,
• hepatic or renal impairment, CV disease
• Do not stop medication abruptly

Inhibits reuptake of dopamine A weak blocker of
norepinephrine serotonin reuptake
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Trazodone and (Serotonin Modulators)
Nefazodone
Antagonize post-synaptic 5HT2 receptors
Inhibits reuptake of serotonin at presynaptic
neurons
Inhibits reuptake of norepinephrine Block
a1-receptors
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Trazodone and Nefazodone(Serotonin Modulators)

• Special Instruction
• Start w/ low dose to minimize
• side effects
• Use w/ caution in patients w/
• seizure disorder, CV or
• cerebrovascular disease,
• mania, severe hepatic or
• renal impairment
• Do not stop medication
• abruptly

Adverse Reaction dry mouth, nausea, dizziness,
constipation, sedation, light-headache, postural
hypotension confusion, memory impairment.
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Mirtazapine ( Noradrenergic Specific
Serotonergic Antidepressant, NaSSA )
Dosage Initial dose15 mg/day Max dose45 mg/day

• Action
• Enhance the release of
• norepinephrine
• Indirectly serotonin through
• blockade of central presynaptic
• adrenergic receptors

• Adverse Reactions
• Sedation, dry mouth, increased appetite,
• wt gain, constipation, dizziness, xerostomia
• Sexual dysfunction is generally lower than
• w/ SSRIs.

• Special Instruction
• Start w/ low dose to minimize side effects
• Use w/ caution in patient w/ seizure disorder,
• hepatic or renal impairment, CV disease
• Do not stop medication abruptly

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Venlafaxine ( Serotonin Norepinephrine Reuptake
Inhibitor, SNRI)
Dosage Initial dose75 mg/day Max dose225 mg/day

• Adverse Reactions
• headache, somnolence, dizziness, insomnia,
• nervousness, nausea, constipation, diarrhea,
• sexual dysfunction, anxiety
• Dose-relatedvasodilation, hypertension

• Special Instruction
• Start w/ low dose to minimize side effects
• Use w/ caution in patient w/ hepatic or renal
• impairment
• Do not stop medication abruptly

Inhibits reuptake of norepinephrine serotonin. We
akly inhibit dopamine reuptake
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???? bupropion, mirtazapine, moclobemide,
nefazodone(trazodone), SNRIs, SSRIs, TCAs, ??????
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???? bupropion, mirtazapine, moclobemide,
nefazodone(trazodone), SNRIs, SSRIs, TCAs,
?????? ??????????TCAs?????,?????? SSRIs??,SNRIs??
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???? ?????????? BupropionNefazodone
BupropionSSRIs NefazodoneSSRIs SSRIsTCAs
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Summary
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Efficacy
Many medications are available for the treatment
of major depression.

• Antidepressants are effective treatment for
  65-75 of all patients with depression.

• An adequate therapeutic trial for an
  antidepressant is generally giving the agent
• at adequate doses continuously for 4-6 weeks.

• SSRIs have largely replaced older TCAs and MAOIs
  as first-line drugs.
• TCAs and MAOIs remain valuable alternatives for
  patients with moderate to
• severe depression.
• Newer agents such as venlafaxine and nefazodone
  appear to be as effective
• as SSRIs in the treatment of depression.
• Trazodone is generally a less effective
  antidepressant and is frequently used
• as a second drug for SSRI-associated sleep
  disturbances.

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Toxicology
Depression is associated with a significant risk
of suicide.

• TCAs and MAOIs have a low therapeutic index.

Doses of 1500 mg of amitriptyline or imipramine
in an adult or 8 mg/kg in a child can result in
severe cardiotoxicity or death.

• Overdosage of TCAs can cause hypotension,
  seizures, cardiac arrhythmias,
• coma and death.

Toxicity is more likely if TCA plasma
concentrations are gt 1, 000 ug/L, however,
cardiovascular toxicity (eg, QRS duration gt 100
msec) may also be seen at lower TCA
concentrations.

• SSRIs have a wide therapeutic index and are
  significantly safer when taken
• in overdose.

• Bupropion and venlafaxine have not at this time
  been associated with lethality
• in overdose. (Rudolph and Derivan, 1996)

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(Franco-Bronson, 1996)
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Washout Periods
Washout periods are recommended when switching
from some antidepressants to others.
Initial dosage should be low and increases
should be gradual and cautiously prescribed.
General anesthesia, cocaine, and local anesthesia
(eg, sympathomimetic vasoconstrictors).
Initial dosage should be low and increases should
be gradual and cautiously prescribed. A
recent case report of serotonin syndrome
following previous treatment with phenelzine has
been reported in association with
venlafaxine therapy. This is a potentially fatal
drug interaction which may occur even after
discontinuing an MAOI for the recommended two
weeks and then initiating an indirect acting
amine or serotonergic agent.
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(Cohen, 1997 Scott et al., 1996)
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t-1/2half-life of drug () or metabolite ()
T-maxtime to maximum concentration
Fbioavailability V-dvolume of distribution
m-CCPm-chlorophenylpiperazine NDno data
NAnot available
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(Cohen, 1997)
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Thanks for your attention