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ANTIDEPRESSANTS
Dr.S.Thamizharasan
Professor
DEPRESSION
 Types
 Symptoms
 Diagnosis
 Causes
 Treatment
BIPOLAR DISORDER
TYPES OF DEPRESSION
 Major depression
 Chronic depression (Dysthymia)
 Atypical depression
 Bipolar disorder/Manic depression
 Seasonal depression (SAD)
 Major depression – recurring and disabling.
Symptoms must last for at least two weeks and
impair one’s ability to interfere with a person's
ability to work, sleep, study, eat, and enjoy once-
pleasurable activities.
 Chronic depression – less disabling than major
depression, but symptoms can last longer,
sometimes being unhappy for two years. More
common in women, affects 10.9 million people.
 Atypical depression, rather than the other two, is
characterized less by pervasive sadness and more
by overeating, oversleeping, sensitivty to rejection
 Bipolar/manic depression oscillates between major
depression and epsidoes of mania (extreme
elation), Bipolar I – episode of mania with or without
depression. Bipolar II – episode of depression with
episode of hypomania or mania.
 Seasonal depression (SAD) – often occurs wehre
winters are short or there is a big change in the
amount of sunlgiht, and often treated with light
therapy.
SYMPTOMS
 persistently sad, anxious, or empty moods
 loss of pleasure in usual activities (anhedonia)
 feelings of helplessness, guilt, or worthlessness
 crying, hopelessness, or persistent pessimism
 fatigue or decreased energy
 loss of memory, concentration, or decision-making capability
 restlessness, irritability
 sleep disturbances
 change in appetite or weight
 physical symptoms that defy diagnosis and do not respond to
treatment (especially pain and gastrointestinal complaints)
 thoughts of suicide or death, or suicide attempts
 poor self-image or self-esteem (as illustrated, for example, by
verbal self-reproach)
CAUSES OF DEPRESSION
 Genetics
 Death/Abuse
 Medications
TREATMENT FOR DEPRESSION
 Psychotherapy
 Electroconvulsive therapy
 Natural alternatives
 Medication
 SSRIs
 MAOIs
 TCAs
 SNRIs
 NDRIs
NEUROTRANSMITTERS AND THE
CATECHOLAMINE HYPOTHESIS
 Neurotransmitters pass along signal
 Smaller amount of neurotransmitters causes
depression
MONOAMINE OXIDASE (MAO) AND
DEPRESSION
 MAO catalyze deamination of intracellular
monoamines
 MAO-A oxidizes epinephrine, norepinephrine, serotonin
 MAO-B oxidizes phenylethylamine
 Both oxidize dopamine nonpreferentially
 MAO transporters reuptake extracellular
monoamine
MONOAMINE OXIDASE INHIBITORS
(MAOIS)
 History
 Isoniazid
 Iproniazid
 Current Drugs
 Mechanism of Action
 Side Effects Isoniazid
Iproniazid
MAOIS ON THE MARKET
 MAO Inhibitors (nonselective)
 Phenelzine
 Tranylcypromine
 Isocarboxazid
 MAO-B Inhibitors (selective for MAO-B)
 Selegiline
MAOIS MECHANISM OF ACTION
 MAO contains a
cysteinyl-linked
flavin
 MAOIs covalently
bind to N-5 of the
flavin residue of
the enzyme
MAOIS SIDE EFFECTS
 Drowsiness/Fatigue
 Constipation
 Nausea
 Diarrhea
 Dizziness
 Low blood pressure
 Lightheadedness,
 Decreased urine output
 Decreased sexual
function
 Sleep disturbances
 Muscle twitching
 Weight gain
 Blurred vision
 Headache
 Increased appetite
 Restlessness
 Shakiness
 Weakness
 Increased sweating
MAOIS SIDE EFFECTS
 Side effects have put MAOIs in the second or third
line of defense despite superior efficacy
 MAO-A inhibitors interfere with breakdown of
tyramine
 High tyramine levels cause hypertensive crisis (the
“cheese effect”)
 Can be controlled with restricted diet
 MAOIs interact with certain drugs
 Serotonin syndrome (muscle rigidity, fever, seizures)
 Pain medications and SSRIs must be avoided
TRICYCLIC ANTIDEPRESSANTS (TCAS)
 History
 Imipramine
 Current Drugs
 Mechanism of Action
 Side Effects
Imipramine
TCAS ON THE MARKET
 Amitriptyline
 Desipramine
 Doxepin
 Imipramine
 Nortriptyline
 Protriptyline
 Trimipramine
TCAS MECHANISM OF ACTION
 TCAs inhibit serotonin,
norepinephrine, and dopamine
transporters, slowing reuptake
 TCAs also allow for the
downregulation of post-synaptic
receptors
TCAS SIDE EFFECTS
 Muscarinic M1 receptor antagonism - anticholinergic
effects including dry mouth, blurred vision, constipation,
urinary retention and impotence
 Histamine H1 receptor antagonism - sedation and
weight gain
 Adrenergic α receptor antagonism - postural
hypotension
 Direct membrane effects - reduced seizure threshold,
arrhythmia
 Serotonin 5-HT2 receptor antagonism - weight gain (and
reduced anxiety)
TCAS SIDE EFFECTS
 Nonselectivity results in
greater side effects
 TCAs can also lead to
cardiotoxicity
 Increased LDH leakage
 Slow cardiac conduction
 High potency can lead to
mania
 Contraindicated with persons
with bipolar disorder or manic
depression
TETRACYCLIC ANTIDEPRESSANTS
(TECAS)
 Current Drugs
 Mirtazapine
 Mechanism of Action
 Same as TCAs
 Side Effects
SELECTIVE SEROTONIN REUPTAKE
INHIBITORS
 Most commonly prescribed class
 Current drugs
 Mechanism of action
 Side effects
Serotonin
SSRIS ON THE MARKET
 citalopram
 dapoxetine
 escitalopram
 fluoxetine
 fluvoxamine
 paroxetine
 sertraline
 Zimelidine (discontinued)
 Indalpine (discontinued)
Fluoxetine 1:1
Sertraline
SSRI’S ACTION
1.Normally serotonin,
a brain chemical is
released from a
nerve cell.
2.Serotonin is then
received by the next
nerve cell.
3.Some serotonin is
then reabsorbed into
the 1st nerve cell.
4.Not having enough serotonin may be
associated with depression & anxiety
disorders. SSRI’s block the re-
absorbtion of serotonin into the 1st
nerve cell.
5.This blocking action results in an
increased amount of serotonin being
available at the next nerve cell.
SSRIS SIDE EFFECTS
 Anhedonia
 Apathy
 Nausea/vomiting
 Drowsiness or
somnolence
 Headache
 Bruxism (involuntarily
grinding of the teeth)
 Extremely vivid and
strange dreams
 Dizziness
 Fatigue
 Changes in sexual
behavior
 Suicidal thoughts
INDICATIONS SSRIS
 Mood disorders
 Anxiety disorders
Off label:
 Premature ejaculation
 Migraine headache,
 Diabetic neuropathy
 Fibromyalgia
SEROTONIN-NOREPINEPHRINE
REUPTAKE INHIBITORS (SNRIS)
 Slightly greater efficacy than SSRIs
 Slightly fewer adverse effects than SSRIs
 Current drugs
 Venlafaxine
 Duloxetine
 Mechanism of Action
 Very similar to SSRIs
 Works on both neurotransmitters
 Side effects
 Similar to SSRIs
 Suicide
Venlafaxine 1:1
Duloxetine
NOREPINEPHRINE-DOPAMINE
REUPTAKE INHIBITORS (NDRIS)
 Current drugs
 Bupropion
 Mechanims of Action
 Similar to SSRIs and SNRIs
 More potent in inhibiting dopamine
 Adverse effects
 Lowers seizure threshold
 Suicide
 Does not cause weight gain or sexual dysfunction (even
used to treat the two)
Bupropion 1:1

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antidepressantS-THAMIZH.ppt

  • 2. DEPRESSION  Types  Symptoms  Diagnosis  Causes  Treatment
  • 3.
  • 4.
  • 6.
  • 7.
  • 8. TYPES OF DEPRESSION  Major depression  Chronic depression (Dysthymia)  Atypical depression  Bipolar disorder/Manic depression  Seasonal depression (SAD)
  • 9.  Major depression – recurring and disabling. Symptoms must last for at least two weeks and impair one’s ability to interfere with a person's ability to work, sleep, study, eat, and enjoy once- pleasurable activities.  Chronic depression – less disabling than major depression, but symptoms can last longer, sometimes being unhappy for two years. More common in women, affects 10.9 million people.  Atypical depression, rather than the other two, is characterized less by pervasive sadness and more by overeating, oversleeping, sensitivty to rejection
  • 10.  Bipolar/manic depression oscillates between major depression and epsidoes of mania (extreme elation), Bipolar I – episode of mania with or without depression. Bipolar II – episode of depression with episode of hypomania or mania.  Seasonal depression (SAD) – often occurs wehre winters are short or there is a big change in the amount of sunlgiht, and often treated with light therapy.
  • 11. SYMPTOMS  persistently sad, anxious, or empty moods  loss of pleasure in usual activities (anhedonia)  feelings of helplessness, guilt, or worthlessness  crying, hopelessness, or persistent pessimism  fatigue or decreased energy  loss of memory, concentration, or decision-making capability  restlessness, irritability  sleep disturbances  change in appetite or weight  physical symptoms that defy diagnosis and do not respond to treatment (especially pain and gastrointestinal complaints)  thoughts of suicide or death, or suicide attempts  poor self-image or self-esteem (as illustrated, for example, by verbal self-reproach)
  • 12. CAUSES OF DEPRESSION  Genetics  Death/Abuse  Medications
  • 13. TREATMENT FOR DEPRESSION  Psychotherapy  Electroconvulsive therapy  Natural alternatives  Medication  SSRIs  MAOIs  TCAs  SNRIs  NDRIs
  • 14.
  • 15. NEUROTRANSMITTERS AND THE CATECHOLAMINE HYPOTHESIS  Neurotransmitters pass along signal  Smaller amount of neurotransmitters causes depression
  • 16. MONOAMINE OXIDASE (MAO) AND DEPRESSION  MAO catalyze deamination of intracellular monoamines  MAO-A oxidizes epinephrine, norepinephrine, serotonin  MAO-B oxidizes phenylethylamine  Both oxidize dopamine nonpreferentially  MAO transporters reuptake extracellular monoamine
  • 17. MONOAMINE OXIDASE INHIBITORS (MAOIS)  History  Isoniazid  Iproniazid  Current Drugs  Mechanism of Action  Side Effects Isoniazid Iproniazid
  • 18. MAOIS ON THE MARKET  MAO Inhibitors (nonselective)  Phenelzine  Tranylcypromine  Isocarboxazid  MAO-B Inhibitors (selective for MAO-B)  Selegiline
  • 19. MAOIS MECHANISM OF ACTION  MAO contains a cysteinyl-linked flavin  MAOIs covalently bind to N-5 of the flavin residue of the enzyme
  • 20.
  • 21. MAOIS SIDE EFFECTS  Drowsiness/Fatigue  Constipation  Nausea  Diarrhea  Dizziness  Low blood pressure  Lightheadedness,  Decreased urine output  Decreased sexual function  Sleep disturbances  Muscle twitching  Weight gain  Blurred vision  Headache  Increased appetite  Restlessness  Shakiness  Weakness  Increased sweating
  • 22. MAOIS SIDE EFFECTS  Side effects have put MAOIs in the second or third line of defense despite superior efficacy  MAO-A inhibitors interfere with breakdown of tyramine  High tyramine levels cause hypertensive crisis (the “cheese effect”)  Can be controlled with restricted diet  MAOIs interact with certain drugs  Serotonin syndrome (muscle rigidity, fever, seizures)  Pain medications and SSRIs must be avoided
  • 23.
  • 24.
  • 25. TRICYCLIC ANTIDEPRESSANTS (TCAS)  History  Imipramine  Current Drugs  Mechanism of Action  Side Effects Imipramine
  • 26. TCAS ON THE MARKET  Amitriptyline  Desipramine  Doxepin  Imipramine  Nortriptyline  Protriptyline  Trimipramine
  • 27. TCAS MECHANISM OF ACTION  TCAs inhibit serotonin, norepinephrine, and dopamine transporters, slowing reuptake  TCAs also allow for the downregulation of post-synaptic receptors
  • 28. TCAS SIDE EFFECTS  Muscarinic M1 receptor antagonism - anticholinergic effects including dry mouth, blurred vision, constipation, urinary retention and impotence  Histamine H1 receptor antagonism - sedation and weight gain  Adrenergic α receptor antagonism - postural hypotension  Direct membrane effects - reduced seizure threshold, arrhythmia  Serotonin 5-HT2 receptor antagonism - weight gain (and reduced anxiety)
  • 29. TCAS SIDE EFFECTS  Nonselectivity results in greater side effects  TCAs can also lead to cardiotoxicity  Increased LDH leakage  Slow cardiac conduction  High potency can lead to mania  Contraindicated with persons with bipolar disorder or manic depression
  • 30. TETRACYCLIC ANTIDEPRESSANTS (TECAS)  Current Drugs  Mirtazapine  Mechanism of Action  Same as TCAs  Side Effects
  • 31. SELECTIVE SEROTONIN REUPTAKE INHIBITORS  Most commonly prescribed class  Current drugs  Mechanism of action  Side effects Serotonin
  • 32. SSRIS ON THE MARKET  citalopram  dapoxetine  escitalopram  fluoxetine  fluvoxamine  paroxetine  sertraline  Zimelidine (discontinued)  Indalpine (discontinued) Fluoxetine 1:1 Sertraline
  • 33. SSRI’S ACTION 1.Normally serotonin, a brain chemical is released from a nerve cell. 2.Serotonin is then received by the next nerve cell. 3.Some serotonin is then reabsorbed into the 1st nerve cell.
  • 34. 4.Not having enough serotonin may be associated with depression & anxiety disorders. SSRI’s block the re- absorbtion of serotonin into the 1st nerve cell. 5.This blocking action results in an increased amount of serotonin being available at the next nerve cell.
  • 35. SSRIS SIDE EFFECTS  Anhedonia  Apathy  Nausea/vomiting  Drowsiness or somnolence  Headache  Bruxism (involuntarily grinding of the teeth)  Extremely vivid and strange dreams  Dizziness  Fatigue  Changes in sexual behavior  Suicidal thoughts
  • 36. INDICATIONS SSRIS  Mood disorders  Anxiety disorders Off label:  Premature ejaculation  Migraine headache,  Diabetic neuropathy  Fibromyalgia
  • 37. SEROTONIN-NOREPINEPHRINE REUPTAKE INHIBITORS (SNRIS)  Slightly greater efficacy than SSRIs  Slightly fewer adverse effects than SSRIs  Current drugs  Venlafaxine  Duloxetine  Mechanism of Action  Very similar to SSRIs  Works on both neurotransmitters  Side effects  Similar to SSRIs  Suicide Venlafaxine 1:1 Duloxetine
  • 38.
  • 39. NOREPINEPHRINE-DOPAMINE REUPTAKE INHIBITORS (NDRIS)  Current drugs  Bupropion  Mechanims of Action  Similar to SSRIs and SNRIs  More potent in inhibiting dopamine  Adverse effects  Lowers seizure threshold  Suicide  Does not cause weight gain or sexual dysfunction (even used to treat the two) Bupropion 1:1

Editor's Notes

  1. Major depression – recurring and disabling. Symptoms must last for at least two weeks and impair one’s ability to interfere with a person's ability to work, sleep, study, eat, and enjoy once-pleasurable activities. Chronic depression – less disabling than major depression, but symptoms can last longer, sometimes being unhappy for two years. More common in women, affects 10.9 million people. Atypical depression, rather than the other two, is characterized less by pervasive sadness and more by overeating, oversleeping, sensitivty to rejection Bipolar/manic depression oscillates between major depression and epsidoes of mania (extreme elation), Bipolar I – episode of mania with or without depression. Bipolar II – episode of depression with episode of hypomania or mania. Seasonal depression (SAD) – often occurs wehre winters are short or there is a big change in the amount of sunlgiht, and often treated with light therapy.
  2. MUST HAVE one of the top two AT LEAST five of the other symptoms Nearly DAILY For at least TWO WEEKS
  3. Psycotherapy/talk therapy – especially useful when combined with meds. Goal is to teach good coping skills for every day stressors ECT – electric shock is applied to scalp through electrodes, results in seizure in the brain. Fast and effecitve in patients with depression or suicidal thoughts (good for suicide bc doesn’t have the same delayed onset as meds). Usually given up to three times a week for two to four weeks Natural alternatives – St. John’s wort (sold in teas and tablets, and in diet pills) not good for severe depression but can help mild depression
  4. SYNAPSE: Neurotransmitter passes along synapse from inside storage vesicles through transporters in the presynaptic cell to receptors in the post synaptic cell. Monoamine hypohtesis suggests that small amount of neurotransmitter causes depression
  5. Both early drugs developed in sixties for anti tuberculosis but found to have antidepressant effects, got off market due to toxicity
  6. Phenelzine – major depression Tranylcypromine – major depression Isocarboxazid – major depression Selegiline – comeback of MAOI (MAO-B inhibitor, more selective, loses selectivity at high doses) because no side effects from diet. Used primarily for treatment for Parkinson’s disease (also approved for major depression) – shows significant improvenemnt when taken with L-DOPA
  7. MAOIs bind to the N-5 of the flavin residue if MAO, which prevents MAO from catalyzing the oxidative deamination of the monoamine, increasing their intracellular concentration so more can be released.
  8. Bold ones are most common
  9. Major side effects have kept MAOI use limitied HUGE PITFALL IS DIETARY RESTRICTION Must avoid foods with high levels of tyramine like avocados, bananas, aged cheese, certain meats and wines This is however not seen with selegiline because that is a MAO-B inhibitor, and since tyramine displaces NOREPINEPHRINE from storage vesicles, it effects MAO-A more Serotonin syndrome is caused by drug interactions with herbal weight loss supplement (St John’s wort) and SSRIs and Pain meds like tramadol and meperidine
  10. Imipramine was first tried as an antipsychoti drug for schizophrenia, proved to be insufficient but proved to have antidepressant qualities, in the 50s around the same time as MAOIs. Imipramine is very good for severe depression, but it’s almost too good – also causes hypomania and mania
  11. Side effects have made them second line of defense to SSRIs but they are good for treatment resistant depression bc they are so strong. Amitriptyline – most widely used, most effectve Desipramine – active metabolite of imipramine, used for neuropathic pain Doxepin – used for depression and insomnia Imipramine – used for major depression and enuresis Nortriptyline – same thing Protriptyline – depression UNIQUE BECAUSE IT IS ENERGIZING rather than sedating Trimipramine – depression, insomnia, and pain
  12. Less selective in which cells they target, will prevent serotonin, norepinephrine, and dopamine reuptake
  13. Also first rationally designed drug class, up until the 70s the antidepressants were sort of found by accident Serotonin is also referred to as 5-hydroxytryptamine
  14. More trade names once patent is over but I kept original trade names Citalopram: Major depression Dapoxetine: Premature Ejaculation Escitalopram: Major depression and various other anxiety disorders Fluxoetine: Major depression, OCD, bulimia, etc Fluvoxamine: OCD Paroxetine: Major depression or anxiety Sertraline: Major depression or anxiety Zimelidine had neurological problems like Guillan Barre Indalpine had problems with fetal low WBC
  15. Venlafaxine is a racemix mixture While SSRIs are less potent than the other classes of drugs, they have more manageable side effects so they’re considered better The mechanism is similar to SSRIs, as are the side effects. However, the rate of suicide for SNRIs has been debateable, especially venlafaxine. Finnish study showed Ven increased suicide risk 1.6 times compared to no treatment while Fluoxetine halved it. FDA study showed 5-fold increase in <25 so it is contraindicated in adolescents.
  16. Bupropion is a racemic mixture