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 Introduction Introduction  Treatment of depression Treatment of depression  Drug treatment Drug treatment 1. Tricyclic Antidepressants (TCA) Tricyclic.

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Presentation on theme: " Introduction Introduction  Treatment of depression Treatment of depression  Drug treatment Drug treatment 1. Tricyclic Antidepressants (TCA) Tricyclic."— Presentation transcript:

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2  Introduction Introduction  Treatment of depression Treatment of depression  Drug treatment Drug treatment 1. Tricyclic Antidepressants (TCA) Tricyclic Antidepressants (TCA) 2. Serotonin - Specific Reuptake Inhibitors (SSRI) Serotonin - Specific Reuptake Inhibitors (SSRI) 3. Monamine Oxidase Inhibitors (MAOI) Monamine Oxidase Inhibitors (MAOI) 4. Heterocyclic Antidepressants Heterocyclic Antidepressants 2

3  “An affective disorder characterized by loss of interest or pleasure in almost all a person’s usual activities or pastimes.” 3

4  Sadness, Despair, Guilt, Pessimism  Decrease in energy  Decrease in sex drive  Insomnia and fatigue  Thoughts of death and suicide  Mental slowing, lack of conc 4

5  Reactive or Secondary (~60%)  Related to some “loss”, physical illness (MI, Cancer),  Drugs, (alcohol, beta blockers, prednisone, reserpine, cocaine)  Other psychiatric disorders (senility)  Melancholic (~25%)  Major or Endogenous  No clear/adequate precipitating event  Bipolar affective(Manic-depressive)  Episodes of mania associated with depression  Depression alone - occasional; Mania alone – rare Non pharmacologic treatment Non pharmacologic treatment Pharmacologic treatment Mood stabilizer (lithium) 5

6  Chronic or Dysthymia (~3-6%)  Less severe, but long lasting (>2 yrs)  Atypical  Patients overeat, oversleep, react strongly to rejection  Seasonal affective disorder  Annual episodes of depression during fall or winter 6

7 Melancholic Depression Reactive Depression

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10  Amine hypothesis: Depression is associated with decreased amine-dependent synaptic transmission. Amine hypothesis  Almost all antidepressants affect metabolism or reuptake of serotonin, NE, or both.  Several brain circuits have also become dysfunctional.  Some are also selective antagonists of serotonin or norepinephrine.  The full clinical effects of drugs requires 4-8 weeks.requires 4-8 weeks. 10

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13  Psychotherapy  Electroconvulsive therapy  Natural alternatives  Medication

14  Drugs first introduced 50 years ago that were were used for treatment of other disorders including:  Anxiety disorders, dysthymia, chronic pain and behavioral problems  Antidepressants discovered accidentally while investigating antipsychotic phenothiazines  Imipramine - first antidepressant discovered 14

15  Drugs & structure Drugs & structure  Mechanism of Action Mechanism of Action  Side effects Side effects  Overdose Overdose 15

16  ایمی پرامین (Imipramine)  دسی پرامین (Desipramine)  آمی تریپتیلین (Amitriptyline)  پروتریپتیلین (Protryptyline)  کلومیپرامین (Clomipramine)  ترمیپرامین (Trimipramine)  نورتریپتیلین (Nortriptyline)  دوکسپین (Doxepin) 16

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18  TCA inhibit the reuptake of the biogenic amines, mostly norepinephrine (NE), as well as serotonin (5HT).reuptake 18

19 TCA mechanism

20  Phenothiazine like “side effects”:  Antimuscarinic (M1): dry mouth, constipation, urinary retention, aggravation of glaucoma  Antihistamine (H1): sedation (tolerance can develop)  Na channel block:  QRS, arrhythmias*  alpha blockade (α1) : orthostatic hypotension, tachycardia** erectile dysfunction 20

21  Are extremely dangerous in overdose  More than 1 g of a tricyclic is potentially lethal  TCAs increase suicidal risks.  Manifestations are: mydriasis, respiratory depression, seizure, cardiac arrhythmia and comacardiac arrhythmia 21

22  Drugs & structures Drugs & structures  MOA & Uses MOA & Uses  Side effects Side effects  Properties of individual drugs 22

23  Fluoxetine  Paroxetine  Sertraline  Fluvoxamine  Citalopram Its active metabolite has a half-life of 7-9 days. 23

24 SSRI

25  Available for the past 15 years  MOA: Allows for more serotonin to be available to stimulate postsynaptic receptors MOA  Available to treat depression, anxiety disorders, ADHD, obesity, alcohol abuse, childhood anxiety, etc. 25

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28 Schematic diagram showing some of the potential sites of action of antidepressant drugs. The primary neuron is shown as releasing a transmitter amine (NT). A modulating neuron may release a second transmitter (NTx), regulating the activity of the primary neuron. The most consistent observed effect of the antidepressants (other than MAO inhibitors) is inhibition of the reuptake transporters (T) for norepinephrine or serotonin. The MAO inhibitors increase the vesicular stores of both NE and 5-HT. Other direct or indirect effects include initial increase in activation of pre- and postsynaptic receptors and subsequent desensitization or down-regulation of transmitter synthesis from an amino acid (AA), receptor numbers, or postreceptor mechanisms. Desensitization resulting from antidepressant use has been reported for a2, b, and 5-HT1A systems (color). VAT denotes a vesicle-associated transporter.

29  Serotonin syndrome:  When a SSRI is used with a MAOI causes marked increases of serotonin in the synapses.  Characterized by: muscle rigidity, myoclonus, hyperthermia & rapid changes in mental status and vital signs. It may be fatal.  Serotonin withdrawal syndrome: within a few days and can persist 3-4 weeks. Symptoms: disequilibrium, gastrointestinal problems, flu-like symptoms, sensory disturbances, sleep disturbances 29

30  Fluoxetine (Prozac) – first SSRI available, long half life, slow onset of action, can cause sexual dysfunction, anxiety, insomnia and agitation, Nausea, Headache, Insomnia, Weight gain  Sertraline (Zoloft) – second SSRI approved, low risk of toxicity, few interactions, more selective and potent than Prozac  Paroxetine (Paxil) – third SSRI available, more selective than Prozac, highly effective in reducing anxiety and posttraumatic stress disorder (PTSD) as well as OCD, panic disorder, social phobia, and chronic headache. 30

31  Fluvoxamine (Luvox) – structural derivative of Prozac, became available for OCD, also treats PTSD, dysphoria, panic disorder, and social phobia  Citalopram (Celexa) – well absorbed orally, few drug interactions, treats major depression, social phobia, panic disorder and OCD 31

32  SSRIs are more selective for 5-HT transporter than NE transporter (300 to 7000).  Trazodone, nefazodone, & mirtazapine antagonize serotonin receptors. 32

33  History, Isoniazid,Iproniazid  MAO and depression MAO and depression  Current Drugs Current Drugs  Mechanism of Action Mechanism of Action  Side Effects Side Effects Isoniazid Iproniazid

34  MAO catalyze deamination of intracellular monoamines (NEP, EP, Serotonin, DA …).  MAO-A oxidizes NEP, EP, Serotonin and DA  MAO-B oxidizes phenylethylamine  Both oxidize dopamine nonpreferentially  MAO transporters reuptake extracellular monoamine

35  Tranylcypromine (non-selective, reversible)  Phenelzine (non-selective, irreversible)  Selegiline (selective MAO-B, irreverisible)  Moclobemide (selective MAO-A, reversible) 35

36 MAOI

37 Reuptake of NE Monoamine oxidase, located on outer membrane of mitochondria; deaminates catecholamines free in nerve terminal that are not protected by vesicles Cocaine blocks the NET Stimulant

38  MAO-A metabolizes norepinephrine, serotonin & tyramine.  MAO-B is more selective for dopamine.  Nonselective MAO inhibitors can lead to hypertensive reactions due to tyramine in ingested food.tyramine in ingested food  Tyramine is found in banana, fermented food (cheese) & fermented beverages. 38

39 Food with tri-amine (pepporoni, sausage, some cheese)- interaction causes promotion of release of accumulated NE stores, thereby causing massive vasoconstriction and excessive stimulation of heart (hypertension) 39

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41  Drug classification:  Serot and NEP Reuptake Inhibitors (SNRIs):  Venlafaxine Venlafaxine  NEP and Dopamine Reuptake Inhibitor (NDRI):  Bupropion Bupropion  Mechanism of Action  Side Effe 41

42  Second generation  Amoxapine  Maprotiline  Trazodone  Bupropion  Third generation  Venlafaxine Venlafaxine  Mirtazapine  Nefazodone  Duloxetin 42

43 Second generation

44 Third generation

45  مکانیسم : مکانیسم مشترکی ندارند  آثارشان دیر ظاهر می شود  عوارض متفاوت و کمتر از TCA 45

46  SNRIs act upon two neurotransmitters in the brain that are known to play an important part in mood.  SNRIs were developed more recently than SSRIs, and there are relatively few of them.  Their efficacy as well as their tolerability appears to be somewhat better than the SSRIs, owing to their compound effect.  Because of their specificity for the serotonin and norepinephrine reuptake proteins, lack most of the adverse side effects of TCA and MAOI. 46

47  Venlafaxine hydrochloride first introduced by Wyeth in  It is used primarily for the treatment of depression, generalized anxiety disorder, and social anxiety disorder in adults.  Venlafaxine is the first and most commonly used SNRI.  Venlafaxine has a single chiral centre and exists as a racemic mixture of R-(–)- and S-(+)-enantiomers. The R-enantiomer exhibits dual presynaptic inhibition of serotonin and noradrenaline reuptake, while the S-enantiomer is predominantly a serotonin reuptake inhibitor.  In vitro, venlafaxine is approximately 3- to 5-fold more potent at inhibiting serotonin than noradrenaline reuptake. It has low affinity for muscarinic cholinergic, histamine H1 and adrenergic receptors. 47

48  Because of its relatively short half-life of 4 hours, Effexor should be administered in divided dosages throughout the day.  Side effects may include nausea, dizziness, sleepiness, abnormal ejaculation, sweating, dry mouth, gas or stomach pain, abnormal vision, nervousness, insomnia, loss of appetite, constipation, confusion/agitation, tremors, and drowsiness. 48

49 Bupropion Norepinephrine and Dopamine Reuptake Inhibitor (NDRI)

50  These are a class of antidepressants that are not really categorized as a special group of antidepressants.  The only antidepressant in this group is Bupropion, which is an antidepressant chemically unrelated to tricyclics or SSRIs. It is similar in structure to the stimulant cathinone, and to phenethylamines in general. 50

51  Bupropion was first synthesized in 1966  It was approved by the FDA in 1985 and marketed under the name Wellbutrin as an antidepressant. 51

52  Bupropion is a selective catecholamine (norepinephrine and dopamine) reuptake inhibitor. 52

53  Bupropion is metabolised in the liver. It has at least three active metabolites; hydroxybupropion, threohydrobupropion and erythrohydrobupropion.  These active metabolites are further metabolised to inactive metabolites and eliminated through excretion into the urine. The half-life of bupropion is 20 hours as is hydroxybupropion's.  Threohydrobupropion's half-life is 37 hours and erythrohydrobupropion's 33 hours. 53

54  Common side effects include dry mouth, tremors, anxiety, loss of appetite, agitation, dizziness, headache, excessive sweating, increased risk of seizure, and insomnia. Bupropion causes less insomnia if it is taken just before going to bed.  Sexual side effects normally accompanying SSRI's do not accompany bupropion. Interestingly, patients commonly report increased libido, perhaps evidence of its dopaminergic properties. 54

55  Comparisons of the antidepressants showed that they are roughly equivalent in efficacy.  Individual patients may respond better to one drug than to another.  Patients depressed enough to be hospitalized respond better to classic TCAs than to SSRIs.  Outpatient studies also show a greater efficacy of TCAs over SSRIs. 55

56  SSRIs are not sedative, safe in overdose and have mild adverse effects so they are widely prescribed.  Finding the right drug and the right dose must be accomplished empirically.  If it is the first depressive episode and if the treatment was satisfactory, withdraw treatment after 6-9 months.  A patient who has had previous episodes of depression is a candidate for maintenance therapy.  The duration of maintenance treatment varies and may continue indefinitely. 56

57  Depression Depression  Panic disorder  Obsessive-compulsive disorders  Enuresis  Chronic pain  Attention deficit hyperkinetic disorder (ADHD) Atomoxetin (NET inhibitor) TCAs are useful, SSRIs have no effect 1. Are acute episodes of anxiety 2. Benzodiazepines are preferred drugs 1. Effect of drug lasts as long as treatment is continued 2. Used for elderly institutionalized patients 3. Drug therapy is NOT the choice treatment Fluoxetine and clomipramine Definitely requires pharmacologic treatment given the high rate of suicide in patients suicide 57

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105 He’s MANIC!!!!! Take Home Message: 105

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107  Effective in treating bipolar (manic - depressive) disorder.  A “mood stabilizer”  Has multiple effects including inhibiting enzymes involved in PI recycling 107

108  In mania, there is increased activity of NTs utilizing DAG/IP 3 2nd messengers  Li “reduces” the response produced by these overactive NTs  Selective depression of “overactive circuits” 108

109  Side Effects: polydypsia, polyuria*, edema, weight gain, thyroid enlargement, hypothyroidism (5%)  Toxicity:  Low dose: nausea & vomiting  High dose: seizures, circulatory collapse, coma  Avoid dehydration, diarrhea, vomiting, diuretics  Alternative drugs for bipolar disorder  Valproic acid & carbamezepine  SSRIs can unmask mania in patients with a bipolar disorder *Li causes the renal collecting duct to become resistant to ADH 109

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111 1) Tricyclics and Tetracyclics (TCA) Imipramine Doxepin Desipramine AmoxepineTrimipramine Maprotiline Clomipramine Amitriptyline NortriptylineProtriptyline 2) Monoamine Oxidase Inhibitors (MAOIs) TranylcypraminePhenelzineMoclobemide 3) Serotonin Selective Reuptake Inhibitors (SSRIs) FluoxetineFluvoxamine SertralineParoxetineCitalopram 4) Dual Serotonin and Norepinephrine Reuptake Inhibitor (SNRI) Venlafaxine Duloxetine 5) Serotonin-2 Antogonist and Reuptake Inhibitors (SARIs) NefazodoneTrazodone 6) Norepinephrine and Dopamine Reuptake Inhibitor (NDRI) Bupropion 7) Noradrenergic and Specific Serotonergic Antidepressant (NaSSAs) Mirtazapine 8) Noradrenalin Specific Reuptake Inhibitor (NRI) Reboxetine 9) Serotonin Reuptake Enhancer Tianeptine 111

112 TCA’s – Less well tolerated in elderly – Less expensive – Higher overdose potential SSRIs & Heterocyclics – Empirical selection – Bupropion has less sexual side effects* & may help smokers “quit” the habit (contraindicated in pts. w/ seizure history) – Escitalopram (Lexapro ®) - no weight gain Atypical Depression – MAOI (phenelzine) Manic-Depressive – Li, carbamazepine, valproic acid 112


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