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داروهای ضد افسردگی By: M. Rabbani, PhD IUMS

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Presentation on theme: "داروهای ضد افسردگی By: M. Rabbani, PhD IUMS"— Presentation transcript:

1 داروهای ضد افسردگی By: M. Rabbani, PhD IUMS

2 Outline of Antidepressants
Introduction Treatment of depression Drug treatment Tricyclic Antidepressants (TCA) Serotonin - Specific Reuptake Inhibitors (SSRI) Monamine Oxidase Inhibitors (MAOI) Heterocyclic Antidepressants

3 Definition of Depression
“An affective disorder characterized by loss of interest or pleasure in almost all a person’s usual activities or pastimes.” وابسته به عاطفه و احساس، عاطفی، انفعالی، خود بهره ورaffective

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

5 Depression types Reactive or Secondary (~60%) Melancholic (~25%)
Non pharmacologic treatment 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 Pharmacologic treatment mel·an·cho·li·a  (mln-kl-)n.A mental disorder characterized by severe depression, guilt, hopelessness, and withdrawal. Mood stabilizer (lithium)

6 Other Types of Depression
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

7 Melancholic Depression
Reactive Depression



10 Molecular bases of depression
Amine hypothesis: Depression is associated with decreased amine-dependent synaptic transmission. 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.



Psychotherapy Electroconvulsive therapy Natural alternatives Medication 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

14 Drug therapy of depression
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

15 ضد افسردگی های سه حلقه ای
Drugs & structure Mechanism of Action Side effects Overdose

16 ضد افسردگی های سه حلقه ای
ایمی پرامین (Imipramine) دسی پرامین (Desipramine) آمی تریپتیلین (Amitriptyline) پروتریپتیلین (Protryptyline) کلومیپرامین (Clomipramine) ترمیپرامین (Trimipramine) نورتریپتیلین(Nortriptyline) دوکسپین (Doxepin)


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

19 TCA mechanism

20 TCA side effects 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

21 Overdose of TCAs 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 coma

22 Serotonin - Specific Reuptake Inhibitors (SSRI)
Drugs & structures MOA & Uses Side effects Properties of individual drugs

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


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



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 SSRI’ side effects 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

30 SSRI’s 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.

31 SSRI’s 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

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

33 MAOIs History, Isoniazid,Iproniazid MAO and depression Current Drugs
Mechanism of Action Side Effects Isoniazid Both early drugs developed in sixties for anti tuberculosis but found to have antidepressant effects, got off market due to toxicity MAOIs were the first class of antidepressants to be developed. They fell out of favor because of concerns about interactions with certain foods and numerous drug interactions. MAOIs elevate the levels of norepinephrine, serotonin, and dopamine by inhibiting an enzyme called monoamine oxidase. Monoamine oxidase breaks down norepinephrine, serotonin, and dopamine. When monoamine oxidase is inhibited, norepinephrine, serotonin, and dopamine are not broken down, increasing the concentration of all three neurotransmitters in the brain. They are also used for treating Parkinson's. Iproniazid

34 MAO & DEPRESSION 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 Current MAOI drugs Tranylcypromine (non-selective, reversible)
Phenelzine (non-selective, irreversible) Selegiline (selective MAO-B, irreverisible) Moclobemide (selective MAO-A, reversible)


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

38 MAOI side effects 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 is found in banana, fermented food (cheese) & fermented beverages.

39 Interaction Between Dietary Tyramine and MAOIs
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)


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

42 Heterocyclic Antidepressants
Second generation Amoxapine Maprotiline Trazodone Bupropion Third generation Venlafaxine Mirtazapine Nefazodone Duloxetin

43 Second generation

44 Third generation

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

46 Venlafaxine 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.

47 Venlafaxine (Effexor)
Venlafaxine hydrochloride first introduced by Wyeth in 1993. 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.

48 Venlafaxine Dosage and Side Effects
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.

49 Bupropion Norepinephrine and Dopamine Reuptake Inhibitor (NDRI)

50 Norepinephrine and Dopamine Reuptake Inhibitor (NDRI)
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.

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

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

53 Bupropion and its Metabolites
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.

54 Bupropion Side Effects
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.

55 Drug Choice 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.

56 Drug Choice Cont,d 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.

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
















































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


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

108 Hypothesis In mania, there is increased activity of NTs utilizing DAG/IP3 2nd messengers Li “reduces” the response produced by these overactive NTs Selective depression of “overactive circuits”

109 Lithium side effects 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 Polydypsia=عطش بیش از حد


111 Antidepressants Available in the Market (Worldwide)1
1) Tricyclics and Tetracyclics (TCA) Imipramine Doxepin Desipramine Amoxepine Trimipramine Maprotiline Clomipramine Amitriptyline Nortriptyline Protriptyline 2) Monoamine Oxidase Inhibitors (MAOIs) Tranylcypramine Phenelzine Moclobemide 3) Serotonin Selective Reuptake Inhibitors (SSRIs) Fluoxetine Fluvoxamine Sertraline Paroxetine Citalopram 4) Dual Serotonin and Norepinephrine Reuptake Inhibitor (SNRI) Venlafaxine Duloxetine 5) Serotonin-2 Antogonist and Reuptake Inhibitors (SARIs) Nefazodone Trazodone 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

112 انتخاب داروهای ضد افسردگی
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

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