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.

13. TREATMENT FOR DEPRESSION
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.

24. SSRI

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)

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
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