This document provides information on various classes of antidepressant drugs, including their mechanisms of action and side effects. It begins by describing the biological basis of depression and the monoamine theory. It then discusses different classes of antidepressants - tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and monoamine oxidase inhibitors (MAOIs). For each class, it provides details on representative drugs, their mechanisms of increasing neurotransmitter levels in the brain, pharmacokinetics, clinical uses and potential adverse effects. It emphasizes the importance of drug interactions and side effects that limit the use of some older antidepressants.

1. ANTIDEPRESSANT
DRUGS
Amene T.(B.Pharm, Msc)
1

2. Session objectives
 Describe MoA and characteristics of TCAs, including
receptor interactions, adverse effects
 Identify the drugs classified as SSRIs and SNRIs, and
describe their characteristics, including clinical uses,
adverse effects and toxicity, and potential drug
interactions.
 Identify drugs thought to act via block of serotonin
receptors, and describe their characteristics including
clinical uses, adverse effects and toxicity, and potential
drug interactions.
 Be aware of the limited role of MAO inhibitors in affective
disorders
2

3. Depression
 An affective disorder characterized by changes in mood;
 Distinct from schizophrenia which produces
disturbances of thought
 For mood there is a complex interrelationship between
noradrenergic, serotonergic (5H-T) and possibly
dopaminergic pathways in the CNS.
3

4. Causes of depression
 Emotional factors;
 Divorce, financial problems, home problems, grief, relationship ending, death in
the family,
 Medical conditions;
 Chronic diseases, hormonal disturbances, metabolic disorders, dehydration.
 Drugs;
 Reserpine, Alpha methyl dopa, Beta blockers, hormonal contraceptives,
corticosteroids.
 Postpartum
 Alcohol abuse 4

5. Classification of Major Affective
Disorders
 The most common mood disorders are
 Major/endogenous depression (unipolar
depression)
 Bipolar disorder (Mania)
 Atypical depression
5

6. Major Endogenous Depression
Core Symptoms (nearly daily): five or more
Depressed mood
Loss of interest in pleasurable activities, Withdrawn
Significant wt. change (loss/gain)
Sleep disturbance
Psychomotor agitation or retardation
Fatigue or loss of energy
6

7. Major Endogenous Depression
Core Symptoms (nearly daily): five or more
Feeling of worthlessness (Low self esteem, feelings
of guilt, inadequacy)
Diminished ability to think or concentrate;
Indecisiveness, loss of motivation.
Recurrent thoughts of death, suicidal ideation
(attempt or plan)
7

8. Biological Basis for Depression
1. Has a genetic component.
2. Depression can be drug-induced.
 Reserpine, a drug used in the treatment of HTN and
schizophrenia can cause depression because it depletes the
vesicular storage of amine NTs (NE, 5-HT, DA).
1. Depression can be treated with Electroconvulsive
Therapy (ECT)
 ECT causes a massive release of NTs &
 Is an effective approach
8

9. Neurons are intact
but the problem is in
neurotransmission
9

10. Biogenic Theory of Depression
 The precise cause of affective disorders remains
elusive.
 Evidence implicates alterations in the firing patterns
of a subset of biogenic amines in the CNS,
Norepinephrine (NE) and Serotonin (5-HT).
 ↓ Activity of NE and 5 -HT systems!.
10

11. NE System
 Almost all NE pathways in the brain originate from the cell
bodies of neuronal cells in the locus coereleus in the midbrain,
which send their axons diffusely to the cortex, cerebellum and
limbic areas (hippocampus, amygdala, hypothalamus,
thalamus).
 Mood: -- higher functions performed by the cortex.
 Cognitive function: -- function of cortex.
 Drive and motivation: -- function of brainstem
 Memory & emotion: -- fun. of the hippocampus & amygdala
 Endocrine response: -- function of hypothalamus.
11

12. 12

13. Serotonin System
 As with the NE system, serotonin neurons located in the pons
and midbrain (in groups known as raphe nuclei) send their
projections diffusely to the cortex, hippocampus, amygdala,
hypothalamus, thalamus, etc. -- same areas implicated in
depression. This system is also involve in:
• Anxiety
• Sleep
• Sexual behavior
• Rhythms (Supra-chiasmatic nucleus).
• Temperature regulation
• CSF production
13

14. 14

15.  Most antidepressants in clinical use today act by
enhancing the neurotransmission of serotonin [5-HT],
norepinephrine [NE], or both.
 They do so either by blocking the reuptake (transport)
of neurotransmitter, blocking the metabolism of
neurotransmitter [i.e., monoamine oxidase (MAO)
inhibitors], or by direct action on a NT receptor.
 Hence, the antidepressants can be classified on the basis
of their putative mechanisms of action.
15

16.  The monoamine theory doesn't fully address the issue of
depression b/c
1. There is a disparity – though antidepressants cause an
increase NT synaptic level immediately, their therapeutic
onset is very slow usually after 2- 4 weeks.
 This may explain there may be involvement of adaptive
response to signal transduction components of increased
synaptic level of NTs which can be related with
therapeutic response.
1. Effective antidepressants are there with a different MOA
16

17. Especially Beta and 5-
HT receptors
17

18. 18

19. Agents that block NT reuptake
Can be further divided into
 TCAs with mixed action: nonselective
 Serotonin-selective reuptake inhibitors (SSRIs),
 NE-selective reuptake inhibitors (NSRI)
 Serotonin & norepinephrine selective reuptake
inhibitors (SNRIs)
Newer non-selective agents are referred that way to
distinguish them from the nonselective TCAs
19

20.  A newer category of antidepressants is the
"Heterocyclic Antidepressants," to differentiate
them from other known antidepressants (most of which
also happen to be heterocyclic!).
20

21. Can also be classified as:-
1. Typical antidepressants w/c includes- TCAs & MAOIs.
2. Atypical antidepressants- they belong to the
different chemical structure are heterocyclic
compounds with again second and third generation
antidepressant classification.
E.g. Amoxapine, Bupropion, Duloxetine,
Maprotiline, Mirtazapine, Nefazodone, Trazodone,
Venlafaxine
21

22. Medication 5-HT NE DA
BA
(Oral)
Protein
Binding
t1/2 (in hours) (Active
Metabolite)
Selective Serotonin Reuptake Inhibitors
Fluoxetine + + + + 0/+ 0 80% 95% 24–72 (146)
Sertraline + + + + 0/+ + >44% 95% 26 (66)
Paroxetine + + + + + 0 64% 99% 24
Citalopram + + + + 0 0 80% <80% 33
Escitalopram + + + + 0 0 80% 56% 27–32
Serotonin Norepinephrine Reuptake Inhibitors
Venlafaxine + + + + + + + 0 92% 27% 4 (10)
Duloxetine + + ++ ++++ 0 50% >90% 12 (8–17)
Norepinephrine Reuptake Inhibitors
Bupropion 0/+ + + >90% 85% 10–21
0, negligible; +, very low; + +, low; + + +, moderate; + + + +, high. 22

23. Antidepressants
1. Tricyclic anti-depressants (TCAs).
Imipramine, desipramine, nortriptyline,
protryptyline, amytriptiline, doxepin.
2. Monoamine oxidase inhibitors (MAOIs).
Isocarboxacid, phenelzine, tranylcypromine.
Both termed as Classical antidepressants
3. Selective serotonin reuptake inhibitors (SSRIs)
Fluoxetine, sertraline, paroxetine, trazodone.
4. Atypical anti-depressants (Others)
New TCAs, amoxapine, bupropion,
alprazolam, maprotiline, nomifensine, mianserin.
23

24. 24

25.  *A - SSRIs and MAOIs desensitize the inhibitory 5-
HT1A somato dendritic receptors.
 *B SSRIs and MAOIs desensitize the inhibitory 5-
HT1B/5-HT1D inhibitory auto receptor on the
presynaptic terminal.
 After acute administration, the TCAs and the SSRIs
inhibit the uptake of 5-HT into the nerve terminal by
binding to the imipramine binding site (or its
equivalent).
 *C TCAs and most non-SSRIs second generation
antidepressants sensitize the postsynaptic 5-HT1A
receptors thereby increasing serotonergic function
25

26.  *D There is experimental evidence that the activity of
the 2nd
messenger system associated with the 5-HT2A
receptor is decreased following chronic
antidepressant treatment.
 There is also circumstantial evidence that the G protein
coupling mechanism between the 5-HT2A receptor and
its second messenger is hypo-functional in depressed
patients but normalizes following effective treatment.
 This suggests that some antidepressants may improve
the receptor–2nd
messenger G protein coupling
mechanism.
26

27. Tricyclic Antidepressants (TCAs)
 Amitriptyline
 Imipramine
 Desipramine
 Nortriptyline
 Protryptyline
 Doxepin.
27

28. Tricyclic Antidepressants (TCAs)
 Between 1960 and 1990 TCAs represented the major
pharmacological treatment for depression.
 They have been considered a homogeneous group of
drugs differing mostly in their potency to inhibit
presynaptic norepinephrine or serotonin uptake and in
their propensity for causing variety of unwanted effects.
28

29. Tricyclic Antidepressants (TCAs)
 The TCAs induce
 Anticholinergic,
 Antihistaminergic, and
 Cardiotoxic SEs which are related to their action
on muscarinic (mainly M1),
 Histamine (H1),
 Adrenergic (α1) receptors and
 Cardiac Na+
and Ca2+
channels.
29

30. Tricyclic Antidepressants (TCAs)
 Most are incompletely absorbed,
 All are metabolized in liver => High first pass effect
1. Transformation of the tricyclic nucleus =>
hydroxylation => conjugation => glucoronides.
2. Alteration of aliphatic side chain => demethylation of
the nitrogen => active metabolites.
 High protein binding,
 High lipid solubility.
30

31. 31

32. Medication 5-HT NE DA
BA
(Oral)
Protein
Binding
t1/2 (in hours) (Active
Metabolite)
Tricyclic Antidepressants
Desipramine + + + + + 0/+ 51% 90% 12–28
Nortriptyline + + + + + 0 50% 92% 18–56
Amitriptyline + + + + + + + + 0 41% 95% 9–46 (18–56)
Imipramine + + + + + 0/+ 27% 95% 6–28 (12–28)
Doxepin + + + + 0 27% 70% 11-23
Others
Mirtazapine + + + + + + + 0 50% 85% 20–40
0, negligible; +, very low; + +, low; + + +, moderate; + + + +, high. 32

33. TCAs: MOA
 Inhibition of NT reuptake.
 Immediate action = >↑ NE and 5-HT in synapse.
 After chronic treatment (2 - 4 weeks) = >
* Adaptive Responses * (dec β-AR & 5HT2A R)
 Takes up to 4 weeks for all TCA to have an effect.
33

34. TCAs: Side Effects
 Atropine-like side effects: dry mouth,
constipation, blurred vision, mydriasis, metallic taste,
urine retention => muscarinic blockade.
 Orthostatic hypotension => α1-AR B
 Drowsiness, sedation and weight gain => Histamine-
Receptor blockade.
34

35. TCAs: Side Effects (cont.)
 Most serious side effect is cardiac toxicity =>
Palpitations, tachycardia, dizziness => excessive
CNS stimulation => ↑NE in Heart.
 Sexual dysfunction, including loss of libido,
impaired erection and ejaculation.
 …↓ COMPLIANCE
35

36. TCAs: Other effects (cont.)
 Metabolism is affected by: Smoking, Barbs, estrogens,
neuroleptics and anticonvulsants.
 Can lower seizure threshold.
 Vagal block, postural hypotension, arrhythmias, sinus
tachycardia.
 Potentiate CNS depressants (BZDs, Barbs, ETOH) =>
coma and death.
 Fatal in overdose (a 2 wk. supply can kill anyone).
 Lethal dose ≥ 2 gram – restriction on dispensed dose for
reducing fatal acute toxicity
36

37. 37

38. MAO Inhibitors
 MAO-A  NE, 5-HT, Tyramine
 MAO-B  DA
 Selective MAOIs:
 Inhibitors MAO-A: Moclobemide, Clorgyline,
Paragyline
 Inhibitors of MAO-B: Selegiline
38

39. MAO Inhibitors
 Are readily absorbed from GI tract and widely
distributed throughout the body.
 May have active metabolites, inactivated by acetylation.
 Effects persist even after these drugs are no longer
detectable in plasma (1-3 weeks).
 Hence they have to be a minimum of 2 weeks gap
before the patient receives MAOIs or after cessation of
use of MAOIs with OTC drugs - wash out period.
39

40. MAO Inhibitors: MOA
 Inhibit MAO enzymes (non-selective):inhibition of
MAOA is relevant for antidepressant effect
1. Irreversible MAO inhibitors
Phenelzine and isocarboxazid => hydrazides
1. Reversible MAO Inhibitors.
Tranylcypromine => non-hydrazide,
prolonged blockade, but reversible within 4hr.
 Decrease metabolism of most biogenic amines
(NE, 5HT, DA, tyramine, octopamine).
40

41. MAO Inhibitors: MOA
 Acute administration causes:
 ↑ NE and 5-HT in synaptic terminals in brain but ↓NE in
PNS. ↓NE synthesis.
 Acute euphoria
 Suppressed REM sleep.
 Chronic administration causes:
 ↓ NE-stimulated cAMP in brain.
 Down regulation of β receptors.
 Down regulation of 5-HT2 receptors.
41

42. MAOIs: Wine-&-Cheese Rxn
 Major limitation, food and drug interaction.
 Fatal interaction with tyramine-containing foods
(fermented foods in particular, such as wine and
cheese).
 ↓ MAO-A => ↑ Tyramine in the body =>↑NE in
circulation => induces hypertensive crisis => can
lead to intracranial bleeding and other organ
damage.
42

43. MAOIs: Wine-&-Cheese Rxn…
 DA & tyramine are metabolized by both MAO
isozymes & both types are inhibited by phenelzine,
tranylcypromine, and isocarboxazid.
 Tyramine is an indirectly acting amines, which must
be taken up by sympathetic neurons to release NE
 Capable of causing – Hypotension (seems
paradoxical), excessive CNS stimulation, wet gain,
atropine like effect
43

44. MAOIs: Negative drug intrxns with
 Any drug metabolized by MAOs* including SSRIs, TCAs
and meperidine, alcohol, CNS depressants,
sympathomimetics, phenylephrine (O/C nasal
decongestants), amphetamines, and other indirect-acting
adrenergic drugs.
 Interaction with drugs metabolized by MAOs (e.g.
Meperidine (opioid analgesics) => hyperpyrexia or “hyper-
excitation syndrome” involving high fever, delirium and
hypertension)
 Other side effects: Hypotension, Hepatotoxicity, Sedation
44

45. SSRIs
 The SSRIs are currently the most widely utilized
class of antidepressants in clinical practice.
 They act within the brain to increase the amount of
the NT, serotonin (5-hydroxytryptamine or 5-HT),
in the synaptic gap by inhibiting its re-uptake.
 Instead of being discovered by accident, SSRIs were
specifically designed while considering the biological
causes of depression.
45

46. SSRIs
 Are described as 'selective' because they affect only the
reuptake pumps responsible for 5-HT, as opposed to earlier
antidepressants, w/c affect other monoamine NTs as well.
 B/se of this, SSRIs lack some of the SEs of TCAs & MAOIs.
 No autonomic side effect
 No food and drug interaction
 While Efficacy is equivalent to TCAs
 But expensive in cost.
46

47. 47

48. SSRI Drugs
 Include many of the popular drugs on market today
• Fluoxetine, Sertraline, Paroxetine, Fluvoxamine
Fluoxetine Sertraline
48

49. Mechanism of action:
 Specific serotonin uptake inhibitors increase 5-HT
by inhibiting reuptake.
 Enhanced stimulation or responsiveness of
postsynaptic 5-HT receptors is particularly
important in the action of antidepressants.
49

50.  Most widely prescribed drugs for depression.
 They have few side effects and seem to be rather safe.
 More rational prescribing & better patient compliance.
 Adverse effects include: nausea, decreased libido,
decrease sexual function.
 Low threat for overdose.
 Suicide may be considered in severe depression.
 Cause weight loss, unlike most antidepressant drugs
SSRIs cause weight loss
50

51. Fluoxetine (Prozac)
 The first of a new class, SSRIs
 ~ 70% pts respond to SSRI therapy at the end of 6 weeks
 Paroxetine & Sertraline have PK similar to TCAs.
 It is chemically unrelated to tricyclic, tetracyclic, or other
available antidepressant agents.
 Eliminated very slowly.
 Half-life after a single dose is 2 days
 20-60 mg/d standard dose
51

52. Fluoxetine (Prozac)
Common side-effects
Anxiety, restlessness, trembling, weakness, skin
rash, Anorgasmia, itching, and a decrease in sexual
drive.
52

53. Fluoxetine & paroxetine
 Inhibit liver enzymes, CYP- 2D6.
 Concomitant therapy with drugs also metabolized
by this enzyme system (such as TCA) may lead to
drug interactions.
 Wide range of D/I, notably with MAOIs
53

54. Drug-Drug interactions:
 Dangerous with other antidepressant drugs, MAOIs in
particular.
 “Serotonin Syndrome”
e.g. MAOIs + SSRIs or SNRIs + lithium.
 hyperthermia, cognitive reactions, muscle rigidity,
myoclonus, rapid changes in mental status and vital signs.
 Thus it is important to wait up to 2- 6 weeks after
medication is stopped, before starting with another
drug.
54

55. Heterocyclics
 2nd generation heterocyclics
 Amoxapine
 Maprotiline
 Trazodone
 Bupropion
 Third generation heterocyclics
 Mirtazapine
 Venlafaxine
 Nefazodone
55

56. Heterocyclics
 As with the TCA's , they all have variable BA
 High protein binding.
 Some have active metabolites.
 Trazodone and Venlafaxine have the shortest plasma
half-lives, which mandates divided doses during the
day.
 Nefazodone and fluvoxamine cause inhibition of
CYP3A4.
56

57. 5-HT & NE Reuptake Inhibitors (SNRIs)
 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.
 These new drugs, because of their specificity for the
serotonin and norepinephrine reuptake proteins, lack
most of the adverse side effects of TCAs & MAOIs.
57

58. Venlafaxine
 The first and most commonly used SNRI.
 Exhibits dual presynaptic inhibition of serotonin and
noradrenaline reuptake
 Active metabolite, O-desmethylvenlafaxine (ODV),
 It is used primarily for the treatment of depression, GAD,
and social anxiety disorder in adults.
 Venlafaxine and ODV have no significant affinity for
muscarinic, histaminergic, or α-1 adrenergic receptors
58

59. Venlafaxine Dosage and Side Effects
 75mg-225mg per day
 Because of its relatively short half-life of 4 hours, should
be administered in divided dosages throughout the day.
 Side effects may include nausea, dizziness, sleepiness,
abnormal ejaculation, sweating, dry mouth, stomach
pain, abnormal vision, nervousness, insomnia, loss of
appetite, constipation, confusion/agitation, tremors,
and drowsiness.
59

60. NE & DA Reuptake Inhibitor (NDRI)
 The only antidepressant in this group is Bupropion,
 Chemically unrelated to tricyclics or SSRIs.
 It is similar in structure to the stimulant cathinone, and to
phenethylamines in general.
 Selective catecholamine (NE & DA) reuptake inhibitor.
 It has only a small effect on serotonin reuptake.
 It does not inhibit MAO.
 Metabolized in the liver; has active metabolites
 The half-life of 20-33 hrs
60

61. Medication Sedation
Agitation/I
nsomnia
Anticholin
ergic
Effects Orthostasis
GI Effects
(Nausea/Di
arrhea)
Sexual
Dysfunctio
n
Weight
Gain
Tricyclic Antidepressants
Desipramine (Norpramin) + + + + + + + + 0/+ + + +
Nortriptyline (Pamelor) + + + + + + + 0/+ + + +
Amitriptyline (Elavil) + + + + 0/+ + + + + + + + + 0/+ + + + + +
Imipramine (Tofranil) + + + 0/+ + + + + + + + 0/+ + + + +
Doxepin (Sinequan) + + + + 0/+ + + + + + + + + 0/+ + + + +
Selective Serotonin Reuptake Inhibitors
Fluoxetine (Prozac) + + + + + 0/+ 0/+ + + + + + + + +
Sertraline (Zoloft) + + + + 0/+ 0 + + + + + +
Paroxetine (Paxil) + + + + + ++ 0 + + + + + + +
Citalopram (Celexa) + + + + 0/+ 0 + + + + ++
Escitalopram (Lexapro) + + + 0/+ 0 + + + + ++
0, negligible; +, very low; + +, low; + + +, moderate; + + + +, high.
61

62. Medication Sedation
Agitation/
Insomnia
Anticholinergic
Effects
Ortho
stasis
GI
Effects
(N/D)
Sexual
Dysfn
Weight
Gain
Serotonin Norepinephrine Reuptake Inhibitors
Venlafaxine
(Effexor)
+ + + + + 0 + + + + + + +
Duloxetine
(Cymbalta)
+ + ++ + 0 + ++ ++ 0/+
Norepinephrine Reuptake Inhibitors
Bupropion
(Wellbutrin)
0 + + + + 0 + 0/+
Others
Mirtazapine
(Remeron)
+ + + + 0 + + 0/+ + 0/+ + + +
62

63. Other uses of Antidepressants
 Enuresis – TCA
 ADHD – TCA
 Neuropathic pain – TCA
 OCD – SSRI / Clomipramine
63

64. Mania
 Mania alone is rare (10%) and
 Most frequently cycles with
major/endogenous depression (manic-
depressive disease, bipolar disorder).
64

65. Core Symptoms for manic episodes
Five or more
 Inflated self-esteem
 Decrease need to sleep.
 More talkative than usual or pressure to keep talking, go
on-and-on about the things they will do.
 Flighty of ideas
 Distractibility (attention too easily drawn)
 Excessive involvement to pleasurable activities
 Psychomotor agitation
 Predominant mood is irritability, violence and impatience
65

66. Anti-Manic Drugs (mood stabilizers)
Lithium (Li+) carbonate or Li+-citrate
DOC for treatment of acute manic episodes
Lithium alone, or in combination with:
 Carbamazepine
 Valproic acid
 Lamotrigine
66

67. MOA of Li+
 Interfere activity of G-proteins (keep in less active state)
 A selective action is to inhibit inositol mono-phosphatase
and thus interfere with phosphatidylinositol pathway.
 This leads to decrease in cerebral inositol concs. interfere
neurotransmission mxms by affecting phosphatidylinositol
pathway.
 Also leads to a decreases in protein kinases fxn in brain
tissue, including PK-C; this effect also is shared with
valproic acid.
 Thus, may alter release of amine NTs.
67

68. Inhibit breakdown of IP2 to IP1 (during PIP hydrolysis) => depletion of DAG
and IP3 and ↓ [Ca2+
] in response to receptor activation (i.e. from 5-HT2R, α1-
AR, glutaminergic receptors and others)
68

69. Adverse effects of Lithium
 Therapeutic conc. of Li should be 0.5- 1.5 mmol/L
 If >1.5 mmol/l comma is possible.
 Toxicity increases by drugs/situations that increase
plasma conc.
 Diuretics leads to depletion of Na+, particularly thiazides
(Li+
clearance is reduced by 25%)
 Some NSAIDs (indomethacin) facilitate PT reabsorption
 In renal disease (reduced GFR)
69

70. Adverse effects of Lithium
 Inhibits ADH => diuresis: polyuria & polydipsia –
nephrogenic diabetes insipidus
 May decrease thyroid function
 Tremors, weight gain, acne; seizures and arrhythmia
 Teratogenic (tricuspid valve malformation)
70

71. Anticonvulsants for bipolar disorder
Valproic acid, carbamazepine: MOA
Reduce flux of ions through voltage gated ion channels such
as Na+, K+, Ca2+
Enhance inhibitory transmission with GABA by increasing its
synthesis, release or inhibiting breakdown
Reducing excitatory neurotransmission with glutamate by
reducing its release
Decreases protein kinases fxn, including PK-C (valproic acid)
71

72. Anti-Manic Drugs: Valproic Acid
 A known antiepileptic that has anti-manic effects
 As effective as lithium during early weeks of treatment
 May be used as first line for mania, although it may not
be as effective in maintenance treatment as lithium for
some pts.
 Nausea being limiting factor in some pts
72

73. THANK YOU
73