Antidepressant_Pharmacology

1. Antidepressant, Anti-anxiety Drugs
Dr. R. K. Dixit
Professor
Pharmacology and Therapeutics
C. S. M. Medical University Lucknow, 226003

4. Classification of Major Affective Disorders
Episodal
Depression
Seasonal
Affective
Disorder
Atypical
Depression
Major/
Endogenous
Depression
Mania Bipolar
depression
Major Affective
Disorders

5. Episodal (reactive) Depression
Adverse life events.
Physical illness.
Drugs.
Other psychiatric disorders.

6. Reactive (episodal) Depression
 More than 60% of all depressions.
 Core depressive syndrome: feelings of misery,
apathy, inadequacy, pessimism, anxiety, tension,
guilt. Ugliness, Low self –esteem,
 Bodily complaints

7.  Withdrawn.
 Loss of interest in pleasurable activities.
 Indecisiveness, loss of motivation.
 Retardation of thought and action.
 Sleep disturbance

8.  In severe cases, it is accompanied by
hallucinations and delusions.
 Recurrent suicidal ideation, a suicide attempt or
a specific suicide plan.
•significant weight change (without dieting )
•Psychomotor agitation or retardation.

9. 1. Has a genetic component.
2. Depression can be drug-induced.
3. Depression can be drug-repressed.
4. Depression can be treated with drugs.
5. Depression can be treated with
Electroconvulsive Therapy (ECT).

10. Mania
Mania alone is rare (10%) and most frequently cycles with
Major/endogenous depression
(Manic-Depressive Disease, Bipolar Disorder).
Core Symptoms:
Characterized by an elevated “high” mood.
Talkative, go on-and-on about the things they will do.
Increased self-esteem.
Auditory hallucinations.
Decrease need to sleep. Expensiveness, unnecessary
buying.
Lack judgment, Supermen

11.  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?.

12. 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 and emotion: -- function of the hippocampus and
amygdala.
Endocrine response: -- function of hypothalamus.

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 involved in:
• Anxiety.
• Sleep.
• Sexual behavior.
• Temperature regulation.
• CSF production.

16. Blocked by antidepressants
Blocked by
antidepressants

17. Serotonin receptors
 5–HT1
 subtypes
 5–HT1A, 5–HT1B, 5–HT1D, 5–HT1E,
5–HT1F
 primarily responsible for the
therapeutic (antidepressant) effects
of increased intrasynaptic serotonin
 5–HT2
 subtypes
 5–HT2A, 5–HT2B, 5–HT2C
 primarily responsible for the toxic
effects of increased intrasynaptic
serotonin

18. Serotonin receptors
 Over all 14 types divided in to 1, 2, 3, and 4-7
family
 All are G-protein coupled receptors except 3
 1- decreases cAMP while 4-7 increase
 3- ligand gated cation channel

19. Alternative Therapies
No way of a priori knowing which therapy will be
best for a patient.
 Light Therapy
 Psychological Treatment
 ECT (patients with suicidal tendency and for quick action)
 St. John’s Wort (Plant)

20. Antidepressants
TCAs
TCAs
TCAs
SSRIs
SSRIs
MAOIs
MAOIs
MAOIs
MAOIs
MAOIs
Venflaxine MAOIs
maprotiline

21. Reversible inhibitor of MAO-A (RIMAs)
Moclobemide ,Clorgyline
 (Isocarboxacid, phenelzine, tranylcypromine.)
Atypical antidepressants
Trazodone, Mianserine
Mirtazapine, Venlafaxine
Duloxetine,Tianeptine
Amineptine, Bupropion
 NA + 5 HT reuptake inhibitor
Imipramine, Amitriptyline
Trimipramine, Doxepin
Dothiepin, Clomipramine
Selective serotonin reuptake
inhibitors (SSRIs)
Fluoxetine, Fluvoxamine
Paroxetine, Sertraline
Citalopram, Escitalopram
Predominantly NA reuptake inhibitor
Desipramine, Nortriptyline
Amoxapine, Reboxetine
Tricyclic antideprssants
(TCAs)
A
N
T
I
D
E
P
R
E
S
S
A
N
T
S
•CM
•RITA-Don't- Copy
•Exams-For-PCS
•MAD-Boy-turned-violent

22. Mechanism of Action
1. Inhibition of MAO enzymes.
(MAOIs).
2. Inhibition of NE and 5-HT reuptake.
(TCAs, SSRIs, Newer TCAs).
3. Prominent alpha blocking and weak 5-HT antagonists.
(Nefazodone, trazodone,)
4. Serotonin and noradrenalin reuptake inhibitor (SNRIs)
(venlafaxine, duloxetine)
5. Noradrenergic and specific serotonergic antidepressants (NaSSA)
(Mirtazapine)
6. Inhibitor of Dopamine and Noradrenalin
(Bupropion)
7. Blockade of pre-synaptic alpha 2 receptors
(Mianserin)
8. Increases rather than inhibiting 5-HT uptake
(Tianeptine, Amineptine)
A
T
Y
P
I
C
A
L

23. MAO ( monoamine oxidase) an enzyme
Two types
MAO – A
-Peripheral adrenergic nerve
endings
-Intestinal mucosa
-Human placenta
-Liver
-Serotonin , Noradrenalin
and dopamine
-Inhibited by
moclobemide
and clorgyline
 MAO-B
-brain ( basal ganglia)
-Platelets
-Liver
-Deaminates dopamine
-Inhibeted by selegiline
(deprenyl)
Isoniazide, iproniazide, phenelzine, isocarboxazide,tranylcypromine were non selective and
irreversible inhibitors (Hit and run drugs) used previously but not used now due to drug
drug and drug food interactions. Linezolide (new drug against MRSA) Cheese and
serotonin syndrome
A-B
C-D

25. Nonselective MAOIs not favorable Cheese Reaction
Cheese, beer, wine,
meat, fish, yeast,
(contain large amount of
tyrammine and other
indirectly acting amines)
Due to irreversible block of
MAO These escape
degradation in intestinal wall
and liver
 Hypertensive
crises, CVA
 Medical Emergency
Reach to circulation Displace
large amount of noradrenalin
from loaded nerves
Tt. I.V. Phentolamine, Prazosin

26. Nonselective MAOIs not favorable
Cold and Cough medicines contain
Ephedrine
(Same result as cheese reaction)
 Levodopa- excitement and hypertension
 Tricyclic antidepressants- excitement, rise in BP,
temperature

27. Reversible inhibitor of MAO-A
(RIMAs)
 Moclobemide-
Reversible and selective MAO-A inhibitor
Short duration of action
Competitive enzyme inhibition
Tyramine is able to displace it
Cheese reaction is less likely
Devoid of anticholenergic, sedative,
cognitive, cardiovascular effects
Good for elderly with heart diseases

28. Tricyclic Antidepressants (TCAs)
 Imipramine represents the class (Prototype)
 Inhibit monoamine reuptake
(serotonin and noradrenalin)
 Increase the concentration of Serotonin and NAat
synapse and potentiate the action (therapeutic effects)
 Other receptors acted (Adverse effects)
 Muscarinic- Anticholinergic side effects
(dryness etc.) #
 Alpha- alpha blocking actions (postural
hypotension etc.) #
 Histamine-Antihistaminic (sedation) #
 Dopamine- antipsychotic (amoxapine,
maprotiline)

29. TCAs actions (CNS)
 In Normal person
- Tiredness
- Light-headedness
- Sleepiness
- Difficulty in thinking
- Difficulty in concentration,
- Gait disturbances
- Provoke anxiety
- Unpleasant
 In Depressed
-Sedation immediately
-Elevation of mood (2-4Weeks)
-Suppresses REM prolongs total
sleep duration
Lower seizure threshold and produce convulsions in overdose
Don’t carry abuse potential, Development of dependence is
less

30. TCAs uptake blockade
is not directly responsible for antidepressant action?
 Uptake blockade occurs quickly but antidepressant
action occurs after months
 Initially
Pre synaptic alpha 2 and 5-HT1 auto receptors are
activated by increased amount of NA and Serotonin in
synaptic cleft resulting in decreased firing
 But on long term
desensitize and down regulation of these receptors and
induce adaptive changes in the number and sensitivity of
receptors and amine turnover leading to enhanced NA and
Serotonin transmission required for antidepressant action.

31. TCAs on other systems
 ANS
 Potent anticholinergic
(dry mouth, blurring of
vision,, constipation,
urinary hesitancy)
 Weak alpha 1 blocking
(postural hypotension,
impairment of ejaculation,)
 H1 antihistaminic
(sedation)
 CVS
 Tachycardia
 Postural hypotension
 Cardiac arrhythmias
(T wave suppression or
inversion) due to intra
ventricular conduction
interference due to NA
and Anti cholinergic
actions
Tolerance to Anticholinergic and
hypotensive actions develop latter on

32. TCAs (Pharmacokinetics)
 Good oral absorption
 Highly bound to Proteins (plasma and tissue)
 Metabolized in liver (oxidation, glucuronide
conjugation and CYP2D6, CYP3A4, CYP1A2
 Many active metabolites may be produced
 Mostly can be given once a day (at bed)
 Have Therapeutic Window
phenomenon (50-200ng/ml of imipramin)

33. TCAs Adverse effects
 Anticholinergic- dry moth, bad taste, constipation,
epigastric fullness, urinary retention (more common in
elderly male), blurred vision, palpitation
 Sedation, mental confusion, weakness
 Increased appetite and weight
 Sweating, fine tremors
 Precipitation of seizures
 Postural hypotension
 Cardiac arrhythmias
 Rashes and jaundice

34. TCAs (Acute Poisoning)
 Usually suicidal attempt
 Presents as
 Excitement
 delirium,
 Anticholinergic
symptoms like
atropine poisoning
 Muscle spasm
 Convulsions
 Respiratory
depression
 Coma
 Treatment
 Gastric lavage
 I.V. line
 Oxygen
 Maintenance of BP and
Temperature
 Diazepam iv
 Propranolol / lignocain

35. TCAs (Interactions)
 Potentiation of sympathomimetics (direct acting)
 Reduce action of sympathomimetics (indirect acting)
 Reduce antihypertensive action of guanethidine and
clonidine ( by preventing their transport in to neurons)
 Potentiate other CNS sedatives
 SSRIs inhibit metabolism of TCAs
 With MAO inhibitors dangerous hypertensive crisis with
excitement and hallucinations
 Retard the absorption of other drugs
 Phenytoin, phenylbutazone, chlorpromazine, aspirin, displace
TCAs and produce toxicity
 Phenobarbitone induce metabolism and inhibit the effect of
the drug

36. Miscellaneous
 Amoxapine
 Tetra cyclic
compound
 Blocks D2 reuptake
also
 Has mixed
antidepressant and
neuroleptic effects
 Good for psychotic
depression
 Reboxetine
 Selective NA
reuptake blocker
 Weak action on 5-
HT mechanism
 Anticholinergic
effects are
minimal

37. Selective Serotonin Reuptake Inhibitors
(SSRIs)
 Limitations of TCAs
 Anticholinergic effects
 Alpha blocking action
 Cardio toxicity
 Sedation, seizures ppt
 Low safety margin
 Weight gain
 Therapeutic window
 Overdose poisoning
common
 Lag of 1 month period
 Incomplete response to
Tt
 Answers may be given by SSRIs
 Selectively inhibit membrane associated
SERT (serotonin transporter)
 More tolerability and better acceptability
 Used in depression as well as in OCD,
phobias
 No sedation, No seizure ppt
 No alpha blocking action
 Less chances of arrhythmia
 No weight gain
 Now 1st choice for OCD, Panic disorders,
Social Phobia, Eating disorders,
Premenstrual syndrome, Post traumatic
stress

38. Important points
TCAs have slightly more efficacy
Some patients not responding to TCAs
may respond to SSRIs,
SSRIs preferred in prophylaxis of recurrent
depression
In severe depression TCAs appear to be
more efficacious

39. Individual compounds
 Fluoxetine
 Prototype of SSRIs
 Longest acting
 Fluvoxamine
 Short acting
 Commonly used in
indoor patients
 Paroxetine
 Short acting
 More GI side effects
 Sertraline
 Less chances of drug
interactions due to low
potency to cause
cytochrome enzyme
depression
Citalopram
•Similar to sertraline but should be
avoided in patients attempting
suicide
Escitalopram
•Active enantiomer of
citalopram side effects are less

40. SSRIs
 Side effects
 Gastric upset
 Nausea
 Interfere with
ejaculation
 Nervousness
 Restlessness
 Insomnia
 Anorexia
 Headache
 Diarrhea
 Epistaxis
 Ecchymosis
 Others
 Inhibit cytochrome
enzymes and elevate the
plasma level of other drugs
 Other serotonergic drug
( MAOIs) is taken may
precipitate Serotonin
Syndrome manifesting as
agitation, restlessness,
sweating, twitching,
convulsions

41. Atypical Antidepressants
 Mianserin
 Unique not inhibit NA
and 5-HT uptake
 Blocks pre-synaptic alpha
2 receptors increases
release and turnover of
NA
 Antagonist at serotonin 2,
1c, and H1 receptors
 Has sedative effect
 Damages liver and bone
marrow (Reserve drug)
 Trazodone
 Blocks 5-HT uptake
 Has prominenent alpha
blocking
 Weak 5-HT2 antagonistic
 No anticholinergic effect
 Bradycardia
 Has anxiolytic action also
 Prolonged and painful
penile erection
(priaprism)

42. Atypical Antidepressants
 Tianeptine / and
Amineptine
 Increasesrather
inhibiting 5-HT uptake
 Neither sedative nor stimulant
 Effective in anxiodepressive
states
 Venlafaxine / Duloxetine
 SNRI selective in action
 Faster onset of action
 Increases BP
 Duloxetine increases
uretheral tone used in urinary
incontinence ( over active
bladder)
 Mirtazapine (NaSSA)
 Noradrenergic and specific
serotonergic antidepressant
 Blocks alpha 2 auto receptor
(on NA neuron) and hetero-
(on 5-HT neuron) receptors
increasing both NA and
serotonin release.
 Bupropion
 Inhibits DA and NA
uptake has excitant effect
 Used to reduce smoking

43. Antidepressant uses
 Depression (ECT may be needed in severely
depressed and patients having suicidal tendency)
 Bipolar affective disorders TCAs and lithium or
SSRIs with lithium or valporate/ lamotrigine
 SSRIs with atypical antipsychotic in psychotic
depression
 Obsessive compulsive disorders (SSRI and
Clomipramine)
 Eating disorders

44.  Anxiety disorders
 Neuropathic pain
 Attention deficit hyperactivity disorder in
children
 Enuresis- (Imipramine 25mg at night)
 Overactive bladder (stress incontinence)
 Migraine prophylaxis
 Pruritus (Topical doxepin)

45. Antianxiety Drugs
 Anxiety - emotional state
- Unpleasant
- Associated with uneasiness
- Discomfort
- Fear
- Undefined threat
- Fear about future
Some amount of anxiety is must for progress
When it becomes excessive, disproportionate, hampers performance
then only
needs treatment

46. Antianxiety Drugs
 Drugs producing restful state of mind without
interfering with normal mental or physical functions.
 Have no effect on thought control
 Don’t produce extra pyramidal side effects
 Can Produce physical dependence
 May Have abuse potential
 Don’t selectively block conditioned avoidance response
in animals
Have anticonvulsant activity

47. Antianxiety Drugs
 Benzodiazepine
 Diazepam
 Chlordiazepoxide
 Oxazepam
 Lorazepam
 Alprazolam
 Azapirones
 Buspirone
 Gepirone
 Ispapirone
 Others
 Beta blocker- Propranolol
 Antihistaminics-
Hydroxyzine
 SSRIs and other
antidepressant drugs
PHO/BIG/DOCLA

48. Benzodiazepines
 Relieve anxiety at low dose ( higher dose induce sleep
and impair performance )
 Selective taming effect
 More selective to limbic system
 Have low side effects in Antianxiety dose
 Lorazapam and clonazepam IM for psychotic and
manic patients
 Act by facilitatingGABAergic transmission

49. Benzodiazepine MOA
α subunit
γ subunit
Others
δεθπ
β subunit
GABA
Cl
GABA- A
Receptor
Diazepam +
DMCM –
Flumazenil- 0
Barbiturates
Cl
More Cl-
intracellular
more polarized
more refractory
Intracellular
Extra-tracellular

50. Benzodiazepines
 Adverse effects
 Sedation
 Light headedness
 Psychomotor impairment
 Cognitive impairment
 Vertigo
 Confusional state
 Increased weight
 Impaired sexual functions
 Potential to produce dependence
 All are almost similar selection is empirical

51. Benzodiazepines (Individual drugs)
 Chlordiazepoxide
 First BZD
 Long lasting effect
 Chronic anxiety
 Diazepam
 Has two phase of metabolism
 Broken in to active metabolites
 Long duration of action
 Oxazepam
 Polar compound
 Penetration In brain is slow
 No active metabolite
 Used in short lasting anxiety
state
 Lorazepam
 Less lipid soluble
 Slow entry in brain
 No active metabolite
 IM
Alprazolam-
high potency, mood elevating in depressed pt. less drowsiness

52. Buspirone
 Does not produce sedation, cognitive
impairment,
 Does not interact with BZD receptor or modify
GABAergic transmission
 No tolerance
 No physical dependence
 No muscle relaxant
 No anticonvulsant property

53. Buspirone
 Relieves mild to moderate generalized anxiety
 Effects develop slowly (not used for acute)
 Partial agonist on 5HT1A (pre-synaptic) and
antagonist on 5HT postsynaptic receptors
 Presynaptic auto-receptors stimulated leading to
reduced activity of dorsal raphe serotonergic
neurones
 Also has weak D2 blocking effect

54.  Hydroxazine
 H1 antihistaminic
 Sedative, anti -emetic and
spasmolytic
 Anti - Pruritus
 Propranolol
 Reduces sympathetic
symptoms like rise in BP,
Tremors, sweating etc.
 Performance or
situational anxiety
(like examination fear, social
phobia, public lecture)

55. Questions
 Classify antipsychotic drugs
 Classify antidepressant drugs
 Pharmacological actions of chlorpromazine
 Pharmacological actions of amitriptyline
 Drug indued parkinsonism
 MOA of antipsychotic
 MOA of antidepressants
 Lithium

56. Questions
 Drug of choice of cheese reaction-Phentolamine
 Moclobemide is reversible and selective MAO-A inhibitor
 All antidepressants don’t inhibit DA uptake except amoxapine, maprotiline, Bupropion
 Antidepressants don’t carry abuse potential
 SSRIs are inhibitor of CYP enzymes
 Serotonin syndrome
 Trazodone – may produce priaprism due to high α1 blocking property
 Mianserin unique not inhibiting NA or 5HT but blocks Pre-synaptic α2 receptors
 Tianeptine, Amineptine - unique increase 5-HT uptake
 Venlafaxine, Duloxetine – SNRI
 Mirtazapine- NaSSA- blocks α2 auto and hetro receptors and enhance NA and 5HT
release
 Nocturnal enuresis- Imipramine
 Benzodiazepines- GABA facilitatory
 Buspirone- partial agonist at 5HT1A autoreceptors,antagonist at 5HT1A postsynaptic
 DOC of performance or situational anxiety- B-blockers

57. Thanks