4. Classification of Major Affective
Disorders
Episodal
Depression
Seasonal
Affective
Disorder
Atypical
Depression
Major/
Endogenous
Depression
Mania Bipolar
depression
Major Affective
Disorders
5. feelings of misery
apathy
inadequacy
pessimism
anxiety
tension
Guilt
Ugliness
Low self –esteem
Bodily complaints
Indecisiveness
Ioss of motivation
Retardation of
thought and
action
Sleep disturbance
Depression
6. • 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.
7. 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, Superman, spiderman.
8. 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.
9. 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.
12. 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
13. 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
• 2- generation of IP3/DAG
• 3- ligand gated cation channel
14. 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 antidepressants (TCAs)
A
N
T
I
D
E
P
R
E
S
S
A
N
T
S
15.
16. 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-HT2 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 uptake
(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
17. 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
18.
19. Nonselective MAOIs not favorable Cheese Reaction
Cheese, beer, wine,
meat, fish, yeast,
(contain large amount of
tyramine 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
20. Nonselective MAOIs not favorable
–Cold and Cough medicines contain
Ephedrine
(Same result as cheese reaction)
21. 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
22. Tricyclic Antidepressants (TCAs)
• Imipramine represents the class (Prototype)
• Inhibit monoamine reuptake
(serotonin and noradrenaline)
• 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 receptor blocking actions (postural
hypotension etc.)
»Histamine-Antihistaminic (sedation)
»Dopamine- antipsychotic (amoxapine,
maprotiline)
23. 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
24. 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.
25. • Signaling via NE or 5-HT increases the
expression of
brain-derived neurotrophic factor (BDNF)
• BDNF- related to the ultimate mechanism of
action of antidepressant drugs
• Increase in BDNF levels
increased neurogenesis in the hippocampus
26. TCAs Adverse effects
• Anticholinergic- dry mouth, 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 (mianserin)
27. TCAs (Acute Poisoning)
• Usually suicidal attempt
• Presents as
– Excitement
– delirium
– Anticholinergic
symptoms like
atropine poisoning
– Muscle spasm
– Convulsions
– arrhythmias
– Respiratory
depression
– Coma
• Treatment
– Gastric lavage
– I.V. line
– Oxygen
– Maintenance of BP
and Temperature
– Diazepam iv
– Propranolol /
lignocaine
28. Miscellaneous
• Amoxapine
– Blocks D2 +
inhibition of NA
reuptake
– 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
29. 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 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
30. 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
31. 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
32. 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
33. Atypical Antidepressants
• Mianserin
–Uniquenot 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
– potent 5-HT2 antagonist
– No anticholinergic effect
– Bradycardia
– Has anxiolytic action also
– Prolonged and painful
penile erection (priapism)
34. Atypical Antidepressants
• Tianeptine / and
Amineptine
–Increasesrather
inhibiting 5-HT uptake
– Neither sedative nor
stimulant
– Effective in anxiodepressive
states
• Duloxetine
– Duloxetine increases
uretheral tone, used in
urinary incontinence ( over
active bladder)
– Used in panic attacks,
diabetic neuropathic pain
• 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
35. 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
38. Lithium
inhibits glycogen
synthase kinase-3
(GSK-3), a
multifunctional
protein kinase.
GSK-3 is a
component of
diverse intracellular
signaling pathways.
inhibition of
inositol
monophosphatase
decreased
cerebral inositol
concentrations
suppresses
inositol signaling
Dec NA and DA, Without affecting 5-HT release
39. S/E of Lithium
• Tremors
• seizures
• Diabetes incipidus
• Goiter, Hypothyroidism
• C/I during pregnancy- may cause congenital abnormalities
(cardiac)
• TDM is required
(maintained level 0.5 - 0.8mEq/L)
Toxicity appears when serum level exceeds 1.5 mEq/L
40. MCQs
Q1. Monitoring of serum lithium concentration
is done because of:
A. Low therapeutic efficacy
B. Adverse effects
C. Long half-life
D. Very low therapeutic index
Ans- D. Very low therapeutic index
41. Q2. Long term use of lithium causes:
A. Peripheral neuropathy
B. Hypothyroidism
C. Anemia
D. Jaundice
Ans- B
42. Q3. Most common congenital anomaly
associated with lithium is:
A. Cardiac malformations
B. Neural tube defects
C. Renal anomaly
D. Fetal hydantoin syndrome
Ans- A
43. Q4. Antidepressant, which is also useful in the
treatment of neuropathic pain and migraine
is
A. Amitriptyline
B. Amoxapine
C. Reboxetine
D. Sertraline
Ans- A
44. Q5. Which of the following antidepressant drug
can also be used for treatment of anxiety,
panic disorder, obsessive compulsive disorder
and posttraumatic stress disorder?
A. Bupropion
B. sertraline
C. reboxetine
D. Moclobemide
Ans- B
45. Q6. Antidepressants are not recommended as
monotherapy for bipolar illness because of
A. ineffectiveness
B. electroconvulsive therapy is the modality of
choice in such patients
C. weight gain
D. the "switch" from a depressed episode to a
manic or hypomanic episode
Ans- D
46. Q7. Electroconvulsive therapy (ECT) is treatment of
choice for agitated, depressed patients with a
high risk of suicide because
A. ADRs are common due to antidepressant drugs
B. antidepressant drugs are not effective
C. antidepressant drugs takes 3-4 weeks before a
measurable therapeutic response becomes
evident
D. antidepressant drugs are not palatable
Ans- C
47. Bibliography
• Essentials of Medical Pharmacology -7th edition by KD Tripathi
• Goodman & Gilman's the Pharmacological Basis of Therapeutics 12th
edition by Laurence Brunton (Editor)
• Lippincott's Illustrated Reviews: Pharmacology - 6th edition by Richard A.
Harvey
• Basic and Clinical pharmacology 11th edition by Bertram G Katzung
• Rang & Dale's Pharmacology -7th edition
by Humphrey P. Rang
• Clinical Pharmacology 11th edition By Bennett and Brown, Churchill
Livingstone
• Principles of Pharmacology 2nd edition by HL Sharma and KK Sharma
• Review of Pharmacology by Gobind Sparsh
