This document discusses depression and its treatment with antidepressants. It defines mood disorders and describes the symptoms of depression. It discusses several theories for the causes of depression, including the monoamine hypothesis and neurotrophic hypothesis. It describes different types of depression and endogenous depression in particular. It explains the pathophysiology of endogenous depression and the mechanisms of action of various classes of antidepressants, including TCAs, SSRIs, SNRIs, and MAOIs. It discusses the pharmacokinetics, uses, and adverse effects of these drug classes.

1. DEPRESSION
PRESENTED BY :
S.KAVIYA
M.PHARM (PHARMACOLOGY) – I

2. INTRODUCTION :
MOOD DISORDERS is a affective disorders. They are a group of psychoses associated
with changes of mood . i.e. DEPRESSION AND MANIA .
DEPRESSION is a common psychiatric disorder but the aetiology of it is not clear.
SYMPTOMS :
1) Emotional symptoms : guilt ,low self esteem ,intense feeling of sadness
2) Biological symptoms : decreased physical activities , sleep disturbances ,loss of
libido (sexual desire )
3) Manic symptoms : Hyperactivity ,mental alertness ,irritability ,impatience and
aggression.
ETIOLOGY :
MONOAMINE THEORY : It was introduced after noticing that Reserpine (a drug
used for treatment of hypertension ,can pass BBB) ,depleting the brain stores of
monoamines ( NA ,5-HT,DA ,etc.,)
Depression

3. CAUSES OF DEPRESSION :
1) Autoreceptor hyper – responsiveness
2) decrease monoamines in the synapse .
TYPES :
1) Unipolar depression
a) Reactive depression
b) Endogenous depression
2) Bipolar depression / Manic depressive illness
3) chronic depression
4) Seasonal depression ( SAD )
5) Atypical depression.
ENDOGENOUS DEPRESSION is a major depression results from
biochemical abnormalities in brain like deficiency of monoamine ( NA ,5-HT) activity
.

4. PATHOPHYSIOLOGY OF ENDOGENOUS DEPRESSION :
Due to deficiency of monoamines in cortical and limbic systems called
monoamine hypothesis (5-HT,NA ,DA)
also explained by Neurotrophic hypothesis .
this hypothesis suggests that certain nerve growth factors like brain derived
Neurotrophic factor (BDNF) ,control neurogenesis .
Loss of neurotrophic effects leads to atrophic changes in certain parts of brain .
associated with depression

5. Anti – depressant drugs / drugs used in affective disorder :
These drugs act by enhancing the monoamines level in brain either
by inhibiting their reuptake or preventing their degradation .
1) Reversible inhibitors of MAO –A (RIMAs)
* Moclobemide * clorgyline
2) Tricyclic anti –depressants (TCAs)
a) predominantly 5-HT reuptake inhibitors :
* Impiramine * Amitryptyline
* Trimipramine * clomipramine
b) predominantly NA reuptake inhibitors :
* Desipramine * Nortriptyline
* Reboxitine

6. 3) Selective Serotonin reuptake inhibitors (SSRIs)
* Fluoxetine * Fluvoxamine
* paroxetine * sertraline
* citalopram * Dapoxetine
4) Serotonin and noradrenaline reuptake inhibitors :
* venlafaxine * Duloxetine
5) Atypical anti-depressants :
* Trazodone * Mianserin
* Mirtazapine * Bupropion

7. TRICYCLIC ANTI-DEPRESSANTS :
MECHANISM OF ACTION :
TCAs block the reuptake of NA and 5-HT into the pre –synaptic
terminals by binding to the transporter ,viz.,serotonin transporter (SERT) ,Nor-epinephrine
transporter (NET) .
Synaptic levels of these monoamines increased and prolong their action on receptors .
cause variable blockade of α1 and to a lesser extent ,pre – synaptic α2 adrenoreceptors
possess central anti-muscarinic properties
TCAs potentiate amine neurotransmission in CNS
Extent of binding and selectivity for SERT and NET varies with each TCA .

8. MAO OF TCA :
80% of NA and 5-HT released into synaptic cleft enters into synaptic neuron
reuptake through SERT ,NET . Reuptake is blocked by TCA .

9. MAO AND ADVERSE EFFECTS OF TCA :

10. PHARMACOKINETICS :
1)ABSORPTION : lipophilic ( tertiary amines ) ,well absorbed from GIT,
cross BBB.
2) DISTRIBUTION : Strongly bound to plasma proteins .e.g. warfarin
3) Metabolism : in liver
phase 1 - gives active metabolite  Nor-triptyline
phase 2 – gives inactive metabolite .
4) EXCRETION : in urine as inactive glucuronides it may take several
days (10-80 hrs ) .
ADVERSE EFFECTS :
* Cardiac arrhythmias ( decrease monoamine uptake )
increase catecholamine activity + bind to Na+ Channels in cardiac membrane
.

11. * Anti- muscarinic action = dry mouth + blurred vision + constipation +
Glaucoma + urine retention .
* α- blockade effect = postural hypotenion
* Anti-histaminic action = sedation + drowsiness
* Delayed ejaculation
SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIs):
Includes fluoxetine ,fluvoxamine are now considered the first line drugs
for drugs for depression .
MECHANISM OF ACTION :
SSRIs inhibits SERT activity
Blocks reuptake of serotonin from synapse into serotonergic nerve endings by
inhibiting serotonin transporter (SERT)

12. about 80% reuptake is inhibited and increased serotonin levels in synapse .
stimulates post- synaptic serotonin receptors
enhance transcription of related proteins
Increased production of BDNF ( Brain –derived Neurotrophic factor or
abineurin , a protein )
This BDNF responsible for the effects of SSRIs
They enhance serotonin levels in synapses
Anti-depressant effect

13. MAO OF SSRIs :
block reuptake of 5-HT and improve serotonergic transmission.

14. PHARMACOKINETICS :
1) Absorption : well absorbed from GIT ,When given orally
2) Metabolism : by Cyt P450
3) Fluoxetine converted to an active metabolite
fluoxetine  Nor-fluoxetine
4) Longer half life than other drugs (7-10 days )
ADVERSE EFFECTS :
* Nausea
* vomiting
* sexual dysfunction (interfere with ejaculation on prolonged use )
* serotonin syndrome
* inhibition of platelet function result in ecchymosis .
* insomnia

15. SEROTONIN NOR-EPINEPHRINE REUPTAKE INHIBITORS ( SNRIs)
MECHANISM OF ACTION :
SNRIs inhibit the reuptake of both 5-HT ,NA at presynaptic neurons
by binding to SERT ,NET like TCAs
Increased level of NA ,5-HT in synapses
Unlike TCA ,SNRIs do not have anti-cholinergic ,α- blocking / anti-histaminic
effects,hence have fewer side effects
SNRIs useful in chronic pain

16. PHARMACOKINETICS :
* Well absorbed and metabolised by Microsomal enzymes .
* short half life
MONOAMINE OXIDASE INHIBITORS ( MAOIs):
MAO is an enzyme which metabolizes NA,5-HT,DA .Drugs which
inhibit this enzyme,enhance the neuronal levels of monoamine like NA,DA,5-HT .
MAO exist as 3 isozymes MAOA , MAOB .
A) MECHANISM OF ACTION OF NON-SELECTIVE ,IRREVERSIBLE MAOAI :
Irreversibly inhibit the enzyme MAO
increase neuronal level of NA,DA,5-HT
anti-depressant effect develop slowly over weeks

17. ADVERSE EFFECTS :
* orthostatic hypotension * anti- cholinergic effects
* Insomnia * weight gain
Abrupt stopping can result in withdrawal syndrome with confusion,
excitement ,psychosis .

18. B) MAO OF REVERSIBLE INHIBITOR OF MAOA (RIMA) :
alternative to TCA
Moclobemide (selective ,reversible ,competitive MAOAI
Effective anti-depressant
Not sedative , does not produce cardiovascular and anti-cholinergic side
effects.
ADVERSE EFFECTS : * Nausea * vomiting
* Headache * liver dysfunction

19. MECHANISM OF ACTION OF MAOB INHIBITORS:
Selegiline /other MAOI
MAO Inhibition
NA,5-HT ,DA escape metabolism
Increased neuronal levels of NA,DA ,5-HT
Anti-depressant effect

20. ATYPICAL ANTI-DEPRESSANTS :
like bupropion act by enhancing monoamine levels in brain either by
inhibiting reuptake /preventing their degradation .
Bupripion (11-14 hrs )
Inhibits NA and lesser extent to DA reuptake
weak anti-depressant
PHARMACOKINETIC :
* Metabolism by liver * active metabolite
ADVERSE EFFECTS :
* Insomnia * anorexia

21. NEWER ANTI-DEPRESSANTS :
SNRIs : * Venlafaxine
* Duloxetine - potent 5-HT ,less potent NA inhibitor .
NARIs : * Reboxetine - selective inhibitor of NA reuptake
5-HT2 antagonist : *Trazadone
* Nefazadone - blocks post –synaptic 5-HT2A and pre-synaptic α2
Miscellaneous : * Bupripion - Inhibits,NA,less extent to DA reuptake ,Weak anti-depressant
* Mirtazapine - as trazadone, high affinity for H2 Receptors .

22. PHARMACOLOGICAL ACTION OF TCA :
1) CNS :
A single dose of 100mg in normal subjects causes drowsiness and
feeling of light headedness .
produce some degree of sedation ,enhance sleep,disrupts obsessive rumination .
drug supresses REM sleep ,increased stage 4 sleep
Repeated administration may produce difficulty in conc. And thinking
Drug has no euphoriant effect and drug dependence is rare
After 2-3 weeks of treatment – elevation of mood occurs

23. 2) CVS :
postural hypotension ,tachycardia (due to blockade of α1-adrenergic and
muscarinic receptors ) ,cardiomyopathy ,heart failure reported in longterm therapy
Imipramine ,amitriptyline may rarely cause inverted/ flattened T wave,
prolongation of QT interval ,depressed ST segment in ECG .
3) ANS :
TCAs have anti-cholinergic properties cause dry mouth ,blurred
vision,constipation ,urinary retention,impotence,rarely hyperpyrexia .
Drug used cautionsly in patients with glaucoma / enlarged prostate .

24. USES :
1)Endogenous depression
2) panic attacks
3) obsessive compulsive disorders (OCD)
4) other anxiety disorders – SSRIs effective in phobias ,post –traumatic stress
disorder .
5) Disorders of pain  SNRIs influence ascending pain pathway, effective in
chronic pain include diabetic neuropathy ,Backache .
6) Psychosomatic disorders  newer anti-depressants  tried to irritable bowel
syndrome
7) Bulimia Nervosa  eating disorders with episodic excess eating  SSRIs

25. 8) Premenstrual syndrome  given SSRI for 2 weeks prior to menstruation  for
women with dysphoria  then cycles repeated .
9) Smoking withdrawal –Bupripion –reduce urge to smoke
10) Nocturnal enuresis  in children treated with anti-depressants
11) Other indications- migraine ,urinary stress incontinence ,chronic alcoholism,
result in depression  anti- depressants given .

26. THANK YOU