Depression is a mental health disorder. Characterized by symptoms like sad mood, loss of interest and pleasure, low energy, worthlessness, guilt, psychomotor retardation or agitation, change in appetite and/ or sleep, melancholia, suicidal thoughts, etc. It may be unipolar (only depression) or bipolar (cycle of mood swings from mania to depression). It is the leading psychiatric disorder. The mood change may have a psychotic basis with delusional thinking or occur in isolation. Antidepresants are the drugs which can elevate mood in depressive illness.

1. Komal Chandra
Assistant Professor (Pharmacology)
Department of Pharmaceutical Sciences, Bhimtal
Kumaun University Nainital

2. *INTRODUCTION
• Depression is a mental health disorder.
• Characterized by symptoms like sad mood, loss of interest
and pleasure, low energy, worthlessness, guilt,
psychomotor retardation or agitation, change in appetite
and/ or sleep, melancholia, suicidal thoughts, etc.
• It may be unipolar (only depression) or bipolar (cycle of
mood swings from mania to depression).
• It is the leading psychiatric disorder.
• The mood change may have a psychotic basis with
delusional thinking or occur in isolation.

3. *ANTIDEPRESSANT DRUGS
These are the drugs which can elevate mood in depressive illness.
Classification:
I. Reversible inhibitors of MAO-A (RIMAs) : Moclobemide, Clorgyline
II. Tricyclic antidepressants (TCAs)
A. NA + 5-HT reuptake inhibitors : Imipramine, Amitriptyline, Trimipramine,
Doxepin, Dothiepin, Clomipramine
B. Predominatly NA reuptake inhibitorsns : Desipramine ,Nortriptyline, Amoxapine,
Reboxetine
III. Selective serotonin reputake inhibitors (SSRIs): Fluoxetine, Fluvoxamine,
Paroxetine, Setraline, Citalopram, Escitalopram, Dapoxetine
IV. Serotonin and noradrenaline reputake inhibitors (SNRIs): Venlafaxine,
Duloxetine
V. Atypical antidepressants: Trazodone, Mianserin, Mirtazapine, Bupropion,
Tianeptine, Amineptine, Atomoxetine

4. Mechanism of action of MAO inhibitors
• A monoaminergic is a chemical which functions to directly modulate
the serotonin, dopamine, nonepinephrine, epinehrine and or histamine
neurotransmitter systems in the brain.
• Monoaminergics include catecholamine (adrenergic and
dopaminergics), serotonergics, and histaminergics.
• Monoamine oxidase (MAO) is a enzyme present in mitochondria of a
cell. They breakdown monoamine and are involved in the oxidative
deamination of biogenic amines (Adr, NA, DA, 5-HT) and leads to
inactivation of monoamine neurotransmitters.

5. • MAO is of two forms:
A.MAO-A : Preferentially deaminates 5-HT and NA, and is inhibited by
clorgyline
B.MAO-B: Preferentially deaminates phenylethylamine and is inhibited by
selegiline.
• Dopamine is degraded equally by both isoenzymes.
• In depression monoamine oxidase enzyme is overexpressed than in normal
condition and leads to deficiency of monoamines such as norepinephrine,
serotonin, dopamine etc. as it breakdowns them. Due to which inactivation
of monoamine neurotransmission also occur.
MAO inhibitors inhibit monoamine oxidase enzyme due to which monoamine
deficiency can be restored and depression can be cured. MAO inhibitors are
also known as first generation antidepressants.

6. Reversible inhibitors of MAO-A(RIMAs)
Moclobemide:
It is reversible and selective MAO-A inhibitor with short duration of
action; full MAO activity is restored within 1-2 days of stopping the
drug.
Inhibition due to moclobemide leads to a decrease in the metabolism
and destruction of monoamines in the neurotransmitters. This results in
an increase in the monoamines, relieving depressive symptoms.

7. It lacks various adverse effects which occur due to tricyclic
antidepressants (TCAs) therefore clinically it is an efficacious
antidepressant comparable to TCAs. Good option for elderly and heart
disease patients.
Dose: 150 mg BD-TDS (max 600mg/day).
Adverse effects: Nausea, dizziness, headache, insomnia, rare
excitement and liver damage.

8. Tricyclic antidepressants (ACAs) : These are the older compounds
congeners of Imipramine an analogue of chlorpromazine which inhibit
NA and 5-HT reuptake into neurones. Imipramine was found to be
selectively benefit in depression during clinical trials in 1958.
Mechanism of action: TCAs and related drug inhibit NET
(Norepinephrine transporter) and SERT(Serotonin transporter) which
mediate active reuptake of biogenic amines NA and 5-HT and thus
potentiate them. Due to which there is increased concentration of the
amines in the synaptic cleft in both CNS and periphery.

9. Adverse effects: Anticholinergic (dry mouth, bad taste, constipation
etc.), sedation, mental confusion, weakness, increased appetite, weight
gain, sweating, sexual distress, cardiac arrhythmias, rashes, jaundice etc.
Acute poisoning: poisoning with TCAs is frequent, usually self-
attempted by the depressed patient and may endanger life.
Manifestations are excitement, delirium and other anticholinergic
symptoms as seen in atropine poisoning, followed by muscle spasm,
convulsion and coma. Respiration is depressed , body temperature may
fall, BP is low etc. Treatment: gastric lavage, respiration assistance, fluid
infusion, maintenance of BP and body temperature. Acidosis must be
corrected by bicarbonate infusion.

10. TCAs:
Amoxapine: It has antidepressants + neuroleptic properties as it also
block D2 receptor and offers advantage for patients with psychotic
depression. Seizures occur in overdose.
Reboxetine: It blocks NA reuptake and has weak effect on 5-HT
reuptake. Usal side effects are insomnia, sexual distress and urinary
symptoms. Dose: 4mg BD or 8mg OD.

11. These are also second generation antidepressants that have a
selective action on amine uptake and inhibit noradrenaline
reuptake and therefore are known as selective noradrenaline
reuptake inhibitors (SNRIs).
Venlafaxine: It inhibits both NA and 5-HT. It has faster onset
of action. Do not produce side effects as TCAs but prominent
side effects are nausea, sweating, anxiety, dizziness etc. Used
in mood changes, anxiety, eating disorders etc.
Duloxetine: A newer SNRIs similar to venlafaxine neither
sedative, nor anticholinergic nor antihistaminics nor α
blockers. Side effects include g.i. and sexual problems,
imsomnia, rise in BP etc.
*Serotonin and noradrenaline reuptake
inhibitors (SNRIs)

12. * SELECTIVE SEOTONIN REUPTAKE INHIBITORS
First generation antidepressants (TCAs) major limitations are:
• Frequent anticholinergic, cardiovascular and neurological
side effects.
• Low safety margin.
• Antidepressants actions manifests after 2-4 weeks.
• Significant n.o of patient respond incompletely and some
do not respond.
They are second generation antidepressants that have a
selective action on amine uptake and inhibit serotonin
reuptake and therefore are known as selective serotonin
reuptake inhibitors (SSRIs). Due to their relative safety and
better acceptability they are first line drug in depression.

13. *SSRIs
Fluxetine:
First SSRIs and longest acting (t1/2 2 days). Its action is slowest
therefore it is not suitable for patient needed rapid effect. It is approved
for children of age 7 or above but it should be used only when
psychotherapy fails.
Fluvoxamine:
It is shorter acting SSRI (t1/2 18 hrs) and do not produce active
metabolite due to which it is used in anxiety and obsessive compulsive
disorder(OSD) rather than for depression. Relative more nausea,
nervousness, discontinuation reactions etc has been reported with its use.
Paroxetine:
Another short acting (t1/2 20 hrs) which does not produce active
metabolite. A higher incidence of g.i. side effects, sexual distress,
agitation etc. has been noted.

14. *SSRIs
Sertraline: It produces longer-lasting active metabolite and its t1/2 is 26
hrs. Recommended for anxiety and post-traumatic stress disorder and
causes less drug interactions.
Citalopram: Cause less interactions and its t ½ is 33 hours. It produce
no active metabolite. Deaths has been recorder due to its overdose hence
it is to be avoided in patients likely to attempt suicide. It is preferred in
mood disorders in premenstrual syndrome.
Dapoxeine: Used to promote delaying premature ejaculation. It acts
rapidly and when combined with behavioural therapy help many
sufferers. Side effects are nausea, vomiting, loose motions, headache etc.
Dose: 60 mg taken 1 hour before sexual intercourse; older patients 30
mg.
Other uses: 1st choice of drugs for OCD, panic disorder, social phobia,
eating disorders etc.

15. *ATYPICALANTIDEPRESSANTS
Trazodone: Less efficiently blocks 5-HT uptake and has
prominent α adrenergic and weak 5-HT2 antagonistic actions
(which is responsible for its antidepressant effect). It is
beneficial in OCD but in depression its use is infrequent.
Mianserin: It blocks presynaptic α2 receptors and thereby
increase release and turnover of NA in brain which may be
responsible for its antidepressant effects. It is a sedative-
relieves associated anxiety and suppress panic attacks.
Mirtazapine: It blocks α2 auto (present on NA neurones) and
hetero (on 5-HT neurones) receptors enhancing both NA and
5-HT release. Efficacy is similar to TCAs in depression.

16. *Bupropion: It is metabolized into an amphetamine like
compound which can cause presynaptic release of DA and
NA. Sustained release formulations is marketed with aid of
smoking cessation. It has infrequent use in depression.
*Tianeptine: Efficacious in anxiodepressive states. Side
effects are dry mouth, epigastric pain, tremor, bodyache etc.
Dose 12.5mg BD-TDS.
Uses:
•Obsessive compulsive and phobic states: Characterized by
unreasonable thoughts and fears that leads to compulsive
behaviours. Preferred drug fluxamine and clomipramine.
•Endogenous (major) depression: It is mood disorder
characterized by persistent and intense feeling of sadness for
extended period of time. SSRIs are first choice of drug with
TCAs as alternatives.
•Anxiety disorders: SSRIs are used with BZDs.

17.  Enuresis (involuntary urination especially by children at night) :
Imipramine 25 mg at bedtime is effective but bed wetting may again
starts when the drug is stopped.
Attention deficit-hyperactivity disorder in children: Prefered drug
TCAs.
Others uses of antidepressants drugs are in premature ejaculation,
migraine, neuropathic pain etc.

18. *