ANTI-DEPRESSANT

DRUGS

DR.SUKANTA SEN
Professor
Deptt. of Pharmacology
 What is depression?
 Depression is characterised by feeling of sadness,
despair, mental slowing, loss of concentration,
pessimistic worry, lack of pleasure, self-
depreciation, variable agitation, insomnia, anorexia or
over eating, depressed energy, depressed libido,
endocrine abnormality etc.
 Two major types of Depression:

 Unipolar(80% cases)-in which the mood swing in

one direction only.
 Bipolar (20% cases)-or manic depressive
psychosis,(MDP)-------
characterized by cyclic manifestations of depression
followed by mania.

 Monoamine hypothesis of endogenous depression-

Depression is caused by a functional deficit of
biogenic amines NE and/or 5-HT,at certain sites of
brain.
 Mania results from functional excess of these
neurotransmitters
 Other mechanisms for depression-------
i) Down regulation of β1, β2 and α2 as well 5-
HT2 receptors.

ii) Neuro-endocrine abnormalities

Monoamine Hypothesis of Depression
 Proposes that depression results from a CNS
deficiency of monoamine (noradrenergic and/or
serotoninergic, 5-HT) function. Although probably
simplistic it has provided a loose 'unifying' theme for
effective antidepressants (ADs) that work by:
 increasing monoamine synthesis (L-tryptophan)

 preventing reuptake of monoamines (tricyclics and

SSRIs)
 preventing breakdown of monoamines (MAOIs)
 BUT fails to explain the action of most of the
newer ‘atypical’ antidepressants e.g.
 Mianserin (may act via central alpha2
receptors)
 Tianeptine (actually enhances 5-HT uptake)

 Trazodone (effective through its metabolite,

mCPP, a 5-HT1A agonist ?)
 CLASSIFICATION OF ANTI-DEPRESSANT DRUGS

 Drugs which block both NE and 5-HT reuptake:

Imipramine,clomipramine,amitryptyline, doxepin

 Drugs which mainly block NE reuptake:

Desipramine, nortriptyline, protriptyline, maprotiline,amoxapine,
lofepramine

 Selective Serotonin reuptake inhibitors (SSRIs):

Sertraline, fluoxetine, fluvoxamine, paroxetine, citalopram.

 Atypical anti-depressants:
Trazodone, nefazodone,bupropion,mirtazapine,mianserin, venlafaxine.

 Antidepressants of natural origin :

St. john’s wart(active principle: hyperforin)
 MAO Inhibitors :
a) Non-selective MAO-A and MAO-B inhibitors—Tranylcypromine
b) Selective MAO-A inhibitors—Moclobemide.
 Tricyclic Antidepressants (TCA):
Mechanism of action

•prevent reuptake of noradrenaline and 5-HT into neuronal stores

•selectivity ratio varies widely (desipramine relatively NA-selective <->
chlorimipramine relatively 5-HT selective)
•onset of action is delayed for 7-14 days possibly due to down
regulation of presynaptic 5-HT and/or alpha2 receptors.
Adverse effects

1)antimuscarinic effects: dry mouth, blurred vision,

constipation and urinary retention
2)postural hypotension (through alpha1 blockade)
3) precipitation of fits (lower seizure thresholds)
4) risk of sudden cardiac death in patients with
myocardial disease*
5) weight gain & sexual disturbances(< SSRIs)
6) sedation
7) they are also frequently fatal in overdose (through
quinidine-like actions on the conduction system).
In the presence of cardiac disease SSRIs are safer
(lofepramine probably the safest TCA).
Significant interactions

 serious interaction with MAOIs

 potentiation of catecholamines and

sympathomimetics (not beta2 agonists)

 potentiates action of methyldopa, other

antihypertensives are safe
 Other nice indications

 nocturnal enuresis in children

 chronic pain syndromes

 pathological laughing and weeping with forebrain disease

 Reboxitine was recently licensed and classified as a

‘noradrenaline re-uptake inhibitor’ (NSRI). It is best
thought of as a TCA without 5HT reuptake inhibition even at
high therapeutic doses.


2. Selective Serotonin Reuptake Inhibitors (SSRIs) e.g. fluoxetine

Mechanism:

prevents reuptake of 5-HT into neuronal stores

 minimal effect on noradrenaline re-uptake at therapeutic doses

Compared with TCAs:

 no evidence of improved efficacy (TCAs may be slightly better)

 safe in overdose

 safer in cardiovascular disease

 original concerns that they might increase suicide risk has

not been substantiated

 less likely to cause weight gain

Adverse effects
Main side-effect is nausea by potentiation of 5-HT action in
CTZ/vomiting centre (remember 5HT3 receptor antagonists
are potent antiemetic agents).
Drug interactions:
SSRIs with MAOIs result in elevated levels of 5-HT in the
synaptic cleft leading to “Serotonin syndrome” characterized
by hyperthermia ,muscle rigidity, tremors, rapid changes
in mental status and cardiovascular collapse.
Higher levels of 5-HT in the synaptic cleft is a combined
effect of--------
(a) reduced metabolism,

(b) inhibited uptake &

(c) pronounced release of 5-HT.
3. Monoamine Oxidase Inhibitors
 Classified as either

 Hydrazines - phenelzine

 Nonhydrazines - tranylcypromine, moclobemide, selegeline

(anti-Parkinsonian)
 Mechanism
Irreversible inactivation of MAO (moclobemide the
exception: its effect is reversible). Note there are 2 isoforms
(MAO-A and MAO-B) and most inhibitors used as
antidepressants are non-selective.
 MAO-A preferentially metabolizes 5-HT & NE.

 MAO-B preferentially deaminates phenylethylamine.

 The non-hydrazines (especially tranylcypromine) have a

significant indirect sympathomimetic action c.f. amphetamine.
Tranylcypromine is a long acting,nonselective ,irreversible MAOI.
Selegiline selectively inhibits MAO-B at lower doses(5-10mg) and is
not effective in treating depresion.

In higher doses ,it becomes non-selective MAOI to exhibit antidepressant and

excitant effects and the adverse effects limit its use.
Moclobemide is a selective & irreversible inhibitor of MAO-A.
Adverse effects
1) Postural hypotension
2) Weight gain
3) Dizziness
4) Sexual dysfunction
5) Less common-headache,insomnia,fatigue,constipation,blurred vision,
6) peripheral edema
Drug interactions:

Well known 'cheese reaction' following ingestion of

tyramine-rich foods (e.g. cheese, yogurt, beer and red

wine) and sympathomimetics (e.g. pseudoephedrine in

OTC 'cold remedies') .

•In the presence of MAOI, tyramine (normally subject to
extensive first-pass) escapes degradation, reaches into systemic
circulation, uptaken by adrenergic neuron and since neuronal
MAO is also inhibited, tyramine also escapes deamination.
•Ultimately it enters the storage vesicles and displaces large
quantities of NE leading to hypertensive crisis.

Indications

•failure of TCA and SSRI

•atypical depression
•hypochondriacal features
•resistant phobic states
Atypical Anti-depressants:
Trazodone -inhibits uptake of 5-HT,causes desensitization of α2-adrenergic and
5-HT autoreceptors.
-also significantly blocks H1 &α1 responsible for sedative effects,postural hypotension
and priapism.

Nefazodone-a congener of trazodone with lesser S/E & better tolerability.

Mianserin- blocks presynaptic α2 receptors and thus increases the release of NE in

brain,but does not effect NE/5-HT reuptake in CNS.

Mirtazapine- acts by blocking presynaptic α2 autoreceptors & 5HT1 heteroreceptors on

noradrenergic neurons, as well as 5HT1 autoreceptors & α2 heteroreceptors on 5-HT
neurons to enhance both NE/5-HT release.

Venlafaxine- increases NE/5-HT & to some extent DA levels in synaptic cleft

But does not interact with cholinergic ,adrenergic or histaminergic receptors.
Bupropion-structurally different,is a weak inhibitor of neural reuptake of NE/5-HT
& DA.

Natural Antidepressants-
St. John’s wort(Hypericum perforatum)-herbal origin,
active substance-hyperforin ,is a monoamine reuptake inhibitor,mild
MAOI
& a stimulant at GABA receptors.
It is potent enzyme inducer.
Therapeutic Uses:

1) Psychiatic uses: for endogenous depression-psychotherapy,pharmacotherapy & ECT.

Pharmacotherapy for three phases-acute phase, continuation phase & maintenance phase.
Drug selection-
 if anti-cholinergic effects to be avoided then SSRI, trazodone.
 If cardiotoxicity is to be avoided then lofepramine or mianserin.
 If wishes to avoid wt. gain- SSRIs not suitable. bupripion or
mirtazapine or nefazodone can be used.
 MAOIs –tranylcypromine or moclobemide preferred for resistant

cases.
Changing and Stopping Antidepressants:
Should be cross tapered, i.e., the doses of new drug should be
gradually increased and that of substituted drug must be decreased.
TCAs and SSRIs should not be introduced until 2-3 weeks
have elapsed from discontinution of MAOI like tranylcypromine.
Similarly, MAOIs cannot safely be introduced within 3 weeks
of stopping SSRIs and TCAs.
2) Panic Disorders- SSRIs (paroxetine and fluoxetine) alone or with
alprazolam.
3) Obsessive compulsive disorders (OCDs)- SSRIs (preferably
fluvoxamine),clomipramine.
4) Attention deficit hyperkinetic disorders(ADHD)- Imipramine,
desipramine (preferred)
5) School phobia, post-traumatic stress disorder and Impulse
control disorders- for school phobia & social phobia- SSRIs. For
post-traumatic stress disorder – paroxetine with alprazolam.
Non-Psychiatric Uses-
1) Enuresis and bed-wetting in children- antidepressants with
anticholinergic S/Es –amitriptyline, desipramine and imipramine are
preferred.
2) Chronic neuropathic pain- imipramine , amitriptyline
or nortriptyline
3) Migraine –TCAs like amitriptyline
4) Miscellaneous uses- atopic dermatitis, bulimia nervosa
(fluvoxamine and fluoxetine), smoking cessation (bupropion)
ANTIMANIC (Mood stabilizing) Drugs Lithium
Carbonate:
Mania is characterized by excessive desire and too
much of euphoria.
Mechanism:
Lithium is a monovalent cation like Na+ or K+.
 Normally ,IP3 and DAG serve as second messengers for α-adrenergic
and muscarinic neurotransmission.
In mania the neuronal circuits become overactive and start producing
more IP3 & DAG, & in turn inositol, to provide a regular supply of PIP2.
Lithium selectively inhibits neuronal transduction in overactive
neurons by blocking the conversion of IP2 to IP1 and of IP1 to inositol.
As a result the supply of free inositol to regenerate PIP2,in the
hyperactive neurons, is interrupted and ultimately the release of IP3 &
DAG is also reduced.
 Lithium also may affect a specific isoform of protein-kinase-C(PKC).
PK:

Readily absorbed from GIT, distributed ECF,

No PPBs, no metabolism

Elimination t1/2 is 24 hrs, excreted kidneys(96%),

saliva & sweat (4%) as well

Narrow therapeutic window(0.8-1.4mEq/L).

Therapeutic plasma levels(0.8-1.4 mEq/L) while (0.5-1mEq/L) are
optimum for maintenanceToxicity if serum level exceed 1.5mEq/L.

Therapeutic Uses:

1) control of mania
2) FIRST LINE THERAPY FOR BIPOLAR
DISEASES
3) prophylaxis of manic-depressive disorder
4) Other uses--- to increase leucocytes count in cancer
chemotherapy induced leukopenia and agranulocytosis.
5) To treat cluster headache.
•Adverse effects
Its use is complicated by its narrow therapeutic index
•Fine tremors & slurred speech
•Diarrhoea, oedema (d/t Na+ retention)
•Other chronic effects include: nephrogenic diabetes
insipidus,
•Renal cellular injury with prolonged use (>5yrs) and
subclinical hypothyroidism by inhibition of TSH-
activated adenyl cyclase.
Drug interactions:
1)Thiazide or loop diuretics, by causing Na+ loss, promote
tubular reabsorption of Li+ producing a rise in Li+ plasma
levels & toxicity.

2) Li+ enhances insulin/sulfonylurea induced hypoglycemia

Alternative drugs to lithium:
1) Valproic acid
2) Carbamazepine
3) Newer anti-convulsants-
a) lamotrigine
b) gabapentin
c) topiramate
4) Atypical antipsychotics- olanzapine, risperidone.