ANTIDEPRESSANTS

PM Dr Win Maw
Mental Depression: mood disorder; affective disorder
May be: - Neurotic: e.g. reactive depression (grief)
- Psychotic: e.g. melancholia (endogenous depression).
- may be - unipolar
- bipolar (manic depressive psychosis)
Feature: - diverse signs & symptoms
- many contributing factors (history)
- may be associated ith an!iety (neurosis)
Treatment: - different drug groups for neurosis and psychosis
- may be very difficult to differentiate - thin red line (patient may not give
true history due to shyness" secrecy etc)
Biochemical Theor o! Depression:
- depression due to deficiency of monoaminergic (noradrenaline" dopamine" serotonin
#-$%) systems in limbic system.
"hoice o! Dru#s:
A$ Se%ati&es' anti-an(iet a#ents: e.g. ben&odia&epines ('eparate (ecture)
- mild" neurotic depression" esp. ith an!iety. 'hort-term for acute onset.
- not effective for long-term treatment of psychotic depression
B$ Anti%epressants:
- for psychotic depression" severe neurotic depression; long-term treatment.
"lassi!ication o! Anti%epressants
I$ Tricclic Anti%epressants )T"A*
II$ Monoamine +(i%ase Inhi,itors )MA+I*
III' Speci!ic Serotonin Reupta-e Inhi,itors )SSRI*
I.$ Atpical Anti%epressants
/eneral principles: ) all anti%epressants*
- Practically all antidepressants affect monoaminergic transmission in the brain in
one ay or the other; and many of them have other associated properties.
- %here is little to choose beteen different classes of antidepressants in terms of
efficacy" so choice should be based on the individual patient)s re*uirements (e.g.
suicide ris+" concomitant disease" previous drugs" etc)
- ,n interval of - ee+s before the antidepressant action ta+es place
- .rug %herapy: - revieed every / 0 - ee+s at start
- continued for at least 1 ee+s (2 ee+s in elderly) before
contemplating sitch
- folloing remission" continue same dose for at least 2 months
(/- for elderly" - years for recurrent depression)
- ithdraal symptoms if stopped suddenly after 3 ee+s or more"
(physical dependence); needs tailing off (1 ee+s or longer)
- at least - ee+s gap in-beteen" hen sitching drugs
I$ Tricclic Anti%epressants )0eterocclic*
- similar to phenothia&ines in chemical structure. Neer preparations may contain one to
four rings" hence heterocyclic 4T"A an% relate% %ru#s1
- inhibit active upta+e of biogenic amines noradrenaline and #-$% into their
respective neurons" increasing their concentration in the synaptic cleft in the 5N'
and periphery.
- 6nhibition of N, and #-$% upta+e is associated ith antidepressant action
- 6ndirectly facilitate dopaminergic transmission stimulant action
- 7hile bloc+ade occurs *uic+ly" antidepressant action develops after ee+s
- may be classified into those ith:
(a) Mar+ed sedation: suitable for an!ious and agitated patients.
- amitriptyline - clomipramine
- trimepramine -dothiepin
- do!epin
(b) (ess sedation: suitable for ithdran and apathetic patient
- imipramine - desipramine
- nortriptyline - amo!apine
Pharmacolo#ical actions:
"NS: - mood elevation of depressed patients )2se*3 may e!tend to e!citement"
hypomania" mania ith sufficient dose; agitation"sei&ures )2nt*
- no mood elevation or euphoria" but causes an!iety in normal persons.
- loers sei&ure threshold" convulsions in overdose )2nt*
- respiratory depression ith overdose )2nt*
ANS: - anticholinergic action atropine-li+e effects )2nt*
- potentiates e!ogenous & endogenous noradrenaline" sympathomimetics )2nt*
".S: - orthostatic hypotension" sinus tachycardia; arrhythmias and cardiac conduction
defect ith overdose )2nt*
II$ Monoamine o(i%ase inhi,itors )MA+I*
- M,8s : en&ymes involved in deamination (degradation) of monoamines hich include
N, and #-$%
- %o sub-types: M,8-," preferentially deaminates #-$% and N,
M,8-9" preferentially deaminates phenylethylamine
)a* Nonselecti&e MA+Is
- inactivate the en&ymes irreversibly
- mood elevation in both normal and depressed patient
- effects last --: ee+s after discontinuation
- Status: much less fre*uently used" because of
(i) 6nteractions:
- 4cheese reaction; ith food containing tyramine" dopamine etc." - cheese"
beer" ines" pic+led meat and fish" yeast e!tract hypertensive crisis
- ith %5,s severe to!icity resembling atropine poisoning
- ith many others including: cold & cough remedies" antipar+insonian
drugs" pethidine" reserpine" guanethidine etc. synergistic" adverse
interactions
(ii) <ntoard effects (adverse reactions)" hich include: 5N' stimulation"
anticholinergic effects" loered convulsive threshold" eight gain" and
hepatoto!icity.
- Preparations: Phenel&ine" isocarbo!a&ide (drugs of choice);
tranylcypromine (most ha&ardous); selegiline" ipronia&id.
),* Selecti&e MA+Is: Meclo,emi%e
- inhibits M,8-, selectively and reversibly
- effective antidepressant" e!cept in severe cases
- lac+s anticholinergic" sedative" psychomotor and cardiaovascular adverse effects
of typical %5,s
- short duration; M,8 activity restored ithin /-- days
- Status: ell tolerated alternative to %5,s in mild to moderate depression;
especially suitable for elderly patients and those ith heart disease.
III$ Selecti&e Serotonin Reupta-e Inhi,itors )SSRI*
- overall antidepressant efficacy similar to %5," less efficacious in more severe
depression
- no significant pharmacodynamic difference" but some pharmaco+inetic
differences among preparations
- in general" ''=6s D+ N+T:
- produce anticholinergic side-effects
- cause postural hypotension" or inhibit cardiac conduction
- precipitate sei&ures
- interfere ith cognitive and psychomotor functions" or cause sedation
- cause eight gain; food and drug interactions
- .isadvantages:
- Mild side-effects: nervousness" restlessness" insomnia" anore!ia" headache"
diarrhoea
- 6mpair performance of s+illed tas+s" e.g. driving; se!ual dysfunctions
- 6nhibit drug metaboli&ing en&ymes pharmaco+inetic interactions
- May produce ithdraal symptoms needs tailing off
- Status: better tolerated and safer in overdose than other classes" should be
considered first-line drugs for treating depression.
- Preparations:
Fluo(etine$ 0 sloer onset" longest acting. 5auses more agitation and
dermatological reactions than other ''=6s.
Flu&o(amine' Paro(etine$ 0 short-acting" no active metabolite. $igher incidence of
gastrointestinal side-effects.
Sertraline$ 0 produces longer-lasting active metabolite. (ess en&yme inhibition.
"italopram$ 0 longer acting" but no active metabolite. (ess drug interactions.
I.$ Atpical Anti%epressants:
)a* Serotonin mo%ulators
- primarily bloc+ #-$%
-
receptor; inhibit #-$% reupta+e
- have antidepressant and an!iolytic effects" but no se!ual dysfunction
Ne!a4o%one$ 5 does not suppress =>M sleep
- interferes ith drug metaboli&ing en&ymes
- associated ith liver failure
Tra4o%one. 0 does not inhibit #-$% reupta+e
- alpha
/
bloc+ade orthostatic hypotension
- very sedating
Mirta4apine$ 5 inhibits #-$% reupta+e
- bloc+s
-
adrenergic" #-$%
-" :
receptors
- - more efficient serotogenic function" increased noradrenergic function
- no cardiac side-effect" no se!ual dysfuntion; minimal action on drug
metaboli&ing en&ymes
- sedation and eight gain" due to $
/
bloc+ade
),* Serotonin-NA reupta-e inhi,itor$ .enla!a(ine' Dulo(etine
- inhibits reupta+e of N, and #-$% (li+e %5,s)
- to!icity li+e ''=6: nausea; no action on drug metaboli&ing en&ymes
- ithdraal symptoms can occur
- for patients ith severe or refractory depression
)c* Dopamine-norepinephrine reupta-e inhi,itor$
- do not affect #-$% system
- favourably influence catecholaminergic" dopaminergic functions by uncertain
mechanism
- Bupropion' the only preparation" is useful for depression ith ,.$." cocaine
dependence" or those trying to stop smo+ing.