Dru gs Used in Men tal Illness:

chapter 33 Ant idep ress ant and

Ant ianx iety Drugs

''l'~-,,il, n and mania are two extreme s• of a psychot ic basis with delusion al thinking or
, 1:11,' r 'i' ,. , __ . ~
,.;,:,.11 n: J isordt-rs which reter to a patholog ical occur in isolation and induce anxiety. On the
~~i,;inf(' in the mood state. Ma!·or depression other hand, patholog ical anxiety may lead to
,~ , h:u-:tl·tcri zed by symptom s hke sad mood, depress ion . Anxiety and depress ion are the
l,f interest and pleasur e. low energy, leading psychiat ric disorder s now.
1,, !-!'
",,rt.h kssness. gu iIt. psychom otor retardat ion
,,r "=- ·t·..•tion . change
a(, 1
- in appetite and/or sleep, ANTIDEPRESSANTS
md!lllch0lia. suicidal thought s, etc. It may be a
unipolar or a bipolar cyclic disorder in which These are drugs which can elevate mood in
.:-n.·les of mood swings from mania to depressi on depressi ve illness. Practica lly all antidepr essants
,~-cur over time. The mood change may have affect monoam inergic transmis sion in the brain

ANTIDEPRESSANTS
I

l I I I
Selective serotonin Atypical
Reversible inhibitors
reuptake inhibitors (SSRls) antidepressants
of MAO-A (RIMAs)
Trazodon e
Moclobemide Fluoxetine Mianseri n
Clorgyline Fluvoxamine Mirtazapine
Paroxetine Bupropion
Sertraline Amoxapine
Citalopra m Tianeptine
Escitalopram Amineptine
Dapoxetine

j Tricycllc antidepressants (TCAs) I Serotonin and noradrenaline

I reuptake inhibitors (SNRls)
I
I I
NA + 5-HT reuptake
inhibitors
Predomi nantly NA
reuptake Inhibitors
Venlafaxine
I Desvenlafaxine
I Duloxetine
lmipram ine Desipram ine
Amitript yline Nortripty line
Trimiprarnine Reboxetine
Doxepin
Dothiepi n
Clomipra mine

other drugs like Protriptyline, Maprotiline, Nafazodone, etc. are marketed in other
countries.
M.any
 DRUGS ACTING ON CENTRAL NERVOUS SYSTEM I
482

111
one way or the other, and many of them
barhituratcs and opioids arc Polcntiafcd
- ---------
respiratory failure. Pethidine admini stered'~~ rn~y c'IJ\t
!~
.
have other associate d prope rties · Over the past
. patients has produ ce~ fever, sweating, cxcitat:°'0 inh~
des
tI1ree deca , '
a large number of antidepressan
k ; ta
ts convul sions _and . respiratory depression. The '°"•
dc:lrrin.,~
with an assortment of effects on reupta e me - thi s intcra~tio_n . 1s : IJle<.:han~ ,~
MAO mh1b1tors retard hydrolysis of nt>tL · •
boli sm of biogenic amines, and on pre/post- .
its demet hy Iat1on.
. Th .•
us, excess ,.,..u11d1ne 1..-
of norpeth 'd• '1\11 r.A
junctional aminergic/cholinergic recept~rs h~ve •
a minor metabolite-see p. 503 ) is produced _>rrrtaJi.
I tne (11(
1
become available so that a cogent class1ficat1on excitatory actions. wt11ch ~
is difficult. A working classification has been The selective MAO-A inhibitors possess anr
property. Selegiline at low doses (5- 10 mg/day) ~~
presented above.
inhibits MA0-8, but these doses are not cffi . ~c1-,
. I .. .
depression. Se eg1 1me 1s meta bo 11zed .
to amph..i-·
Cct1 ve ~

MAO INHIBITORS . b w ... 11,1ne ar.i

at higher doses 1t ecomes nonselective MAO inh'bi .
MAO is a mitochondrial enzyme involved in the oxidative such doses ex h1'b'1t anti'd epressant an d excitanl pr~ I l(x
therefore not clinically useful. ·
deamination of biogenic amines (Adr, NA, DA, 5-HT). Two
isoenzyme forms of MAO have been identified.
Dopamine is degraded equally by both isoenzymes. Reversible inhibitors of MAO-A (RIMAs)
MAO-A: Preferentially deaminates 5-HT and NA, and
Moclobemide It is a reversible and selective
1s inhibited by clorgyline, moclobemide.
MAO-B: Preferentially deaminates phenylethylamin e MAO-A inhibitor with short duration of action;
and is inhibited by selegiline. full MAO activity is restored within 1-2 days
Distribution of MAO-A and MAO-B also differs. of stopping the drug. Because of competitive
Peripheral adrenergic nerve endings, intestinal mucosa and
human placenta contain predominantly MAO-A, while
enzyme inhibition, tyramine is able to displace it
MAO-B predominates in certain areas (mainly serotonergic) from the enzyme, so that potentiation of pressor
of brain and in platelets. Liver contains both isoenzymes. response to ingested amines is insignificant, and
Two hydrazine drugs-isoniazid and iproniazid were dietary restrictions are not required. Clinical trials
used for tuberculosis in 1951; the latter was found to
cause disproportionate elevation of mood. Its capacity to
have shown moclobemide to be an efficacious
inhibit degradation of biogenic amines was soon discovered antidepressant, except in severe cases. It lacks the
and was believed to be responsible for the mood elevat- anticholinergic, sedative, cognitive, psycho~
ing action. Its less hepatotoxic congeners like phenelzine and cardiovascul ar adverse effects of typical
and isocarboxazid and some nonhydrazine MAO inhibitors
(related to amphetamine) like tranylcypromine were used
TCAs and is safer in overdose. This makes
as antid epressants in the l 960s. They inhibited MAO it an alternative option in elderly patients and
irreversibly and were nonselective for the two isoforms. in those with heart disease.
Because of high toxicity and interaction with foods and Dose: 150 mg BD--TDS (max 600 mg/day)
• other drugs, they have become unpopular. RIMAREX, TRIMA 150, 300 mg tabs.
. · ss ea
h d-
These MAO inhibitors frequently produce postural
h ypotensi on , restlessness, insomnia and interfere with
Adverse effects are nausea, dizzme d r ver
ache, insomnia rarely excitement an th1 er
~exual function (impotence, loss of libido, anorgasmia). ' · with o
Mure importantly they interact with many foods and drugs. damage. Chances of interact10n . n is
• Cheese reaction Certain varieties of cheese, beer drugs and alcohol are remote, b~ t . cauuo
ssRls
wines, pickled meat and fish, yeast extract contain Iarg; advised while coprescribing pethidine,
quantities of tyramine, dopa, etc. In MAO inhibited
patients these indirectly acting sympathomimetic amines
and TCAs. . I bobia.
esca~ de~adation in the intestinal wall and liver ➔ Moclobemide is also useful in socia p
reachmg mto systemic circulation they di splace and
release l~rge amounts of NA from transmitter loaded (TCAs)
adrenerg1c nerve endings ➔ hypertensive crisis, cere-
TRICYCLIC ANTIDEPRESSANTS
brovascular accidents. aiioe
lmipramine an analogue of c h)orprol11 . Is (J 958
)
~:s. Simil~ reacti~n can occur with cough and cold rem-
~h 1~ . con~~n ephedrine or similar drugs, as well as
~1 1r1_cyc _1c anti epressanis, SSRl s, SNRJs and levodopa.
(CPZ) was 'found durmg • • • J tria
chnica
lo selectively benefit depresse d but no
. ed
t 3g1tst
· d
. inhib1te
a 11 uc1~tha t1o~shal~d at_ropi nt! poisonin g like sympto ms
occur w1 antlc o merg.ics. Alcohol, lledative-antihista minics,
psychotics. In contrast to CPZ, it A Jarge
. urones.
NA and 5-HT reuptake mto ne
 ANTIDEPRESSANT AND ANTIANXIETY DRUGS
483
weeks of continuous treatment , the mood 1,

~ CH Ct-t,CH 2N,
; CH,
gradually elevated, patien Lc, hecomc more com-
municative and start taking interest in self and
surroundings. Thus, TCA s are not cuphorient<;
2 "~
but only antidepressants. In depressed patienlc;
IMIPRAMINE
who have preponderance of REM sleep, thi s
rs were soon added and phase is suppressed and awakenings durin g
f congen e . .
O night are reduced. The EEG effects of low
n11n1t,cr ther are ca lied tricycl1c anlldepressants
h
th 6 ' wge addition to uptake bloc_kade, t ese doses are similar to hypnotics but high doses
,f(.451- In d mpounds have d1rect effects cause desynchronization . Sedative property
d ,elope co . h' . . varies among different compounds (see Table
,arlY e ic cholinerg1c and 1stammerg1c
,n adrenergd ' referred to as 'first generation 33.1 ). The more sedative ones are suitable for
l an are
r,ceptors, ' depressed patients showing anxiety and agitation.
d ·essants • d The less sedative or stimulant ones are better
0111i epi ntly produced secon genera-
Th e ~~~ nts have more selective . .
action for withdrawn and retarded patients.
ti depress a .
1io 11 an ke· are either Selective serotonin The TCAs lower seizure threshold and pro-
amine upta ' . d duce convulsions in overdose. Clomipramine and
on . h·b·rors tSSRls), or Serotonin an
iake in I I I' . h
bupropion have the highest seizure precipitating
,-eup 1. reuptake inhibitors. (SNRls) wit. I
adrena1ne potential. Respiration is depressed in overdose only.
nor .
direct acti· on on cholinerg1c/adrenerg1c.
no . ergic receptors, or have some atyp1- Mechanism of antidepressant action The
h1sramrn 1· · d t f
cal features. They . have a .1m1te spec rum o TCAs and related drugs inhibit NET and SERT
. resulting m fewer side effects.
acuon which mediate active reuptake of biogenic
amines NA and 5-HT into their respective
PHARMACOLOGICAL ACTIONS neurones and thus potentiate them by increasing
their availability in the synaptic cleft (see Fig.
The most prominent action of TCAs is their
33 .1). Antidepressants, however, differ markedly
ability to inhibit norepinephrine transporter
in their selectivity and potency for different
(NET) and serotonin transporter (SERT) located
amines, and are classified on this basis. Most
at neuronal and platelet membrane. They also
of the compounds do not inhibit DA uptake,
interact with a variety of receptors viz. musca-
except bupropion. Moreover, amphetamine and
rinic, a adrenergic, histamine H1, 5-HT,, 5-HT2
cocaine (which are not antidepressants but CNS
and occasionally dopamine D2. However, relative
potencies at these sites differ among different stimulants) are strong inhibitors of DA uptake.
compounds. The actions of imipramine are Tentative conclusions drawn are:
described as prototype. • Inhibition of NA and 5-HT uptake is asso-
ciated with antidepressant action.
1. CNS Effects differ in normal individuals • Inhibition of DA uptake correlates with
and in the depressed.
stimulant action.
In normal individuals It induces a peculiar
Monoaminergic hypothesis of depression
clumsy feeli ng, tiredness, light-headedness,
This hypothesis supposes that depression
sl~epiness, difficulty in concentrating and
th is caused by deficient noradrenergic and/or
inking, unsteady gait. These effects tend to
provoke anx1cty.
· Tl1ere . • serotonergic transmission in the brain (mainly
or euph · 1s no mood elevatton in cortical and limbic areas). This hypothesis
ona; c!Tects are rather unpleasant is supported by the observation that reserpine
In depres<··J t· .
are Y ,, pa 1ents Little acute ef.r-1ects depletes NA and 5-HT from brain and p_roduces
d Produc<:(! except sedation (in the case of depression; and that all classes of antidepres-
rugs which "· d .
••dV C se at1ve property). Aft er 2- 3 sants (TCAs, SNRls, SSRls, atypical) enhance J
 DRUGS ACTING ON CENTRAL NERVOUS SYSTEM
484

TP
Hydroxylase

Oecarboxylase -"~- - ~

5-HIAA'---+1

• ·---------
0

Fig. 33.1: Schematic depiction of cerebral serotonergic synapse and sites of action of tricyclic antidepressants
(TCAs). selective serotonin reuptake inhibitors (SSRls), serotonin and noradrenaline reuptake inhibitors (SNRls),
and monoamine oxidase inhibitors (MAOls)
TP- Tryptophan; 5-HTP-5-Hydroxytryptophan; VMAT-2-Vesicular monoamine transporter-2; MAo-Monoamine oxidaSe:
5-HIAA-5-Hydroxy indole acetic acid; SERT-Serotonin transporter; SHT, -R / 5-HT -R - 5-HT, and 5-HT receptors.
2 2

synaptic availability of NA or 5-HT or both, in induce other adaptive changes in the number
one way or the other. However, uptake block- and sensitivity of pre- and postsynaptic ~A
ade doe~ not appear to be directly responsible and/or 5-HT receptors as well as in · am10e
for the anudepressant effect, because uptake .
turnover of brain, the net er~1ec t Of which.
hlod,ade occ urs quickly. while antidepressant . enhanced
1s . an d rotoneruic
noradrenerg1c se •
dlL<.t de, dop!, 0\ er severa l weeks. Explanation transmission. Thus, uptake blockade appea;
otkred for thi.., discrepa ncy is-initially the to initiate a series of time-dependent chang ·
prny11.:ip111.. ,1 rn ,J 5-HT autoreceptors are
1 that culminate in antidepressant effect. .
dltf\ atc d by tt L 1ncn:ased amount of NA/5- ·on Thrs
H f 111 ll1L "}r•..1pt1l· 1..k li resulting in decreased Neurotr~phic hypothesis of d~pre~s~ssociat~
fm ng ol lolU' l• 11:111lcu!) (noradrenergic) and hypothesis proposes that depression I trophic
n,phe (M.·ro tu1 1L '!!IL J 1H:uro11es. After, long-term with deficiency of brain derived neu: factors
factor (BDNF) and other nerve gro~t enio-
admini i.trat1011 a1111d1:prc!> san ts desensitise the . feeling 5,
(NGFs) in brain areas regulatmg d 1bnt
pre!>ynapt1c u._, 5 Il'I IA' 5-1ff 10 autoreccptors and tion. cognition, hedonia, behaviour, etc., an
 ANTIDEPRESSANT AND ANTIAN
XIETY DRUGS

ri:,snn 1
ts ,romo tc elabo ration of NG rs. The
. k'
48S
. 11 1id,'P ·. receptor tyrosm e mases (RTK s) Tolerance and d
,I •• , c(I V:l 1C . . ependence
~(ii-~ '1 ., axona l/dcn dntt c grow th, prom ote Toler ance to the .
' 1ilr1nc1.: , . ant1ch 1· ·
.~11 d i: ·c •con1 1l~ ,,·tion and impro ve neura l plasticity. effect s of imipr amine -~itcr g1c and hypotensive
~,-n:1Pll_ f ooNF k vcls and neura l mass in dually , but antid
· •t11'n
~t' l1tll
° .
. . ,:,._ has been demo nstrat ed m depre
s-
.
A dd1ct ion to th
e drugs develops ora-
epressant act' • c,
•~n is sustained .
li111b1l· .111:, . . .
ti1e1r acute effects ese drugs
tht' . , ,n)kw ed anttdr cssan t treatm ent has is rare, becau se
. ,,·hi 1l 1 e · are not pleasant
11 Th ere 1s
~1l' • • i to elevate BDN F levels as welt as som .
·n h'\llll . . e evidence of h ..·
lx'- • , nc\ll'l.)\!Cnests and synap tic conne ctions . dence occur ring h P ys1cal depen-
•nh:lllll ~ . . d h' h for long period s w en l .
high d
'
Thi: n1(,nonm , mergtc an neuro trop 1c ypoth - -ma a1se, chill oses are used .
l.,.-~ h:1Ye been _reconciled_ by ~onte ndin~ that may occur on discon tinu t' s, muscle pain
consi dered withd rawal ah1on and have been
en· 1i:111 c'men
c
t ot mono amme rg1c trans missi on
. hd p enom ena
rl 1 ged antide press ant thera py indire ctly wit rawal is recom mend ed but ant1·d·e Gradu a I
~' P 1 0 11 ~ . . .. lb . d0 ' pressants
p~omotes neurogenes1s m _cnt1c a ram areas by not carry abuse potential.
increasing BDNF produ ction. These grow th fac-
PHARMACOKINETICS
tors activate RTKs and initia te axona l/dend ritic
proliferation and forma tion of synap tic conne c- The oral absor ption of TCAs is good, though
rions. The therap eutic respo nse is delay ed due often_ slow. They are highly bound to plasma
to the time taken for neuro genes is to occur
and tissue protei ns, therefore have large volumes
.
of diStfib_ution ~-2~ L/kg). They are extensively
2. ANS Most TCAs are poten t antich oliner - ?1~tabol_1zed m liver; the major route for
gics-c ause dry mout h, blurr ing of visio n, 1m1pramme and amitriptyline is demethylation
constipation and urina ry hesit ancy as side where by active metab olites --desi prami ne and
effect. The antich oliner gic poten cy is grade d nortri ptylin e respe ctivel y are forme d. Both
in Table 33. l. these metab olites predo minan tly block NA
The TCAs poten tiate exog enou s and reupta ke. Few other TCAs also produce active
endogenous NA by block ing uptak e, but also metab olites . Inacti vation occur s by oxidation
have weak a 1 adren ergic block ing action . Some , and glucu ronid e conju gation . Vario us CYP
e.~. amitriptyline, doxep in, trimip ramin e have isoen zyme s like CYP2 D6, CYP3A4, CYPl A2
shght H I antihi stami nic action as well. and other s metab olise tricyl ic and relate d
3· CVS antide press ants. Metab olites are excre ted in
Effects on cardio vascu lar funct ion are
urine over 1-2 week s. The plasm a t½ of
prominent, occur at therap eutic conce ntrati ons
amitr iptyli ne, imipr amine and doxep in range
and become dange rous in overd ose.
betwe en 16-24 hours . The t½ is longe r for
T:chy~a~dia: due to antic holin ergic and NA some of their active metabolites. Becau se of
~ tentiatmg actions.
relativ ely long t½s, once daily dosing (at bed
/sdt_ura/ hypot ensio n: due to inhib ition of time) is practicable in the maintenance phase.
ar 1ovasc
ECG ha u lar re fl exes and a block ade. An unusual therapeutic window phenomenon
1
sup c .nges and cardi ac arrhy thmia s: T wave has been observed, i.e. optimal antidepressant
chanPress1o
. n or invers1. on 1s
.
the most consi.stent effect is exerted at a narrow band of plasma
gem ECG A h h . . conce ntratio ns (between 50-20 0 ng/ml of imipra-
mainly d : rr yt m1as occur m overd ose
C:0ndu . ue to interf erenc e with intrav entric ular mine , amitriptyline, nortriptyline).
ction. The NA . . .
blOCk.in . poten tlatm g + c h o 1·merg1.c Wide variation in the plasm a concenrrauon
depressf actions along with direc t myoc ardial attain ed by different individuals given th(' sam('
Older P~; compound the proar rhyth mic poten tial. dose has been noted. Thus, doses ne('.d to be
SNR1 s aiednts are more susce ptible . The SSRi s, indivi dualiz ed and titrate d with th~ r~sp~nst",
·
1 n at · •
n this YP•cal antid epres sants are safer but plasm a conce ntrati ons ar~ -not a _r~hall k
regard. guide for adjusting the dose ot TC A~-
486 DRUGS ACTING ON CENTRAL NERVOUS SYSTEM

I
Table 33.1: Comparative properties of antidepressants
Drug Sedation Anti-muscarinic Hypotension Cardiac Seizure
arrflythmia precipitation Dai e I
Tricyclic antidepressan ts (TCAs) (ftlg) I

1. lmipramine + ++ ++ +++ ++
2. Amitriptyline +++ +++ +++ +++ S0-20o
++
3. Trimipramine +++ ++ ++ +++ S0-20o
++
4 . Doxepin 50-150
+++ ++ ++ +++ ++
5. Clomipramine 50-150
++ ++ + +++ +++
6. Dothiepin 50-150
++ ++ ++ ++ ++
(Dosulepin) S0-150
7. Nortriptyline + ++ + ++ +
S0-150
Selective serotonin reuptake inhibitors (SSR/s)
1 . Fluoxetine :t:
:t
20-40
2. Fluvoxamine :t:
50-200
3 . Paroxetine + +
20-50
4. Sertraline
50-150
5 . Citalopram :t + 20-40
6 . Escitalopram :t
10-20
Serotonin and noradrenaline reuptake inh,bitors (SNRls)
1. Venlafaxine :t
75-150
2. Duloxetine + ++ 30-80
Atypical antidepressants
1. Trazodone +++ + :t 50-200
2. Mianserin ++ + ++ + ++ 30-100
3. Bupropion
+++ 150-300
4. Amoxapine + + ++ 100-300
++ ++
5. Mirtazapine +++ + :t 15-45
+ to +++ indicates increasing intensity of that action; - indicates absence of that action

ADVERSE EFFECTS
3. Increased appetite and weight gain is noted
Side effects are common with TCAs because of with most TCAs and trazodone, but not wi'th
which SSRis, SNRis and atypical antidepressants SSRis, SNRJs and bupropion.
have become the first line drugs. 4. Some patients receiving any antidepres-
I. Anticholinergic: dry mouth, bad taste, consti- sant may abruptly 'switc h over• to a
pation, epigastric distress, urinary retention · Proba-
dysphoric-agitated state or to mania.. he
( especially in males with enlarged prostate), bly, these are cases of bipolar depression'. ~
blurred vision, palpitation. other pole being unmasked by th e anti e-
2. Sedation, mental confusion and weakness, pressant. . ) and
especially with amitriptyline and more seda- · · action
5. Sweating (despite antimuscanntc
tive congeners. fine tremors are relatively common.
 ANTIDEPRESSANT AND ANTIANXIETY DRUGS 487

, l-i 7111 ,, threshold is lowered- fit s may be pre- 2. TC As potenti ate CNS depre.v.vant.v, including
,, :-,J'i l:tll'\l. especi all y in _children. Dupropion, alcohol and antihistaminics.
, 1,, 111 ipramme. nmoxapme have greater pro- 3. Phenytoin. phenylbutazone, aspirin and CPZ
l'cn~i t~·. ":hilc_desipramine. SSRls and SNRls can displace TCAs from protein bind ing sites
:ire ~a fc r 111 thi s regard . and cause transient overdose symptoms.
- r,,stura I hypotension. especially in older 4. Phenobarbitone competitively inhibits as well
patients. It is less severe with desipramine-like as induces imipramine metaboli sm.
d nH!S and insignificant with SSRis/SNRis. Carbamazepine and other enzyme inducers
~- Sex:al distress: especially delay or interfer- enhance metabolism of TCAs.
ence with erection, ejaculation and occasion- 5. SSRis inhibit metabolism of several drugs
ally with orgasm. (see later) including TCAs---dangerous toxicity
9. Cardiac arrhythmias , especially in patients can occur if the two are given concurrently.
with ischaemic heart disease. Arrhythmias 6. By their anticholinergic property, TCAs delay
may be responsible for sudden death in these gastric emptying and retard their own as
well as other drug's absorption.
patients.
7. MAO inhibitors- dangerous hypertensive
1o. Rashes and jaundice due to hypersensitivity
crisis with excitement and hallucinations has
are rare. Mianserin is more hepatotoxic.
occurred when given with TCAs.
Acute poisoning Poisoning with TCAs is
frequent ; usually self-attempted for suicide, Preparations of TCAs

and may endanger life. Manifestations are: I. lrnipramine: DEPSONIL, Ai'-TTTDEP 25 mg tab. 75 mg SR
cap.
Excitement, delirium and other anticholinergic 2. Amitriptyline: AMLINE, TRYPTOMER , SAROTENA
symptoms as seen in atropine poisoning, fol- 10, 25, 75 mg tabs.
lowed by muscle spasms, convulsions and coma. 3. Trimipramine: SURMONTIL I 0, 25 mg tab.
4. Doxepin: SPECTRA, DOXCN, DOXETAR I 0. 25. 75
Respiration is depressed, body temperature mg tab/cap.
may fall , BP is low, tachycardia is prominent. 5. Clomipramine : CLOFRANIL 10. 25. 50 mg tab, 75
ECG changes and ventricular arrhythmias are mg SR tab. CLONIL, ANAFRANIL 10, 25 mg tab
common. 6. Dothiepin (Dosulepin): PROTHIADEN , EXODEP 25.
50, 75 mg tab.
Treatment is primarily supportive with gastric 7. Nortriptyline: SENSIVAL, PRJMOX 25 mg tab.
lavage, respiratory assistance, fluid infusion, 8. Reboxetine: 4 mg BO or 8 mg OD; NAREBOX 4. 8
maintenance of BP and body temperature. mg tab.

Acidosis must be corrected by bicarbonate

infusion. SELECTIVE SEROTONIN REUPTAKE
Diazepam may be injected i.v. to control INHIBITORS (SSRls)
convulsions and delirium. Most important is
the treatment of cardiac arrhythmias, for which
The major limitations of TCAs (first generation •
antidepressants) are:
propranolol/lidocaine may be used. The class • Frequent anticholinergic, cardiovascular and
1A and IC antiarrhythmics and digoxin them- neurological side effects.
selves depress cardiac conduction; are therefore • Relatively low safety margin. They are haz-
comraindicated. ardous in overdose; fatalities are common.
• Significant number of patients respond
INr ,- -·ACTIONS incompletely and some do not respond.
I . I CAs pot.entiate directly acting sympatho- To overcome these shortcomings, a large number
1111metic amines (present in cold/asthma of newer (second generation) antidepressants
re medi es) . Adrenaline containing local have been developed since I980s. The most
anaesthetic should be avoided. significant of these are the SSRls and SNRls
488 DRUGS ACTING ON CENTRAL NERVOUS SYSTEM

" hich selecti, cl y inh ibit membrane assoc iated ri bl oc ke rs, so m e UZDs and c •·trh·.imuzc ·
SERT or hoth SERT a nd NET. Tho ugh, some 'Serotonin .,y ndmme' ma ni fcsting UH : fl 1n1:.
p:u ients may not respond even to these dru gs, restl essness, r1·g 1t
· 11ty,
- h
yperthcrmi tt· dag1ta1i
, . . 0 n,
the e t'lkacy of second generation antidepressan ts . . h. ,. 11 • e 1Iri lJ Ill
sweating, tw1tc 1ngs o o wed by con • ,
is rated higher th an older TCAs and RIMA s. . . d h vu 1K1ons
can be prec1p1tate w e n uny scrotonergic d
Some pa t ie nt s no t res ponding to one type (e.g. MAOls, tra mado l, pethidine) is tak . ru~
of drug ma y respond to another type. More a patient receivin g SS R Is. So me deu en hy
impo rtantly the new er drugs have improved . orec of
tolerance to the antH.leprcssan t action of SSRI
tolerability at therapeutic doses, as well as safety has bee n _no ted . in ~cw patie_nts after month:
in o, ·erdose . It has been claimed that certain of use. 1?•sco ntmua t1 on reactio n cons isting of
drugs (bupropion, venlafaxine, mirtazapine) have paresthes ,as, bodyachc, bowel ur,sct, agitation
fas ter onset of antidepressan t action, but this and sleep di sturba nces occurs in some patients
has not been unequivocally established. However, ri sk of switching o ver to hypomani~
The relative safety and better acceptability during treatment is less with SSIHs than with
of SSRi s ha s made them I st line drugs in TCAs.
d epress ion and allowed their exten s ive us e Because of freedom fro m psychomotor and
in anxie ty, phobias, panic, OCD and related cognitive impa irment, SS Ri s arc preferred over
d isorders. The SSRis produce little or no TC As for prophylaxis of recurrent depression
sedation, do not interfere with cognitive and (should be combined with lithium/valproatc).
psyc bomotor function or produce anticholinergi c Metaanalys is of comparative trials has shown
side effects. They are devoid of a adrenergic no s ignificant difference in efficacy among
blocki n g action-postu ral hypotension does individual SSRls, but there are pharmacokinctic
not occur, making them suitable for elderly differences and incidence of pa rticular side
pati ents. They hav e practically no s eizure efTects di fTers somewhat.
pre ci p itatin g propensity and do not inhibit Fluoxetine A bicyclic compound, it is the
card iac conduction--- 0verdose arrhythmias are first SSRI to be introduced, and the longest
not a problem. Prominent side effects are acting. Its plasma t½ is 2 days and that of its
gastrointestin al; all SSRls frequently produce active demethylated metabolite is 7- 10 days.
nausea (due to 5-HT3 receptor stimulation), but It has been approved for use in children 7
tol erance develops over time. Loose motions years or older for depression and OCD on the
a re due to 5-HT uptake blockade in the gut basis of similar efficacy and side efTcct profile
and activation of 5-HT receptors on enteric as in adults, but should be given to children
plex us neurones . Weight gain is not a problem only when psychotherap y fails. Agitation and
·.;. ith SS R1 s. but they more commonly interfere dermatologica l reactions are more frequent than
.,. · ·:: eJac ulatio n o r orgasm. A new constel- with other SSRls. Because of slower onset of
·- • · :-: r f mi ld side effects, viz. nervousness, antidepressan t effect, it is considered less suitable
, . , :' ,:,e,s, insomn ia, anorexia, dyskinesia and for patients needing rapid efTect, but is more
r.-: ,~sr.t ;-. associated with them, but patient appropriate for poorly compliant patients.. 11'
::.cc.:p.::1~! ;1,} is good . Increased incidence of stimulant effect could worsen patients showing
.:p1 sta.x 1s and ecchymosis has been reported, agitation. . UPAR
probably d ue to im pairment of platelet func- FLUDAC 20 mg cap, 20 mg/5 ml suHp., PLUN IL. l' L '
tio n. G a smc b lood loss due to NSAIDs may PRODAC I 0, 20 mg cap.
be increased by SSRl s. Fluvoxamine It is a shorter-acting SSRI w_itth
The SSRh inh ibi t drug metabolizing iso- a t ½ of 18 hours and no active . mctabo 1' c.
d for
e nzymes C YP2D6 and CYP3A4: elevate plasma It has been specifically recommc nd coCD-
le ve ls o f TC As, ha loperidol , clozapine, warfarin, generalized anxiety di sorder (GAD) a n<l

1111
 AN TID EP RE SS AN T AN D AN TIA
NX IET Y DRUGS

. nau sea , dys pep sia, flat ule nce ,

489
I n101e . . . I hou r be~ .
.\ati''e Y d di sco nt11 . ore sex
R· ,ss an
1uat1on rea ctio
•
ns hav e wit h beh avi our al thual inte.
rco urs e C
.
.
·
·"·(1t1 s 1w• d vilh ftuv oxa mtn
1 e. to hel era p,es , it has beeom bm ed
n found
• rcP 0 rte '
1, 11t
1,,·L 11 ,. , soi,,,-sr ·. ·,o, 100 mt,; t.ib~. lo ear~y :j:~ ul: ~~ ere r; .~f sex ual
1, \ l \ --, , distress due
IS
11 L' • Ano ther sho rt acti
ng SSR I (t ½ 20 vom itin g I n. . t e effe cts are nau sea ,
g paro,cettne . ·I does not pro duc e acti.ve met a bo 11te. ·
'
and occ asiooos e mo tion s hea dac h d' .
n II .
1,,,\11'~ 1 ,,h1.Ll·idence ol • g. t.. st'd e e 11·ects a Y tnsomn1?a . e, 1zz mess
y , sex ual Dos e: 60 mg take n I hou r .
. i,cr Jtll patie nts 30 mg. .
f ~ \1t!c' . iion and d 1sco
'
ntm
.
uat1
.
on . befo re interco urse; older
.-, :1g1t:l rea ctio n SUSTI NEX , DUR AL/ \ ST, KUT UB
s ,\l~trt~-· ·r SSRl s has bee n not ed. Sed atio . 30
ith l'' 1l 1 • n mg. (10 mg tahc.
s 1h:111 '' . -c:1rinic .
effe cts are rml d. Other uses of SSRls The SSRI
i 11t1111 ll~ ' •
I s t c h O1c s are now.
f ~111 ~ \ l\)Fl'-·C R 10, 20, 30, 40 mg tabs . · I e dru gs for OC D p
\ 11 1 \ •
soc ta pho bia , eat ing diso rde , ant.e d .tsor der
sertra. . ls "'
.
ti ne This SSR l has gam ed pop ula .
nty , PTS D. _The y_ are also bei ng inc~
rs PMDD d
· clinical tna . ts
1ewer pat ien easingly, u::d
:I ix· -au,e ' 11 stop ped for anx1~ty d1sor_d ers, bod y dys mor
' -. e due to side effe cts. Effi cac y in juv e- phi c diso rder,
1 ,ertT31111 c?mpuls_ive buy mg , klep tom ania
-. d"pression has bee n dem ons trat . and pre mat ure
01\e ~ ed, and 1t eJa cul atlo n. Ele vat ion of mo od
j . ended for anx iety an d pos t-tr aum .
. and incr eas ed
1, rec atic
001111 wo r~ cap acit y _has bee n rep orte
.
: '" d·,sorder (PT SD) as wel l. Dru g mte . d in postmyo-
r ,tre~~ rac tlon s car dia l infa rcti on and oth er chr
due to inhibition of CY P isoe nzy me s are less oni c som atic
~llness pati ents . Thu s, SSR is are
lei\ bein g use d to
\I • to occur wit h sert rali ne. Its pla sma t½ is ~mprove out loo k on life and to feel
,6 hours and it pro duc es a stil l lon goo d, eve n
ger -las ting m app are ntly non dep ress ed pati ents
acti\'e metabolite. . Wis dom of
suc h use tho ugh is que stio nab le.
5ERENTIA,SERLIN , SERTIL 50, 100 mg
tabs ., ZOSERT
S ,50, 100 mg tabs . SEROTONIN AND NORADRENAL
INE
Citalopram Thi s SSR I sha res wit REUPTAKE INHIBITORS (SNRls
h sert rali ne )
a lower propensity to cau se dru g inte 1. Ve nla fax ine A nov el ant
ract ion s. ide pre ssa nt
Its t½ is 33 hours and no acti ve met ref err ed to as SN RI, bec aus
abo lite is e it inh ibit s
known. However, Q-T pro lon gat ion upt ake of bot h NA and 5-HT but,
and few in con tras t to
deaths due to ove rdo se of cita lop ram old er TC As, doe s not interact with
are on cholinergic ,
record, because of whi ch it is to adr ene rgic or hist ami ner gic rece
be avo ide d pto rs or hav e
in patients likely to atte mp t suic ide . sed ativ e property. Trials hav e sho
Cit alo pra m wn it to be as
1s the preferred SSR I for mo od effe ctiv e anti dep ress ant as TC As
dis ord ers in and may wor k a
premenstrual dysphoric diso rde r (PM in som e resi stan t cases. A faster ons
FELIZ, CITADEP, CELICA I 0, 20, 40 mg
DD). et of action ~
tabs. is clai med . Mo od cha nge s and I
hot flas hes in
Esc~talopram It is the acti ve S(+ ) men opa usa l syn dro me, soc ial anx
r of ~tta\opram, effe ctiv e at hal f the
ena ntio mer
ing diso rde rs are also benefited by
iety and eat-
dos e, wit h venlafaxine.
Similar properties, but Q-T pro lon gat It doe s not pro duc e the usu al side
ion is not effe cts of
rep~rted. Currently, it is a pop ula TC As; tend s to rais e rath er than dep
r SSR I for ress BP and
anxio-depressive diso rde rs. Mo des t is safe r in overdose. Pro min ent side
reli ef from effects are
menopausal hot flas hes has bee n nau sea , swe atin g, anxiety, dizzines
obt ain ed in s, imp oten ce
women wh
are . °
cannot take estr oge ns. Sid e effe cts
and wit hdr awa l reac tion s on disc
VENLOR
ontinuation.
Eso; '1der and
safe ty is imp rov ed.
, SENTOSA 25, 37.5 , 75 mg tabs ., VEN
37.5 , 75, 150 mg ER cap s.
lZ-XR
O ' FELlZ-S, N EXITO 5, 10, 20 mg tabs
.
apoxetine Th. 2. Desvenlafaxine lt is desmet hylvenlafax-
Panic is SSR I is bei ng pro mo ted
a P uIarly for dela yin g pre mat ure ejac ine , an acti ve met abo lite of ven
lafa xin e ,vith
ropeny ula tion sim ilar acti ons , use s, and side effe
TCAs. Da com_mon to man y SSR ls , cts.
and som e Dos e: 50-1 00 mg/day;
poxetine acts rap idly and can be tak D -VE N1Z , NEW VEN , \lEN Z-O O
en 50, 100 m~ t.,k
r'

490 DRUGS ACTING ON CENTRAL NERVOUS SYSTEM

3 . Duloxetine A nc,H' r SN RI si mil ar to caused seil'.ures in overdose. I lowc vcr uvc .1

, ruosc
,cn laf:n111l' . 11 ,~ mildl y sedating with some fatality is low. Re ports of blood dyscrasias '
. h . anu
an 1111111~c;irinic effec t~. but no t an antihis - li ver dysfunction ave restricted its use.
1;11111111-:- l"' r o hind.er. S ide effects. includ- I ETR A DFI ', SE RIDA C 10, 20, J O, mg t,i bs .
111~ ~ -'- and ~eu1al problems are milder. but 3 . Mirtazap ine This antidepressant acts b
a~11 a11on. insnmnia and rise in BP can occur a novel mechanism, viz . blocks a 2 auto- (o~
111 le" . Antidepressant efficacy is comparable NA neurones) and hetero- (on 5-HT neurones)
10 TC A!:> . Duloxetine is particularly indicated receptors enhancing both NA and 5-HT release.
111 dia betic and other types of neuropathic pain, The augmented NA further increases firing of
fibromya lg ia and stress urinary incontinence in serotonergic raphe neurones via a, receptors.
women (because it increases urethral tone). It Selective enhancement of antidepressive 5-HT
has also been used for maintenance therapy receptor action is achieved by concurrent block~
in panic di sorder. ade of 5-HT2 and 5-HT3 receptors which are
C Y',18.\LTA 20. 30. 60 mg tab. D E LOK, DU LANE 20,
held responsible for some of the adverse effects
:<O. 40 mg cap~.
of high serotonergic tone. Accordingly, it has
been labelled as "noradrenergic and specific
A TYPICAL ANTIDEPRESSANTS
serotonergic antidepressant" (NaSSA). It is a H
1. Trazodone It is the first atypical anti- blocker and moderately strong sedative, but onl;
depressant; less efficiently blocks 5-HT uptake, mildly antimuscarinic and not antidopaminergic.
but bas prominent a adrenergic and weak 5-HT2 Efficacy in mild as well as severe depression
antagonistic actions. However, its metabolite is is reported to be comparable to TCAs. Given
a strong 5-HT2 blocker. Antidepressant effect is once daily at bed time, it is particularly suitable
modest. It is sedative but not anticholinergic, for those with insomnia. Increased appetite and
causes bradycardia rather than tachycardia, weight gain is frequent. Sexual dysfunction is
does not interfere with intracardiac conduction, not a problem with mirtazapine.
therefore less prone to cause arrhythmia. Nausea M IRT 15, 30, 45 mg tabs, M IRTAZ, MATIZ 15, 30 mg tab.
is felt, especially in the beginning. Inappropriate, 4. Bupropion This inhibitor of DA and NA
prolonged and painful penile erection (priapism) uptake has excitant rather than sedative prop-
occurs in few recipients resulting in impotence in erty. It is metabolized into an amphetamine-like
a fraction of these. The a, adrenergic blocking compound which can cause presynaptic release
property has been held responsible for this effect of DA and NA. A sustained-release formulation
as well as for postural hypotension. Trazodone is marketed as an aid to smoking cessation. In
is infrequently used now in depression; unless clinical trials it has been found to yield equiva-
associated with insomnia. lent smoking abstinence and quitting rates as
T RAZODA C 25, 50 mg ta b, TRA Z ONJL, TRAZALON
nicotine replacement, and higher than placebo.
25. 5U. J(JO mg ta bs.
Bupropion may be acting by augmenting the
2 . M ianserin It is unique in not inhibit- dopaminergic reward function. Better results are
in g e ith e r NA or 5-HT uptake; but blocks obtained when it is combined with nicotine patch.
pre sy napt ic u rece ptors th e reby increasing The nicotine withdrawal symptoms were less
rtlea!:>t: anJ ,t;rn o ver o f NA in brain which severe in bupropion recipients. However, long-
may be n -.r,Jn~:hk Jor the antidepressant effect. term efficacy is not known, while it can cause
A nt.ag<Jfl ... 11c ., .t•<J11 ·1, 5-IIT 2 , 5-HT,, as well insomnia, agitation, dry mouth and nausea, but
a~ H 1 , ·•ho bee n shown. It is a not sexual side effects. Seizures occur in over
!>ci:iat1 ve ,1..111.\v, ... ,t i.1tcd anxiety and sup- dose and in predisposed patients due to lowering
preM,t~ p a.n ic .itLJ,'J Wh ile anticholinergic and of seizure threshold. The dose of 150 mg BD
(.,j rdta(.: 1>id<.: d J,·, 1. 1, i..: ... s prominent, it has should not be exceeded. It is contraindicated
 ANTIDEPRESSANT AND ANTIANXIETY DRUGS 491

. disorders and in bipolar illness. Bu- properties (sedative, anticholinergic. hypoten-

. ca11ng • .
111 . · infrequently used to treat depression sive, cardiotoxic, seizure precipitating. etc.)
11011 IS
pr<'I. those with atypical features, or it may as described above, and past history of drug
~xc~rdt ·d to a SSRI as an augmenting drug. It response, if available. The SSRJs are currently
I1~• ad c ·,able for treatment o f anxiety
· d.1sorders. used as first choice for their better tolerability,
·. not SUI
IS " ,u 1r 150 m g tab . safety and may be higher efficacy as well. The
... ~1( TV.
SNRls and newer atypical agents also offer
Amoxapine This tetracycli~ compound is
5· , 1 in that it blocks dopamine D2 recep- advantages. The only antidepressants clearly
11 shown to be effective in juvenile depression
unusl·n
, addition to m
· h'b" ·
1 1tmg NA reuptake. It
1ors 1 . . are fluoxetine and sertraline. The TCAs are
. .• ically related to the ant1psychot1c drug
IS C1lC 111 . . now used only as alternatives in non-responsive
· ine and has mixed antidepressant + neu-
loxap . b d , . cases or in those not tolerating the second
tic properties; may e use ,or patients
1
roe P . . h generation antidepressants. Substituting a drug
- psychotic depression unresponsive to ot er
111 with a different pattern of aminerg1c action may
w\idepressants. Risk of extrapyramidal side
anffects is also there. S e1zures
· (.me1ud.mg status succeeds in nonresponsive cases. However, few
patients fail any single antidepressant. In such
:pilepticus) occur in its overdose.
oEMOLOX SO, I 00 mg tab.
cases, augmenting the initially selected drug
(usually a SSRJ) with an atypical antidepressant
6 _ Tlaneptine This antidepressant is reported to increase
rather than inhibit 5-HT uptake, and is neither sedative nor like bupropion or with valproate/lithium is an
stimulant. It has shown efficacy in anxiodepressive states, option. Another option is to add a second
particularly with p~ycho~omatic symptoms, as wel~ as in generation antipsychotic drug in refractory cases.
endogenous depression . Side effects arc dry moulh, ep1gastnc Psychotic depression needs to be treated
pain, f1atulcncc, drowsiness or insomnia, tremor and bodyache.
with a combination of a SSRI with an atypical
Dose: 12.5 mg BD- TDS; STABLON 12.5 mg tab.
antipsychotic like olanzapine, aripiprazole or
7. Amlneptine Like tiancpline it enhances 5-HT uptake,
and has antidepressant property. It produces anticholinergic
quetiapine. In case of bipolar depression., it is
side cfTccts including tachycardia, confusion and delirium. Pos- essential to combine the antidepressant (SSRI/
tural hypotension, conduction disturbances and armythmias can SNRJ/fCNatypical) with valproate or lithium
occur, especially in patients with heart disease. or lamotrigine to avoid the risk of switching
Do!ie: I 00 mg BD ot breakfast and lunch .
over to mania.
SU RVECTOR I 00 mg tabs.
After a depressive episode bas been con-
trolled, continued treatment at maintenance
USES
doses for months is recommended to prevent
1. Endogenous (major) depression: The relapse. Discontinuation of the antidepressant
aim of therapy is to relieve symptoms of may be attempted after 6-12 months. Long-
depression and restore normal social behaviour. term therapy may be needed in patients who
While antidepressants are not the answer to tend to relapse. ECT may be given in the
every grief, loss, set-back or other sad events severely depressed, especially initially while
that are part of life, but the less toxic and effect of the antidepressant is developing,
more patient-friendly SSRls/SNRis/atypical because no antidepressant bas been clearly
antidepressants are now more readily prescribed demonstrated to act fast enough to prevent
in depressive illness. Major depression clearly suicide.
requires antidepressant medication and these Moclobemide, a reversible inhibitor of MAO-A.
drugs are of proven value, but response takes is a relatively well tolerated option for mild-
at least 2- 3 weeks to appear, full benefits take to-moderate depression and atypical depression.
still longer. Choice of a particular drug for an It is less risky than TCAs for patients with
indi vidual patient depends on the secondary cardiovascular risk factors.
r

492 DRUGS ACTING ON CENTRAL NERVOUS SYSTEM

2. Obsessive-compulsive disorder (OCO): 6. Premature ejaculation

• •
· It re"e
11 rs to
The SS Rl s. particularly fluoxaminc, are the drugs occurrences of ejaculation before Or shon1repeated
. . . .
of choice due lo belier pati ent acceptability. penelrat1on, or with minimal sexual . Y1·after
. st1mu1 1
TC As. especia lly clomipramine. arc also highly It 1s a very common sexual complai ~ on.
• . d nt, Wh1 ch is
elkctin· in OCD . Over 50% patient s obtain o f ten mlerprete as sexual weaknes .
s, can c
cons1.dera bl e 1stress and dissatisfact' . ause
d.
signi fica nt improvement in OCD rating sca le,
· · h.1s partner. Som ion. 1n th c
as weII as 111
but l0ngn response time of 2- 3 months and patient
h
. has unreasonable expectation ehmes b Ie
rl'la1in·l~1 highn doses are genera lly needed than subject
0111 the
fo r depress ion. SS Rl s and TCAs also reduce optimal/desirable length of intercou;s:
compulsi,·e eating in bulimia, and help patients Most SSR(s and some TCA s e · .
with hod1· dys11101 phic disorde,; compulsive buy- clomipramine have the common 'pr:Pecially
ing and kleptomania, though these habits may delaying and in some cases inhibitingpe_rty of
. ( h. . If eJacula
not completely die. tton t 1s 1tse can cause sexual distress)· The·
.
pnmary .treatment of premature ejaculat'ion is .
3. Anxiety disorders: Antidepressants, espe- .
cia lly SSRls and SNRfs, exert a delayed but counsellmg and behavioural therapy, but this
sustained beneficial effect in many patients of can be supplemented by drugs. Dapoxeti·ne .IS
. .
social anxiety and generalized anxiety disorder. a SSRr which has been specifically introduced
They may be used along with a short course for this purpose. It acts rapidly; 60 mg taken
of BZDs, which act rapidly, to cover exacerba- I hour before intercourse has helped man
tions. They have also proven helpful in phobic subjects. Clomipramine I0-25 mg three time~
disorders, long term treatment of panic attacks a day is a slow acting drug which needs to
and in post-traumatic stress disorder (PTSD) . be taken regularly for maximum benefit. For
Mood swings and hot flashes in menopausal on demand use, 25 mg may be taken 6 hours
women may be partly relieved by certain SSRrs before sex.
when HRT is contraindicated. 7. Smoking cessation: Only bupropion is
4. Neuropathic pain: Amitriptyline and other approved as an aid to smoking cessation, though
TCAs afford considerable relief in diabetic and some TCAs have also been found to reduce
some other types of chronic pain. Amitriptyline craving, albeit inconsistently. In controlled
reduces intensity of post-herpetic neuralgia in trials, quitting rates were significantly higher
~50% patients. The SSRrs are less effective in in bupropion recipients, than among placebo
these conditions. Duloxetine, a SNRI, is now recipients. Abstinent subjects on bupropion
the first line drug for diabetic neuropathy, fibro- experienced fewer distress symptoms and mood
myalgia, etc. Other drugs useful in neuropathic swings. Benefits were comparable to those with
pain are pregabalin and gabapentin. Combina- nicotine gum, and the two were additive.
tion of duloxetine + pregabalin may work if 8 Enuresis: In children above 5 years, imipra·
monotherapy is not satisfactory. mine 25 mg at bedtime is effective, but bed
wetting may again start when the drug is
5. Attention deficit-hyperactivity disorder
stopped. Eldery subjects with bed wetting have
(ADHO) in children: TCAs with less depres-
also benefited.
sant properties like imipramine, nortriptyline
and amoxapine are now first line drugs in this 9. Migraine: Amitriptyline has some prophy-
disorder, comparable in efficacy to amphetamine- lactic value, especially in patients with mixed
like drugs, with the advantage of less fluctuating headaches.
action and fewer behavioural side effects. Ato- 10. Pruritus: Some tricyclics have antipruritic
moxetine is a NA reuptake inhibitor unrelated action. Topical doxepin has been used to relieve
to both TCAs as well as amphetamine, which itching in atopic dennatitis, lichen simplex, etc.
is used specifically in ADHD. NOCTA DERM 5% cream.