Newer Antidepressants

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THEDRUGS

26.NEWER ANTIDEPRESSANTS: NRIs,SNRIs, NaSSAs AND OTHERS

NORADRENALINREUPTAKEINHIBITORS

O f the o lder TCAs th e m ost select ive for inh ib i t io n o f no radr enal in as

op po sed to 5-H T or do pam ine reuptake was desipram ine (w i th a rat ioof abo ut 240 for no radr enalin ::::: 5-H T) . Th e dru gs no w called no radr enalinreup take inh ib i tor s (N RIs) are devoid of th e recepto r-b lockin g act ionso f th e TCAs, at H

1, acetylchol ine-M, and noradrenal in--1 recept or s.

Th ey sh ou ld also lack m em br ane-stabi l isin g act iv i ty. The f i rst dr ug t obe d escribed as an NRI w as rebo xetine. H o w ever, th e old er tet racycl icdr ug m apr ot i l ine can b e inc luded in th is categor y.

Mechani sm s of act i onTheir pr imary pharmacological act ion of the NRIs is to inhib i t nor-adr enalin reup take and th ereby increase th e con centration o f nor adr en-al in in t h e synaptic cleft , and in crease the st im u lat io n o f no radren al in-1, no radren al in -2 and n or adr enal in - recept or s. The act ion at p re-synap tic (-2) autor ecepto rs tend s to redu ce nor adr enal in cel l f i r ing(e.g. in t h e locus coeru leus), th ereby redu cing th e release of n or adr en-al in. H ow ever, over several days, do w n regulat ion occu rs in - an d -

recept or s. The r edu ct ion in sensi t iv i ty of p re-synapt ic aut o-recepto rstends to restore noradrenal in re lease, whi le the downregulat ion ofpostsynaptic -recept or s ten ds to red u ce th e po st-synaptic resp o nse.O veral l th e level of t r ansm ission (w h ich can be jud ged, for instance byno cturn al m elato nin secret ion f rom th e pin eal g land ), is increased.

Noradrenal in i s tho ught to be im po r tant in reward-dr iven behav iou r(v ia th e vent ral no radr energic bun dle) and in arou sal (v ia th e locuscoeruleus) ( see ch ap ter 7) .

The v iew that enhanced no radrenalin fun ct ion is im po r tant in th erecovery of depressive i l lness using non-specif ic MARIs (such as theTCAs) is sup po rted b y find ings wi t h in tervent ion s designed to low erbrain no radr enal in fun ct ion acutely. Th e adm inist rat ion o f -methy lpara - ty ros ine , wh ich i nh ib i t s t y ros ine hydroxy lase , l owers b ra inn or adr enal in levels. This inter vent io n leads to a relap se of d epr essivesymp tom s in p at ients wh o have im pro ved o n desipram ine, tho ugh n otin th ose wh o have im p ro ved on SSRIs.

Noradrenal in may be more involved in the symptoms of anergia,fat igue and loss of d r ive in d epr ession , and 5-H T m ay be m or e involvedin t h e al terat ion in subject ive m oo d and anxiety, bu t th ere is as yet noconsistent ev idence that a part icular c l in ical pat tern of depressivei l lness is m or e l ikely to b enefi t f ro m an N RI th an fr om an SSRI.

A theo ret ical rat ion ale do es exist fo r u sin g an NRI as augm ent at io nin p at ient s w h o h ave resp on ded on ly part ial ly to an SSRI, al th ou gh t h isis not yet suppor ted by c l in ica l data . Th is s t ra tegy would appearpreferable to, for instance, increasing the dose of an SNRI, which


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would lead to unnecessar i l y h igh leve ls o f inh ib i t ion o f seroton inreu p take, with a con sequ ent in crease in side-effects.

Maprot i l i neTh is is a tetr acycl ic an t id epr essan t, c losely related in str u ctu re to th eTCAs. In ter estin gly, i t is no t effective in p an ic d iso rd er. It s u se is alsol im ited b ecau se i t has a greater t end ency th an o th er ant idep ressant sto low er th e seizur e th resho ld and to cause f i ts.

Reboxetine

Structure and mechanism of action

The molecule has chemical s imi lar i ty to f luoxet ine. However, i t isre lat ively select ive for in h ib i t in g th e reup take o f no radr enal in and isdescribed as an NRI (see Table 26.1).

Clini cal uses

In th e acute t reatm ent o f m ajor dep ression , rebo xet in e is of sim i laref ficacy to f luoxet ine. In on e stu dy, in o ut -pat ients wi th dep ression ,reboxet ine was more e f fec t ive than f luoxet ine in improv ing soc ia lfunct ion in g. Th is inc luded greater im pro vem ent o n i tems m easur in gw or k, sp on taneou s act iv i ty, fam i ly relat io nship s and th e abi l i ty to cop ewi th f inances. The use of reboxet ine in the e lder ly has not beenadequ ately explo red, but th e lack o f po stu ral hyp ot ension m ay be anadvantage.

Side-effects

Th ese are m ainly aut on om ic effects, p ro bably rep resentin g sym p ath eticover-st im ulat ion and cent ral inh ib i t ion of t h e parasym p ath et ic system(see Table 26.2) . Insomnia and sweat ing are t roub lesome. Sometolerance to the side-effects may develop, as reboxetine has beenwel l to lerated in long-term t reatm ent .

Pharmacokinetics and dosage

Rebo xetine is rapid ly abso rbed after o ral do ses. It is m ainly m etabo lisedin the l iver and has an el iminat ion hal f - l i fe of about 13 hours. Thestar t in g do se is 4 m g, increasing t o tw ice dai ly and a m axim um do se of12 m g a day. Rebo xetine is no t in d icated for use in t h e elderly; i f i t isused, hal f th ese do ses (24 m g a d ay) sho u ld be given.

ToxicityNo fatal overd oses h ave been rep or ted .

Interactions

Reboxe t i ne i s h i gh l y p ro te i n -bound and may t he re fo re i n t e rac tt empora r i l y w i t h o the r p ro te i n -bound d rugs , e .g . p rop rano l o l o rdipyr idamide.


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THEDRUGS

TTTTT a b l e 2 6 . 1a b l e 2 6 . 1a b l e 2 6 . 1a b l e 2 6 . 1a b l e 2 6 . 1 A f fi n i t i e s o f a n t i d e p r e ssa n t s fo r r e u p t a k e s i t e s a n d r e c e p t o r s o f h u m a n bA f fin i t ie s o f a n t id e p r e s sa n t s fo r r e u p t a k e s it e s a n d r e c e p t o r s o f h u m a n bA f fi n i t i e s o f a n t i d e p r e ssa n t s fo r r e u p t a k e s i t e s a n d r e c e p t o r s o f h u m a n bA f fin i t ie s o f a n t id e p r e s sa n t s fo r r e u p t a k e s it e s a n d r e c e p t o r s o f h u m a n bA f fi n i t i e s o f a n t id e p r e s sa n t s fo r r e u p t a k e s it e s an d r e c e p t o r s o f h u m a n b

D ru g N R I SR I D RI H1

A c e t

B u p r o p io n 0 .0 0 2 0 .0 1 0 .2 0 .2

M ap r o t ilin e 9 0 .0 2 0 .1 5 0

M ian se r in 1 0 .0 3 0 .0 1 2 5 0

M iln ac ip r an 1 .2 1 1 0 .0 0 1 0 .0 0 8

M ir t az e p in e 0 .0 2 0 .0 0 1 0 .0 0 1 7 0 0N e faz o d o n e 0 .3 0 .5 0 .3 5

R e b o x e t in e 1 4 2 0 .0 0 9 0 .3

Tr azo d o n e 0 .0 1 0 .6 0 .0 1 0 .3

Ve n lafax in e 0 .0 9 1 1 0 .0 1 0

N R I, n o r a d r e n a lin e r e u p t a k e in h i b i tio n ; SR I, se r o t o n in r e u p t a k e in h i b i tio n ; D R I, d o p a m in e r e u p t a

A f f i n i t y i s exp ressed as 1 /10 7 K d , w h e r e K d is e q u i lib r iu m d i sso c ia tio n c o n s t an t i n m o la r it y. T h u s,

fig u r e s in t h e r o w s sh o w h o w m an y t im e s m o r e p o t e n t t h e d r u g is in t h e t w o ac t io n s. N o t e t h at

t h e d r u g a n d i t s m e t a b o lit e s in t h e b o d y .A d a p t e d f r o m L e o n a r d a n d R i c h e l s o n ( 2 0 0 0 ) .


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Discontinuation reactions

No d iscon t in ua t ion symp tom s have been repo r ted . Reboxet ine i s

available as tablets of 4 mg.

SEROTONINAND NORADRENALINREUPTAKEINHIBITORS

These drugs block the reuptake of serotonin and noradrenal in ( l ikeTCAs such as am i t r ip ty l ine) b ut d i f fer f rom th e TCAs by th ei r lack o frecept or -blo ckin g act iv i ty at H

1, acetylch ol in e-M and n or ad ren al in -

1 and -2 recept o rs. Th ey sh ou ld also lack m em br ane-stabilising activity.Th ey sh ou ld th erefor e not cause sedat io n o r po stu ral hypo tension orfatal i ty in overd o se.

Venlafaxine

Structure and mechanism of action

Venlafaxine is a b icyc l ic com p ou nd . I t is abo ut f ive t im es m or e po tent

in b lock ing th e reuptake of 5-H T th an t hat o f nor adrenal in in th e body(see Table 26.1). I t has also a weak act ion blocking the reuptake ofdo pam ine. At low do ses (u p to 75 m g daily) i ts act ion s resem ble th oseof SSRIs , but a t h igher doses (up to 300 mg da i ly ) i t a lso b locksno radrenalin and to som e extent d op am ine reuptake.

Clini cal uses

I t h as been stu d ied m ain ly in dep ression . At lo w do ses (75 m g da ily )i t is sim i lar in ef f icacy to f lu o xet ine. H ow ever, at h igh er d o ses ( 150t o 3 0 0 m g d a i l y ) i t i s m o r e e f f e c t i v e t h a n f l u o x e t i n e i n s e v e r ed e p r e s s i o n i n c l u d i n g i n - p a t i e n t s a n d t h o s e w i t h m e l a n c h o l i cdepress ion. A t these h igher doses, i t i s s imi lar in e f f i cacy to theb roade r - spec t rum T CA s such as i m i p ram i ne and c l om i p ram i ne .Ven lafaxin e is also effect i ve in gen eral ised anxiet y disor d er, w h ere i tis used at a d ose of 75 m g d ai ly

TTTTT a b l e 2 6 . 2a b l e 2 6 . 2a b l e 2 6 . 2a b l e 2 6 . 2a b l e 2 6 . 2 C o m m o n s i d e - e f f e c t s o f r e b o x e t i n eC o m m o n s i d e - e f f e c t s o f r e b o x e t i n eC o m m o n s i d e - e f f e c t s o f r e b o x e t i n eC o m m o n s i d e - e f f e c t s o f r e b o x e t i n eC o m m o n s i d e - e f f e c t s o f r e b o x e t i n e

Sid e - e ffe c t P lace b o - ad ju st e d (% )

D r y m o u th 1 1C o n st ip at io n 9

In so m n ia 9

Sw e at in g 7

Im p o t e n c e 5

Tach y car d ia 3

U r in ar y h e sitan cy 3

Ve r t igo 2

I n t h is a n d o t h e r t a b l e s t h e r a t e o n p l ac e b o is su b t r a ct e d f r o m t h e r a t e o n d r u g ,so t h at a fig u r e fo r n u m b e r s n e e d e d t o h ar m ( N N H ) can b e c alc u lat e d ( se e

c h a p t e r 5 ) .


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THEDRUGS

Side-effects

D iscon tin uat io n rates for adverse events are sim i lar t o th ose for SSRIs

at lo w er d oses and alm ost as h igh as for TCAs at h igher d oses ( seeTable 26.3).


Venlafaxine is wel l -absorbed after oral administrat ion. I t is subjectto f i rst-pass metabol ism, producing an act ive metabol i te, desmethyl-venlafaxine, which is pharmacological ly simi lar. I ts el iminat ion hal f-l i fe of abou t 4 h ou rs is sh or t, an d i ts act ive m etabo l i te h as a h al f-l i fe ofo nly abo u t 8 h ou rs. Th is m eans i t is usually adm in istered tw ice dai ly,and is l iable to pr od uce discont inu at ion pr ob lem s. The star t in g do se is37.5m g tw ice dai ly. A su stained-release (X L) for m u lat io n (75 m g an d150 m g cap su les) is also available for o n ce daily use. Th e do se can beincreased gradual ly to a maximum of 375 mg dai ly (225 mg for XLform) .

ToxicityO verd oses pr od uce tach ycard ia and Q T p ro lon gat ion , and seizur es( 0.3%) h ave been r epo rt ed. Fatal i ty is rare.

Interactions

I t is dem ethylated and also h ydro xylated (b y CYP I ID 6). I t d oes no ts ign i f i cant ly inh ib i t cy tochrome CYP enzymes. Tox ic in terac t ions

(seroton in syndro m e) w i th MAOIs are to be expected.


Severe discont inuat ion symptoms have been reported, resembl ingth ose of SSRIs (see chapter 25), even after m issin g on ly on e or tw od oses. Th is m ay ref lect bo th th e sh or t h al f-l i fe an d a st im u lan t act io nar ising f rom do pamin e reuptake inh ib i t ion. Af ter 6 w eeks or m ore o f

TTTTT a b l e 2 6 . 3a b l e 2 6 . 3a b l e 2 6 . 3a b l e 2 6 . 3a b l e 2 6 . 3 S i d e - e f f e c t s o f v e n l a f a x i n eS i d e - e f f e c t s o f v e n l a f a x i n eS i d e - e f f e c t s o f v e n l a f a x i n eS i d e - e f f e c t s o f v e n l a f a x i n eS i d e - e f f e c t s o f v e n l a f a x i n e

Sid e - e ffe c t Place b o - ad ju ste d (% )

N au se a 2 5So m n o le n c e 1 4

D iz z in e ss 1 2

D r y m o u th 1 1

Sw e at in g 1 0

Se x u al d y sfu n c t io n 1 0

In so m n ia 9

C o n st ip at io n 9

A st h e n ia 7

N e r vo u sn e ss 7Raise d b lo o d p r e ssu r e 5 (at d o se s ab o v e 2 0 0 m g)

Se iz u r e s 0 .3


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I t is rap id ly abso rb ed b u t after f i rst-p ass m etabol ism o nly abo ut 50%reaches the systemic circulat ion. The el iminat ion hal f- l i fe is 2040

h ou rs ( lo n ger in th e elderly) , so th at steady-state levels are r eachedafter 49 days. I ts m etabo l ism in t h e l iver is by fou r o r m or e di f ferentcytoch ro m e CYP enzym es, and th e m etabo li tes h ave l i t t le or n o activity.

Th e start in g d ose is 1530 m g. I t is claim ed t h at sedatio n is less w iththe higher dose. The opt imal dose is 1545 mg taken at n ight , form ost pat ients.

Toxicity

O verdo ses h ave resu l ted in sedation , bu t n o r epo rt ed card iovascularor ECG changes. The ra te o f se izures repor ted is lower than forimipramine.

Interactions

Mirtazapine is only about 85% bound to p lasma proteins, and onlyweakly inhib i ts cyto chro m e CYP enzym es. I ts p ot ent ia l for p harm aco-

k inet ic in terac t ions w i th o th er dr ugs is therefore low. I t sho uld no t b epr escr ibed w i th , or wi t h in 14 days of sto p pin g, an M AOI.

It in terferes ph arm acod ynam ically w ith th e action s of clon idin e, w hichare exerted via -2 recept or s.

Discontinuation reaction

No ne h as been repo rted and th e lon g hal f -l i fe sh ou ld h elp avoid th isp ro blem . Mir tazap in e is avai lable as tablets o f 30 m g.

Mianserin

Mianserin ( Bolv idon , Norval ) w as w i thd rawn f rom the UK m arke tafter th e intr od uct ion of m irtazapin e. I t is sedative and pr od uces weightgain. Bon e m arro w dep ression wi th agranu locytosis occurred in abou ton e in 5000 pat ients and was m or e com m on in th e elder ly, tend ing tooccur a f ter 46 weeks o f t reatment and be ing usual ly revers ib le .

Arth ralgia, p olyarth ro p ath y and rash es also o ccurr ed.

SEROTONINANTAGONISTAND REUPTAKEINHIBITORS

Nefazod on e h as com p lex act ion s bu t i ts m ain on es h ave led to i t beingclassed an SARI. Trazodone can be included in the same class. Bothd ru gs blo ck 5-H T-1A an d 5-H T-2, as w ell as H

1and no radr enal in -1

an d -2 r ecep to rs.

Trazodone

Trazod o ne w as develop ed in t h e 1970s fro m anim al m od els based o naversive cond i t ion ing, and is no t ef fect ive in o th er anim al m od els ofdep ression . I t d oes no t d ow nr egulate no radr enal in -recep to rs as m o stot h er ant idep ressant s do.


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THEDRUGS

Str ucture and mechanism of action

I t is a p hen ylp iperazine, wi th com p lex ph arm acological act ion s (seeTable 26.1) . I t b lock s th e reup take o f 5-H T, and block s m or e p ot ent ly

5-HT-2A and noradrenal in -1 receptors, and less potent ly H 1 an dnoradrenal in -2 recept or s. It also blo cks sub typ es of 5-H T-1 recept or s,bu t i t s m etabo l i te m eta-chlo ro ph enylpip erazine ( m CPP) is an agon istat 5-H T-1, -2A and -2C recepto rs and m ight ot h erw ise in crease an xiety.Trazodone lacks anticholinergic activity.

Clini cal uses

I t was used extensively in the US as an ant idepressant before the

in tr o d u ctio n o f SSRIs. Like t h e SSRIs, i t t en d s to be less effective th anbroader-spectrum d ru gs such as venlafaxine and am itr ipt yline. It r em ainsin use for i ts sedative pr op ert ies, esp ecial ly in d epr ession , an d i t alsoim p ro ves anxiety. I t h as been show n to be ef fect ive in bu l im ia ner vosabu t n ot in O CD. Th e star t in g do se is 150 m g at n ight , increasing to atleast 300 m g, w i th th e m ax imu m do se be ing 600 m g ( for th e e lder ly100 m g increasing to 300 m g m ax im um ).

Side-effects

Th e m ost com m on side-effects are sedation and p ostural h ypo tension .It red u ces REM sleep . Sexual sid e-effects in clu d e per sisten t er ectio n s,an d even d an gerou s p riapism . Th is usual ly occurs early in tr eatm entand men should be warned to d iscont inue t razodone i f pers is tente rect i on s occu r spo n t aneo usl y. I n wo m en , i nc reased l i b i d o andsp on taneou s or gasm can occur.

Rarely reported s ide-ef fects inc lude chronic act ive hepat i t is andagranulocytosis.


I t is m or e than 90% pro tein-bo un d in p lasm a and is m etabo l ised in th el iver p art ly by CYP IID 6, w ith a h al f-l i fe of 59 hou rs. Th e m etabo l i tesin clud e m -CPP, w h ich h as a half-l i fe o f 414 ho ur s.

Toxicity

Even w ith large o verd o ses fatal i t ies are rare u n less tr azod o n e is takenin com bin at ion w i th ano th er CNS dep ressant . Pat ients sho uld haveth e ir b lood p ressure m on i tored.

Interactions

I t potent ia tes o ther CNS depressants , and inh ib i ts the ac t ions o fc lon id ine. I t has po tent ial to cont r ibu te to seroton in syndro m e, butth is h as been rare.


Withdrawal should be tapered over one month, as react ions occurw it h m alaise, m yalgia, n ausea an d r estl ess legs. Trazod o n e is availabl e


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as tablets of 150 mg; CR tablets of 150 mg; capsules of 50 mg and100 m g; and l iqu id at 50 m g/5 ml .

NefazodoneStructure and mechanism of action

Th is is also a ph enylpip erazine, related to trazod on e. It p ot ent iates 5-H T(and to a lesser extent n oradrenalin) transm ission by inh ibit ing r eup take,and it blo cks 5-H T-2A recep to rs. Th e overall effect is to increase 5-H T-1(and 5-HT-3) function. Blocking H

1receptors, it is sedative but less so

th an t razod on e. It also b locks nor adr enalin -1 and -2 receptor s. It hasactive m etabo lites, w ith sim ilar pr opert ies, and also m CPP.

Clini cal uses

It is an an tid epr essant w ith sedative pro pert ies. It also im p ro ves anxiety,includin g panic disor der. It im p ro ves sleep w ith an in crease in REM sleep .

Side-effects

Th e m ain o nes are som no lence, p ostur al h ypo ten sion , tho se associated

with SSRIs, weight gain, weakness and palinopsia (visual streaking).Blocking 5-HT-2A receptors. I t is dist inguished by i ts lack of sexualsid e-effects an d can h elp to cou n ter act sexual sid e-effects exp erien cedon ot h er d r u gs (see Table 26.6).


I t is rapid ly absorbed but extensively metabol ised, and mCPP is a

m etabo li t e; th is is an agon ist at 5-H T-1, -2A an d -2C recept o rs an d cancause anxiety. More is formed i f the CYP I ID6 enzyme is reducedeith er gen etical ly o r b y ot h er d ru gs su ch as SSRIs.

T he ha l f - l i f e o f ne fazodone i s 24 h o u r s , b u t l o n g e r f o r t h emetabol i tes . The in i t ia l dose is 100 mg tw ice da i ly (50 mg in theelderly) , increasing by 50100 m g tw ice dai ly each w eek to a do se of300600 m g daily (less in th e elder ly) . It can also b e given as a sin gledo se at n ight .

Toxicity

I t ap p ears to be safe in o verdo se an d for use in ep i lepsy. Ther e is l i t t leinfor m at ion on i ts use in p regnancy.

TTTTT a b l e 2 6 . 6a b l e 2 6 . 6a b l e 2 6 . 6a b l e 2 6 . 6a b l e 2 6 . 6 C o m m o n s i d e - e f f e c t s o f n e f a z o d o n eC o m m o n s i d e - e f f e c t s o f n e f a z o d o n eC o m m o n s i d e - e f f e c t s o f n e f a z o d o n eC o m m o n s i d e - e f f e c t s o f n e f a z o d o n eC o m m o n s i d e - e f f e c t s o f n e f a z o d o n e

Sid e - e ffe c t Place b o - ad ju ste d (% )

D r y m o u th 8

So m n o le n c e 6

D izz in e ss 6

N au se a 6

C o n st ip at io n 3

B lu r r e d v isio n 3

Po stu r al h y p o te n sio n 3


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THEDRUGS

Interactions

I t is a w eak inh ib i tor of CYP I ID 6 and IA2. I t is a po tent inh ib i to r o f CYPIIIA4, and sh ou ld n ot be given w ith terfenadin e, cisapr ide o r cyclospo rin ,

a n d u s e d c a u t i o u s l y w i t h a l p r a z o l a m a n d p e r h a p s o t h e rbenzod iazepines. I t sho uld no t be com bined w i th M AOI s.


I t shou ld be w i thdrawn s low ly , because o f i t s shor t ha l f - l i f e andsero to ner gic pr o p ert ies. Nefazodo ne is avai lable as tablets of 100 m gand 200 m g and a star ter p ack w i th 50 m g.

DOPAMINEANDNORADRENALINREUPTAKEINHIBITORS

Th e fi rst D NRI was no m ifensine, bu t i t was w i th dr aw n. Bupr op ion isan ot h er D NRI, used in th e US as an an tid epr essan t, an d also u sed as anaid to stop sm ok ing.

Bupropion

Str ucture and mechanism of action

I t is a unicycl ic aminoketone. Bupropion does not have a t r icyc l icstru ctur e. As a resu lt i t h as l i t t le blo ckin g effect o n r ecep to rs. Bup ro pio ni tsel f inh ib i ts th e reupt ake of do p am ine and no radr enal in bu t w eakly.I t is m etabol ised to h ydroxybupr op ion, wh ich is a m ore po tent inh ibi tor.

Clini cal uses

I t is preferred for use in b ipo lar d epression and retard ed o r atypicald ep ressio n , because it h as activatin g pr o p ert ies. It m ay carr y less ri skof induc ing mania . I t i s used (as amfebutamone) to ass is t in thediscon t inu at ion of c igaret te sm ok ing, i ts on ly l icensed ind icat io n inth e UK. I t m ay im pr ove AD H D in ch i ld ren and adu l ts.

Side-effects

These are most ly due to dopamine over-st imulat ion. They inc ludenausea, insomnia, agi tat ion, dry mouth, dizziness, weight loss andp sycho sis. It p ro d u ces few er sexu al sid e-effects th an an y SSRI. It d o esn ot red u ce REM sleep.


I t is m etabo l ised m ainly by CYP II D 6 and th e term inal hal f-l i fe is abo u t

14 ho ur s. The m axim um do se is 400 m g daily.

Toxicity

I t lo w ers th e seizur e thr esh old in a dose-dep end ent m ann er, and f i tsoccur in up to 0.5% of people over 2 years. Overdoses lead to f i ts,hal lucinat ions, tachycardia and loss of consciousness; deaths haveoccu r red . T hose seve re adve rse reac t i ons seem to occu r morefrequent ly du r ing u se in sm ok ers.


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USE OF DRUGS

278

Interactions

I t should be used caut ious ly w i th o ther drugs that may lower theseizur e thr esh old , inc lud ing ot h er ant idep ressant s. I t sh ou ld n ot be

used in com binat ion wi t h d op am ine agon ists or M AOIs. I t in creasesvalp ro ate levels. Its o w n l evel is d ecreased b y carb am azepin e.


It sh ould be w ith dr aw n slow ly. It is available as tablets ( Zyban : m od i fiedrelease) 150 mg.

FURTHERREADING

Berm an, R. M., Narasim h an, M., Anand , A., et a l (1999) Transient dep ressive relapseind uced by catecholamin e deplet ion. Archi ves of Gen er a l Psychia tr y, 5656565656, 395403.

Leonard, B. & Richelson, E. (2000) Synapt ic effects of ant idep ressant s: relat ion shi p to

th eir th erapeu t ic and adverse effects. In Sch izoph ren i a an d Mood D i so r der s: The

New Dr u g Thera pies in Cl in ica l Pra ctice, pp . 6784. Oxford: Butterworth H einem ann.Sach s, G. S., Lafer, B., Sto ll , A. L., et a l (1994) A do uble-b l ind t r ial o f b up rop ion versus

desipram ine for b ip olar depression . Jou r n a l o f Cl i n i ca l Psychia t r y , 5555555555, 391393.

Wilens, T. E., Spencer, T. J., Bied erm an, J., et a l(2001) A cont rolled clinical trial of bupr op ionfor at tent ion def ic it h yperact iv ity d isorder in adu l ts. Am er i can Jou r n a l Psych ia t r y ,

1 581 581 581 58158, 282288.

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