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Serotonin syndrome
Shameem Mir and David Taylor

Aimsand method To define serotoninsyndromeand malignant syndrome (Lane & Baldwin, 1997):
its symptoms and to discover which drugs or drug the two syndromes share some features and
combinations are likelyto cause it. A review of literature may be difficult to distinguish. Gillman (1999)
(including case reports) relating to serotonin syndrome has helpfully observed that hyperkinesia is
collated from searches of MedlJne and Micromedex common to serotonin syndrome, but that
covering the period January 1991to July 1998. bradykinesia often characterises neuroleptic
Results Most of the data found were either individual malignant syndrome.
case reports or reviews of case reports. Reports of
serotonin syndrome seem to be growing, certainly since
the introduction of selective serotonin reuptake Causes of serotonin syndrome
inhibitors. Particular combinations seem most likely to
induce serotonin syndrome. Awareness of thissyndrome Theoretically, any drug or combination of drugs
as a distinct clinical entity seems to be growing. that result in a net increase in central seroto
Clinical implications Serotoninsyndromeismore likely nergic neurotransmission have the potential to
to occur with drug combinations, especially those induce serotonin syndrome.
In Sternbach's (1991) review of 38 reports of
involving monoamine oxidase inhibitors. It can also
occur when swapping antidepressant therapy, serotonin syndrome, 35 were a result of combi
especially if changing from a long acting anti- nation therapy. The most commonly reported
depressant such as fluoxetine. Caution isneeded when drug combination to be associated with seroto
changing antidepressants and particularly when they
nin syndrome was that of L-tryptophan and a
are used in combination. monoamine oxidase inhibitor (MAOI), with or
without lithium. This was followed in frequency
by a combination of fluoxetine and MAOIs or L-
tryptophan (note that this review essentially pre
Serotonin syndrome appears to be a new dates widespread use of selective serotonin
phenomenon. Certainly, awareness of this syn reuptake inhibitors (SSRIs)).
drome seems to have increased in the last In a later review. Lane & Baldwin (1997) found
decade. Early reports date back to the 1950s the most profound serotonin syndrome reactions
and often describe adverse effects of serotonergic had been reported with a combination of MAOIs
agents rather than defining a particular syn and SSRIs. Their review focused on SSRI-
drome (Gillman, 1999). Sternbach (1991) was induced serotonin syndrome, the findings of
the first to collate and review these case reports. which are summarised and updated in Table 1.
In this review, Sternbach suggested certain Gillman's still later review (1999) notes the
criteria for the diagnosis of 'serotonin syndrome' occurrence of serotonin syndrome even with
(see Appendix), thus helping clinicians to recog short-acting MAOIs such as moclobemide in
nise its symptoms and so ultimately furthering combination with fairly weak serotonin reuptake
knowledge about it. inhibitors such as pethidine and imipramine.
The incidence of serotonin syndrome is un Thus, it seems virtually any combination of
known; one possible reason for this is that serotonergic drugs can cause serotonin syn
symptoms still go unrecognised, particularly drome.
the milder symptoms, and it is therefore likely Serotonin syndrome has also been described
to be under-reported. with other drug combinations. For example,
True symptoms of serotonin syndrome include with sertraline and amitriptyline (Alderman &
mental state changes (confusion, hypomania), Lee, 1996), phenelzine and dextromethorphan
agitation, myoclonus, hyperreflexia, diaphoresis, (Nierenberg & Semprebon, 1993), a combination
shivering, tremor, diarrhoea, incoordination and of SSRIs (Lane & Baldwin, 1997) and nefazodone
fever. These are sometimes mild and usually with sodium valproate (Brazelton et al, 1997).
occur within a few hours of a dose or drug Also, since its recent introduction, there have been
change. In some, however, symptoms can be a number of reports of serotonin syndrome with
more severe and in a very few the syndrome venlafaxlne in combination with tranylcypromine
can be fatal. Symptoms of serotonin syndrome (Brubacher et al 1996; Hodgman et al 1997),
are often confused with those of neuroleptic phenelzine (Weiner et cd, 1998) and fluoxetine

742 Psychiatric Bulletin (1999), 23, 742-747

 DRUG INFORMATION QUARTERLY

Table 1. Selective serotonin reuptake inhibitor (SSRI)induced serotonin syndrome adapted from Lane
& Baldwin (1997)
Drug combined with serotonin
reuptake inhibitor Comments

Lithium In practice, generally well tolerated. However, there are reports of serotonin
syndrome with the following combinations: fluoxetine and lithium (Muly et
al. 1993); trazodone, lithium and amitriptyline (Nisijima et al. 1996). lithium
and paroxetine (Sobanski et al. 1997) and lithium and venlafaxine (Mekler &
Woggon, 1997).

L-tryptophan Many reports of serotonin syndrome (see Sternbach, 1991).

Buspirone May be used to augment SSRItherapy and treat antidepressant-induced

sexual dysfunction. There have been two reports of serotonin syndrome,
but combination generally well tolerated.

Trazodone Serotonin syndrome has been reported, this combination should be

Nefazodone avoided.

Selegiline (selecive MAO-B inhibitor) Appears to be well tolerated as MAO-A shows a preference for the
metabolism of serotonin. Manufacturers warn against the use of SSRIswith
selegiline.

Moclobemide Serotonin syndrome has been reported, combination is potentially toxic,

although Hilton et al (1997) found moclobemide safer than older MAOIs.
This was later supported by Dingemanse et al (1998) who found
moclobemide and fluoxetine to be a safe combination in 18 subjects.

Opiates Serotonin syndrome has been reported with a combination of an SSRIand

pentazocine, morphine, tramadol and dextromethorphan (found in some
cough mixtures). Case reports of serotonin syndrome have been described
for tramadol and paroxetine (Egberts et al, 1997) and tramadol and
sertraline (Mason & Blackburn, 1997).

Sumatriptan (5-HT, agonist) Although serotonin syndrome has been reported, sumatriptan has been
shown to be well tolerated with SSRIs and moclobemide, lithium and
buspirone. However, the risk is unclear as sumatriptan can give rise to
similar symptoms as serotonin syndrome when given alone. See Gardner &
Lynd (1998) for a review of use of sumatriptan with SSRIs,lithium and MAOIs.

Dihydroergotamine (5-HT1Aagonist) Serotonin syndrome has been reported. Crosses the blood-brain barrier
more readily than sumatriptan.
MAO-A, monoamine oxidase-A; MAO-B. monoamine oxidase-B; MAOI. Monoamine oxidase inhibitor.

(Bhatara et al 1998). In general, with all drugs the use, for example, with L-tryptophan and with
more severe cases involve the use of MAOIs. fluvoxamine (Lejoyeux et ai, 1994) and more
Serotonin syndrome can also result from recently with clomipramine (Rosebush & Mar-
changing drug therapy. Table 2 provides some getts, 1999). Serotonin syndrome has also been
illustrative examples of switching-induced sero reported as occurring following use of 3,4-
tonin syndrome. methylenedioxymetamphetamine (MDMA or
It is worthy of note that not all the cases Ecstasy) (Demirkiran et al 1996; Mueller &
of serotonin syndrome listed above involved Korey, 1998). Serotonin syndrome is thus likely
changing to or from an MAOI. Indeed, a straight to present in casualty departments as well as in
swap (generally from fluoxetine) to another SSRI psychiatric practice.
can clearly induce serotonin syndrome. Reports of serotonin syndrome with drug
Apart from combination therapy and changing overdoses are rare, but in many cases, fatal.
drug therapy, serotonin syndrome has also Neuvonen et al (1993) reported five fatal cases of
been reported, albeit rarely, with single drug serotonin syndrome with the combination of

Serotonin syndrome 743

DRUG INFORMATION QUARTERLY

Table 2. Reports of serotonin syndrome as a result of changing drug therapy

Drug -> drug Comments
Clorgiline (MAO-A inhibitor) -»clomipramine Clomipramine started four weeks after Clorgiline was discontinued
(Sternbach, 1991) -»serotonin syndrome

Fluoxetine -»MAOIs (Lejoyeux et al, 1994) Serotonin syndrome has been demonstrated when MAOIs have
been given less than five weeks after discontinuation of fluoxetine
Clomipramine -> moclobemide (Spigset & Clomipramine stopped, moclobemide started, next day -»serotonin
Mjorn-Dal, 1993) syndrome
Fluoxetine -»moclobemide (Benazzi, 1996) Fluoxetine 20 mg stopped and moclobemide 150mg started the
next day -»serotonin syndrome

Trazodone -> nortriptyline (Fink, 1996) Trazodone 150mg twice daily stopped and three days later
nortriptyline started -> serotonin syndrome

Fluoxetine -»sertraline (Bhatara & Fluoxetine stopped and sertraline started after a 24-hour washout
Bandettini, 1993) -> serotonin syndrome

Fluoxetine -»paroxetine (Mills, 1995) Fluoxetine stopped and two days later paroxetine started
-»serotonin syndrome

Fluoxetine -»venlafaxine (Bhatara, 1994) Fluoxetine 30 mg stopped abruptly and venlafaxine 37.5 mg twice
daily started, 24 hours later -> serotonin syndrome

Moclobemide -»clomipramine (Gillman, Moclobemide 750 mg daily stopped and clomipramine 50 mg

1997) daily started 12 hours later -> serotonin syndrome

Selegiline -> venlafaxine (Gitlin, 1997) Sodium valproate, selegiline and nortriptyline stopped and 16 days
later venlafaxine 37.5 mg daily started -> serotonin syndrome within
six hours
Nefazodone -»paroxetine (John ef a/, Nefazodone withdrawn gradually and paroxetine started one day
1997) after the last dose of nefazodone
Phenelzine -> venlafaxine (Diamond et al, Four reports of serotonin syndrome when patients were swapped
1998) from phenelzine to venlafaxine

moclobemide and citalopram or moclobemide mechanism is generally thought to involve

and clomipramine. Also, Singer & Jones (1997) brainstem and spinal cord activation of 5-HT1A
describe one case of fatal serotonin syndrome receptors (Sternbach, 1991), although stimula
from an overdose of moclobemide and paroxetine. tion of 5-HT2A receptors may also be causative
Overall, there have been 23 deaths reported to be (Gillman, 1999).
linked to serotonin syndrome in the last 10 years The combination of MAOIs and SSRIs appears
(Gillman, 1999). This probably represents an to be particularly toxic. This is probably a result
underestimate of the total number, since many of simultaneous blockade of serotonin reuptake
cases may not have been reported because of by SSRIs and the inhibition of serotonin degrada
medico-legal reasons. tion by MAOIs, leaving essentially no mechanism
Surprisingly, there have been reports of recov to control serotonin concentration in the synapse.
eries after overdose with moclobemide and clomi
pramine (Francois et al, 1997) and moclobemide
and venlafaxine (Roxanas & Machado, 1998). Managing serotonin syndrome
Serotonin syndrome is often self-limiting and
symptoms usually resolve within 24 hours of
Biochemical mechanism of serotonin discontinuing the causal agent. Severe cases
syndrome may require the use of a serotonin antagonist
A number of possible mechanisms underlying or supportive care. The management will,
serotonin syndrome have been suggested. The therefore, largely depend on the symptoms of

744 Mir & Taylor

 DRUG INFORMATION QUARTERLY

Table 3. Summary of suggested management of serotonin syndrome

Treatment Drug Comments

Sedatives Lorazepam or diazepam Has been used as a sedative and is usually hypothermie
Chlorpromazine but may further lower seizurethreshold (fairly potent
antagonist).
Serotonin
antagonistsAnticonvulsants 5-HTreceptor antagonist.
Chlorprothixene 5-HT2Aantagonist; not used in UK.
antagonist.of
5-HT,Areceptor
PropranololBenzodiazeplnesHyperthermla

Cooling blanketCyproheptadine is usually a sign severe serotonin syndrome and so carries risk
of complications and death.Non-specific
aggressive therapy is needed.higher

serotonin syndrome is summarised in Table 3 Discussion

and reviewed fully by Brown et ai (1996), Lane & Awareness of serotonin syndrome and its
Baldwin (1997) and Gillman (1999). Note that symptoms has rapidly increased and it is now a
treatments have a largely theoretical basis; none recognised adverse effect of antidepressant
has been robustly, clinically tested. therapy. The symptoms are often mild, but in
some can prove fatal.
The risk of serotonin syndrome is difficult to
Avoiding serotonin syndrome establish, but from the available literature it
Many of the episodes of serotonin syndrome appears that combinations including an MAOI
reviewed in this article could have been avoided. are likely to be more toxic than others and
Many recommended drug combinations aim should therefore probably be avoided, except in
specifically to increase serotonergic function specialist centres treating refractory depression.
and so predictably increase the risk of serotonin In addition, when changing drug therapy, wash
syndrome. Combinations including MAOls and out periods may be necessary before starting the
L-tryptophan should therefore be used with new drug.
extreme caution. Management of serotonin syndrome in most
A combination of two drugs can also occur cases is simple, the first step being to discontinue
inadvertently, for example, when changing drug drug therapy after which in many cases, symp
therapy from a drug with a long half-life. In such toms resolve within 24 hours. In theory, more
cases, there may also be the potential for a severe cases may require a serotonin antagonist
pharmacokinetic interaction which may increase such as chlorpromazine, cyproheptadine or pro-
the risk of serotonin syndrome, for example, if pranolol (for which there is largely only a
both drugs are serotonergic in action and one theoretical basis for their use) and where appro
inhibits the metabolism of the other. When priate supportive measures should be provided.
changing drug therapy, the half-life of the dis
continued drug should be taken into considera
tion as well as potential pharmacodynamic and Appendix
perhaps, more importantly, pharmacokinetic
interactions between the old and new drug. For Diagnostic criteria, for the serotonin syndrome
example, SSRls are not only potent inhibitors of (Sternbach. 1991)
serotonin reuptake, but some, such as, fluox-
(a) Coincident with the addition of or an
etine. paroxetine and fluvoxamine are also potent increase in dosage of a known serotonergic
inhibitors of the cytochrome P450 isoenzyme
agent to an established medication regi
system and therefore have the potential to men. At least three of the following clinical
increase levels of other serotonergic drugs. Indeed,
features must be present:
all SSRIs (except citalopram) have been shown
significantly to increase tricyclic plasma levels (a) mental status changes (e.g.
when given in combination (Taylor, 1995). There confusion, hypomania);
fore, when considering switching from a drug with (b) agitation;
a long-half, such as fluoxetine, long wash-out (c) myoclonus;
periods are often necessary in order to avoid the (d) hypereflexia;
risk of serotonin syndrome. Shorter wash-out (e) diaphoresis;
periods may be necessary with other SSRIs. (f) shivering;

Serotonin syndrome 745

DRUG INFORMATION QUARTERLY

(g) tremor; GILLMAN,P. K. (1997) Serotonin syndrome - clomipramine

(h) diarrhoea; too soon after moclobemide. /ntema(ionol Clinical
Psychopharmacologu, 12. 339-342.
(i) incoordination; —¿(1999) The serotonin syndrome and its treatment.
(j) fever. Journal of Psychopharmacology, 13, 100-109.
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(c) An antlpsychotic drug has not been syndrome and drug combinations: focus on MAOI and
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Neurosciences, 247, 113-119.
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HODGMAN,M. J., MARTIN,T. G. & KRENZELOK.E. P. (1997)
Serotonin syndrome due to venlafaxine and
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Experimental Toxicology, 16. 14-17.
JOHN, L., PERREAULT.M. M.. TAO, T., et al (1997) Serotonin
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BRUBACHER,J. R.. HOFFMAN,R. S. & LURIN.M. J. (1996) Serotonin syndrome produced by a combination of
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746 Mir & Taylor

 DRUG INFORMATION QUARTERLY

TAYLOR.
D. (1995) Selectiveserotonin reuptake inhibitors Shameem Mir, Senior Clinical Pharmacist: and
and tricyclic antldepressants In combination: »David Taylor, Chief Pharmacist, Maudsley
Interactions and therapeutic uses. British Journal of u •¿i »
r> i LT-II r j oc-c 0/1-7
Psychiatry, 167, 575-580. Hospital. Denmark Hdl London SES 8AZ
WEINER,L. A.. SMYTHE. M. & CISEK,J. (1998) Serotonin
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Interaction. Phormacotherapy, 18. 399-403. 'Correspondence

Recent Topics from Advances in Psychiatric Treatment, Volume 2

Affective and Non-Psychotic Disorders
Edited by Alan Lee
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Serotonin syndrome 747