INTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY

Int J Geriatr Psychiatry 2001; 16: 484±493.

DOI: 10.1002/gps.367

Hyponatraemia and selective serotonin re-uptake inhibitors in

elderly patients
Dianne Kirby1 and David Ames2*
1
Senior Registrar in Psychiatry, Caul®eld General Medical Centre, Caul®eld, VIC 3162, Australia
2
Associate Professor of Psychiatry of Old Age, Department of Psychiatry, Royal Melbourne Hospital, VIC 3050, Australia

SUMMARY
Hyponatraemia (serum sodium arbitrarily de®ned as less than 135 mmol/L) is an increasingly recognised adverse effect of
selective serotonin re-uptake inhibitors (SSRIs). Its precise prevalence and incidence in the elderly are hard to determine
because of confounding factors including other prescribed medications and medical conditions. Although hyponatraemia
has been reported with all SSRIs and venlafaxine, most studies are small, restrospective, limited by confounding variables or
are individual case reports. The risk of developing hyponatraemia while on an SSRI seems to increase with age, female, sex,
previous history of hyponatraemia and the concomitant use of other medications known to include hyponatraemia. The
sodium concentrations of most patients with SSRI associated hyponatraemia return to normal within days to weeks of SSRI
withdrawal. A few cases of SSRI rechallenge indicate that hyponatraemia may sometimes be a transient effect with tolerance
developing over time. There is an urgent need for controlled, rigorous studies to con®rm the extent of the association
between SSRIs and hyponatraemia. Older drugs such as tricyclic antidepressants also need systematic study. It remains quite
unclear whether any speci®c SSRI or venlafaxine has a stronger association with hyponatraemia than any other antidepres-
sant drug. Copyright # 2001 John Wiley & Sons, Ltd.

key words Ð Hyponatraemia; selective serotonin reuptake inhibitors (SSRIs); elderly

INTRODUCTION tive studies which suggest there may be a higher inci-

Selective serotonin re-uptake inhibitors (SSRIs) are a
common treatment for depression in the elderly (Pre-
skorn, 1996), because of their favourable side-effect
pro®le and their relative safety in overdose. However,
an increasingly recognized adverse effect is that of
hyponatraemia, possibly due to the syndrome of inap-
propriate secretion of antidiuretic hormone (SIADH).
Although ®rst recognized with ¯uoxetine, all SSRIs
have been associated with hyponatraemia (Hwang
and Magraw, 1989; Bouman et al., 1998). Systematic
and controlled studies are lacking. Most information
comes from case reports and a few limited retrospec-
*Correspondence to: Prof. D. Ames, Department of Psychiatry, 7th
Floor, Charles Connibere Building, Royal Melbourne Hospital,
VIC 3050, Australia. Tel: ‡ 61 3 9342 2515. Fax: ‡ 61 3 9379
3120. E-mail: cain@unimelb.edu.au
Copyright # 2001 John Wiley & Sons, Ltd.
dence of SSRI-induced hyponatraemia in the elderly
and that trials excluding the elderly, together with a
reliance on voluntary reporting of this adverse effect,
may have underestimated its risk (Liu et al., 1996;
Bouman et al., 1998).
SELECTIVE SEROTONIN REUPTAKE
INHIBITORS (SSRIs)
Currently ®ve SSRIs are available for use in Austra-
lia: ¯uoxetine, sertraline, paroxetine, ¯uvoxamine
and citalopram. Venlafaxine, the only available sero-
tonin and noradrenaline re-uptake inhibitor (SNRI)
antidepressant, is also widely used, but mirtazapine
is unavailable here.
All ®ve SSRIs show a selective blockade of pre-
synaptic serotonin re-uptake, thus potentiating the
action of serotonin (5HT). They differ in chemical
Received 14 June 2000
Accepted 19 September 2000
 hyponatraemia and ssris
structure and pharmacokinetics (Bauman and Rochat,
1995; Bonwick, 1998).
Although venlafaxine inhibits the presynaptic
uptake of both serotonin and noradrenaline, its
potency in inhibiting serotonin reuptake is approxi-
mately ®ve times that of its noradrenaline re-uptake
inhibitory activity (Holliday and Ben®eld, 1995).
In low doses (75 mg/day) venlafaxine primarily inhi-
bits the presynaptic uptake of serotonin and hence
acts similarly to an SSRI (Harvey and Preskorn,
1997).
Although studies have failed to demonstrate any
clear difference in ef®cacy between classes of anti-
depressants (Hirschfeld, 1999), SSRIs and SNRIs
have in general replaced tricyclic antidepressants
(TCAs) as the ®rst-choice treatment in patients with
depression here (NIH Consensus Development Panel
on Depression in Late Life, 1992; Bauman and
Rochat, 1995; Devane, 1995; Preskorn, 1996;
Bonwick, 1998).
AGE AND REGULATION OF SODIUM
AND WATER BALANCE
Sodium and water metabolism are closely related.
Plasma osmolality and its principal determinant,
plasma sodium concentration, are normally kept
within a narrow range (280±300 mOsm/kg and
135±145 mmol/L, respectively). This is achieved
through an integrated homeostatic system that regu-
lates water intake and urine output via changes in
thirst and the secretion of antidiuretic hormone
(ADH or vasopressin). Osmoreceptors located in the
hypothalamus detect small changes in extracellular
¯uid (ECF) osmolality, while baroreceptors respond
to changes in effective circulating volume (Kovacs
and Robertson, 1992; Levinsky, 1994).
A number of physiological changes in water
homeostasis may predispose elderly people to hypo-
natraemia. This predisposition is exacerbated by
some drugs, including SSRIs (Sunderam and Manki-
kar, 1983; Miller, 1998).
In elderly people there is a reduction in total body
water, diminished renal blood ¯ow and a decrease in
glomerular ®ltration rate (GFR) (Phillips, 1996;
Sharma and Pompei, 1996; Miller, 1998). With age-
ing, renal tubular concentrating and diluting capacity
become impaired. There is a decrease in the renal
responsiveness to ADH and a decrease in renal
sodium conservation. ADH secretion may be slightly
increased and the ADH response to osmolar stimuli is
greater in the elderly than in young control subjects.
This increased osmosensitivity may increase the risk
Copyright # 2001 John Wiley & Sons, Ltd.
485
of SIADH (Phillips, 1996; Sharma and Pompei, 1996;
Chan, 1997; Miller, 1998).
HYPONATRAEMIA
De®nition
Hyponatraemia may be de®ned as a serum sodium of
134 mmol/L. The `normal' serum sodium range is
between 135 and 145 mmol/L. The early clinical
symptoms of hyponatraemia are often vague and non-
speci®c (McAskill and Taylor, 1997).
Causes of hyponatraemia
Many medical conditions are associated with hypona-
traemia. A wide range of psychotropic drugs have
been associated, although the majority of reports are
of single cases (McAskill and Taylor, 1997). SIADH
is felt to be the most important mechanism underlying
drug-induced hyponatraemia, although in many cases
the exact mechanism has not been formally elucidated
(Sharma and Pompei, 1996).
Hyponatraemia may be due to excessive water
ingestion or decreased water excretion. Episodic
polydipsia and hyponatraemia have been reported to
occur in 3±5% of patients in psychiatric institutions.
Most of these patients have, in addition to polydipsia,
some abnormality in water excretion (Kramer and
Drake, 1983; Goldman et al., 1988; Illowsky and
Kirch, 1988; Riggs et al., 1991).
The aetiologies of hyponatraemia can be classi®ed
into three types according to the patient's volume sta-
tus. Hence the evaluation of a hyponatraemic patient
®rst requires an assessment of the extracellular ¯uid
volume, which may be elevated, low or normal, lead-
ing to hypervolaemic hyponatraemia, hypovolaemic
hyponatraemia and euvolaemic hyponatraemia,
respectively (Druckenbrod and Mulsant, 1994;
Vieweg et al., 1994). Most euvolaemic hyponatrae-
mia is due to SIADH.
Syndrome of inappropriate secretion of antidiuretic
hormone (SIADH)
SIADH is the most common cause of hyponatraemia
in hospitalized patients (Wilson et al., 1998). In
SIADH, ADH or an ADH-like substance stimulates
retention of water in the absence of appropriate phy-
siological stimuli.
The cardinal signs, ®rst described by Bartter and
Schwartz (1967), are as follows: (a) hyponatraemia
(serum sodium concentration <135 mmol/L) with
Int J Geriatr Psychiatry 2001; 16: 484±493.
486 d. kirby and d. ames
corresponding hypo-osmolality of the serum and extra-
cellular ¯uid (osmolality <280 mOsm/kg water); (b)
urine osmolality >100 mOsm/kg water, particularly
if the urine is hypertonic relative to the plasma; (c)
absence of clinical evidence of ¯uid volume deple-
tion; (d) normal renal function; (e) normal adrenal
function.
Hence, the diagnosis is supported by hyponatrae-
mia and hyperosmolar urine without the development
of oedema or features of intravascular volume deple-
tion such as tachycardia or orthostatic hypotension.
The diagnosis of SIADH can only be established in
the absence of other potential causes of hyponatrae-
mia such as the use of diuretics, hyper- or hypovolae-
mia, hypothyroidism or renal dysfunction (Bartter and
Schwartz, 1967). SIADH should be suspected in
patients who develop hyponatraemia in the absence
of excessive thirst or polydipsia (Siegel et al., 1998).
The diagnosis of SIADH is not straightforward. It
is extremely dif®cult to assess minor variations in
volume status. Urinary sodium excretion varies
depending on sodium and water intake. In addition,
urine osmolality is rarely measured in clinical prac-
tice. Elevated ADH concentrations are sometimes of
value, but may be physiologically appropriate and do
not necessarily indicate SIADH (Meinders, 1993). In
addition, SIADH is not always accompanied by ele-
vated ADH concentrations (Wilson et al., 1998).
SIADH may be idiopathic or secondary to disease
or drugs. The mechanisms are often unclear. Many
cases are idiopathic (Kovacs and Robertson, 1992).
The disorders most often associated with SIADH
can be grouped into ®ve general categories: (1)
Ectopic production of ADH may occur in a variety
of malignancies. (2) Certain pulmonary disorders
are associated with excess pituitary production of
ADH. (3) Disorders of the central nervous system
(CNS) may be associated with SIADH. (4) General
surgery has been complicated by SIADH. (5) A grow-
ing number of drugs have been reported to produce
SIADH. In addition to SSRIs, most published reports
concern vasopressin and its analogues, chlorpropa-
mide, carbamazepine, antipsychotics, antidepressants
and nonsteroidal anti-in¯ammatory drugs (NSAIDs)
(Kovacs and Robertson, 1992; Ball and Herzberg,
1994; Chan, 1997).
Drugs associated with hyponatraemia
The administration of many drugs has been associated
with hyponatraemia. In most, but not all cases, this is
due to SIADH. Most reports are of single cases and it
is impossible to determine the incidence or prevalence
Copyright # 2001 John Wiley & Sons, Ltd.
of hyponatraemia induced by medications with any
accuracy (Chan, 1997).
Thiazide antidiuretics may be the commonest cause
of drug-induced hyponatraemia (Chan, 1997). Hypo-
glycaemic agents, especially chlorpropamide and tol-
butamide, have been associated with hyponatraemia,
and hypoglycaemia can itself cause inappropriate
ADH secretion (Chan, 1997).
Antineoplastic agents, NSAIDs, antiepileptics,
angiotensin converting enzyme inhibitors, vasopres-
sin analogues, dopaminergic drugs such as apomor-
phine, bromocryptine, amantadine and L-dopa,
vasopressin and its analogues, somatostatin, mor-
phine, methadone, nicotine patches, lorcainide, phe-
noxybenzamine, clo®brate, methyldopa, clonidine
and omeprazole have all been associated with hypo-
natraemia (Chan, 1997).
A number of psychotropic drugs apart from SSRIs
are associated with hyponatraemia: lorazepam, clona-
zepam, promethazine and most classes of antipsycho-
tics, although the latter have been infrequently
associated (Chan, 1997).
TCAs, monoamine oxidase inhibitors and mood
disorders themselves have all been implicated in some
cases of hyponatraemia associated with SIADH
(Spigset and Hedenmalm, 1995). There have been
no reports of hyponatraemia appearing with mian-
serin or moclobemide (McAskell and Taylor, 1997;
Spigset and Hedenmalm, 1997).
Clinical features of hyponatraemia
There is great individual variability in the relationship
between serum sodium concentration and clinical
symptoms. Symptoms of hyponatraemia generally
do not appear until serum sodium falls below
130 mmol/L. In chronic hyponatraemia, approxi-
mately 50% of patients are asymptomatic even with
serum sodium concentrations below 125 mmol/L
(Miller, 1998; Wilson et al., 1998). Mild hyponatrae-
mia is commonly asymptomatic, or the early symp-
toms are vague and nonspeci®c. The symptoms may
mimic those of depression so the diagnosis may be
missed or delayed, particularly in the elderly
(Misra and Mansharamani, 1989; Boczkowski and
Levine, 1991).
Common symptoms include lethargy, fatigue, anor-
exia, sleep disturbance, muscle cramps and head-
aches. They may progress as the hyponatraemia
worsens to include nausea and vomiting, confusion,
seizures, coma and, ultimately, death. When hypona-
traemia is symptomatic, there is substantial morbidity
Int J Geriatr Psychiatry 2001; 16: 484±493.
 hyponatraemia and ssris
and mortality but asymptomatic hyponatraemia is
often benign (Wilson et al., 1998).
Both the magnitude and rate of development of
hyponatraemia are important determinants of the
severity of clinical symptoms. The rate of fall in
serum sodium concentration is more signi®cant in
producing neurological symptoms than the absolute
magnitude of the fall (Moses and Streeten, 1994).
Elderly patients are more likely to become sympto-
matic. Severe hyponatraemia (serum sodium concen-
tration <120 mmol/L) can present as delirium and
has been associated with a mortality rate as high as
40% (Arieff et al., 1987; Hirshberg and Ben-Yehuda,
1997). Symptomatic hyponatraemia is usually asso-
ciated with cerebral oedema (Arieff et al., 1987).
Management of hyponatraemia
Treatment involves identi®cation of the underlying
cause, discontinuing causative medication(s) and cor-
recting volume abnormalities. The immediate man-
agement of hyponatraemia is dependent upon its
severity and duration. SIADH is usually treated by
¯uid restriction unless dehydration is suspected, when
normal saline infusion should be used (Arieff, 1993).
Psychotropic drug-induced hyponatraemia and
SIADH generally respond quickly and completely
to discontinuation of the causative agent and ¯uid
restriction. Rarely, patients with severe, symptomatic
hyponatraemia require treatment with intravenous
hypertonic saline (Sharma and Pompei, 1996).
Overly rapid correction of hyponatraemia risks
central pontine and extrapontine myelinolysis, spastic
quadriparesis, pseudobulbar palsy, coma and death.
For this reason the treatment, and particularly the rate
of correction, of hyponatraemia is controversial. The
patients at greatest risk of cerebral demyelination
with rapid correction of hyponatraemia are those with
severe chronic hyponatraemia (Sterns, 1990).
In the longer term, sodium concentrations should
be monitored. For antidepressants, the risk of hypona-
traemia seems highest during the ®rst weeks of
treatment. The time at risk during treatment with anti-
psychotics seems to be considerably longer (Spigset
and Hedenmalm, 1995).
In some cases (e.g. treatment-resistant depression)
it is desirable to continue treatment with the drug
implicated in causing SIADH. In such situations, a
number of methods have been tried to prevent mani-
fest hyponatraemia. Long-term ¯uid restriction has
been used successfully in some cases, although
long-term compliance is often poor. Demeclocycline,
a drug that inhibits ADH at the kidneys, has been used
Copyright # 2001 John Wiley & Sons, Ltd.
487
successfully in patients with SIADH who have been
unresponsive to ¯uid restriction or found it intoler-
able. Fludrocortisone and, in resistant cases, lithium,
have also been used successfully in some cases
(Spigset and Hedenmalm, 1995; Phillips, 1996;
McAskill and Taylor, 1997; Wilson et al., 1998).
The association between SSRIs and hyponatraemia
Hyponatraemia has previously been reported as a rare
side effect of SSRIs (Pillans and Coulter, 1994;
Devane, 1995). Pillans and Coulter (1994) calculated
the incidence of hyponatraemia associated with ¯uox-
etine to be 5.4 per 1000 for patients aged > 65 years.
However, increasing evidence points to hyponatrae-
mia as a relatively common side effect.
Studies investigating the association between
SSRIs and hyponatraemia have been few, small, retro-
spective and uncontrolled. Most of the literature con-
sists of isolated case reports. Reporting is voluntary so
the true incidence of the problem cannot be accurately
calculated. The market share of the drugs varies
widely between drugs and between national markets.
The patients tend to be elderly, often with confound-
ing factors (e.g. treatment with diuretics). Thus the
relationship between SSRI use and the development
of hyponatraemia may be hard to elucidate (Ball
and Herzberg, 1994).
Although most authors have described SSRIs as
leading to SIADH, in most cases this was suspected
rather than proven because of an absence of data per-
taining to renal function, serum and urine osmolality
and urine electrolytes.
Fluoxetine-associated SIADH was ®rst reported
following the introduction of the drug in the USA
(Hwang and Magraw, 1989). Since then, there have
been numerous reports (Cohen et al., 1990; Gommans
and Edwards, 1990; Staab et al., 1990; Vishwanath
et al., 1991; Blacksten and Birt, 1993; Pillans and
Coulter, 1994; Jackson et al., 1995; Taylor and
McConnell, 1995; Burke and Franker, 1996a;
Schattner and Skurnik, 1996; Ten Holt et al., 1996;
Flint et al., 1996).
Reports of hyponatraemia with all SSRIs have fol-
lowed. It has been reported with sertraline (Crews et
al., 1993; Doshi Dinesh and Borison, 1994; Llorente
et al., 1994; Jackson et al., 1995; Leung and Remick,
1995; Taylor and McConnell, 1995; Thornton and
Resch, 1995; Adverse Drug Reactions Advisory
Committee, 1996; Bradley et al., 1996; Catalano
et al., 1996; Goldstein et al., 1996; Kessler and
Samuels, 1996; Ayonrinde and San®lippo, 1997;
Bouman et al., 1997a; Woo and Smythe, 1997),
Int J Geriatr Psychiatry 2001; 16: 484±493.
488 d. kirby and d. ames
paroxetine (Goddard and Paton, 1992; Chua and
Vong, 1993; Ayonrinde et al., 1995; Flint et al.,
1996), citalopram (Voegeli and Baumann, 1996; Bou-
man et al., 1997b) and ¯uvoxamine (Baliga and
McHardy, 1993; Ball, 1993). Cases have also been
reported with venlafaxine (Gupta and Saravay,
1997; Meynaar et al., 1997; Ranieri et al., 1997;
Masood et al., 1998).
Liu et al. (1996) reviewed reported cases (both
published and unpublished) of hyponatraemia and
SIADH associated with SSRIs. They identi®ed 736
reported cases of hyponatraemia and SIADH asso-
ciated with SSRI use. Fluoxetine was involved in
554 (75.3%) of the cases, paroxetine in 91 (12.4%),
sertraline in 86 (11.7%) and ¯uvoxamine in 11
(1.5%). The median time to onset of hyponatraemia
was 13 days (range 3±120 days). Eighty-three per cent
of the published cases involved patients aged  65
years. In all cases the patient's condition returned to
normal 2±28 days after SSRI discontinuation. Liu
et al. found no association between SSRI dose and
the time of onset, or severity, of hyponatraemia in
any published case.
The Adverse Drug Reactions Advisory Committee
(1996) published data from 33 reports of hyponatrae-
mia associated with SSRIs. Subjects' ages ranged
between 71.5 and 80 years with 76% being female.
Serum sodium concentrations were between 111
and 123 mmol/L.
Kirchner et al. (1998) reviewed published case
reports of hyponatraemia associated with SSRI use
in patients aged > 60 years and reports made to the
UK Committee on Safety of Medicines (CSM). Of
the latter cases, 202 had suf®cient information for
analysis. Mean time to detection of hyponatraemia
was approximately 3 weeks after commencing SSRIs,
with a wide range of time to detection (1±253 days).
The lowest recorded sodium concentration was
98 mmol/L with a mean of 118 mmol/L. The mean
time to normalization of serum sodium concentration
upon cessation of the SSRI was 9±10 days.
Demedts et al. (1998) did not ®nd an association
between elevated serum concentrations of ¯uoxetine
and SIADH in elderly patients.
Prevalence of hyponatraemia
Background prevalence. Bouman et al. (1998), in
their retrospective review involving 108 admissions to
a psychogeriatric ward over 1 year, estimated the
background prevalence of hyponatraemia to be 7.7%
for the whole sample. Siegler et al. (1995) reviewed
1905 psychiatric inpatients of all ages and found 64
Copyright # 2001 John Wiley & Sons, Ltd.
(3.4%) cases of hyponatraemia. Although the inci-
dence in the elderly could be as high as 11%, once
cases associated with medication and physical co-
morbidity were excluded, age itself was not a
signi®cant risk factor for hyponatraemia.
Prevalence of hyponatraemia associated with
SSRIs. Bouman et al. (1998) found that eight of
32 patients treated with an SSRI developed hypona-
traemia; in four cases this was con®rmed as being
due to SIADH using the criteria of Bartter and
Schwarz (1967). The mean age of these four
patients was 79.3 years; two were female, three were
symptomatic and two were taking a diuretic. Four
patients developed asymptomatic hyponatraemia
without a con®rmed diagnosis of SIADH. In these
cases the hyponatraemia was mild (130±135 mmol/L)
and associated with diuretic use or co-morbid
physical illness.
A casenote review by Strachan and Shepherd
(1998) reported that, of 53 elderly patients on SSRIs,
28% of those treated with ¯uoxetine and 22% of those
treated with paroxetine had hyponatraemia.
Differences between SSRIs in terms of developing
hyponatraemia
As yet, there have been no clear differences between
the SSRIs identi®ed in their propensity to cause hypo-
natraemia. Strachan and Shepherd (1998) studied
only ¯uoxetine and paroxetine. They found no differ-
ence in the risk of developing hyponatraemia between
these drugs. Liu et al. (1996), in their review of
reported cases, found that the proportion of sponta-
neous reports of adverse reactions received by the
WHO documenting hyponatraemia or SIADH was
similar between the different SSRIs.
Time frame of hyponatraemia complicating SSRI use
Strachan and Shepherd (1998) found that for eight of
53 patients, the time from starting the SSRI to lowest
serum sodium concentration was known and ranged
from 4 to 28 days (average 12.5 days). The severity of
the hyponatraemia ranged from 119 to 134 mmol/L.
In the cases reviewed by Liu et al. (1996) the median
time to onset was 13 days. Three quarters of the cases
presented within 30 days after the start of therapy.
However, there was a wide range in the time to doc-
umentation of hyponatraemia; 29% of the patients
presented > 3 months after starting SSRI therapy.
Kirchner et al. (1998) also noted a wide range of time
to detection (1±253 days). Their mean time to detec-
Int J Geriatr Psychiatry 2001; 16: 484±493.
 hyponatraemia and ssris
tion of hyponatraemia following SSRI initiation was
approximately 3 weeks.
Risk factors for the development of hyponatraemia
In a general hospital population, about 1% of patients
of all ages develop hyponatraemia, whereas in psy-
chiatric patients the prevalence has been reported to
range from 3.3% to 12.2% (McAskill and Taylor,
1997).
Siegler et al. (1995) concluded that once drugs and
co-morbid physical illnesses are accounted for, age
does not appear to be an independent risk factor for
hyponatraemia, but the majority of studies ®nd that
the risk of developing hyponatraemia does increase
with age (Pillans and Coulter, 1994; Advere Drug
Reactions Committee, 1996; Liu et al., 1996; Chan,
1997; Spigset and Hedenmalm, 1997).
Miller et al. (1996), in a study of community-resid-
ing, ambulatory geriatric patients, found ageing to be
a risk factor for the development of SIADH-like
hyponatraemia. Advanced age has been indepen-
dently reported to increase the likelihood of develop-
ing SIADH (Goldstein et al., 1983). The risk of
developing hyponatraemia appears to be higher in
females (Pillans and Coulter, 1994; Spigset and
Hedenmalm, 1995, 1997; Adverse Drug Reactions
Advisory Committee, 1996; Liu et al., 1996; Chan,
1997; Strachan and Shepherd, 1998).
Spigset (1999), in a survey of adverse reactions to
SSRIs submitted to the Swedish Adverse Drug Reac-
tions Advisory Committee, noted that hyponatraemia
was more common in the elderly and in women.
Kirchner et al. (1998), in their review of the popula-
tion aged >60 years, found that those aged >70
years are at particular risk of developing hyponatrae-
mia when on SSRIs. They also found a female pre-
ponderance. Although Woo and Smythe (1997)
found no association between hyponatraemia and
advancing age, they noted that recovery took longer
in older patients. In the review of case reports by
Liu et al. (1996), 60% were female and 20% male;
in the remaining 20% the sex was not stated.
Other risk factors for the development of hypona-
traemia include: treatment with other medications
known to cause hyponatraemia (e.g. thiazide diure-
tics) particularly when used in combination; a pre-
vious history of hyponatraemia; and excessive ¯uid
intake (Spigset and Hedenmalm, 1995; Chan, 1997;
Spigset and Hedenmalm, 1997; Siegel et al., 1998).
Of the 736 cases reviewed by Liu et al. (1996), 193
were receiving drugs also known to cause SIADH or
Copyright # 2001 John Wiley & Sons, Ltd.
489
hyponatraemia. The most commonly implicated
drugs were diuretics (30% of cases in which concomi-
tant drug use was reported), antipsychotics (15.1%),
narcotics (6.7%) and oral hypoglycaemic agents
(4.1%). Despite the use of medications that may have
contributed to hyponatraemia, in 112 (58%) of the
193 cases the serum sodium concentrations returned
to normal after withdrawal of the SSRI. Hyponatrae-
mia persisted in only three cases (2%), and in 78
(40%) the results of SSRI discontinuation were not
reported.
Symptoms and outcome of hyponatraemia
associated with SSRIs
In the majority of cases hyponatraemia resolved
within 2 weeks of discontinuing the SSRI (Hwang
and Magraw, 1989; Cohen et al., 1990; Gommans
and Edwards, 1990; Vishwanath et al., 1991; Black-
sten and Birt, 1993; Doshi Dinesh and Borison,
1994; Llorente et al., 1994; Ayonrinde et al., 1995;
Taylor and McConnell, 1995; Adverse Drug Reac-
tions Advisory Committee, 1996; Voegeli and Bau-
mann, 1996; Meynaar et al., 1997). There have been
case reports suggesting that SSRI-induced hypona-
traemia may be transient and may not necessarily
recur with other SSRIs. Bell and Anderson (1998)
described a 69 year old woman who developed
marked hyponatraemia on ¯uoxetine, con®rmed by
rechallenge; she then developed mild hyponatraemia
with paroxetine but not with citalopram.
In nine cases reviewed by Strachan and Shepherd
(1998), serum sodium concentration returned to nor-
mal while the SSRI was continued. In seven patients,
concentrations were monitored once hyponatraemia
was recognized. The average time taken for the serum
sodium concentration to return from its lowest record-
ing to the normal range, while the patient continued
on the SSRI, was 6.9 days (range 4±16 days). These
and other authors have postulated that hyponatraemia
is a transient phenomenon most evident on ®rst expo-
sure, that adaptation may occur with continued or
repeated SSRI treatment and that the development
of mild hyponatraemia may be a common SSRI class
effect, with the potential to become severe in a small
number of cases. The reason the hyponatraemia spon-
taneously resolves may be due to a correction in ADH
concentrations over time.
Hyponatraemia associated with SSRIs may in the
majority of cases be mild and asymptomatic. Strachan
and Shepherd (1998) found that, of 13 patients who
developed hyponatraemia while on ¯uoxetine or par-
Int J Geriatr Psychiatry 2001; 16: 484±493.
490 d. kirby and d. ames
oxetine, only two became symptomatic, requiring dis-
continuation of the SSRI. Both patients also had ser-
ious physical co-morbidity; the ®rst had chronic
obstructive airways disease and lobar pneumonia,
the second renal impairment and an ileostomy follow-
ing colectomy for ulcerative colitis. In the study by
Bouman et al. (1998) 12.5% of patients with hypona-
traemia were symptomatic, but the symptoms were
not speci®ed. Burke and Franker (1996a,b) investi-
gated case reports of ¯uoxetine-induced hyponatrae-
mia and found that the majority of cases resolved
within 14 days following drug discontinuation. They
did note, however, some instances of hyponatraemia
lasting > 28 days despite drug discontinuation and
¯uid restriction.
Druckenbrod and Mulsant (1994) described an
elderly female who twice showed a protracted recov-
ery time (4±5 weeks) following discontinuation of
¯uoxetine, in spite of aggressive treatment of her
hyponatraemia.
Effect of SSRI rechallenge
Drug rechallenge would give more accurate informa-
tion about the true incidence of hyponatraemia related
to speci®c medications. However, there are few pub-
lished case reports, probably because drug rechal-
lenge is considered potentially dangerous (McAskill
and Taylor, 1997).
In the cases reviewed by Liu et al. (1996), rechal-
lenge with the implicated SSRI was attempted in 27
patients. In 18 of these hyponatraemia recurred. Staab
et al. (1990) describe a patient developing hypona-
traemia on initial treatment with ¯uoxetine but not
on rechallenge. Thornton and Resch (1995) reported
a milder recurrence of hyponatraemia, manageable
with ¯uid restriction, in a patient re-trialled on sertra-
line because of a lack of response to other antidepres-
sants.
Catalano et al. (1996) reported a 75 year old
woman who developed hyponatraemia on two sepa-
rate occasions following treatment with sertraline.
The hyponatraemia was signi®cant and developed
within 7 days of initiation of therapy both times.
Doshi Dinesh and Borison (1994) reported a case of
hyponatraemia secondary to sertraline and carbama-
zepine. The hyponatraemia resolved following with-
drawal of the sertraline and did not recur after
rechallenge.
There have been single case reports of patients
developing SIADH with more than one SSRI. Flint
et al. (1996) reported recurrent hyponatraemia with
separate trials of ¯uoxetine and paroxetine, and Jack-
Copyright # 2001 John Wiley & Sons, Ltd.
son et al. (1995) reported recurrent hyponatraemia
with ¯uoxetine and sertraline.
Ayonrinde and San®lippo (1997) reported a case of
accidental rechallenge. They described paroxetine-
induced hyponatraemia in a 67 year old woman,
who was subsequently found to have previously had
an isolated episode of hyponatraemia (sodium con-
centration 129 mmol/L) coincident with an unsuc-
cessful 6 week treatment with ¯uoxetine.
Crews et al. (1993) described a patient who devel-
oped hyponatraemia on sertraline after earlier devel-
oping it secondary to amitriptyline.
Mechanism of hyponatraemia associated with SSRIs
Hyponatraemia associated with SSRIs has been
described as secondary to SIADH, although in the
majority of case reports this remains speculative
(Liu et al., 1996).
There are three ways in which drugs can affect
water homeostasis: they can increase ADH secretion
centrally, potentiate the effect of endogenous ADH
at the renal medulla, and reset the osmostat, lowering
the threshold for ADH secretion (Liu et al., 1996). The
exact mechanism of SSRI-induced SIADH remains
unknown, although studies in rats have implicated a
possible stimulatory effect of serotonin on ADH secre-
tion, possibly mediated via 5HT2 and 5HT1c recep-
tors (Liu et al., 1996; Spigset and Mjorndal, 1997).
Hyponatraemia associated with SSRIs may be a
manifestation of a drug interaction. By inhibiting
the metabolism of concomitant drugs such as antipsy-
chotics, adverse effects on sodium metabolism may
be augmented (Liu et al., 1996).
Clinical relevance of hyponatraemia
The clinical impact of hyponatraemia is variable and
depends on the degree and abruptness of onset (Spig-
set and Hedenmalm, 1995). The Adverse Drug Reac-
tions Advisory Committee (1996) received 33 reports
of hyponatraemia in connection with SSRI use up to
and including 1995. The most common presenting
symptoms were confusion (six reports), delirium or
¯uctuating consciousness (six reports), somnolence
(®ve reports), convulsions (three reports), fatigue
(three reports), hallucinations (two reports), urinary
incontinence (two reports), hypotension (two reports)
and vomiting. Other neurological symptoms
described included agitation, anxiety, impaired cogni-
tion, syncope, hyperre¯exia, hypertonia, nystagmus,
ataxia, impaired coordination and tremor. Twenty-
six patients made a full recovery; one patient died
Int J Geriatr Psychiatry 2001; 16: 484±493.
 hyponatraemia and ssris
after a stroke; six patients had not recovered at the
time of reporting.
Kirchner et al. (1998), in their review of published
cases and cases reported to the CSM, noted that symp-
toms were reported in 29 of the 46 published case
reports. Confusion, weakness, lethargy and drowsi-
ness were commonest. In 202 cases analysed from
the CSM, symptoms were poorly documented.
However, there were serious sequelae reported: sei-
zures, falls and three fatalities. The majority of cases
had severe hyponatraemia (sodium concentration
<124 mmol/L), with a mean of 118 mmol/L. On ces-
sation of the SSRIs, serum sodium concentration nor-
malized by 16 days in most cases and by 32 days in all
cases. In addition to confusion, falls, seizures,
lethargy, lightheadedness, anorexia and malaise,
many cases have been asymptomatic, or have had
symptoms indistinguishable form depression.
(Gommans and Edwards, 1990; Vishwanath et al.,
1991; Blacksten and Birt, 1993; Chua and Vong,
1993; Ball and Herzberg, 1994; Ayonrinde et al.,
1995; Spigset and Hedenmalm, 1995; Thornton and
Resch, 1995; Adverse Drug Reactions Advisory
Committee, 1996; Bradley et al., 1996; Burke and
Franker, 1996b; Catalano et al., 1996; Flint et al.,
1996; Goldstein et al., 1996; Kessler and Samuels,
1996; Gupta and Saravay, 1997; Meynaar et al.,
1997).
Strachan and Shepherd (1998) found that although
sodium concentrations ranged between 119 and
134 mmol/L, only two of 13 hyponatraemic patients
were symptomatic. In all 736 cases of SSRI-asso-
ciated hyponatraemia reported by Liu et al. (1996),
the patients' condition returned to normal 2±28 days
after discontinuation of the SSRI.
CONCLUSION
The elucidation of causal factors in the development
of hyponatraemia remains complex, particularly in
the elderly, because of the multitude of medications
and medical conditions associated with hyponatrae-
mia. Although SIADH is felt to be an important
mechanism underlying drug-induced hyponatraemia,
in many cases this has not been formally elucidated.
The elderly are at risk of hyponatraemia as a conse-
quence of age-related renal changes. In addition, there
appears to be a slight increase in ADH secretion and
an increased ADH response to osmolar stimuli in the
elderly.
Hyponatraemia has been reported with all SSRIs
and with venlafaxine, but most publications have
been isolated case reports. Studies have been small,
Copyright # 2001 John Wiley & Sons, Ltd.
491
retrospective and limited by confounding variables
such as the use of other medications or medical con-
ditions also associated with hyponatraemia. They sug-
gest that the risk of developing hyponatraemia whilst
on an SSRI increases with age, female sex, previous
history of hyponatraemia and the concomitant use of
other medications known to induce hyponatraemia.
The risk is greater in psychiatric inpatients.
In most case reports hyponatraemia associated with
SSRIs has been moderate to severe (sodium concen-
tration < 125 mmol/L) with a wide range of time to
detection (median 13±21 days). In the vast majority
of cases, sodium concentrations returned to normal
within days to weeks of withdrawal or cessation of
the SSRI (Liu et al., 1996; Kirchner et al., 1998; Stra-
chan and Shepherd, 1998).
Although asymptomatic hyponatraemia has been
noted in a few uncontrolled retrospective reviews
(Bouman et al., 1998; Strachan and Shepherd, 1998),
the prevalence is unclear. Most reported cases have
been detected because of symptom development. Less
commonly hyponatraemia has been a chance ®nding.
There is some evidence, based on cases of rechal-
lenge, that hyponatraemia may be a transient effect of
SSRI use, with tolerance developing over time.
Although the increasing number of case reports
suggests that there is a signi®cant association between
hyponatraemia and SSRIs, there is a need for con-
trolled, rigorous studies to con®rm this association.
Older drugs such as TCAs also need systematic study
as their relationship with hyponatraemia may have
been underestimated. Although many case reports
have indicated that SSRIs cause hyponatraemia as a
consequence of SIADH, in many instances this is
not con®rmed by laboratory investigations.
It remains unclear whether any speci®c SSRI has a
stronger association with hyponatraemia than others,
or, aside from symptomatic cases, whether there is a
signi®cant prevalence of asymptomatic hyponatrae-
mia.
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