# 186 - Antipsychotic associated hyponatraemia

# Antipsychotic-associated hyponatraemia

186
The Maudsley® Prescribing Guidelines in Psychiatry
CHAPTER 1
Antipsychotic-­associated hyponatraemia
Hyponatraemia can occur in the context of:
■
■Water intoxication, where water consumption exceeds the maximal renal clearance capacity. Serum and urine osmolality are low. Cross-sectional studies of 
chronically ill, hospitalised, psychiatric patients have found the prevalence of 
water intoxication to be 6–17%.1,2 A longitudinal study found that 10% of severely 
ill patients with a diagnosis of schizophrenia had episodic hyponatraemia secondary to fluid overload.3 The primary aetiology is poorly understood. It may be 
driven, at least in part, by an extreme compensatory response to the anticholinergic adverse effects of some antipsychotic drugs.4 An alternative theory is that postsynaptic dopamine receptor antagonism results in receptor supersensitivity, 
increased presynaptic dopamine release, and elevated dopamine in the hypothalamus, driving thirst and polydipsia.5 The fact that many reported cases occur in 
patients with long illness histories and treatment with antipsychotics with high D2 
receptor affinity (and that clozapine can improve polydipsia independent of 
improvement in psychosis) appears to support this suggestion.5
■
■Drug-­induced syndrome of inappropriate antidiuretic hormone (SIADH), where 
the kidney retains an excessive quantity of solute-­free water. Serum osmolality is 
low and urine osmolality relatively high. The prevalence of SIADH may be as high 
as 11% in acutely ill psychiatric patients.6 Risk factors for antidepressant-­induced 
SIADH (increasing age, female gender, medical comorbidity and polypharmacy) 
seem to be less relevant to the population of patients treated with antipsychotic 
drugs.7 SIADH usually develops in the first few weeks of treatment with the offending drug8 but can appear at a later time.8 Case reports/series7,9–30 implicate various 
phenothiazines, haloperidol, pimozide, risperidone, paliperidone, quetiapine, 
­olanzapine, aripiprazole, cariprazine and clozapine. Systematic review31 and 
case–­control studies32,33 suggest a clear increase in risk of hyponatraemia with 
antipsychotics. One large Swedish study found a stronger association for first-­
generation antipsychotics than for SGAs.33 Analysis of pharmacovigilance reports 
appears to support this.34 Another review35 confirmed that drug-­induced 
hyponatraemia is associated with concentrated urine and suggested that antipsychotic treatment was five times more likely than water intoxication to be the cause 
of hyponatraemia. Overall prevalence of antipsychotic-­induced hyponatraemia 
has been estimated at 0.004%36 and 26.1%.37 It is assumed that the true figure is 
somewhere between these two widely different extremes. Desmopressin, when 
used for clozapine-­induced enuresis, can also result in hyponatraemia.38 Other 
drugs, including antidepressants and anticonvulsants (especially carbamazepine),39 
valbenazine40 and many drugs for physical health conditions (diuretics, angiotensin-­
converting-­enzyme [ACE] inhibitors, angiotensin II receptor blockers, proton 
pump inhibitors), have also been implicated.41 The risk of hyponatraemia is probably additive with concomitant prescriptions.42–44
■
■Severe hyperlipidaemia and/or hyperglycaemia lead to secondary increases in 
plasma volume and ‘pseudohyponatraemia’.4 Both are more common in people 
treated with antipsychotic drugs than in the general population and should be 
excluded as causes.

Schizophrenia and related psychoses
CHAPTER 1
Mild to moderate hyponatraemia presents as confusion, nausea, headache and lethargy. 
As the plasma sodium falls, these symptoms become increasingly severe, and seizures 
and coma can develop.
Monitoring of plasma sodium is desirable for all those receiving antipsychotics, 
particularly if several risk factors for hyponatraemia are present. A risk-­scoring algorithm has been proposed.45 Signs of confusion or lethargy should provoke thorough 
diagnostic analysis, including plasma sodium determination and urine osmolality 
(Table 1.42).
Tolvaptan,46 a so-­called vaptan (non-­peptide arginine-­vasopressin antagonist, also 
known as aquaretics because they induce a highly hypotonic diuresis),47 shows promise 
in the treatment of hyponatraemia of various aetiologies, including that caused by 
drug-­related SIADH and psychogenic polydipsia.48
Table 1.42  Treatment of hyponatraemia associated with antipsychotic treatment.4,6
Cause of 
hyponatraemia
Antipsychotic drugs 
implicated
Treatment
Water intoxication 
(serum and urine 
osmolality low)
Only very speculative 
evidence to support drugs 
as a cause.
■
■Fluid restriction with careful monitoring of serum sodium, 
particularly diurnal variation (Na drops as the day progresses). Refer urgently to specialist medical care if Na 
<125 mmol/L. Note that over-­rapid correction of sodium 
levels can cause irreversible osmotic demyelination 
syndrome.49
■
■Consider treatment with clozapine, which has been shown 
to increase plasma osmolality into the normal range and 
increase urine osmolality.50,51 These effects are consistent 
with reduced fluid intake but are not clearly related to 
improvements in mental state.52
■
■There are both7 positive and negative reports for olanzapine53 and risperidone54 and one positive case report for 
quetiapine.55 Compared with clozapine, the evidence base is 
weak.
■
■There is no evidence that either reducing or increasing the 
dose of an antipsychotic results in improvements in serum 
sodium in water-­intoxicated patients56 although reducing the 
number and dose of antipsychotics prescribed may decrease 
dopamine receptor supersensitivity and drug adverse effects5
■
■Demeclocyline may be used57,58 and it is included in some 
practice guidelines for psychogenic polydipsia.59 However, it 
exerts its effect by interfering with alcohol dehydrogenase 
and increasing water excretion, which is already at capacity 
in these patients. Any rationale for its use in the absence of 
SIADH is therefore debatable (and some cases in the 
literature may have been complicated by undiagnosed 
SIADH).60 A single small RCT showed no benefit.61
■
■Many other drugs have been used (naloxone, enalapril, 
clonidine, naltrexone, acetazolamide, captopril, propranolol, 
losartan, carbamazepine, fluoxetine, bupropion, trazodone, 
mianserin) but data are limited.62 Successful use of the 
carbonic anhydrase inhibitor acetazolamide has also been 
reported.63,64
Core part of illness in a 
minority of patients (e.g. 
psychotic polydipsia)
(Continued)