Hospital Pharmacy Midden-Brabant, Tilburg, and Utrecht Institute for Pharmaceutical Sciences, Utrecht
Atrium Medical Centre, Heerlen
Utrecht Institute for Pharmaceutical Sciences, Utrecht
St Elisabeth Hospital, Tilburg
Hospital Pharmacy Midden-Brabant, Tilburg, and Utrecht Institute for Pharmaceutical Sciences, Utrecht
Correspondence: Professor dr Antoine Egberts, Department of Pharmacoepidemiology and Pharmacotherapy, Utrecht Institute for Pharmaceutical Sciences, PO Box 80082, 3508 TB Utrecht, The Netherlands. Tel: 30 253 7324; fax: 30 253 9166; e-mail: A.C.G.Egberts{at}pharm.uu.nl
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ABSTRACT |
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Aims To estimate the prevalence of polyuria associated with the use of lithium and to identify additional risk factors.
Method A 4-month prospective follow-up study in an out-patient lithium clinic. The 75 participants were asked to provide 24-h urine samples; polyuria was defined as a urine volume greater than 3 litres per 24 h. Risk factors examined included demographic variables, medications and medical comorbidities.
Results The prevalence of polyuria among lithium users was 37%. Concomitant use of serotonergic antidepressants was strongly associated with polyuria (odds ratio 4.25, 95% CI 1.15-15.68) compared with patients not using these agents.
Conclusions Our data confirm the high prevalence of lithium-induced polyuria. Physicians should be aware that concurrent use of serotonergic antidepressants and lithium significantly enhances the risk of its occurrence. Although limited polyuria is not harmful, it may be troublesome for the patient. In many cases cessation of lithium therapy is not an option because of difficulty in controlling the manic or depressive symptoms.
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INTRODUCTION |
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Early studies found that 24-h urine volumes were increased and urinary osmolality was decreased in patients using lithium concurrently with psychotropic medication (Bone et al, 1980; Bendz et al, 1983). However, these studies were conducted before the introduction of many new psychotropic drugs, especially the second-generation antidepressants. More recently, it has been found that patients treated with both lithium and unspecified psychotropic drugs had a lower urinary concentrating capacity and glomerular filtration rate than patients taking lithium alone (Bendz et al, 1994).
The objectives of our study were to estimate the prevalence of polyuria associated with the use of lithium and to identify additional risk factors, especially concurrently used medication, that predispose patients on lithium to develop polyuria.
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METHOD |
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Outcome
The primary end-point of this study was the presence of polyuria, defined
quantitively as a daily (24-h) urine volume greater than 3 litres
(Baylis, 1996). Patients were
given clear instructions (both verbal and written) regarding the collection of
the urine samples and were encouraged to contact us when there were any
questions. The volume of the urine was determined and creatinine
concentrations and osmolality were measured by standard laboratory methods. If
the urinary creatinine content was less than 6.0 mmol per day, the 24-h urine
collection was considered inaccurate. Fluid intake was estimated by means of a
written questionnaire, asking patients to report fluid consumption during the
24-h urine sampling period.
Determinants
Serum lithium concentrations were measured in the routine laboratory
therapeutic drug monitoring programme. The cumulative amount of ingested
lithium was expressed as the product of time on lithium and the average daily
dosage, determined from medical records. Patients were defined as current drug
users if the prescription lasted until the day of the visit to the lithium
clinic. A psychiatrist or nurse practitioner obtained drug prescription data
during the patient's visit, and the community pharmacy was consulted. Data on
comorbidity and smoking behaviour were obtained from medical records.
Antidepressant drugs were classified into two groups. The first group consisted of antidepressants predominantly acting on the serotonergic system (serotonergic antidepressants), which included clomipramine, fluoxetine, paroxetine, sertraline, trazodone and venlafaxine. The second group consisted of antidepressants that have less potency to inhibit the serotonin reuptake mechanism, including amitriptyline, imipramine, maprotiline and nortriptyline. Clomipramine, trazodone and venlafaxine were included in the first group because these compounds are known to be potent antagonists of the serotonin reuptake mechanism (Tatsumi et al, 1997).
Data analysis
For all patients the prevalence of each characteristic on the inclusion
date was determined. An analysis of variance (Student's t-test) was
used to compare frequencies of continuous variables for participants with and
without polyuria. Differences in proportions of categorical variables were
assessed for significance by a chi-squared test.
To estimate a possible association between potential risk factors and
polyuria, crude and adjusted odds ratios were calculated as measures of
relative risk using logistic regression and were presented with a 95%
confidence interval. The final logistic regression model included age and
gender and all univariately associated (at P 0.1) risk factors
for polyuria. In order to study and adjust for potential confounding factors,
additional data on concomitant medication (antidepressants, diuretics,
antihypertensives, neuroleptics) and comorbidity (diabetes mellitus,
hypertension, thyroid disease) were collected. All calculations were carried
out using the Statistical Package for the Social Sciences, version 10.0.
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RESULTS |
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After adjustment for potential confounding factors, the clear association between the use of serotonergic antidepressants and polyuria in this cohort of lithium users remains: adjusted relative risk 4.25 (95% CI 1.15-15.68) compared with non-recipients. The most frequently used serotonergic antidepressants were clomipramine and paroxetine. Stratified analysis showed that patients using lithium for 3 years or more were at a higher risk (OR=2.65, 95% CI 0.87-8.07) of polyuria compared with patients exposed for a shorter period, but again that was not statistically significant.
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DISCUSSION |
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Context of the results
Polyuria is a frequent complication in patients receiving lithium. The
prevalence found in this study is in line with other published values,
although reported rates of lithium-associated polyuria vary widely
(Boton et al, 1987).
Prior evidence identifying serotonergic agents as potential risk factors for
polyuria during lithium therapy is lacking. Our findings are similar to those
of Bendz et al (1994),
who reported that patients treated with both lithium and psychotropic agents
had a decreased urinary concentration capacity and increased 24-h urinary
volume. In their study, however, the psychotropic agents were not assessed
separately and no relative risk estimate was given.
High serum levels of lithium have been reportedly associated with significantly more cases of polyuria than have low serum levels (Maj et al, 1986). However, our study found no statistically significant relationship between serum lithium levels and polyuria. The small number of cases might be a reason for this observation. It has been suggested that lithium administration in a single daily dose rather than multiple daily doses might accelerate the tubular regeneration process and decrease the risk of polyuria (Bowen et al, 1991). However, researchers are not unanimous. O'Donovan et al (1993) found that switching to a single daily dose of lithium did not reduce the 24-h urine volume. In our study urine volume was not significantly related to the dosing regimen. Both thiazides and potassium-sparing diuretics have been shown to ameliorate lithium-induced polyuria (Martin, 1993). Diuretics were not used in our patient population.
Smoking impairs urine excretion by increasing endogenous arginine vasopressin (AVP) secretion (Allon et al, 1990). However, in our study smoking was not found to be associated with a decreased urinary volume. Patients with thyroid disorder seemingly had a lower risk of polyuria. No possible pharmacological explanation was found in the research literature.
Pharmacological explanation
The mechanism of lithium-induced polyuria is biologically explicable. Under
normal physiological circumstances AVP binds to vasopressin type 2 receptors
located in the basolateral membrane of the renal collecting-duct cells. This
binding initiates a cascade, triggering the insertion of vesicles containing
the aquaporin-2 water channel into the normally watertight apical membrane, to
cause increased water permeability followed by water resorption, leading to
concentrated urine production (Deen &
Knoers, 1998). In rat models lithium appeared to cause polyuria
through downregulation of aquaporin-2 expression
(Marples et al,
1995), which has been confirmed in humans in healthy individuals
under lithium treatment (Baumgarten et
al, 2000). It has been suggested that lithium acts by
inhibiting adenylate cyclase activity in the collecting-duct cells, preventing
the production of cyclic adenosine monophosphate (cAMP), the second messenger
for vasopressin.
A pharmacological explanation for serotonergically induced polyuria has not been explored. So far, it has been accepted that antidepressants are effective through interaction with certain key receptors in serotonergic, noradrenergic and/or dopaminergic neurotransmission systems (Stahl, 1998). It is thought that lithium enhances antidepressant efficacy by increasing serotonergic transmission. The value of lithium augmentation has been demonstrated with a wide range of antidepressants, including serotonergic agents (Zullino & Baumann, 2001). No clinically relevant pharmacokinetic interaction has been found between lithium and serotonin reuptake inhibitors (Mitchell, 1997). Double-blind trials have not demonstrated that adverse effects occurred frequently using the combination of lithium and serotonergic antidepressants (Fava et al, 1994); however, these trials were not designed to estimate the prevalence of such adverse effects, including polyuria.
Serotonergic antidepressants are associated with urinary problems in daily clinical practice. It has been recorded that serotonergic drugs can induce hyponatraemia (Movig et al, 2002), supposedly by inappropriate secretion of antidiuretic hormone, which eventually leads to a decrease in urine production. Since we found a statistically significant additional effect of serotonergic antidepressants on lithium-induced polyuria, it is likely that the effect of serotonergic medication on lithium-induced polyuria is explained by a drug interaction at the tubular level.
Limitations of the study design
Our study has some potential limitations. Selection bias is a potential
threat to study validity and occurs whenever the inclusion of patients is in
some way associated with the outcome of interest. However, the psychiatrists
were not informed about the primary objective of this study; they only
recruited the patients and instructed them in the urine collection protocol.
It is therefore unlikely that users of serotonergic agents were more
frequently included than patients using other (or no) antidepressants. A
second concern is the possibility of observer bias. This was minimised by
medical record review after the patient had visited the lithium clinic to
verify the study forms filled in by the psychiatrist.
Although the study was sufficiently powerful to detect a number of risk factors, it was somewhat limited by its small size. The wide confidence intervals around some of the odds ratios are a reflection of this limitation.
A dichotomous cut-off point of 3 litres of urine per day for polyuria has been used in the logistic regression model. Such a cut-off level is widely accepted for research purposes (Baylis, 1996), but it still might be arbitrary. Therefore, we also performed analyses using continuous measures of 24-h urine output as the dependent variable, i.e. linear regression analysis. We found that patients who had been treated with selective serotonin reuptake inhibitors (SSRIs) and lithium salts concurrently had significantly greater urinary output (mean difference 941 ml, 95% CI 280-1601; P=0.006) than patients treated with lithium only. The logistic regression model provided a comparable statistically significant P value, and in essence the same result, for the association between polyuria and treatment with both lithium and SSRIs compared with lithium use only.
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Clinical Implications and Limitations |
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LIMITATIONS
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REFERENCES |
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Received for publication April 25, 2002. Revision received October 18, 2002. Accepted for publication October 30, 2002.
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