Effect of amiloride on polyuria and well being in lithium treated patients

Lithium is the most effective treatment for bipolar affective disorders. A
frequently seen complication of lithium therapy is development of nephrogenic
diabetes insipidus (DI). It occurs in 20% of all patients uring lithium.
Oficially diabetes insipidus is diagnosed based on insufficient urine
concentration. However in some reports up to 50% of patients using lithium
report polyuria. In our experience patients reporting polyuria and polydipsia
may benefit from therapy even as having partial diabetes insipidus. Typically
amiloride is used to treat lithium-induced diabetes insipidus. We ai mto prove
that amiloride therapy significantly reduces urine volume in patients that
experience polyuria but do not necessarily classify as having diabetes
insipidus. Additionally we aim to show that reduction in polyuria improves and
sleep and increases quality of life.

Primary objective: to investigate the effect of amiloride on urine volume and
urinary concentrating ability in patients on chronic lithium therapy suffering
from polyuria.

We hypothesize that amiloride therapy will improve urinary concentating ability
and reduce polyuria in patients using lithium.

Patients will be approached in the psychiatric outpatient clinic of Antes,
Delta Zorgboulevard. When patients report polyuria, a blood sample will be
taken to obtain baseline measurements of sodium, potassium, lithium and
creatinine, after which they will be screened by collecting a 24-hour urine
sample. Patients with a 24-hour urine volume more than 3L, will be included in
the study. Assessment of quality of life and sleep of participants will occur
by means of filling out two questionnaires: the Short Form 36 Health Survey
(SF-36) and the Insomnia Severity Index (ISI).
24-hour urine samples will be delivered at the outpatient department of
nephrology and will be analyzed on volume, creatinine, albumin and aquaporin-2
excretion. An overnight water deprivation test will be performed on all
participants to quantify renal concentrating ability. Patients will be
instructed to deprive themselves of water intake during the night for at least
8 hours. Following water deprivation, patients will visit the outpatient
department of nephrology for measurement of blood pressure, taking a blood
sample (plasma sodium, potassium, creatinine, osmolarity, lithium, renin and
co-peptin) and delivering a 24-hour urine sample (sodium, potassium,
creatinine, osmolarity).

After randomization, patients will be assigned to a amiloride or placebo
period. Patients will receive a daily dose of 10mg amiloride or placebo for 6
weeks. Two weeks after treatment initiation plasma lithium- and potassium
concentrations will be measured. If necessary, lithium dose will be adjusted.
After 6 weeks, blood samples and 24-hour urine samples will be collected, SF-36
and ISI-questionnaires will be filled out and an overnight water deprivation
test will be performed. Plasma lithium- and potassium concentrations will be
measured again 2 weeks into the washout period. After a washout period of 6
weeks subjects will crossover to the other study arm. After 18 weeks, blood
samples and 24-hour urine samples will be collected, questionnaires will be
filled out and overnight water deprivation tests are performed. After 20 weeks
final plasma lithium- and potassium concentrations will be measured.

In total each participant has 4 visits to the nephrology outpatient department
to take blood samples, deliver urine samples, check blood pressure and evaluate
general well being. Three more visits to the hospital are necessary to take
blood samples for evaluation of lithium treatment, 2 weeks after initiation of
the study, 2 weeks into the washout period and 2 weeks after completing the
study. Outcome of blood and urinary analysis will be monitored and interpreted
by the coordinating researcher. Any adjustment of lithium dosage will be
performed by the treating psychiatrist.

The intervention consists of 12 weeks of treatment, 6 weeks amiloride, 6 weeks
placebo. Additionally, patients are instructed to undergo a water deprivation
test three times, to fill out questionnaires three times and to collect 24-hour
urine samples on four occasions.

The burden for all participants consists of filling out a questionnaire three
times, taking a daily dose of one tablet for a total of 12 weeks (6 weeks
placebo, 6 weeks amiloride), collecting 24 hour urine-volume on 4 different
occasions performing an overnight water deprivation test three times,
subsequently followed by hospital visits to take on blood sample and measure
urine volume and osmolarity.

Additionally blood samples will be taken at baseline, after the first water
deprivation test, 2 weeks after treatment initiation, at week 6, at week 8, at
week 18 and at week 20