Clin Exp Nephrol (2006) 10:6367
DOI 10.1007/s10157-005-0397-0
CASE REPORT
Robert M. Perkins Christina M. Yuan Paul G. Welch
Dipsogenic diabetes insipidus: report of a novel treatment strategy and
literature review
Received: July 6, 2005 / Accepted: November 8, 2005
Abstract
Dipsogenic diabetes insipidus is a syndrome of disordered
thirst, in patients without psychiatric disease, which may be
confused with partial central diabetes insipidus. Distin-
guishing these entities involves monitored water testing.
Therapy with antidiuretic hormone in patients with
dipsogenic diabetes insipidus is thought to be contraindi-
cated for fear of inducing water intoxication. We report a
case of a 26-year-old woman without psychiatric illness re-
ferred for longstanding polyuria and polydipsia. Otherwise
healthy, she complained of near-constant thirst and fre-
quent urination, causing severe disruption of her personal
and professional life. She had been consistently eunatremic
and polyuric, with low urine osmolality. Results of extensive
water testing revealed intact urinary concentrating and
diluting capacity, physiologic though blunted antidiuretic
hormone (ADH) release, and an abnormally low thirst
threshold, consistent with the diagnosis of dipsogenic diabe-
tes insipidus. To control her polyuria we initiated treatment
with intermittent, low-dose, intranasal desmopressin and
strict water restriction during drug dosing. In follow-up she
reported excellent control of polyuria and significant func-
tional improvement. The reviewed literature demonstrates
a limited number of reports about dipsogenic diabetes in-
sipidus, and no prior report of a similar treatment strategy.
Dipsogenic diabetes insipidus is an uncommonly (and not
universally) recognized disorder, requiring monitored test-
R.M. Perkins (*) C.M. Yuan
Department of Medicine/Nephrology Service, Walter Reed Army
Medical Center, 6900 Georgia Ave NW, Washington, DC
20307-5001, USA
Tel. +1-202-782-6462; Fax +1-202-782-0185
e-mail: robert.perkins@na.amedd.army.mil
P.G. Welch
West Virginia University Health Sciences Center, Dorothy
McCormack Center, Martinsburg, WV, USA
The opinions expressed are solely those of the authors and do not
represent an endorsement by the Department of Defense. This is a US
government work. There are no restrictions on its use
Japanese Society of Nephrology 2006
ing in order to distinguish it from incomplete forms of cen-
tral diabetes insipidus. Though therapy with desmopressin
cannot be recommended based on the results of a single
case, the outcome presented here is intriguing and suggests
that larger studies in such patients is warranted to assess the
broader application of such an intervention.
Key words Dipsogenic diabetes insipidus Partial central
diabetes insipidus Polydipsia Polyuria Water restriction
Introduction
Dipsogenic diabetes insipidus is a syndrome of disordered
thirst in which the osmotic threshold for thirst is abnormally
low, below the threshold for antidiuretic hormone (ADH)
release. A subset of primary polydipsia, the term was first
used in 1987 in a report of three patients, and the syndrome
occurs in patients without psychiatric illness.1 The condition
is characterized by polydipsia and polyuria, consistently low
urine (but normal plasma) osmolality under basal con-
ditions, and intact urinary concentrating capacity under
test-induced hypertonic stress. The term was coined to dis-
tinguish this subset of patients with primary polydipsia but
without psychiatric illness from those psychiatric patients
with so-called psychogenic diabetes insipidus, a condition of
abnormal water intake marked by polyuria and urine and
plasma hypoosmolality. It is important to note that the
condition is not universally accepted as a distinct
pathophysiologic state; some authors do not distinguish
between primary polydipsia and dipsogenic diabetes
insipidus.2
The diagnosis of dipsogenic diabetes insipidus requires a
history of excessive thirst, no history of psychiatric illness,
documentation of polyuria with low urine osmolality, and
confirmation of intact urinary concentrating ability. The
latter is accomplished with monitored water deprivation
and/or the infusion of hypertonic saline. As the incomplete
form of central diabetes insipidus can closely mimic these
findings, including variable degrees of urinary concentra-
64
tion in the cases of mild partial diabetes insipidus, the dis-
tinction is often not immediately evident. Helpful clinical
clues to the diagnosis of dipsogenic diabetes insipidus
include normonatremia as opposed to the often mild
hypernatremia seen with partial central diabetes insipidus
and the more pronounced rise in urine osmolality with
administration of desmopressin in patients with partial
central diabetes insipidus.3 Also helpful is direct measure-
ment of ADH levels during hypertonic stress testing.4
However, polyuria itself, regardless of etiology, may induce
impairment of urinary concentration due to loss of
medullary tonicity, and it has been reported that patients
with primary polydipsia may downregulate ADH release
under conditions of osmotic stress.5 This observation may
further confound attempts to differentiate patients with
partial central diabetes insipidus and dipsogenic diabetes
insipidus.
Treatment options for primary polydipsia are limited.
Traditionally, the use of antidiuretic therapy has been con-
traindicated because of the risk of water intoxication in
these patients who cannot limit their water intake. The
limited number of relevant, published studies was primarily
undertaken in psychiatric patients with psychogenic poly-
dipsia. A number of agents have been used in an attempt to
control water intake in these patients, including propanolol
and captopril.6 The opiod antagonist naloxone, and the tet-
racycline derivative demeclocycline, likewise, have not
been shown to be effective.7
The following case illustrates the diagnostic approach to
a non-psychiatric patient with polyuria in whom the diagno-
sis of dipsogenic diabetes insipidus was ultimately made. In
addition, we outline a novel therapeutic strategy combining
targeted, low-dose desmopressin therapy with strict, time-
limited water restriction, which successfully and safely con-
trolled her polyuria.
Case report
A 26-year-old Caucasian woman was referred to our service
for evaluation of polyuria, confirmed on a previous 24-h
urine collection (total volume, 6 l; creatinine index, 20.2 mg/
kg). She described chronic, debilitating urinary frequency
(approximately 1214 times each day) for approximately 7
years. The onset of her symptoms had been gradual over a
period of 34 months, and she could not identify a precipi-
tating event. She also described chronic thirst and was quite
clear that her excessive fluid intake was responsible for her
frequent urination. She did not generally ingest fluids at
night unless she woke for other reasons, and she denied
nocturia. She was a successful lawyer and was increasingly
troubled by her symptoms, which frequently disrupted
meetings and inconvenienced her during travel. She had no
history of head trauma, obstetrical complications, central
nervous system (CNS) infections, granulomatous disease,
or multiple sclerosis. She denied any history of psychiatric
disease and had never been prescribed lithium, antidepres-
sants, or psychotropic medications. A review of her medical
chart confirmed the absence of any psychiatric disease. She
had delivered a healthy boy 10 months previously, who was
breast-fed for 6 months uneventfully. Menses had been
regular since menarche.
Her past medical history included only tension head-
aches. She had recently started oral contraceptive therapy,
and denied use of any over-the-counter medications,
supplements, or herbal therapies. Laboratory results avail-
able to us at the time of our initial evaluation included a
modified water deprivation test 7 months prior, during
which she was able to concentrate her urine to 826 mOsm/
kg, though plasma ADH levels were barely detectable, at
1.1 pg/ml. A comprehensive metabolic panel was within
normal limits, to include serum sodium (141 mEq/l). Several
urinalyses obtained in the past several years for unrelated
reasons were remarkable for lack of glucosuria and were
consistently dilute (specific gravity of 1.0011.003). Tests of
thyroid function were normal. Because of the possibility of
central diabetes inspidus, a magnetic resonance image
(MRI) of the brain had been previously obtained. Preserva-
tion of the normal, T1-weighted posterior pituitary bright
spot was noted on this study. A small (6 mm), anterior pitu-
itary microadenoma was also identified. There was no com-
pression of the posterior pituitary, and no hypothalamic
abnormalities were identified.
On physical evaluation, she was a healthy-appearing
woman. Blood pressure was 110/62 mm Hg; heart rate, 65
beats per min; and weight, 69 kg. There were no pertinent
physical findings noted on examination.
Because our initial differential diagnosis included partial
central diabetes insipidus and dipsogenic diabetes insipidus,
we scheduled the patient for a series of tests which were
performed in our outpatient infusion clinic. All tests were
performed on separate days under conditions outlined
below. Urine and serum osmolality were measured by
freezing point depression, using the Fiske 2400 Osmometer
(Fiske Associates, Norwood, MA, USA). Serum ADH
levels were measured by radioimmunoassay (Quest Diag-
nostics/Nichols Institute, San Juan Capistrano, CA, USA)
under parameters previously described.8
A hypertonic saline infusion test was performed initially
in our clinic under the guidance of a nephrologist and one-
on-one nurse monitoring. Monitored hypertonic saline infu-
sion, sometimes referred to as the Hickey-Hare test, is an
accepted and safe alternative to standard water deprivation,
often allowing for more efficient diagnostic testing in pa-
tients considered low-risk for hypervolemic complications.9
Three percent saline (NaCl 513 mEq/l) was infused at a rate
of 100200 ml/h. Urine osmolality, plasma osmolality, se-
rum sodium, and urine output were measured and recorded
hourly. The infusion rate was adjusted within the preset
parameters based on the serial osmolality and sodium re-
sults. Testing was stopped when laboratory work confirmed
intact urinary concentrating ability in the setting of detect-
able plasma ADH levels. Based on the results of this test,
we established the patients osmotic threshold for ADH
release 303304 mOsm/kg. The assays lower detection
threshold is 1.0 pg/ml, and so it is possible that lower levels
of ADH were present at a plasma osmolality between
 65

Table 1. Hypertonic saline infusion Table 3. Hypotonic water infusion after 12-h water fast
Time Urine Plasma Serum Plasma Time Plasma osmolality Serum sodium Thirst (cm)
(h:min) osmolality osmolality sodium ADH (h:min) (mOsm/kg) (mEq/l)
(mOsm/kg) (mOsm/kg) (mEq/l) (pg/ml)
0:00 296 139 9.7
0:00 274 299 142 0 0:30 289 137 9.5
1:00 397 298 143 0 1:00 293 137 8.7
2:00 699 300 143 0 1:30 291 137 8.2
3:00 605 303 144 0 2:00 289 137 7.3
4:00 597 304 147 3 2:30 284 136 6.3
5:00 622 309 149 1.6 3:00 284 135 5.5
6:00 649 309 149 2.9 3:30 287 135 5.8
a a a
7:00 312 5.1 4:00 134 6.75
a
4:30 279 132 6.8
Laboratory samples were misplaced, and data points were not 5:00 282 133 7.4
available 5:30 280 131 7
6:00 283 132 7.3
a
Data point missing
Table 2. Modified water deprivation
Time Plasma osmolality Serum sodium Thirst (cm)
(h:min) (mOsm/kg) (mEq/l)
treatment regimen which would directly target this patients
chief complaint socially and professionally disruptive
0:00 288 138 0 polyuria. The patient was counseled about the risks of such
0:15 0 testing prior to implementation.
0:30 0.5
0:45 1.1 For the hypotonic infusion testing, the specifications
1:00 289 138 1.6 were determined as follows. Based on a weight of 69 kg,
1:15 2.2 total body water volume was estimated at 34.5 l. At the start
1:30 3.2 of testing, plasma sodium was 139 mEq/l. In order to deter-
1:45 2.9
2:00 287 140 3.4 mine the lower threshold for thirst, we targeted a plasma
2:15 3.6 sodium of 131 mEq/l. Based on these data, we calculated she
2:30 5.2 would need approximately 1.96 l of water (infused as 5%
2:45 5.4 dextrose in water). To minimize urinary free water losses
3:00 291 142 5.5
3:15 6.3 during testing, we gave the patient 6.5 units aqueous
3:30 6.9 desmopressin (DDAVP) subcutaneously at the start of test-
3:45 7.2 ing. We also estimated approximately 400 cc of urine output
4:00 293 140 8 during testing, and did not account for any additional insen-
sible losses. We therefore targeted an infusion rate of 350
400 ml/h to achieve the target endpoint within 68 h. The
testing was performed with 30-min monitoring of the pa-
299 mosm/kg and 303 mosm/kg. Table 1 lists the obtained tient by a nephrologist and continuous one-on-one monitor-
data for this test. ing by nursing staff, and was started after a 12-h (overnight)
We then attempted to establish the patients osmotic period of water deprivation. Laboratory results were sent
threshold for thirst with a modified water deprivation test. every 30 min, and thirst was measured with the aforemen-
The test was started with the patient in a water-replete state tioned visual analog scale. The test was stopped when she
by definition, she was not thirsty at the start of testing. developed a headache, which occurred at a plasma osmola-
Over 4 h, under identical monitored conditions as described lity of 280 mOsm/kg, corresponding to a serum sodium of
above, she water-fasted and recorded her thirst on a visual 131 mEq/l. Her thirst improved appropriately with hypo-
analog scale which had been previously validated.10 Plasma tonic fluid infusion, though it is notable that she remained
osmolality and serum sodium were measured hourly. thirsty at the conclusion of the test. Linear regression
The test was stopped when her thirst reached 8 cm on a 1 to defined her osmotic thirst threshold 266 mOsm/kg under
10-cm scale. As expected, thirst increased linearly with ris- conditions of nonoral water replacement, significantly
ing plasma osmolality, though the osmotic set point was lower than under conditions of pretest oral fluid intake. We
shifted downward. Linear regression defined her osmotic suspect the difference (286 mOsm/kg vs 266 mOsm/kg) be-
thirst threshold 286 mOsm/kg under conditions of pre- tween the two tests was due to the impact of nonosmotic
test oral fluid intake. Table 2 shows the results of this test. stimuli upon the sensation of thirst, as discussed below.
The final test consisted of hypotonic fluid infusion. Table 3 outlines the results of this test.
Because we suspected this patient had a substantial In summary, this patient with nonglucosuric polyuria dis-
nonosmotic thirst stimulus, this testing was performed to played intact urinary concentrating function in the presence
specifically determine her osmotic threshold for thirst under of adequate ADH levels, though the osmotic threshold for
conditions of pretest water fasting and without oral reple- ADH release appeared to be shifted higher and the levels of
tion during testing. While not a standard method of testing, this hormone may have been reduced modestly. Most
we designed the testing method to safely determine a interesting, her osmotic threshold for thirst was shifted
66
downward, occurring at a lower set point than the osmotic
threshold for ADH release, consistent with the diagnosis of
dipsogenic diabetes insipidus. Our testing also allowed us to
precisely determine the amount of water she might safely
ingest prior to developing mild symptoms of water intoxica-
tion, which occurred during our testing at a serum sodium
concentration of 131 mEq/l.
In an attempt to control her polyuria, the patient was
initially prescribed desmopressin, 10 g intranasally dosed
each morning. She was instructed to restrict her fluid intake
to 1400 cc for a period of 6.5 h after each dosing. These
parameters were designed to prevent reduction of her se-
rum sodium below 132 mEq/l, and were based on a body
weight of 69 kg, a baseline serum sodium of 139140 mEq/l,
and a drug half-life of 75.5 min. On the third day after
initiating therapy, she acutely developed nausea and a
headache after ingesting more than 2 l of water within
3 h after dosing with desmopressin. Serum sodium obtained
at an outside clinic revealed hyponatremia (128 mEq/l).
The medication was discontinued and she was seen in fol-
low up. When the patient again expressed a desire for relief
of symptoms, and after thorough counseling about the
importance of water restriction after drug dosing, we re-
initiated therapy with lower-dose desmopressin (2.5 g in-
tranasally) in concert with a period of strict water restriction
(1400 cc) for 6.5 h after use of the drug. She was advised
not to use the drug on a daily basis but to target its use
to control polyuria during important social or professional
functions. In two subsequent follow-up appointments
over the following 6 weeks, she reported excellent, short-
term control of polyuria with targeted use of the drug
and adherence to water restriction. She had no subsequent
episodes of hyponatremia or symptomatic water
intoxication.
Discussion
The hypothalamic and extrahypothalamic mechanisms re-
sponsible for thirst have been extensively studied in animals
and humans. It is well-recognized that control of thirst and
ADH release may be disordered independently of each
other in pathophysiologic states, accounting for the various
disorders of water homeostasis. Different authors have de-
scribed various ranges of normal for both the osmotic ADH
and thirst thresholds, but most have found that the sensa-
tion of thirst generally occurs at a substantially higher os-
motic threshold than does ADH release.11,12 Not all authors
agree, however. Thompson et al.,10 in a study of ten healthy
patients, described a similar threshold for both ADH re-
lease and thirst, occurring across a broad range of values.10
Despite these reported discrepancies, what is clear is that an
osmotic thirst threshold below that of ADH release, as in
our patient, is distinctly abnormal.
We defined a substantially different thirst threshold in
our patient depending on the mechanism of hypertonic
stress-testing. Under conditions of pretest liberal oral fluid
intake, her thirst threshold was 287 mOsm/kg, yet under
conditions of pretest fluid deprivation, the threshold was
much lower 266 mOsm/kg. The difference may be ex-
plained by the presence of nonosmotic thirst receptors or a
neuroendocrine reflex mediated by oropharyngeal or
gastrointestinal mechanisms, as has been previously
hypothesized.13
Use of antidiuretic hormone to control polyuria in a
patient with a primary disorder of thirst has been previously
described.14 This report of a single such patient parallels our
own in many respects. As with our subject, this patient
presented with similar longstanding complaints of polyuria
and chronic thirst. Repeated water-deprivation testing con-
firmed an abnormally low osmotic threshold for thirst
(274 mOsm/kg) and intact urinary concentrating ability.
The authors successfully treated her polyuria with anti-
diuretic hormone, but did not prescribe concomitant water
restriction. Interestingly, they did not report frank water
intoxication with this approach, though she did consistently
develop abdominal cramping when using the medication,
suggesting the possibility of symptomatic hyponatremia.
Ferrer et al.15 reported the first case of acute water intoxica-
tion manifesting as seizure in a patient with dipsogenic dia-
betes insipidus treated with intranasal desmopressin, and
advised the importance of distinguishing diagnostically be-
tween cases of primary polydipsia (specifically dipsogenic
diabetes insipidus) and central diabetes insipidus prior to
initiating therapy. However, the patient in their case was
not prescribed concomitant water restriction.15 Our patient
developed symptoms of early and mild water intoxication
soon after initiating therapy when she failed to restrict fluid
intake, as had been advised in conjunction with use of
antidiuretic hormone. However, subsequent use of the
medication, in conjunction with a specified water restriction
over the effective life of the dose, successfully controlled
her polyuria while maintaining plasma osmolality in a safe
range. The detailed water testing we performed under
monitored conditions allowed us to prescribe a specific
amount of water our patient could safely ingest without
becoming water-intoxicated.
We cannot definitively rule out the possibility that this
patient also has some degree of impaired central ADH
production or release. The relatively elevated osmotic
ADH threshold and the small microadenoma noted on her
MRI (though located in the anterior pituitary and without
compressive effect upon the posterior pituitary) are notable
findings in this regard. However, several features of her case
argue against this possibility, most notably her ability to
maintain full urinary concentrating function when osmo-
tically stimulated. In addition, loss of the normal
hyperintense signal on T-1 weighted MR imaging of the
posterior pituitary, which our patient did not exhibit, is
thought to be highly sensitive for central diabetes insipi-
dus.16 We feel that the somewhat blunted ADH response to
hypertonic stimulus in our patient instead represents a nor-
mal and protective response to her lowered thirst threshold,
guarding against water intoxication. This possibility has
been previously hypothesized, and may explain why the
basal serum sodium concentrations and plasma osmolality
in our patient were consistently normal. This may also be an

important feature distinguishing dipsogenic diabetes insipi-
dus from psychogenic polydipsia.17
In conclusion, this case demonstrates the importance of
careful diagnostic evaluation of patients with nonosmotic
polyuria in order to properly differentiate partial central
diabetes insipidus and dipsogenic diabetes insipidus. Both
thirst and ADH response to hypertonic stress are key com-
ponents of any evaluation protocol. In addition, we have
described a novel approach to the management of polyuria
in a patient with dipsogenic diabetes insipidus. Though we
cannot recommend the broad institution of such a strategy
in all patients with dipsogenic diabetes insipidus, additional
prospective studies of patients with dipsogenic diabetes
insipidus using this strategy are warranted, given the
results reported here. Our strategy would not be appropri-
ate in psychiatric, pediatric or adult, noncompliant popula-
tions, and careful patient selection is essential. Several
interesting features of this case suggest potential future
avenues of study, such as the possibility of retraining the
osmotic thirst threshold (through biofeedback, perhaps).
What impact such an intervention might have on the
blunted osmotic threshold for ADH release and other asso-
ciated abnormalities observed in these patients remains
theoretical.
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