Review Articles A Review of Disorders of Water Homeostasis in Psychiatric Patients ANN T. RIGGS, M.D. MAURICE W. DYSKEN, M.D. SUCK WON KIM, M.D. JOHN A. OPSAHL, M.D.

Disorders ofwater homeostasis are common in psychiatric patients and include compulsive water drinking, the syndrome ofinappropriate antidiuretic hormone secretion (SIADH), and the syndrome ofself-induced water intoxication (SIW/). Although water intoxication was recognized nearly 70 years ago, the physiological basis ofthese disorders ofwater metabolism still remains elusive. This review will provide a historical overview, critique current studies on compulsive water drinking and SIWI, discuss possible etiologies, and present current approaches to treatment ofthese disorders. Because ofthe complexity ofthe subject, a review ofnormal water homeostasis and the SIADH will be included.

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ompulsive water drinking, first reported before the availability of phenothiazines,l-3 is defined as an excessive intake of water and is typically associated with a psychological disturbance. Water intake has been reported to range from 4 to 10 L a day, but has exceeded as much as 25 L in a 24-hour period. Secondary polyuria results; urine output in this group of patients has been documented to be between 2.1 and 7.8 L per 24 hours. In some cases excessive intake has been attributed to delusions that include attempts to "wash out parasitic worms,,,4 to "keep the body pure,"s and to "cleanse the body of sins.'>6 Compulsive water drinkers may have a variety of psychiatric diagnoses that include chronic undifferentiated schizophrenia, alcohol abuse, manicdepressive psychosis, and psychotic depression. Compulsive water drinking and its resultant polyuria are associated with a number of serious complications, including water intoxication, urinary tract abnormalities (such as a large atonic bladder, urinary incontinence, hydronephrosis), VOLUME 32· NUMBER 2· SPRING 1991

and even parenchymal dysfunction with renal failure secondary to urinary tract obstructionY Cardiomegaly as well as projectile vomiting, malnutrition, and hypocalcemia9 have also been reported. Self-induced water intoxication (SIWI), a disorder characterized by hyponatremia, is a frequent complication of compulsive water drinking.IO,1I Most studies confmn that patients who develop SIWI are most likely to have a diagnosis of chronic undifferentiated schizophrenia4,6.8,12-24 Other associated disorders include manicdepressive psychosis, psychotic depression, and Received June 13, 1990; revised October 2, 1990; accepted October II, 1990. From the Departments of Medicine and Psychiatry, University of Minnesota, Minneapolis; Minneapolis VA Medical Center; and the Hennepin County Medical Center, Minneapolis. Address reprint requests to Dr. Dysken, GRECC Program (II G), Minneapolis VA Medical Center, One Veterans Drive, Minneapolis, MN 55417. Copyright © 1991 The Academy of Psychosomatic Medicine,

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mental retardation. Signs and symptoms of water intoxication depend on the rapidity of development of hyponatremia. In general, acute hyponatremia is associated with more fulminant symptoms and a higher morbidity and mortality rate. 25 Acute manifestations include nausea, vomiting, muscle twitching and tremor, and ataxia; when serum sodium concentration is less than 120 mmollL, seizures, stupor, and coma can develop. Under chronic conditions, patients tolerate lower serum sodium concentrations but may experience headache, constant thirst, anorexia, and exertional dyspnea. SIWI in psychiatric patients may result from I) ingestion of a volume of fluid that exceeds the normal renal excretory capacity (pure water intoxication), 2) impaired renal water excretion, or 3) a combination of both mechanisms. Whether or not the first mechanism alone can cause the SIWI is controversial because the normal kidney is capable of excreting very large quantities of water. Two different estimates of maximal free water excretion are quoted in the medical Iiterature. One estimate is based on the observation that 20% of the glomerular filtrate reaches the diluting segment of the nephron. In the absence of any antidiuretic hormone, this volume theoretically could be excreted, producing a total urinary output of 25 L/day. Under these conditions, SIWI would be highly unlikely to develop because of the enormous excretory capacity of the kidney. Another estimate of maximal free water excretion is based on the observation that the minimum possible urinary osmolality is approximately 50 mosmollL. If normal subjects generate and excrete 600-750 mosmol of solute per day, then the maximum daily urine volume will be 10-15 L (750 mosmollL+50 mosmollL = 15 L/day). Under normal conditions, then, the kidney's excretory capacity for water will be overwhelmed ifacute ingestion exceeds 10-15 L. Some clinical evidence exists to support both estimates of maximal free water excretion. Urinary osmolalities below 50 mosmollL have been observed. If urinary osmolality drops to 30-40 mosmollL, then maximal renal water excretion could reach 20-25 Llday. Several cases of SIWI that were thought to be secondary to pure water intoxication have 134

been reported. 5,'4,'7,'8,26-32 Impaired renal water excretion secondary to inappropriate release of vasopressin, the second mechanism that may account for water intoxication, is commonly associated with polydipsia and psychosis. Although psychosis is known to be associated with the syndrome of inappropriate antidiuretic hormone secretion (SIADH), the mechanism is not known. Careful investigation of psychotic patients with polydipsia and hyponatremia suggests that SIWI actually results from a number of disturbances in water metabolism, including abnormal thirst regulation, a reduced osmotic threshold for vasopressin release, and enhanced renal sensitivity to vasopressin. 33-35 The prevalence of disorders of water metabolism in psychiatric patients is surprisingly high. Early epidemiologic studies found that 6.6%36 to 17.5%37 of patients in a state hospital setting have a history of compulsive water drinking. In addition, los and Perez-Cruet36 found that 50% of patients with compulsive water drinking develop SIWI. They relied on nursing and house staff to identify polydipsic patients, while Blum et a1. 37 used a retrospective chart review for low urinary specific gravity in a recent prospective study of 60 consecutive admissions to a state hospital. Lawson et a1. 38 found that 20% of schizophrenic patients had urine volumes greater than two standard deviations above normal, which compares favorably with Blum's earlier prevalence figure of 17.5%. Lawson also found that hyponatremia developed in 24% of patients with polyuria. Vieweg and co-workers have demonstrated that abnormal water homeostasis as defined by excessive diurnal weight gain is present in 600/0-70% of chronic schizophrenics and is complicated by intermittent water intoxication in approximately 7% of those patients. 39-42 In one of their studies, Vieweg and co-workers reviewed the records of 60 consecutive patients who died before the age of 54 in a state mental hospital. 39 A total of 27 patients (45%) had a schizophrenic disorder, and 5 (18.5%) died of complications due to SIWI. These data, although limited to institutionalized patients, suggest that SIWI is a major cause of mortality and should be anticipated in high-risk groups. PSYCHOSOMATICS

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OVERVIEW OF THE PHYSIOLOGY OF THIRST, VASOPRESSIN RELEASE, AND SIADH The maintenance ofplasma volume and osmolality is a fmely regulated process involving integration of thirst sensation and the release of vasopressin. It is a very logical system as many stimuli affect both vasopressin release and thirst. Vasopressin and thirst work in the same direction to prevent loss of water and to maintain normal osmolality in the organism. Increases in plasma osmolality and decreases in plasma volume are the most important stimuli to increase thirst and vasopressin release, whereas other stimuli are probably ancillary and serve to modify or adjust incoming stimuli. Vasopressin, a hormone produced by the paraventricular nucleus (PVN) and the supraoptic nucleus (SON) of the hypothalamus, produces an antidiuresis by enhancing water reabsorption in the collecting ducts of the kidney. The physiologic stimuli for release of vasopressin can be divided into osmotic and non-osmotic factors. Volume depletion is probably the most powerful non-osmotic stimulus; however, other factors such as temperature, emotion, and pain have been shown to produce an effect. Acetylcholine, norepinephrine, dopamine, the neuroactive peptides, and opiates are neurotransmitters that are known to mediate this effect, although the role of each has not been fully elucidated. The final pathway begins with the production of vasopressin in the PVN and SON. Vasopressin is then transported down axons into the neurohypophysis, and the hormone is released after these neurons are stimulated. Extrahypothalamic projections are thought to terminate upon these nuclei and influence their rate of firing. Forebrain afferents from limbic structures (lateral septum, bed nucleus of stria terminalis, ventral subiculum, and medial amygdala) project to the hypothalamus,4J.-46 but their significance remains obscure. Osmoreceptors, located outside the bloodbrain barrier in the paraventricular area of the third ventricle, send cholinergic projections to the PVN and SON, which are known to have VOLUME 32· NUMBER 2· SPRING 199\

excitatory, nicotinic receptors. Plasma vasopressin concentrations are normally low or undetectable when plasma osmolality falls below 280 mosmol/L. Above this threshold, the plasma vasopressin concentration rises in direct proportion to plasma osmolality and may be estimated by the equation: plasma vasopressin =0.38 (plasma osmolality-280). This means that a change in plasma osmolality of only 1% (2.8 mosmol/L) will increase the plasma vasopressin concentration by about 1 pg/ml. Volume-mediated release of vasopressin occurs via baroreceptors that are located in the systemic circulation and that send projections to the PVN and SON via the ventro-medial medulla. This is a noradrenergic, inhibitory system. 47 The threshold for volume-mediated release occurs with a 10%-15% reduction in blood volume. With blood volume loss of greater than 10%, plasma vasopressin concentration rises in a nearly exponential fashion. 48 The interplay between osmotic and volume-mediated stimuli is such that reductions in plasma volume will cause a lowering of the osmotic threshold, whereas increases in blood volume will increase the threshold.49 Research on the dopaminergic system has yielded contradictory results, and the role of dopamine in vasopressin release remains speculative. Milton and Paterson found that injections of dopamine into the nucleus accumbens of cats or into the third ventricle of rats produced an increase in vasopressin release. so In a later study in which cats were used, intracranial injections of 6-hydroxydopamine, which destroys dopaminergic neurons, caused failure of hypertonic saline to elicit release of vasopressin. Some in vitro data also support an excitatory role for dopamine in vasopressin release. Incubation of an isolated hypothalamic preparation with dopamine produced a release of vasopressin. 51 Other investigators have found that dopamine does not affect vasopressin release. Kendler et al. gave seven volunteers 1.0 mg of haloperidol, a dopamine blocker, and found that plasma prolactin concentrations increased, indicating that dopamine receptor blockade had occurred; however, plasma vasopressin concentrations did not 135

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change.52 Similarly, Raskind et at. and Rowe et at. demonstrated that antipsychotic drugs (like dopamine antagonists) do not alter plasma vasopressin concentrations in normal subjects or schizophrenic patients. 53.54 Lightman and Forsling found that infusions of L-dopa, a dopamine precursor that crosses the blood-brain barrier, suppressed basal vasopressin release and inhibited the release of vasopressin induced by headup tilt. 55 As with the conflicting data for norepinephrine, variability in dopamine effect on vasopressin release may occur because of peripheral vs. central effects or simply because of experimental error. Thus, the role of dopamine in the regulation of vasopressin secretion remains unknown. The physiology of thirst is a highly complex process that must be orchestrated by a variety of somatomotor, autonomic, and endocrine responses to ensure survival. Drinking may be initiated by water deficit (primary drinking) or a cognitive response (secondary drinking). Sequential stages of this adaptive behavior include I) an initiation phase that involves detection of peripheral and central deficits, 2) a procurement phase that involves a general state of behavioral arousal and foraging behavior that utilizes locomotor activity, sensory information, and previous information, and 3) a consummatory phase that includes preprogrammed motor responses such as licking, swallowing, and the integration of taste and smell. Increases in plasma osmolality or decreases in plasma volume are potent dipsogenic (or thirst) stimuli. A rise in effective plasma osmolality of only 2%-3% produces a strong thirst sensation, with the osmotic thirst threshold averaging 295 mosmollL in normal adults. 48 Osmoreceptors are contiguous with vasopressin receptors in the anterior wall ofthe third ventricle. The pathway for osmotically mediated dipsogenesis, however, is unknown. The pathway for the dipsogenesis mediated by volume depletion is probably closely related to those that mediate vasopressin release and involves atrial stretch receptors and arterial baroreceptors that initiate thirst sensation directly and indirectly through sympathetic efferents activating the renin-angiotensin n system. 136

Angiotensin II is now thought to play an integral role in the regulation of thirst. Angiotensin II receptors have been localized to the subfomical organ and the organum vasculosum of the lamina terminalis in the anterior wall of the third ventricle, areas that are devoid of a bloodbrain barrier.56 The medial preoptic area also contains a heavy concentration of angiotensin n receptors. 57 Secondly, studies using radioimmunoassay and histochemical binding techniques suggest that all of the enzymes and peptide precursors necessary for the synthesis of angiotensin II are endogenous to the brain. 58 Other stimuli thought to induce thirst include local warming of the preoptic area and vasopressin itself. Although the induction of drinking behavior by osmotic stimuli is the most important, the mechanism by which this occurs is still unknown. In their comprehensive review, Swanson and Mogenson 57 developed a model that outlines the neurocircuitry subserving drinking. In this model hypovolemic stimuli act to increase angiotensin II, which is the primary stimulus. This model accounts for mechanisms involved in initiation, procurement, and consummatory phases, and it integrates autonomic, somatomotor, and endocrine responses in this adaptive behavior. In the Swanson and Mogenson model, a single "drinking center" does not exist, but, rather, a "functionally related circuitry contains within it a variety of nuclei or areas that are involved in different aspects of an overall response." The medial preoptic area has been implicated during the initiation phase and is responsive to angiotensin II; it may receive thirstrelated sensory information from the oropharynx and liver via the nucleus of the solitary tract. Efferents from the medial preoptic nucleus presumably play a role in the expression of the response. Two descending projections exist. One descends through the medial forebrain bundle to innervate the lateral hypothalamus, the ventromedial nucleus of the hypothalamus, the mamillary bodies, and the ventral tegmental area (VTA). The other descends through the periventricular system to innervate the periaqueductal gray and the periventricular nucleus to produce an angiotensin II-mediated vasopressin PSYCHOSOMATICS

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release. The VTA and nucleus accumbens are important areas and appear to be involved in the modulation of motor responses during the procurement and consummatory phases of drinking. Efferents from the VTA include ascending projections to the limbic system and nucleus accumbens and descending projections to the central gray and parabrachial nuclei. Efferents from the nucleus accumbens include the globus pallidus, which in tum projects to the motor cortex, the substantia nigra, and the VTA. The limbic system is thought to exert modulatory influences over the hypothalamus. For instance, septal lesions produce polydipsia, suggesting an inhibitory role. Unilateral projections to the nucleus accumbens and bidirectional projections to the VTA, the hypothalamus, and the medial preoptic area have been established. The precise role of the limbic system in modulating drinking behavior has not been determined, but because of complex connections to cortical association areas, it may mediate cognitive influences during the procurement phase, initiate secondary drinking, or determine behavioral priorities in the face of competing needs. From its multiple connections with the lateral hypothalamus, medial preoptic area, VTA, and superior colliculus, the dorsal parts of the midbrain reticular formation may play a critical role in cortical arousal mechanisms during the initiation phase and modulation of skeletal motor responses during procurement phases. Finally, head and eye movement coordination may be integrated by the superior colliculus. The medial preoptic area projects to the nucleus accumbens, which projects to the substantia nigra and in tum to the superior colliculus. Thus, in the face of extracellular dehydration, the medial preoptic area is stimulated by angiotensin II. In addition, sensory information from the oropharynx and liver help initiate complex drinking behavior. Through its multiple unidirectional and bidirectional connections with the limbic system, nucleus accumbens, VTA, paraventricular nucleus, reticular formation, and spinal cord, the orchestration of endocrine, somatomotor, and autonomic responses is achieved. This is a very short synopsis of the model. For further details, we VOLUME32·NUMBER2·SP~NGI~1

refer the reader to the review article by Swanson and Mogenson. 57 Studies implicating the neurochemical mediators of drinking were reviewed by Setler.59 In short, the drinking response to cellular dehydration (osmotic stimuli) appears to be mediated by cholinergic and alpha-adrenergic systems. Drinking behavior is blocked or attenuated by cholinergic antagonists and by norepinephrine. Carbachol-induced drinking is not significantly attenuated by the dopamine blocker haloperidol, and it is unaffected by chemical destruction of catecholaminergic pathways. On the other hand, extracellular thirst (hypovolemic stimuli and the angiotensin II system) appears to be mediated by catecholaminergic nerve pathways independent of cholinergic mechanisms. Angiotensin 11- and isoproterenol-induced drinking are reduced by dopamine receptor blockade and destruction of catecholaminergic nerve terminals. Nigrostriatal and mesolimbic dopaminergic neurons are involved in the angiotensin II thirst circuit and probably play an important modulatory role in neural thirst mechanism, particularly in motor responses involved in drinking. 60 Dysregulation of this system of water homeostasis can have serious consequences. SIADH, for example, is characterized by hyponatremia and hyposmolality. In this disorder, plasma concentrations of vasopressin remain elevated despite a reduction in the plasma osmolality and result in impaired renal water excretion. Bartter and Schwartz summarized the cardinal findings in SIADH: I) hyponatremia with corresponding hyposmolality ofserum and extracellular fluid, 2) continued renal excretion of sodium, 3) absence of clinical evidence of fluid volume depletion, 4) osmolality of urine greater than that appropriate for the concomitant tonicity of the plasma, i.e., less than maximally dilute, 5) normal renal function, and 6) normal adrenal function. 61 SIADH may be characterized by several different patterns ofvasopressin secretion, but vasopressin release is permissive, and continued water intake is obligate in the clinical expression of the syndrome.62 Robertson et al. have demonstrated that at plasma vasopressin concentrations greater than 5 pg/ml, maximal urine osmolality is present; 137

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further increases in plasma concentration have very little effect on water excretion (Le., the rate of change of free water excretion becomes increasingly smaller as the hormone level increases).49 Consequently, the severity of SIADH is determined largely by the rate of water intake and not the magnitude of vasopressin release. In the reset osmostat variant of SIADH, a threshold function of vasopressin release is preserved but occurs at an inappropriately low plasma osmolality. Patients with this disorder, therefore, maintain the ability to produce maximally dilute urine, and the severity of plasma hyposmolality is limited. In practice, this means that SIADH of this type cannot be excluded when hyposmolality is associated with low urine osmolality until an abnormal osmotic threshold for vasopressin release is demonstrated or excluded. This requires serial determinations of urine and plasma osmolalities. If an abnormal threshold for vasopressin release is present (reset osmostat), the urine will remain maximally dilute, and vasopressin will be maximally suppressed until the threshold is reached. Thereafter, urinary osmolality will rise but at an inappropriately low plasma osmolality. HISTORICAL OVERVIEW Rowntree introduced the concept of water intoxication when he reported that fluid ingestion in excess of the kidneys' excretory capacity can lead to hyponatremia, which is manifest by a variety of symptoms and signs that include restlessness, asthenia, frequency of urination, diarrhea, nausea and vomiting, muscle tremor, frothing of the mouth, stupor, and coma.63 Later, Hoskins and Sleeper introduced the notion of compulsive water drinking.' In a large-scale study of urine volumes in schizophrenic patients, they found that the average 24-hour urinary volume of schizophrenics was two times that of normal controls (2.6 L/day and 1.3 L/day, respectively). They speculated that the relationship between polydipsia and psychosis was possibly due to an abnormality in the hypothalamus. Three years later, however, Sleeper and Jellinick refuted this notion, claiming that polydipsia was a 138

psychogenic rather than a biochemical or physiological abnormality. 2 They based this new hypothesis on differences between polyuric patients with either high or low urine volumes. They found that patients with high urine volumes tended to have higher blood pressure, sympathetic reactivity, and IQs, as well as less emotional deterioration than the low-volume polyuric patients. Barahal documented the first case of water intoxication in a psychotic patient. 64 He reported a 31-year-old schizophrenic patient who drank an excessive quantity of tap water, developed convulsions, and went into a coma. Although no electrolytes were reported, the patient was initially oliguric but subsequently had a profound diuresis with complete recovery that suggested a transient defect in free water excretion. Barlow and deWardener characterized the clinical features of compulsive water drinkers. 3 Their patients had a variety of psychiatric disturbances ranging from depression and agitation to frank hysterical behavior. They observed plasma osmolalities that were significantly lower than normal; however, the patients failed to develop water intoxication unless exogenous vasopressin was administered. Concomitantly, SIADH was elucidated by Schwartz et al.65 Bartter and Schwartz later defined diagnostic criteria for SIADH.61 In 1963, Hobson and English suggested for the first time that water intoxication in the psychiatric patient could be caused by SIADH.66 They demonstrated a defect in renal diluting capacity in a psychotic patient by performing a water load test. A water load test is a useful measure of one's ability to excrete free water. Normally a person should excrete more than 65% of a 20 ml/kg water load within 4 hours, with the urinary osmolality falling to less than 100 mosmollL during the test. Failure to excrete the water or maximally dilute the urine suggests that vasopressin is not completely suppressed. Since Hobson and English did not show resolution of SIADH following disappearance ofthe psychotic state, they could not show a cause/effect relationship and concluded that the association between PSYCHOSOMATICS

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psychosis and SIADH must be considered incidental. 66 Anhidrosis and hyperpyrexia were seen in their patient, and they suggested a temporary non-osmotic release of vasopressin that possibly was caused by autonomic hyperactivity. The above studies demonstrated that compulsive water drinking exists and that compulsive water drinkers are at risk for becoming water intoxicated (i.e., developing symptomatic hyponatremia). Hobson and English's study suggested that water intoxication in psychiatric patients may be caused by an inappropriate release of vasopressin during psychosis.66 Recent studies of water homeostasis in psychiatric patients can be divided into three categories: I) those that investigate the triad of psychosis, water intoxication, and polydipsia, and define the mechanism behind water intoxication; 2) those that implicate drugs rather than psychosis as the cause of SIADH; and 3) those that define characteristics of high-risk groups and attempt to find a marker for early detection. THE TRIAD OF PSYCHOSIS, POLYDIPSIA, AND WATER INTOXICATION Since Barahal's first report of water intoxication in a schizophrenic patient,64 a number of similar cases have been documented. All reports describe an association between psychosis, polydipsia, and hyponatremia. In many cases pure water intoxication was thought to be the cause of the hyponatremia,s.14.17.18.26-32 while in others it was ascribed to SIADH.4.6.8.16-19.21.23.28.3O.34.3S.66.67 Others suggested that the hyponatremia was multifactorial and due to defects in both thirst regulation and renal water excretion. 33 In many of the reported cases, concomitant diuretic use or inadequate laboratory data rendered classification impossible. Smith and Clark suggested that a single mechanism does not exist. Based on a study of 21 cases of water intoxication, they postulated that three subtypes exist. 18 In their study, four (20%) had pure water intoxication, and seven (28%) had probable water intoxication (urine specific gravity < 1.004). One (5%) had SIADH; two (10%) had probable SIADH (urine VOLUME 32· NUMBER 2· SPRING 1991

specific gravity =1.006-1.(08); and three (14%) had diuretic-induced hyponatremia. The other patients had incomplete lab values so that accurate classification was not possible. It must also be noted that many of the patients presented with seizure activity. The inappropriate release of vasopressin may be caused by the seizure, a variable that confounds much of the literature. It seems likely that hyponatremia in psychotic patients is multifactorial and is due to defects in both thirst regulation and renal water excretion. 33-3S Vieweg et al. have demonstrated erratic vasopressin release and inadequate suppression of vasopressin in response to hyponatremia in some schizophrenic subjects with psychosis, intermittent hyponatremia, and polydipsia (the PIP syndrome).34.JS Goldman et al. performed an extensive assessment of water homeostasis in eight patients with chronic psychiatric illness (seven schizophrenic/one organic delusional syndrome patient) who had a history of polydipsia and one or more previous episodes of water intoxication.J3 They performed similar studies in seven control patients with chronic psychiatric illness (six schizophrenic/one organic delusional syndrome patient) who were receiving similar treatment but who had no history of polydipsia, polyuria, or hyponatremia. They found that the patients with a history of water intoxication had multiple disturbances in water homeostasis compared to the controls, including I) increased thirst for any given plasma osmolality, 2) a reset osmostat, 3) higher vasopressin level for any given plasma osmolality, and 4) increased renal sensitivity to vasopressin, which probably explained their mild basal hyponatremia. Thus, a clear separation of abnormalities in thirst or vasopressin regulation is not possible in most patients. Hariprasad et aI.,3O Linquette et aI.,68 and Bourgeois et aI. 23 have speculated that hyponatremia in psychotic patients is a complication of psychosis-induced compulsive water drinking and that the resetting of the osmotic threshold for vasopressin release is secondary to the polydipsia. To explain the history of water intoxication in their patients, Goldman et aI. could only speculate about which elements of 139

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water homeostasis changed acutely.33 They question whether psychosis itself was "fundamentally involved." Despite the large number of reports linking psychosis, intermittent psychosis, and polydipsia to SIADH, only three provide a causal relationship to an acute psychotic process. In each case, resolution of the hyponatremia occurred with successful treatment of the psychosis. Dubovsky et al. were the first to suggest that acute psychosis be added to the list of causes of SIADH, documenting a temporal relationship in a 25-year-old schizophrenic subject who became comatose following several grand mal seizures. 6 Serum sodium was 102 meqlL: serum osmolality was 228 mosmollL: and urinary osmolality was 229 mosmollL. Water intoxication diminished with resolution of the acute psychosis, and a subsequent water load test showed normal diluting capacity. One month later the patient decompensated and was readmitted with severe hyponatremia and obtundation. On recovery, normal diluting capacity was again documented. Raskind et al. 16 and Zubenko et al. 21 reported two similar outcomes in five patients with psychotic depression. Neuroleptics and nonspecific factors such as stress48 and nicotine69 have also been implicated in the pathogenesis of water intoxication. In a study of to patients, Blum found that heavy smokers had the highest risk for developing hyponatremia.69 He later reported a case of a compulsive water drinker who could secrete only 44% of a water load while smoking compared to 80% while not smoking. Yium also found that most patients who developed hyponatremia were heavy smokers. 70 When he compared, however, normonatremic schizophrenic to hyponatremic patients, the rate of smoking was not different. Surgical stress is also a well-known cause of SIADH, and the psychotic process itself may be stressful. Raskind et al. hypothesized that the clinical triad of psychosis, intermittent hyponatremia, and polydipsia represents a primary increase in dopaminergic activity:6 This hypothesis stemmed from clinical observations that hyponatremia and psychosis resolve simultaneously 140

with adequate neuroleptic treatment. To support this view, they pointed out the proximity between centers regulating thirst and vasopressin release and their interconnections to the limbic lobe, a site implicated in the pathophysiology of psychosis. They cited Milton and Paterson's studies showing that destruction of dopaminergic pathways abolished central receptor-induced release of vasopressin and that microinjection of dopamine into the nucleus accumbens produces an outpouring of the hormone.so They also cited Seder's experiments in which 1) dopamine proved to be an effective dipsogen in rats when injected into the lateral ventricle, and 2) blockade of dopamine receptors stopped drinking induced by water deprivation after injection of haloperidol into the lateral hypothalamus.59 Finally, there are two purely speculative theories regarding the interrelationships between psychosis and polydipsia. Ferrier71 suggested that some projections from the limbic lobe to the hypothalamus may be vasopressin-containing neurons, and he cited work by Woodset al.,n who demonstrated that electric stimulation of the amygdala and hippocampus alters secretion of vasopressin. Snyder showed a 20-fold increase in sensitivity of opiate receptors with lowered sodium concentrations. 73 This has caused some speculation that these patients may be addicted to water! DO PSYCHOTROPIC DRUGS CAUSE SIADH? Along with studies linking psychosis to hyponatremia were numerous reports linking the use of psychotropic drugs to SIADH. Sandifer74 reviewed 19 cases involving eight different drugs, including amitriptyline,75-4lO thiothixene,81 thioridazine,82-35 fluphenazine,86.87 haloperidol,83.88--90 desiprarnine,90·91 and tranylcypromine. 92 Carbamazepine also has been cited in the literature as a potential cause of water intoxication.93 Of these reports, only four convincingly demonstrated a causative role by water loading or by rechallenge. 75 .81.88.90 Luzecky et al. described a 51-year-old who developed severe hyponatremia on two separate occasions with arnitriptyline. 75 PSYCHOSOMATICS

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Ajlouni et al. documented thiothixene-induced hyponatremia by both rechallenge and a water load test. 81 Peck and Shenkman implicated haloperidol with a water load test. 88 Dhar and Ramos90 and Peterson et al.92 reported an abnormal water load excretion in patients on desipramine and tranylcypromine, respectively. In the latter case, however, tranylcypromine was continued without recurrence of water intoxication. Although not mentioned in Sandifer's review, chlorpromazine has also been implicated as causative in SIADH. Shah et al. investigated vasopressin levels in patients who experienced weight gain on chlorpromazine therapy.94 They found elevated vasopressin levels after 18 days of chlorpromazine therapy in both schizophrenic and neurotic patients. Electrolyte values and the sensitivity of the vasopressin assay were not reported; therefo~, the study must be viewed with skepticism. Dyball found that chlorpromazine actually inhibited vasopressin release in an animal model, even after severe hemorrhage. 95 In an attempt to demonstrate dopaminergic control of vasopressin, Kendler et al. injected 12 healthy volunteers with haloperidoI. 52 They could not show increases or decreases in vasopressin, but prolactin levels were elevated, showing that doparninergic blockade had occurred. Similarly, Raskind et al. were unable to demonstrate any effect of intramuscular chlorpromazine on plasma vasopressin levels in normal volunteers. 53 Only isolated incidences of neuroleptic-induced SIADH have occurred. This by no means proves that these agents caused the syndrome in all cases, but it does suggest that antipsychotic drugs may contribute to the disordered water homeostasis observed in some psychiatric patients. A variety of hypotheses have been proposed to account for drug-induced SIADH. Dyball suggested that derivatives of the phenothiazine molecule may determine whether a phenothiazine promotes or inhibits vasopressin release. 95 He has shown that chlorpromazine with a 3 carbon straight side chain inhibits release, whereas promethazine with a 3 carbon branched chain promotes release. Kendler proposed that differential ability to release vasopressin is based on the relative norepinephrine-blocking capacity of the VOLUME 32· NUMBER 2· SPRING 1991

neuroleptic. 52 He suggested that chlorpromazine, which may increase vasopressin secretion in humans, blocks alpha-adrenergic systems and causes a disinhibition. In a similar manner, many of these drugs produce orthostatic hypotension. This could produce a reflex volume-mediated increase in plasma vasopressin concentrations. Finally, these drugs may act at the distal convoluted tubule to enhance sensitivity to vasopressin, although this has not been studied. Most of the evidence suggests that in most cases SIADH is not iatrogenic. The syndrome can occur in patients who are not taking psychotropic drugs, can be present before their use, and has not been consistently observed with any drug. CHARACTERISTICS OF HIGH-RISK GROUPS It is very difficult to predict which patients are at risk of developing hyponatremia. Although no definitive studies have been performed, several trends have emerged. As previously mentioned, compulsive water drinking represents a variety of disorders, but 80% of patients who become hyponatremic are schizophrenic. Common antecedents61 •96 show a predominance of females (61%-69%) and smokers (69%). Because of the small number of subjects, however, these studies must be considered preliminary. Several investigators have tried to identify the polydipsic patient at risk of developing hyponatremia. In a prospective study of urine volumes in 35 schizophrenic patients, Lawson et al. 38 found that 20% had substantially elevated urine output (>2 standard deviations above normal) and that 4.8% became hyponatremic. The seven polyuric patients had significantly better premorbid adjustment scores than the other schizophrenics as well as a positive outcome of neuroleptic use consistent with type I schizophrenia. The group of patients who developed hyponatremia were the only polyuric patients with tardive dyskinesia and enlarged ventricles on CT scans, the latter suggesting possible type II schizophrenia, as defined by Crow. 91 Work by Kirch et al. supported Lawson's findings. 98 Common characteristics of eight chronic undifferen141

Water Homeostasis in Psychiatric Patients

tiated schizophrenics who were chronically hyponatremic included an early onset of illness, extended hospitalizations with minimal response to neuroleptic medications, a relatively high frequency of tardive dyskinesia, and brain cr scan abnormalities. A major problem in this study was overt preselection. Since only patients with clinically symptomatic hyponatremia were chosen for the study, patients with asymptomatic hyponatremia may have been excluded. The authors studied urine volumes in a large number of schizophrenic patients and concluded that normonatremic patients with more severe polydipsia were more likely to be taking psychotropic medication and to present with predominantly "positive" rather than "negative" symptoms. Finally, Hoskins and Sleeper also found a good premorbid adjustment and less emotional deterioration in the high-volume polyuric patients. I Thus, taken together, the three studies suggest a trend toward two subtypes of patients: one group with structural brain damage at high risk for water intoxication and another with apparently low risk for water intoxication, possibly corresponding to Crow's type I schizophrenia. 91 The duration from onset of psychiatric illness to development of hyponatremia has also been studied. Jos and Evenson studied 13 patients who had 21 episodes of self-induced water intoxication. 67 Eleven of the 13 patients had a functional psychosis. The mean interval between onset of mental illness and the first episode of water intoxication was 19 years (range 11-36 years). Vieweg et al. found that the mean age (±SD) of onset of the illness was 19.5±3 years, whereas the development of clinical hyponatremia did not occur until a mean age of 34±4.4 years, an interval of 15 years.8.22.39 In a study of 20 patients, Hariprasad et al. found that chronicity of psychosis was not significantly related to the induction of hyponatremia. 30 They saw a latency period from onset of illness to clinical hyponatremia ranging from 3 months to 39 years. All authors have agreed that polydipsia had been present several years before the onset of water intoxication. Vieweg et al. claimed that morning hyposthenuria (urine specific gravity < 1.004), a marker for large volumes of fluid intake, may be 142

a biological marker for schizophrenic groups that are at high risk for developing self-induced water intoxication. 8.39 They have published several studies showing that all patients who became hyponatremic had developed hyposthenuria several years before. Recently Vieweg et al. have demonstrated that the incidence of abnormal water homeostasis, as defined by excessive diurnal weight gain, is as high as 60%-70% in institutionalized chronic schizophrenics. 39-42 These patients gain excessive amounts of weight during the day, which correlates well with a marked diurnal variation in serum sodium concentrations and even with alterations in mentation.99-I04 Since the risk of water intoxication is significant in these patients, attempts have been made to identify the high-risk patients. In fact, weighing patients twice daily and intervening if the weight gain exceeds 3%-5% should prevent a decrease in serum sodium concentration of greater than 5-10 mmol/L and has been suggested as an effective prophylactic measure for patients prone to water intoxication. 102-104 TREATMENT The goal oftreatment ofdisordered water homeostasis in the psychiatric patient is to prevent neurologic complications of water intoxication. Patients with compulsive water drinking and chronic mild hyponatremia may not require therapy, although they are at risk for water intoxication if any defect in renal water excretion should develop or worsen (Le., nicotine or drug-induced vasopressin secretion or worsening of psychosis). As discussed previously, several investigators have demonstrated that close monitoring of diurnal weight gain and prompt intervention can effectively prevent water intoxication in highrisk institutionalized patients.99-I04 Whether some variant of that approach would be effective in the outpatient setting remains to be determined. There is currently no therapy available that effectively decreases thirst, although angiotensin-converting inhibition with captopril has successfully decreased polydipsia and polyuria in one patient with psychogenic polydipsia. 105 AtPSYCHOSOMATICS

" Riggs et al.

tempts to decrease thirst with angiotensin-eonverting inhibitors in other disease states have met with limited success. 106.107 Inhibition of angiotensin n generation or its effects in the central nervous system or kidneylOS may have favorable effects on thirst or water excretion in these patients, but further study is needed. Although the degree of central nervous system dysfunction and risk of death from cerebral edema in water-intoxicated patients depends both on the rate of development and severity of the hyponatremia, considerable controversy surrounds the treatment of acute symptomatic hyponatremia:09-113 Clinically, it is not always possible to determine the rate of development of hyponatremia, and many patients probably have some acute component complicating chronic hyponatremia. While patients with very acute hyponatremia (rate of decrease in serum sodium concentration >0.5 mmol/L/hr) may safely benefit from aggressive intervention, it appears that rapid correction (rate of increase in serum sodium concentration >0.5 mmol/L/hr) in patients with chronic hyponatremia may induce central pontine myelinolysis-a crippling neurologic disorder characterized by dysarthria, dysphagia, and para- or quadriparesis:09·llo.112 Thus, restriction of water intake is the mainstay of therapy and should be sufficient in all but the most severe cases of acute hyponatremia. In the setting of acute symptomatic hyponatremia (serum sodium generally < 120 mmol/L), hypertonic saline (514 mmol/L NaCl) should be infused at a rate of 100 ml/hour to raise serum sodium concentration by 5-6 mmol/L. 1I2 While hypertonic saline alone may result in a significant transient increase in serum sodium concentration,61.114.IIS it may not be effective in patients with high urinary osmolalities (>500 mosmol/L):ls Additionally, use of hypertonic saline alone carries some risk of volume overload. The rate of correction and efficacy of hypertonic saline can be enhanced by the simultaneous administration of a loop diuretic, such as furosemide, which decreases urinary osmolality and enhances renal water excretion. I 16119 Generally the serum sodium concentration should be rapidly increased by 5-6 mmol/L using VOLUME 32 • NUMBER 2 • SPRING 199\

these methods and then normalized by restricting water intake. As emphasized above, the mainstay of therapy for acute and chronic non-life-threatening hyponatremia (minimally symptomatic) is fluid restriction. This is often difficult in the noncompliant patient. Treatment with sodium chloride tablets may increase the serum sodium concentration in some patients. l20 However, since sodium homeostasis is normal in these patients, most would be expected to excrete the additional sodium with little change in the serum sodium concentration. Combined treatment with furosemide (to interrupt renal concentrating mechanisms) and sodium chloride tablets (to replace urinary losses and prevent intravascular volume depletion) appears to be quite effective in the long-term management of hyponatremia: 18.119 When water restriction and combined furosemide and salt tablets are ineffective, pharmacologic intervention to increase renal water excretion may be appropriate. Two drugs known to produce a state of nephrogenic diabetes insipidus-{jemeclocycline and lithium carbonatehave been moderately effective in the chronic management of patients with hyponatremia, but both carry significant risk of nephrotoxicity. White and Fetner successfully treated a 53-yearold alcoholic suffering from chronic hyponatremia with 300 mg tid of lithium carbonate. 121 Within several hours of the first dose, a prompt diuresis occurred that was sustained for 48 hours after the drug was discontinued. Natriuresis was only transient. Singer and Rotenberg were able to replicate these findings. III Although the mechanism is unknown, Vieweg et al. have demonstrated that treatment with combined phenytoin and lithium carbonate can be effective in some patients who do not respond to lithium carbonate alone. 123 Lithium carbonate, however, is infrequently used in the treatment of chronic hyponatremia because of the high frequency of side effects associated with its use and the more consistent effects of demeclocycline. '24 Demeclocycline has been shown to be beneficial in the treatment of both acute and chronic hyponatremia secondary to SIADH. 124-128 A tet143

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(serum sodium concentration 6, 1976 52. Kendler KS. Weitzman RE. Rubin RT: Lack of arginine vasopressin response to central dopamine blockade in normal adults. ] Clin Endocrinol Metab 47:204-207. 1978 53. Raskind MA. Courtney N. Murburg MM. et al: Antipsychotic drugs and plasma vasopressin in normals and acute schizophrenic patients. Bioi Psychiatry 22:453462. 1987 54. Rowe lW. Shelton RL. Helderman H. et al: Influence of the emetic reflex on vasopressin release in man. Kidney 1m 16:729--735. 1979 55. Lightrnan SL. Forsling M: Evidence for dopamine as an inhibitor of vasopressin release in man. Clin Endocrinol (Ox/) 12:39-46. 1980 56. Evered MD: Neuropeptides and thirst. Progress in Neuro-psychopharmacology and Biological Psychiatry 7:469-476. 1983 57. Swanson LW. Mogenson OJ: Neural mechanisms for the functional coupling of autonomic. endocrine and somatomotor responses in adaptive behavior. Brain Res 228: 1-34. 1981 58. Printz MP. Ganten D, Unger T. et al: Minireview: the brain renin angiotensin system. in The Renin Angiotensin System: A Model for the Synthesis of Peptides in the Brain. Edited by Ganten D. Printz MP. Phillips MI. et al. New York. Springer-Verlag. 1982 59. Setler PE: The role of catecholamines in thirst. in Neuropsychology ofThirst. Edited by Epstein AW, Klissileff HR. Stellar E. New York. Winston. 1973. pp 279-291 60. Dourish CT: Dopaminergic involvement in the control of drinking behavior: a review. Progress in Neuro-psychopharmacologyand Biological Psychiatry 7:487-493. 1983 61. Banter FC, Schwartz WB: The syndrome of inappropriate secretion of antidiuretic hormone. Am] Med 42:790801. 1967 62. Zerbe RL. Stropes L. Robertson GL: Vasopressin function in the syndrome of inappropriate antidiuresis. Annu Rev Med 31:315-327. 1980 63. Rowntree LG: Water intoxication. Arch 1m Med 32: I57174. 1923 64. Barahal HS: Water intoxication in a mental case. Psychiatr Q 12:767-771. 1938 65. Schwartz WB. Bennett W. Curelop S. et al: A syndrome of renal salt wasting and hyponatremia probably resulting from inappropriate secretion of antidiuretic hormone. Am] Med 23:529-542. 1957 66. Hobson lA. English IT: Self-induced water intoxication: case study of a chronically schizophrenic patient with physiological evidence of water retention due to inappropriate release of antidiuretic hormone. Ann Intern Med 58:324-332. 1963 67. los Cl. Evenson RC: Antecedents of self-induced water

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intoxication. J Nerv Menl Dis 168:498-500. 1980 68. Linquette M. Fossati p. Lefebvre J. et aI: Acute water intoxication from compulsive drinking. Br Med J 2:365. 1973 69. Blum A: The possible role of tobacco smoking in hyponatremia of long-term psychiatric patients. JAMA 252:2864-2865. 1984 70. Yium JJ: Tobacco smoking and hyponatremia in psychiatric patients (letter). }AMA 253:2459. 1985 71. Ferrier I: Water intoxication in patients with psychiatric illness. Br Med J 291: 1594-1596. 1985 72. Woods WHo Hollan RC. Powel EW: Connections of cerebral structures functioning in neurohypophysial hormone release. Brain Res 12:26-46. 1969 73. Snyder SH: Drug and neurotransmitter receptors in the brain. Science 224:22-31. 1984 74. Sandifer MG: Hyponatremia due to psychotropic drugs. J Clin Psychiatry 44:301-303, 1983 75. Luzecky MH. Burman KD. Schultz ER: The syndrome of inappropriate antidiuretic hormone secretion associated with amitriptyline administration. South Med } 67:495-497. 1974 76. Martin DW. Watts HD. Smith LH: Inappropriate antidiuretic hormone from fluphenazine therapy. West} Med 82:811-812.1975 77. Beckstrom D. Reding R. Cerletty J: Syndrome of inappropriate antidiuretic hormone secretion associated with amitriptyline administration. } AMA 241: 133. 1979 78. Hamburger S. Langley H. Bowers G: The syndrome of inappropriate secretion of antidiuretic hormone associated with amitriptyline or trifluoperazine administration. }ournal of the Kansas Medical Society 81:469-470, 1980 79. Solammadevi SV: Inappropriate antidiuresis during amitriptyline therapy. South Med J 74:775-776. 1981 80. Madhusoodanan S. Osnos R: Amitriptyline-induced hyponatremia: a case repon. Mt SinaiJ Med 18:431-433. 1981 81. Ajlouni K. Kern MW, Teres JF. et aI: Thiothixene-induced hyponatremia. Arch Intern Med 134: 1103-1105. 1974 82. Rao KJ. Milier M, Moses A: Water intoxication and thioridazine (MeHaril) (letter). Ann Intern Med 82:61. 1975 83. Matuk F, Kalyanaraman K: Syndrome of inappropriate secretion of antidiuretic hormone in patients treated with psychotherapeutic drugs. Arch Neurol34:374-375. 1977 84. Gibson WT, Price TRP: Inappropriate ADH in a psychiatric setting. PsychiaJric Opinion 15:43-46. 1978 85. Miller M. Moses AM. Rao KW: Water intoxication and thioridazine. Ann Intern Med 82:852. 1975 86. DeRiveria ILG: Inappropriate secretion of antidiuretic hormone from fluphenazine therapy. Ann Intern Med 6:811-812, 1975 87. Kosten TR, Camp W: Inappropriate secretion of antidiuretic hormone in a patient receiving piperazine phenothiazines. Psychosomatics 21 :351-355. 1980 88. Peck V. Shenkman L: Haloperidol-induced syndrome of

VOLUME 32· NUMBER 2· SPRING 1991

inappropriate secretion of antidiuretic hormone. Clin Pharmacol Ther 26:442-444. 1979 89. Husband C. Mai FM, Carruthers G: Syndrome of inappropriate antidiuretic hormone in a patient treated with haloperidol. Can} Psychiatry 26:1%--197.1981 90. Dhar SK. Ramos RR: Inappropriate antidiureses during desipramine therapy. Arch Intern Med 138:175~1751, 1978 91. Weitzel WO, Shraberg D. Work J: Inappropriate ADH secretion: the role of drug rechallenge. Psychosomatics 21 :771-779. 1980 92. Peterson JC. Pollack RW. Mahoney JJ.et al: Inappropriate antidiuretic hormone secondary to a monoamine oxidase inhibitor.JAMA 239:1422-1423,1978 93. Kimura T. Matsui K. Sato T, et aI: Mechanism of carbamazepine (Tegretol)-induced antidiuresis: evidence for release of antidiuretic hormone and impaired excretion of a water load. ) Clin Endocrinol Metab 38:356362. 1974 94. Shah DK. Chaudhury RR. Wig NN: Antidiuretic hormone levels in patients with weight gain afterchlorpromazine therapy. Indian J Med Res 61:771-776. 1973 95. Dyball RE: The effects of drugs on the release of vasopressin. Br J Pharmacal 33:329-341. 1968 %. Beresford HR: Polydipsia, hydrochlorothiazide and water intoxication. }AMA 214:879-883. 1970 97. Crow TJ: The two-syndrome concept: origins and current status. Schizophr Bull II :471-486. 1985 98. Kirch 00, Llewellyn B. Bigelow MD. et aI: Polydipsia and chronic hyponatremia in schizophrenic inpatients.} Clin Psychiatry 46:179-181, 1985 99. Goldman MB. Luchins DJ: Prevention of episodic water intoxication with target weight procedure. Am} Psychiatry 144:365-366. 1987 100. Vieweg WVR. Yank GR. Rowe WT, et al: Diurnal variation of sodium and water metabolism among patients with psychosis, intermittent hyponatremia. and polydipsia (PIP syndrome). Bioi Psychiatry 22:224-227, 1987 101. Koczapski AB. Ibraheem S. Ashby YT. et aI: Early diagnosis of water intoxication by monitoring diurnal variations in body weight. Am} Psychiatry 144:1626. 1987 102. Delva NJ, Crammer JL: Polydipsia in chronic psychiatric patients: body weight and plasma sodium. Br} Psychiatry 152:242-245. 1988 103. Godleski LS. Vieweg WVR, Leadbetter RA. et aI: Dayto-day care of chronic schizophrenic patients subject to water intoxication. Annals afClinical PsychiaJry I: 179185,1989 104. Vieweg WVR. Hundley PL. Godleski LS. et aI: Diurnal weight gain as a predictor of serum sodium concentration among patients with psychosis. intermittent hyponatremia. and polydipsia (PIP syndrome). Psychiatry Res 26:305-312.1988 105. Goldstein JA: Captopril in the treatment of psychogenic polydipsia (letter). } Clin Psychiatry 47:99. 1986 106. Yamamoto T. Shimizu M. Morioka M. et al: Role of

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119. Decaux G. Watercot Y. Genene F. et aI: Inappropriate secretion of antidiuretic hormone treated with furosemide. Br Med J 285:89-90. 1982 120. Vieweg WV. Rowe WT. David JJ. et 31: Oral sodium chloride in the management of schizophrenic patients with self-induced water intoxication. J Clin Psychiatry 46:16-19. 1985 121. White MG. Fetner CD: Treatment of the syndrome of· inappropriate secretion ofantidiuretic hormone with lithium carbonate. N Engl J Med 292:390-392. 1975 122. Singer I. Rotenberg D: Demec1ocyc1ine induced nephroAmJ Med78:897-902, 1985 genic diabetes insipidus. Ann Intern Med 79:679-683. 110. Cluitmans FHM. Meinders AE: Management of severe hyponatremia: rapid or slow correction. Am J Med 1973 123. Vieweg WVR. Weiss NM, David JJ. et 31: Treatment of 88:161-166.1990 psychosis. intermittent hyponatremia, and polydipsia III. Cheng J. Zikos D. Skopicki HA. et aI: Long-term neurologic outcome in psychogenic water drinkers with severe (PIP syndrome) using lithium and phenytoin. Bioi Psysymptomatic hyponatremia: the effect of rapid correcchiatry 23:25-30. 1988 124. Forrest IN. Cox MC. Hong C. et aI: Superiority of tion. Am J Med 88:561-566. 1990 112. Stems RH: The treatment of hyponatremia: first. do no demec1ocyc1ine over lithium in the treatment of chronic syndrome of inappropriate secretion of antidiuretic horharm. Am J Med 88:557-650. 1990 113. Black RM: Diagnosis and management of hyponatremia. mone. N EnglJ Med298:173-1TI, 1978 Journal of Intensive Care Medicine 4:205-220. 1989 125. Chervill DA, Stote RM. Birge JR. et al: Demec1ocyc1ine 114. Nolph Schrier RW: Sodium. potassium. and water metreatment in the syndrome of inappropriate antidiuretic tabolism in the syndrome of inappropriate antidiuretic hormone secretion. Ann Intern Med 83:654-656. 1975 126. DeTroyer A: Demeclocyc1ine: treatment for syndrome hormone secretion. Am J Med 49:434-445. 1970 115. Rose BD: New approach to disturbances in the plasma of inappropriate antidiuretic hormone secretion. JAMA sodium concentration. Am J Med 81: 1033-1040. 1986 237:2723-2726. 1977 116. Ayus JC, Olivero JJ. Frommer JP: Rapid correction of 127. Nixon RA. Rothman JS. Chin W: Demec1ocyc1ine in the severe hyponatremia with intravenous hypenonic saline prophylaxis of self-induced water intoxication. Am J solution. Am J Med 72:43-48. 1982 Psychiatry 136:82lHl30. 1982 117. Hantman D. Rossier B. Zohlman R, et 31: Rapid correc- 128. Goldman MD. Luchins DJ: Demec1ocyc1ine improves tion of hyponatremia in the syndrome of inappropriate hyponatremia in chronic schizophrenics. Bioi Psychiatry secretion of antidiuretic hormone: an alternative to hy20:1149-1155.1985 penonic saline. Ann Intern Med 78:870-875. 1973 129. Vieweg WVR. Wilkinson EC, David JJ. et 31: The use of 118. Decaux G. Watercot Y, Genene F, etal: Treatment of the demec10cycline in the treatment of patients with psychosyndrome of inappropriate secretion of antidiuretic horsis. interminent hyponatremia. and polydipsia (PIP synmone with furosemide. N Engl J Med 304:329-330. 1981 drome). Psychiatr Q 59:62-68. 1988 angiotensin II in the pathogenesis of hyperdipsis in chronic renal failure. JAMA 256:604-608. 1986 107. Oldenburg B, MacDonald GJ. Shelley S: Controlled trial of enalapril in patients with chronic fluid overload undergoing dialysis. Br Med J 296: 1089-1091. 1988 108. Rouse D. Dalmeida W. Williamson A... et aI: Captopril inhibits the hydroosmotic effect of ADH in the cortical collecting tubule. Kidney Int 32:845-850. 1987 109. Ayus JC. Krothapalli RK. Arieff AI: Changing concepts in the treatment of severe symptomatic hyponatremia.

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