Abstract
Background: For unclear reasons, life-threatening water intoxication often coincides with acute psychosis in polydipsic schizophrenic patients with chronic hyponatremia. In contrast, most polydipsic schizophrenic patients are normonatremic and never manifest hyponatremia. To explore whether the effect of acute psychosis on water balance differs in these 2 schizophrenic subgroups, we compared their responses to drug-induced psychotic exacerbations.
Methods: Matched polydipsic schizophrenic patients with (n=6) and without (n=8) hyponatremia were identified based on past and current indexes of fluid intake and hydration. A transient psychotic exacerbation was induced with an infusion of the psychotomimetic methylphenidate hydrochloride (0.5 mg/kg of body weight over a 60-second period). Antidiuretic hormone levels, subjective desire for water, and factors known to influence water balance were measured at 15-minute intervals for 2 hours.
Results: Except for the expected differences in plasma osmolality and sodium, basal measures were similar in the 2 groups. Following methylphenidate administration, antidiuretic hormone levels increased more in the hyponatremic patients (P<.02), despite their consistently lower plasma osmolality (P<.007). No known or putative antidiuretic hormone stimulus could account for this finding. Only basal positive psychotic symptoms (P<.09) and plasma sodium (P<.18) were even marginally associated with the peak antidiuretic hormone responses, but neither factor could explain the difference in the response by the 2 groups.
Conclusion: Psychotic exacerbations are associated with enhanced antidiuretic hormone secretion, for unknown reasons, in schizophrenic patients with hyponatremia and polydipsia, thereby placing them at increased risk of life-threatening water intoxication.
Arch Gen Psychiatry. 1997;54:443-449
Three percent to 5% of patients with chronic schizophrenia are hyponatremic and experience episodes of life-threatening water intoxication. [1] Their basal hyponatremia compromises neuropsychological functioning, [2] and water intoxication can cause seizures, delirium, irreversible neurologic deficits, [3] and death. [1] These patients show increased water intake and impaired water excretion. The enhanced intake manifests as a defect in osmotic and oropharyngeal regulation of the subjective desire for water, [4-6] and usually is not associated with increased thirst or hydrophilic delusions. [7] The impaired excretion is a consequence of increased release and perhaps action of the antidiuretic hormone arginine vasopressin (AVP). [4,6,8,9] The aforementioned defects can account for these patients' chronic mild hyponatremia, but not for the profound hyponatremia associated with water intoxication, for which an additional factor must be invoked. [4,6,8]
Water intoxication often coincides with exacerbations of schizophrenia, but the significance of the association is unclear. [9] Some contend that the aggravated water imbalance is a consequence of psychotic exacerbations, [10-13] others have come to the opposite conclusion, [14] and a third group argues that the 2 events are indirectly related. [15-17] Those who favor the first interpretation point out that transient elevations of plasma AVP during acute psychosis have been observed in hyponatremic [6,18] and some normonatremic schizophrenic patients. [19,20] Within this group of investigators, some argue that the increased AVP levels are fundamentally related to the psychotic exacerbation, and others believe that recognized or putative AVP stimuli are responsible (eg, hypotension, stress, adaptation to polydipsia, and long-term treatment with neuroleptic medication). [9] Those who contend that exacerbated psychosis is a consequence of water intoxication point out that many schizophrenic patients with polydipsia remain normonatremic during psychotic exacerbations, [1] that profound hyponatremia may aggravate psychosis, and that water intoxication-induced seizures or hyponatremia may stimulate AVP release. [13,14] Finally, those who believe the 2 events are indirectly related observe that the introduction of recognized or putative AVP stimuli (eg, increased smoking and adjustment of neuroleptic dose) often coincide with psychotic exacerbations. [12,14]
To clarify if, and how, acute psychosis contributes to water intoxication, we pharmacologically induced psychotic exacerbations in polydipsic schizophrenic patients with and without hyponatremia. We chose polydipsic schizophrenic patients without a history of hyponatremia as controls, because this group resembles the hyponatremic patients but their history suggests that their water balance is unaffected by acute psychosis.
MATERIALS AND METHODS
Subjects were recruited from among the 2000 beds of acute- and extended-treatment units of Illinois state psychiatric facilities. We reviewed the medical charts of patients who were diagnosed as having schizophrenia or schizoaffective disorder who were competent and voluntarily admitted to the hospital, between 21 and 55 years of age, and without factors known to affect water balance.
Serum sodium concentrations and urine specific gravities from current and previous laboratory records were then inspected in qualifying patients who had been identified by the clinical staff as having polydipsia. Potential subjects were initially classified as follows: those with multiple morning spot urine samples of a specific gravity of less than 1.008 and serum sodium concentrations of less than 125 mmol/L and at least 1 serum sodium sample of less than 120 mmol/L were classified as potentially having hyponatremic polydipsia; those with equally severe hyposthenuria but no current or previous serum sodium values of less than 133 mmol/L were classified as potentially having normonatremic polydipsia. We attempted to balance groups for age, sex, duration of psychiatric illness, and current neuroleptic dose (chlorpromazine hydrochloride equivalents). We initially recruited subjects from both sexes, but later limited patients to men because of the recommendation of a funding agency.
Subjects who met this first stage of selection were transferred to the Psychiatric Institute, University of Illinois at Chicago. Definitive psychiatric diagnosis (based on criteria in the DSM-III-R ) [21] was determined in a multidisciplinary diagnostic conference. To provide further validity to the grouping process, we measured morning plasma osmolality and afternoon urine osmolality 3 times each week for 2 weeks. [22] Based on these findings, final group assignment was as follows: hyponatremic patients (n=6; 1 woman) had mean morning plasma osmolalities of less than 280 mmol/kg and mean afternoon urine osmolalities of less than 150 mmol/kg; and normonatremic patients (n=8; all men) had mean plasma osmolalities of more than 285 mmol/kg and mean urine osmolalities of less than 150 mmol/kg. Duration of polydipsia was estimated by determining when hyposthenuria (urine specific gravity <1.008) consistently occurred in the laboratory record.
Because (1) methylphenidate hydrochloride reliably induces transient psychotic exacerbations in schizophrenic patients even when they are receiving neuroleptic medication, [23,24] (2) the effects of exacerbated psychosis should be most apparent when baseline psychosis is minimal, (3) neuroleptic medications block stimulant-induced nausea and emesis (which independently stimulate AVP release), [25] (4) neuroleptic washout has been linked to water intoxication [17] and does not eliminate defects in AVP secretion in hyponatremic patients, [26] (5) water intoxication occurs in schizophrenic patients never treated with neuroleptic medications and in those who have not received the drug for a prolonged period, [9-11] and (6) neuroleptic medications do not seem to alter AVP secretion in the absence of recognized stimuli, [20] we continued neuroleptic medication. The subject was switched, on admission to the hospital, from his or her previous neuroleptic medication to an equivalent dose of fluphenazine hydrochloride, which was then adjusted during 1 to 2 weeks by the attending psychiatrist to optimize clinical response. The subject was then maintained at this dose for 2 weeks before the study.
Patients who participated provided informed, written consent. Consent was obtained before transfer to the research unit in the presence of a staff member who was unaffiliated with the research. Family members were asked to participate in the consent process. Patients and family members were told that methylphenidate could temporarily worsen the patient's clinical condition.
PROCEDURE
Methylphenidate was chosen over other psychotomimetics because it seems to have a lower incidence of hypotension and nausea, [23,27] both of which independently stimulate AVP release. [25] Smoking, food, and water were restricted from the night before the study until its completion (total time=12 hours). Smoking was restricted because it stimulates AVP release; food and water because they affect plasma osmolality, the main physiological stimulus for AVP. Compliance with the smoking restriction was assessed by measuring expired-air carbon monoxide, from which carboxyhemoglobin content can be determined with a carboxyhemoglobin analyzer (Ecolyzer 211, National Draeger, Inc, Pittsburgh, Pa). [28] Throughout the study, subjects remained supine (except for the measuring of upright vital signs immediately following the 30-minute sample) to minimize the influence of postural change on AVP. [29]
At 8 AM, a cuff was attached over the brachial artery, and blood pressure and pulse were recorded every 15 minutes for the duration of the study. Continuous monitoring of cardiac rhythm was performed with an electrocardiogram. An intravenous catheter was inserted into an arm vein, and, starting 30 minutes later, 3 baseline blood samples were obtained at 15-minute intervals. Methylphenidate hydrochloride (Ritalin, IND 27083, Ciba-Geigy Corp, Summit, NJ), 0.5 mg/kg, was then infused over a 60-second period. Blood samples were drawn, and abdominal discomfort, nausea, and desire for water were assessed every 15 minutes for the next 2 hours by the research nurse. Abdominal discomfort and nausea were assessed by direct inquiry; desire for water was estimated by asking the subject, while displaying a 250-mL cup, how many cups of water he or she would like to drink. [4,5] Thirty minutes before and after the methylphenidate infusion, 2 unblinded trained raters completed the Brief Psychiatric Rating Scale (BPRS) (16 items, 0=absent to 6=extremely severe) [30] and the Dyskinesia Identification System Condensed User Scale (individual score >or= to 5 suggests tardive dyskinesia). [31] Ad lib water intake was measured for 10 minutes at the end of the study.
LABORATORY STUDIES
Blood was placed in chilled heparin-treated tubes, and spun down (1800 g for 10 minutes at 4 degrees C) within 1 hour. Plasma and urine osmolality were determined by freezing-point depression (model 2D, Advanced Instruments, Needham, Mass). Other chemistries were determined at the University of Chicago Clinical Research Center core lab (ASTRA IV autoanalyzer, Beckman Instruments Inc, Palo Alto, Calif). Plasma samples were stored at -20 degrees C before measuring AVP (intra-assay coefficient of variation at 2.6 pg/mL=6.2%; interassay coefficient of variation at 2.7 pg/mL=13.0%, at 0.8 pg/mL=26%), [32] human growth hormone (hGH RIA kit, INCSTAR Corporation, Stillwater, Minn), and cortisol (Coat-a-count, Diagnostic Products Corporation, Los Angeles, Calif) by radioimmunoassay, and plasma homovanillic acid (HVA) by high-performance liquid chromatography with electrochemical detection [33] (assayed only on 0-, 30-, and 120-minute samples). Growth hormone and plasma HVA were measured because they reflect central dopaminergic activity, which has been posited to be enhanced in some schizophrenic patients. [24,34,35] Cortisol was measured because its release seems to be closely tied to that of AVP [36,37] and also may be enhanced in schizophrenic patients with water imbalance. [38]
STATISTICAL ANALYSIS
For the analysis of recurrent measures, if the 3 baseline values did not vary within groups, they were averaged; otherwise all time points were included in the analysis. We relied on univariate or multivariate analysis of variance for repeated measures, depending on whether the compound symmetry assumption (ie, equal variances and covariances across time) was met. Reported F values are from the univariate procedure unless otherwise noted. In either approach, if the time effect or group X time interaction was significant, the response was more precisely characterized by examining only the linear, quadratic, and cubic components of the polynomial time contrast. Results are expressed as mean +/- SD unless otherwise noted. Two-tailed probability tests (alpha=.05) are reported throughout.
RESULTS
DEMOGRAPHIC, PRESTUDY, AND BASELINE MEASURES
Demographic and prestudy measures were similar in the 2 groups except for mean morning plasma osmolality, which was, as expected, lower in the hyponatremic patients (Table 1). On the day of the infusion, total BPRS scores were almost identical in the 2 groups (Table 2). Plasma AVP, subjective desire for water, and other factors implicated in water-balance regulation were stable during the 3 baseline time points and similar across groups, except for the expected differences in plasma osmolality and sodium (Table 3). Plasma growth hormone and cortisol fell slightly during the 3 baseline time points but also were similar across groups.
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Table 2. Behavioral Profile 30 Minutes Before and After Methylphenidate Administration*
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Table 3. Baseline Measures of Water Balance and Related Variables*
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BEHAVIORAL AND CARDIOVASCULAR RESPONSES TO METHYLPHENIDATE
Behavioral response to methylphenidate peaked within 30 minutes and rapidly dissipated during the next half hour. Total BPRS scores tended to increase more in the hyponatremic patients (Table 2). Positive psychotic symptoms increased in both groups and tended to be consistently higher in the hyponatremic patients, but negative psychotic symptoms decreased and anxiety and depression tended to increase to a similar extent in the 2 groups. Ratings of tardive dyskinesia increased to a slight, but significantly greater, extent in normonatremics.
Mean arterial pressure rose sharply and then fell slowly to a similar extent in both groups (Figure 1) (time effect, F[3,36]=2.89, P<.05; cubic trend, F[1,36]=10.35, P<.05; group X time interaction, F[3,36]=1.35, P<.30). Heart rate showed a similar response (data not shown). On standing 30 minutes after methylphenidate administration, mean arterial pressure increased to the same extent that it had at baseline, and the response was similar in the 2 groups (data not shown).
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Figure 1. Effects of methylphenidate hydrochloride (0.5-mg/kg intravenous push) (arrow) on plasma vasopressin levels and related variables (mean +/- SEM) in polydipsic schizophrenic patients with (solid squares) and without (open squares) hyponatremia. LD indicates limit of detection of the vasopressin assay.
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RESPONSE OF PLASMA AVP, DESIRE FOR WATER, AND OTHER RELATED VARIABLES
After methylphenidate administration, AVP rose sharply and rapidly returned to baseline in the hyponatremic patients; the response in the normonatremic patients was blunted (Figure 1). Statistical analysis confirmed the impressions that the overall (group X time interaction, multivariate F[3,10]=5.52; P<.02) and the peak responses (hyponatremic, 1.9 +/- 0.7 pg/mL; normonatremic, 1.0 +/- 0.7 pg/mL; independent t test=2.37; P <.05, 95% confidence interval for difference, 0.1-1.4 pg/mL) were greater in the hyponatremic patients. These comparisons remained significant when the single female hyponatremic subject was excluded.
Desire for water seemed to increase similarly in both groups (Figure 1), but due to considerable individual variation, the response did not achieve statistical significance (time effect, F[3,36]=2.35, P<.10; group X time interaction, F[3,36]=0.69, P<.60). Plasma osmolality fell slightly and to a similar extent in both groups (Figure 1) (time effect, F[3,36]=4.43, P <.02; linear trend, F[1,36]=8.7, P <.02; group X time interaction, F[3,36]=0.82, P<.35), and values remained consistently lower in the hyponatremic patients (group effect, F[1,12]=11.83; P<.007). Plasma sodium showed a similar response (data not shown). Plasma potassium, glucose, urea, and creatinine levels and hematocrit were unchanged and remained similar across the groups (data not shown). All subjects denied nausea and abdominal discomfort. Ad libitum water consumption after the study was similar (hyponatremic patients, 1.5 +/- 1.01; normonatremics, 1.3 +/- 0.8; P<.65).
Because no recognized factors could account for the enhanced AVP response in the hyponatremic patients, the demographic, physiological, and behavioral variables (Table 1) s 1 through 3, and the mean responses to methylphenidate were added individually as covariates into an analysis of covariance (ANCOVA) comparing the peak AVP response in the 2 groups. Only the addition of basal plasma sodium (t=1.47; P<.18) and basal positive psychotic symptoms approached statistical significance (t=1.92; P<.09), but neither factor accounted for the different response in the 2 groups (ANCOVA with sodium, group F[1,11]=8.32, P<.02; ANCOVA with basal psychotic symptoms, group F[1,11]=5.28, P <.05).
RESPONSES OF OTHER HORMONES AND HVA
Plasma cortisol levels seemed to increase slightly with methylphenidate administration but varied considerably within individuals, so the response was not statistically significant and values remained similar across groups (data not shown). Growth hormone levels rose, peaked at 45 minutes, and slowly returned to baseline and remained similar throughout in the 2 groups. Plasma HVA levels did not change, and remained similar in the 2 groups.
COMMENT
We found that psychotic exacerbations are associated with enhanced release of the antidiuretic hormone in polydipsic schizophrenic patients with chronic hyponatremia. The data also support the interpretation that exacerbated psychosis is responsible for the enhanced AVP release, rather than the reverse, or that the events are only indirectly related. These conclusions are based on the observation that a pharmacologically induced psychotic exacerbation elevated antidiuretic hormone levels in a sample of these patients. If levels remained even slightly elevated as plasma osmolality continued to fall, life-threatening water intoxication would soon ensue. [29] The conclusions are tempered by the small sample size and by our limited knowledge of the extent to which methylphenidate replicates naturally occurring psychotic exacerbations. [23,24] Still, the finding is consistent with a considerable literature showing that water excretory capacity diminishes in this subgroup of schizophrenic patients during psychotic relapses. [9-13,18]
In contrast to the hyponatremic subjects, AVP levels rose little, if at all, in a closely matched group of normonatremic polydipsic schizophrenic patients. This blunted response in the normonatremic patients is in keeping with the observation that they never manifest hyponatremia and is especially striking because their higher plasma osmolality might be expected to enhance their response. [25,39] Although many others have observed that psychotic exacerbations are associated with enhanced plasma AVP in some schizophrenic patients, [9,11-13,18-20] in this study, we varied the severity of psychotic symptoms and assessed recognized and putative AVP stimuli in 2 closely matched groups of polydipsic schizophrenic patients, 1 with, and 1 without, a history of impaired water excretion. Thus, this controlled demonstration of a difference in the AVP response to psychotic exacerbations provides a unique opportunity to explore the cause of the finding.
The difference in the AVP response in the 2 groups cannot be accounted for by recognized AVP stimuli, although we admittedly have weak power to eliminate them from consideration. Thus, patients with factors known to alter water excretion were excluded from the study. Regular measurements of vital signs, hematocrit, and plasma chemistries enable us to discount the role of hypotension, hypovolemia, and hypoglycemia. The similar histories of cigarette smoking, the length of the smoking restriction, and the equivalent levels of expired-air carbon monoxide across groups make nicotine ingestion or withdrawal an unlikely explanation. The absence of subjective reports of epigastric discomfort and nausea and the fact that neuroleptics block these responses to dopamine agonists [25,40] indicate that this stimulus probably can be dismissed.
Most putative factors also seem to be unlikely explanations. Polydipsia can be discounted, not only because indexes of the severity and the duration of polyuria were similar across groups but also because polydipsia blunts AVP responses. Similarly, neuroleptic medications and neuroleptic-induced dopamine supersensitivity are unlikely explanations, not only because duration of illness and neuroleptic dosage were similar across groups but also because dyskinetic movements, a presumptive marker of drug-induced supersensitivity, were less apparent in the hyponatremic patients after methylphenidate administration. Although a few case studies suggest neuroleptic treatment or withdrawal promote water intoxication, [9,15,17] more controlled studies do not [1,9,41,42] (although neuroleptic medications may increase renal sensitivity to AVP). [6] That all subjects had a long history of neuroleptic treatment, however, leaves open the possibility that these drugs are involved. Gender is an unlikely factor, because it is not known to influence AVP response to nonosmotic stimuli and, in any event, the main finding of the study was not altered by excluding the single female subject. Finally, we explored the role of other epidemiologic, behavioral, and biochemical variables by adding them as covariates to the analysis comparing peak AVP responses in the 2 groups. Only basal positive psychotic symptoms and plasma sodium even marginally predicted the AVP response, although these factors could not explain the group differences.
Besides the different AVP responses, the only differences in the 2 groups were the hyponatremic patients' lower plasma osmolality and sodium, and their trends toward a consistently higher rating of positive psychotic symptoms and a greater increase in global psychopathologic symptoms (ie, total BPRS) following methylphenidate administration. One might posit that hyponatremia causes greater accumulation of neuronal AVP, which in turn is released by methylphenidate. [43] Such an explanation, however, is inconsistent with studies in chronically hyponatremic animals, [39] the responses of hyponatremic schizophrenic patients to other AVP stimuli, [6] and the almost significant positive correlation between plasma sodium and peak AVP in this study. Alternatively, one might attribute the enhanced AVP response to greater stress, because hyponatremic patients seemed to display more intense positive psychotic symptoms and an exaggerated behavioral response to methylphenidate. Stress (ie, a factor that enhances measures of arousal and threatens the well-being of the organism), however, does not increase, and probably diminishes, AVP release in the absence of recognized AVP stimuli. [44-47]
The difference in the AVP response of the 2 groups may be more fundamentally related to differences in the nature or severity of their psychiatric illnesses. Some propose that dopaminergic hyperactivity accounts for the association between exacerbated psychosis and enhanced AVP release, [9,20,43] although the similarity of plasma HVA and growth hormone levels in our 2 groups, their equally poor clinical response to dopaminergic antagonists, and the unclear role of the dopaminergic system in schizophrenia or AVP release cast doubt on this interpretation. Medial temporal lobe dysfunction is implicated in schizophrenia, and this region seems to be smaller (and associated cognitive functions may be more impaired) [48,49] in hyponatremic patients compared with the normonatremic schizophrenic patients. [50,51] Furthermore, this region may normally restrain behavioral and neuroendocrine (including AVP) [52-55] responses to psychological stress. [56,57] Because peripheral AVP is precisely regulated [29] and these regulatory influences are well-characterized, [58] our findings may provide an ideal opportunity to explore the mechanisms underlying neuroendocrine and psychiatric illnesses.
The clinical implication of our finding is that hyponatremic patients should be closely monitored for signs and symptoms of latent water intoxication (eg, lethargy, confusion, nausea, ataxia, coarse tremor, and large diurnal weight gain) [1] during periods of incipient psychosis or when neuroleptic dosage is reduced. Clinicians also may want to consider a trial of clozapine in appropriate patients, because it seems to correct the hyponatremia and may prevent water intoxication. [59]
Accepted for publication May 15, 1996.
Supported in part by the Brain Research Foundation, an affiliate of the University of Chicago, Chicago, Ill, the Scottish Rite Program for Schizophrenia Research, Lexington, Mass, and a Clinical Research Center grant (RR-00055) and a First Award (MH43618) from the National Institute of Mental Health, Bethesda, Md.
Presented at the Society for Neuroscience, Miami, Fla, November 17, 1994.
We thank Robert C. Marks, MD, Lesley Blake, MD, Miljana Petkovic, BS, John Savaglio, RN, Annette Miller, RN, Jackie Imperial, RN, Javaid Javaid, PhD, John Davis, MD, Rajiv Sharma, MD, Barbara Brown, MS, Nijole Grazulis, MS, the staffs of the Clinical Research Center at the University of Chicago, the Psychiatric Research Unit at the Psychiatric Institute, the University of Illinois at Chicago, and the Elgin (Ill) Mental Health Center; and the Department of Mental Health and Developmental Disabilities, State of Illinois, for their assistance.
Reprints: Morris B. Goldman, MD, Department of Psychiatry, MC 3077, University of Chicago Medical Center, 5841 S Maryland Ave, Chicago, IL 60637.
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Antidiuretic Hormones; Hyponatremia; Polydipsia; Psychotic Disorders; Schizophrenia; Vasopressins; Water Intoxication
Accession Number: 00000756-199705000-00007