Primary polydipsia: Update.

In primary polydipsia pathologically high levels of water intake physiologically lower arginine vasopressin (AVP) secretion, and in this way mirror the secondary polydipsia in diabetes insipidus in which pathologically low levels of AVP (or renal responsiveness to AVP) physiologically increase water intake. Primary polydipsia covers several disorders whose clinical features and significance, risk factors, pathophysiology and treatment are reviewed here. While groupings may appear somewhat arbitrary, they are associated with distinct alterations in physiologic parameters of water balance. The polydipsia is typically unrelated to homeostatic regulation of water intake, but instead reflects non-homeostatic influences. Recent technological advances, summarized here, have disentangled functional neurocircuits underlying both homeostatic and non-homeostatic physiologic influences, which provides an opportunity to better define the mechanisms of the disorders. We summarize this recent literature, highlighting hypothalamic circuitry that appears most clearly positioned to contribute to primary polydipsia. The life-threatening water imbalance in psychotic disorders is caused by an anterior hippocampal induced stress-diathesis that can be reproduced in animal models, and involves phylogenetically preserved pathways that appear likely to include one or more of these circuits. Ongoing translational neuroscience studies in these animal models may potentially localize reversible pathological changes which contribute to both the water imbalance and psychotic disorder.

Diabetes insipidus.

Diabetes insipidus (DI) is a disorder characterized by excretion of large amounts of hypotonic urine. Central DI results from a deficiency of the hormone arginine vasopressin (AVP) in the pituitary gland or the hypothalamus, whereas nephrogenic DI results from resistance to AVP in the kidneys. Central and nephrogenic DI are usually acquired, but genetic causes must be evaluated, especially if symptoms occur in early childhood. Central or nephrogenic DI must be differentiated from primary polydipsia, which involves excessive intake of large amounts of water despite normal AVP secretion and action. Primary polydipsia is most common in psychiatric patients and health enthusiasts but the polydipsia in a small subgroup of patients seems to be due to an abnormally low thirst threshold, a condition termed dipsogenic DI. Distinguishing between the different types of DI can be challenging and is done either by a water deprivation test or by hypertonic saline stimulation together with copeptin (or AVP) measurement. Furthermore, a detailed medical history, physical examination and imaging studies are needed to ensure an accurate DI diagnosis. Treatment of DI or primary polydipsia depends on the underlying aetiology and differs in central DI, nephrogenic DI and primary polydipsia.

Circuit activity underlying a distinct modulator of prepulse inhibition.

Prepulse inhibition (PPI), the diminished eye blink response to a startling pulse induced by a prepulse, is regulated by brainstem, and modulated by cerebral, processes. Attentional modulation by the prepulse (AMP), a potential biomarker of psychotic disorders, differs from other modulatory processes because it only occurs if the interval between the prepulse and pulse exceeds 100 ms (>PP100). Videotaped eye blinks were measured during fMRI scanning in 15 healthy subjects hearing 64 pulse alone, 64 PP60 and 64 PP120 trials in a rapid event-related design. Because attentional influences on PPI vary spontaneously, we posited AMP could be isolated by comparing eye blink and Blood Oxygen Level Dependent covariation during the two PP trial types. Behavioral regressor coefficients reflecting significant covariation covered the insula and auditory cortices during PP120 but not PP60 trials. Clusters within the right anterior insula and auditory cortex were specific to AMP. Functional connections (FCs) between cerebral ROIs implicated in PPI were stronger during PP120 trials. The four FCs that were individually stronger during PP120 trials involved the right insula or auditory cortex and three were not present during PP60 trials. Converging evidence indicates the right insula is the hub of a network underlying AMP.

Stimulus intensity determined by dose-titration versus age-based methods in electroconvulsive therapy in Thai patients.

OBJECTIVES: This study aimed to compare the accuracy of the stimulus intensity (SI) calculated by age-based methods with that using the dose-titration method. METHODS: The initial seizure threshold (IST) was determined using a standardized dose titration in hospitalized Thai patients treated with right unilateral (RUL, n=32) and bilateral (BL, n=57) electrode placement. The correlation between the IST and clinical variables was analyzed. The estimated SI based on the patient's age was compared with the SI determined by dose titration. RESULTS: Age was highly predictive of the IST for both groups (RUL, P=0.012; BL, P=0.045). Gender (P=0.006) and anticholinergic drug use (P=0.025) predicted the IST for the BL group. For the RUL group, the mean±SD (median) SI estimated using the half-age and age methods was 158±46 (169) mC and 315±92 (338) mC, respectively. The SI determined using the dose-titration method was higher compared with the half-age method and lower compared with the age method. For the RUL group, 31% of subjects using the half-age method and 22% of subjects using the age method would have received an SI within ±20% of that computed using dose titration. Additionally, 19% of subjects using the half-age method and 19% using the age method would have received unacceptably low (<50%) or high (>200%) intensities. For the BL group, 18% of subjects using the half-age method and 32% using the age method would have received an SI within ±20% of that computed using dose titration. Additionally, 39% with the half-age method and 18% with the age method would have received an unacceptably low or high SI, respectively. CONCLUSION: Age strongly predicts the IST, but it does not robustly predict the SI compared with dose titration because the SI calculated using age-based methods results in an unacceptably low or high SI that is associated with a marked risk of adverse effects or inadequate response. We recommend the dose-titration method to determine the SI.

Default mode functional connectivity is associated with social functioning in schizophrenia.

Individuals with schizophrenia display notable deficits in social functioning. Research indicates that neural connectivity within the default mode network (DMN) is related to social cognition and social functioning in healthy and clinical populations. However, the association between DMN connectivity, social cognition, and social functioning has not been studied in schizophrenia. For the present study, the authors used resting-state neuroimaging data to evaluate connectivity between the main DMN hubs (i.e., the medial prefrontal cortex [mPFC] and the posterior cingulate cortex-anterior precuneus [PPC]) in individuals with schizophrenia (n = 28) and controls (n = 32). The authors also examined whether DMN connectivity was associated with social functioning via social attainment (measured by the Specific Levels of Functioning Scale) and social competence (measured by the Social Skills Performance Assessment), and if social cognition mediates the association between DMN connectivity and these measures of social functioning. Results revealed that DMN connectivity did not differ between individuals with schizophrenia and controls. However, connectivity between the mPFC and PCC hubs was significantly associated with social competence and social attainment in individuals with schizophrenia but not in controls as reflected by a significant group-by-connectivity interaction. Social cognition did not mediate the association between DMN connectivity and social functioning in individuals with schizophrenia. The findings suggest that fronto-parietal DMN connectivity in particular may be differentially associated with social functioning in schizophrenia and controls. As a result, DMN connectivity may be used as a neuroimaging marker to monitor treatment response or as a potential target for interventions that aim to enhance social functioning in schizophrenia. (PsycINFO Database Record

Rapid Rechallenge with Clozapine Following Pronounced Myocarditis in a Treatment-Resistant Schizophrenia Patient.

Clozapine is an atypical antipsychotic which is often effective in patients who fail to respond to other antipsychotics, but its use carries substantial risk. Myocarditis is one of the life-threatening adverse effects, which occurs in about 1% of exposed patients. Rechallenge with clozapine is controversial, particularly shortly after the occurrence of the myocarditis, and when there is clear and convincing evidence of cardiac damage. Aggressive use of clozapine, however, may be critical for the recovery of patients early in the course of their illness. Here we report a successful case of clozapine rechallenge following an initial aggressive dosage titration in an inpatient setting.

Alterations in brain activation during cognitive empathy are related to social functioning in schizophrenia.

Impaired cognitive empathy (ie, understanding the emotional experiences of others) is associated with poor social functioning in schizophrenia. However, it is unclear whether the neural activity underlying cognitive empathy relates to social functioning. This study examined the neural activation supporting cognitive empathy performance and whether empathy-related activation during correctly performed trials was associated with self-reported cognitive empathy and measures of social functioning. Thirty schizophrenia outpatients and 24 controls completed a cognitive empathy paradigm during functional magnetic resonance imaging. Neural activity corresponding to correct judgments about the expected emotional expression in a social interaction was compared in schizophrenia subjects relative to control subjects. Participants also completed a self-report measure of empathy and 2 social functioning measures (social competence and social attainment). Schizophrenia subjects demonstrated significantly lower accuracy in task performance and were characterized by hypoactivation in empathy-related frontal, temporal, and parietal regions as well as hyperactivation in occipital regions compared with control subjects during accurate cognitive empathy trials. A cluster with peak activation in the supplementary motor area (SMA) extending to the anterior midcingulate cortex (aMCC) correlated with social competence and social attainment in schizophrenia subjects but not controls. These results suggest that neural correlates of cognitive empathy may be promising targets for interventions aiming to improve social functioning and that brain activation in the SMA/aMCC region could be used as a biomarker for monitoring treatment response.

Brain circuit dysfunction in a distinct subset of chronic psychotic patients.

OBJECTIVE: To identify the mechanism of unexplained hyponatremia and primary polydipsia in schizophrenia and its relationship to the underlying psychiatric illness. METHODS: Briefly review previous studies that led to the conclusion the hyponatremia reflects altered hippocampal inhibition of peripheral neuroendocrine secretion. In greater detail, present the evidence supporting the hypothesis that circuit dysfunction associated with the hyponatremia and the polydipsia contributes to the underlying mental disorder. RESULTS: Polydipsic patients with and without hyponatremia exhibit enhanced neuroendocrine responses to psychological stress in proportion to structural deformations on their anterior hippocampus, amygdala and anterior hypothalamus. Nonpolydipsic patients exhibit blunted responses and deformations on other hippocampal and amygdala surfaces. The deformations in polydipsic patients are also proportional to diminished peripheral oxytocin levels and impaired facial affect recognition that is reversed by intranasal oxytocin. The anterior hippocampus is at the hub of a circuit that modulates neuroendocrine and other responses to psychological stress and is implicated in schizophrenia. Preliminary data indicate that other measures of stress reactivity are also enhanced in polydipsics and that the functional connectivity of the hippocampus with the other structures in this circuitry differs in schizophrenia patients with and without polydipsia. CONCLUSION: Polydipsia may identify a subset of schizophrenia patients whose enhanced stress reactivity contributes to their mental illness. Stress reactivity may be a symptom dimension of chronic psychosis that arises from circuit dysfunction that can be modeled in animals. Hence polydipsia could be a biomarker that helps to clarify the pathophysiology and heterogeneity of psychosis as well as identify novel therapies. Clinical investigators should consider obtaining indices of water balance, as these may help them unravel and more concisely interpret their findings. Basic researchers should assess if the polydipsic subset is a patient group particularly suitable to test hypotheses arising from their translational studies.

A systematic review of the ability of urine concentration to distinguish antipsychotic- from psychosis-induced hyponatremia.

Life-threatening hyponatremia in psychotic patients is common and typically is attributable to either antipsychotic medication or to acute psychosis in those with the polydipsia-hyponatremia syndrome. The preferred treatment for one situation may worsen the hyponatremia if caused by the other situation. Hence it is critical to distinguish between these two possibilities. Case reports and series were identified through electronic databases. Fifty-four cases of hyponatremia without recognized causes in psychotic patients were divided into those with dilute (plasma osmolality) urine. The distribution of urine concentration and measures likely to be associated with psychotic illness and its treatment were compared in both groups. Naranjo׳s scale was utilized to determine the probability hyponatremia was drug-induced. Urine osmolality fit a bimodal distribution (intersection 219mOsm/kg) better than a unimodal distribution. 'Probable' drug-induced cases occurred 6.8 (95%CI=1.6-28.9) times more often in those with concentrated urine. Acute psychotic exacerbations occurred 4.5 (95%CI=0.4-54.1) times more often in those with dilute urine. These findings, as well as several other trends in the data, indicate that measures of urine concentration can help distinguish between antipsychotic-induced and psychosis-induced hyponatremia.

Cannabis-related working memory deficits and associated subcortical morphological differences in healthy individuals and schizophrenia subjects.

Cannabis use is associated with working memory (WM) impairments; however, the relationship between cannabis use and WM neural circuitry is unclear. We examined whether a cannabis use disorder (CUD) was associated with differences in brain morphology between control subjects with and without a CUD and between schizophrenia subjects with and without a CUD, and whether these differences related to WM and CUD history. Subjects group-matched on demographics included 44 healthy controls, 10 subjects with a CUD history, 28 schizophrenia subjects with no history of substance use disorders, and 15 schizophrenia subjects with a CUD history. Large-deformation high-dimensional brain mapping with magnetic resonance imaging was used to obtain surface-based representations of the striatum, globus pallidus, and thalamus, compared across groups, and correlated with WM and CUD history. Surface maps were generated to visualize morphological differences. There were significant cannabis-related parametric decreases in WM across groups. Similar cannabis-related shape differences were observed in the striatum, globus pallidus, and thalamus in controls and schizophrenia subjects. Cannabis-related striatal and thalamic shape differences correlated with poorer WM and younger age of CUD onset in both groups. Schizophrenia subjects demonstrated cannabis-related neuroanatomical differences that were consistent and exaggerated compared with cannabis-related differences found in controls. The cross-sectional results suggest that both CUD groups were characterized by WM deficits and subcortical neuroanatomical differences. Future longitudinal studies could help determine whether cannabis use contributes to these observed shape differences or whether they are biomarkers of a vulnerability to the effects of cannabis that predate its misuse.

Rapid Re-challenge with Clozapine Following Pronounced Myocarditis in a Treatment-Resistance Schizophrenia Patient.

Clozapine is an atypical antipsychotic which is often effective in patients who fail to respond to other antipsychotics, but its use carries substantial risk. Myocarditis is one of the life-threatening adverse effects which occurs in about 1% of exposed patients. Re-challenge with clozapine is controversial, particularly shortly after the occurrence of the myocarditis and when there is clear and convincing evidence of cardiac damage. Aggressive use of clozapine, however, may be critical for the recovery of patients early in the course of their illness. Here we report a successful case of clozapine rechallenge following an initial aggressive dosage titration in an inpatient setting.

The effect of propofol-remifentanil anesthesia on selected seizure quality indices in electroconvulsive therapy.

BACKGROUND: Use of a short-acting opiate to potentiate anesthetic induction agents has been shown to increase seizure duration in electroconvulsive therapy (ECT), but little is known of the effect of this combination on indices of seizure quality. OBJECTIVE: To determine whether anesthetic modality affects commonly provided indices of seizure quality. METHODS: Twenty-five subjects were given propofol 2 mg/kg body weight for their first ECT session, at which time seizure threshold was titrated. Subjects thereafter alternated between that anesthetic regimen or propofol 0.5 mg/kg plus remifentanil 1 mcg/kg. Linear mixed models with random subject effect, adjusting for electrode placement, electrical charge, and number of treatments, were fit to estimate effect of anesthesia on seizure duration and several standard seizure quality indices (average seizure energy, time to peak electroencephalography (EEG) power, maximum sustained power, interhemispheric coherence, early and midictal EEG amplitude, and maximum sustained interhemispheric EEG coherence). RESULTS: Propofol-remifentanil anesthesia significantly lengthened seizure duration and was associated with longer time to reach maximal EEG power and coherence as well as maximal degree of interhemispheric EEG coherence. No effect was seen on early ictal amplitude or average seizure energy index. CONCLUSIONS: Propofol-remifentanil anesthesia prolongs seizure duration and has a significant effect on some, but not all, measures of seizure quality. This effect may be of some benefit in cases where adequate seizures are otherwise difficult to elicit. Varying anesthetic technique may allow more precise investigation of the relationships between and relative impacts of commonly used seizure quality indices on clinical outcomes and ECT-related cognitive side effects.

Alcohol use disorders contribute to hippocampal and subcortical shape differences in schizophrenia.

BACKGROUND: Alcohol abuse and dependence have been reported to exacerbate the clinical course of schizophrenia. However, the neurobiological basis of this co-morbid interaction is unknown. The aim of this study was to determine the relationship of co-morbid alcohol use disorder (AUD) with brain structure abnormalities in schizophrenia patients. METHODS: T1-weighted magnetic resonance images were collected from schizophrenia patients without a history of any substance use disorder (SCZ_0, n=35), schizophrenia patients with a history of AUD only (SCZ_AUD, n=16), and a healthy comparison group without a history of any substance use disorder (CON, n=56). Large-deformation, high-dimensional brain mapping was used to quantify the surface shapes of the hippocampus, thalamus, striatum, and globus pallidus in these subject groups. Analysis of variance was used to test for differences in surface shape measures among the groups. RESULTS: SCZ_AUD demonstrated the greatest severity of shape abnormalities in the hippocampus, thalamus, striatum, and globus pallidus as compared to SCZ_0 and CON. SCZ_AUD demonstrated a combination of exaggerated shape differences in regions where SCZ_0 also showed shape differences, and unique shape differences that were not observed in SCZ_0 or CON. CONCLUSIONS: Shape differences in schizophrenia were compounded by a history of co-morbid AUD. Future research is needed to determine whether these differences are simply additive or whether they are due to an interaction between the underlying neurobiology of schizophrenia and alcoholism. The consequences of such shape differences for the clinical course of schizophrenia are not yet understood.

Divergent effects of two different doses of intranasal oxytocin on facial affect discrimination in schizophrenic patients with and without polydipsia.

RATIONALE: Hyponatremia and dexamethasone resistance in polydipsic schizophrenic patients are attributable to changes in hippocampal-modulated antidiuretic and stress hormone activity, respectively. The relationship of the neuroendocrine findings to the psychiatric illness, however, is unknown. An impaired ability to identify facial emotions has been linked to core features of schizophrenia and to diminished levels of the closely related hormone, oxytocin, in the polydipsic subset. Intranasal oxytocin enhances facial affect discrimination in healthy subjects. OBJECTIVE: The aim of this study is to explore if oxytocin reverses impaired facial affect discrimination in schizophrenic patients with, relative to that in patients without, polydipsia. METHODS: Intranasal oxytocin (10 or 20 IU) and placebo were administered on three occasions to five polydipsic schizophrenic patients, eight nonpolydipsic patients, and 11 healthy controls. Subsequently, subjects rated the presence and intensity of six facial emotions. RESULTS: Emotion recognition fell in both patient groups following 10 IU of oxytocin due to an increased propensity to identify all emotions regardless of whether they were displayed. By contrast, emotion recognition improved following 20 IU in polydipsic relative to nonpolydipsic patients due primarily to divergent effects on the bias to identify fear in nonfearful faces. CONCLUSION: The effects of 20 IU oxytocin support the hypothesis that altered neuroendocrine function in polydipsic patients contributes to their psychiatric illness. Further studies are warranted to confirm these findings and assess if oxytocin treatment improves social functioning in this subset. This is the first psychopharmacologic study to compare different doses of oxytocin in the same subject, thus the significance of the opposing responses is unclear.

Structural pathology underlying neuroendocrine dysfunction in schizophrenia.

Polydipsic hyponatremic schizophrenic (PHS) patients exhibit altered neuroendocrine activity that has been linked to their life-threatening water imbalance, as well as to impaired function and reduced volume of the anterior hippocampus. Polydipsic patients without hyponatremia (polydipsic normonatremic schizophrenics: PNS) exhibit similar, albeit less marked, changes in neuroendocrine activity and anterior hippocampal function, but not reduced anterior hippocampal volume. Indeed, reduced anterior hippocampal volume is seen in patients with normal water balance (nonpolydipsic normonatremic schizophrenics: NNS) whose neuroendocrine activity and anterior hippocampal function differ markedly from those with polydipsia. In an effort to reconcile these findings we measured hippocampal, amygdala and 3rd ventricle shapes in 26 schizophrenic patients (10 PNS, 7 PHS, 9 NNS) and 12 healthy controls matched for age and gender. Bilateral inward deformations were localized to the anterior lateral hippocampal surface (part of a neurocircuit which modulates neuroendocrine responses to psychological stimuli) in PHS and to a lesser extent in PNS, while deformations in NNS were restricted to the medial surface. Proportional deformations of the right medial amygdala, a key segment of this neurocircuit, were seen in both polydipsic groups, and correlated with the volume of the 3rd ventricle, which lies adjacent to the neuroendocrine nuclei. Finally, these structural findings were most marked in those with impaired hippocampal-mediated stress responses. These results reconcile previously conflicting data, and support the view that anterior lateral hippocampal pathology disrupts neuroendocrine function in polydipsic patients with and without hyponatremia. The relationship of these findings to the underlying mental illness remains to be established.

The assessment and treatment of water imbalance in patients with psychosis.

Polydipsia and episodic life-threatening water intoxication remain important clinical problems for a significant portion of persons with schizophrenia. The disorders are associated with increased morbidity and mortality from a number of causes. With a basic understanding of the pathophysiology, one can easily diagnose and assess the clinical conditions. We review here the scope and pathophysiology of disordered water imbalance, including both primary and secondary polydipsia and hyponatremia. Reversible factors and possible interventions are reviewed. Treatment options for preventing water intoxication have expanded from discontinuation of offending agents, targeted fluid restriction, and clozapine therapy to the addition of oral vasopressin antagonists. The latter, however, are extremely potent and must be carefully monitored.

The mechanism of life-threatening water imbalance in schizophrenia and its relationship to the underlying psychiatric illness.

Impaired water excretion was noted to coincide with psychotic exacerbations in the first decades of the past century. In the ensuing decades, life-threatening water intoxication and elevated plasma levels of the antidiuretic hormone, arginine vasopressin (AVP) were reported in a subset of persons with schizophrenia. Subsequent studies demonstrated that the osmotic set point for AVP secretion was transiently reset in these patients by an unknown process and that this was further exacerbated by acute psychosis. More recent studies indicate that the AVP dysfunction is a manifestation of a hippocampal-mediated impairment in the regulation of both AVP and HPA axis responses to psychological, but not other types of, stimuli. Of potential significance, is that schizophrenic patients without water imbalance exhibit the opposite pattern of responses. Preliminary data indicate those with water imbalance also demonstrate a closely linked deficit in central oxytocin activity which may account for their diminished social function. These latter behavioral deficits are perhaps the most disabling and treatment resistant features of schizophrenia, which recent studies suggest, may respond to oxytocin agonists. Together these findings support the view that schizophrenia is a heterogeneous disorder, and provide novel biomarkers and approaches for exploring the pathophysiology and treatment of severe mental illness.

Neuropsychological impairment in patients with schizophrenia and evidence of hyponatremia and polydipsia.

Patients with schizophrenia and water imbalance may represent a subset of patients with distinct pathophysiological abnormalities and susceptibility to cognitive impairment. Specifically, patients with polydipsia and hyponatremia have been shown to have smaller anterior hippocampal volumes, which are also associated with various impairments in neuroendocrine function. To determine whether abnormalities in patients with water imbalance extend to the cognitive realm, the present study evaluated neuropsychological functioning in three groups of patients with schizophrenia: polydipsic hyponatremic, polydipsic normonatremic, and nonpolydipsic normonatremic. Participants were administered cognitive tests assessing intelligence, attention, learning/memory (verbal, nonverbal, emotional), and facial discrimination. Hyponatremic patients showed poorer overall neuropsychological functioning relative to all other patients, and polydipsic normonatremic patients performed intermediate to the other two groups. Results indicate that patients with schizophrenia and polydipsia, and particularly those with hyponatremia, show prominent cognitive deficits relative to patients without water imbalance. The clinical, neuroendocrine, and cognitive abnormalities in these patients may arise from pathology within the anterior hippocampus and associated prefrontal/limbic brain regions.

A case of negative-pressure pulmonary edema after electroconvulsive therapy.

Pulmonary edema after electroconvulsive therapy (ECT) is a rarely reported condition that can result in serious morbidity and even death if not promptly recognized and treated. We report the case of 21-year-old man with FG syndrome and schizophrenia who developed negative-pressure pulmonary edema after his 28th ECT. The patient developed acute hypoxemia requiring positive-pressure ventilation and was observed overnight in the intensive care unit. He recovered fully and received 43 subsequent ECT treatments without complication. This case illustrates the importance of taking steps to prevent airway obstruction as well as recognizing this rare but serious complication.

Neuroendocrine responses to a cold pressor stimulus in polydipsic hyponatremic and in matched schizophrenic patients.

Schizophrenia, many believe, reflects an enhanced vulnerability to psychological stress. Controlled exposure to stressors, however, has produced inconclusive results, particularly with regards to neurohormones. Some of the variability may be attributable to the nature and psychological significance of the stimulus and failure to control physiologic confounds. In addition, it is possible that the heterogeneity of schizophrenia is an important factor. In a carefully designed study and in a controlled setting, we measured the neuroendocrine response of eight polydipsic hyponatremic (PHS), seven polydipsic normonatremic (PNS), and nine nonpolydipsic normonatremic (NNS) (ie normal water balance) schizophrenic in-patients as well as 12 healthy controls (HC) to two different stressors: one of which appears to influence neuroendocrine secretion through its psychological (cold pressor) and the other (upright posture) through its systemic actions. Subjects in the three psychiatric groups were stabilized and acclimated to the research setting, and all received saline to normalize plasma osmolality. Following the cold pressor, plasma adrenocorticotropin and cortisol levels showed a more prolonged rise in PHS patients relative to PNS patients. NNS patients, in contrast, exhibited blunted responses relative to both of the polydipsic groups and the HC. Peak vasopressin responses were also greater in PHS and blunted in NNS patients. Responses to the postural stimulus were similar across patient groups. These findings provide a mechanism for life threatening water intoxication in schizophrenia; help to reconcile conflicting findings of stress responsiveness in schizophrenia; and potentially identify a discrete patient subset with enhanced vulnerability to psychological stress.