clozapine and Hyponatremia

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.

Topics: Antidiuretic Hormone Receptor Antagonists; Antimanic Agents; Antipsychotic Agents; Benzazepines; Clozapine; Combined Modality Therapy; Diagnosis, Differential; Drinking; Humans; Hyponatremia; Lithium Carbonate; Randomized Controlled Trials as Topic; Receptors, Vasopressin; Risk Factors; Schizophrenia; Schizophrenic Psychology; Sodium Chloride Symporter Inhibitors; Tolvaptan; Water Deprivation; Water Intoxication; Water-Electrolyte Balance

Hyponatremia/hypoosmolemia causes marked morbidity and prolongs hospital stays in a significant subset of schizophrenic patients. Case reports with methodological limitations suggest clozapine ameliorates this water imbalance. To more conclusively assess this possibility, we completed a 24-week open-label study in 8 male polydipsic hypoosmolemic schizophrenic inpatients. Subjects were treated initially for 6 weeks with a conventional neuroleptic, which was replaced by 300, 600, and 900 (if tolerated) mg/day of clozapine for sequential 6-week periods. On clozapine, mean plasma osmolality rose an average of 15.2 mosm/kg (95% CI: 5.5-25.0). Dosage of 300 mg/day of clozapine was sufficient to normalize plasma osmolality and was generally well tolerated. Clozapine appears to be the first effective pharmacotherapy for severe water imbalance in schizophrenia.

Topics: Adult; Analysis of Variance; Antipsychotic Agents; Clozapine; Compulsive Behavior; Dose-Response Relationship, Drug; Drinking; Humans; Hyponatremia; Male; Middle Aged; Osmolar Concentration; Prospective Studies; Schizophrenia; Treatment Outcome; Water Intoxication

Topics: Antipsychotic Agents; Clozapine; Humans; Hyponatremia; Inappropriate ADH Syndrome; Male; Middle Aged; Schizophrenia

The antipsychotic drug (APD) clozapine (CLZ) is under-prescribed because of concerns about its safety. We evaluated in separate protocols the frequency of cardiomyopathy and hyponatraemia, which are adverse drug effects, where few comparative studies are available.. Cross-sectional studies in subjects treated for at least 3 consecutive months with the same drug were conducted. Cardiomyopathy: Patients undergoing treatment either with CLZ (n = 125) or with other typical or atypical APDs (n = 59) were examined by a cardiologist who also recorded echocardiograms and electrocardiograms in order to diagnose cardiomyopathy. Hyponatraemia: Fasting sodium levels were assessed in patients receiving any of the following treatments: CLZ (n = 88), other atypical APDs (n = 61), typical APDs (n = 23), typical + atypical APDs (n = 11), and other drugs/drug-free (n = 36).. Cardiomyopathy: No case of cardiomyopathy was detected. The frequency of abnormal ventricular ejection fraction (< 55%) was similar in both treatment groups (p = 1). Hyponatraemia: The frequency of hyponatraemia (percentage; 95% CI) was: CLZ (3.4%; -0.7, 7.1); other atypical APDs (4.9%; -0.5, 10.3); typical APDs (26.1%; 8.2, 44.0); typical + atypical APDs (9.1%; -7.8, 26.0); other drugs/drug-free (0%). None of the CLZ hyponatraemia subjects were on monotherapy.. Our results are at odds with previous studies of CLZ-associated cardiomyopathy. However, they must be compared to further cross-sectional or prospective studies because most published data come from either case reports or pharmacovigilance systems. The frequency of hyponatraemia during CLZ administration was similar to that observed with other atypical APDs, and it was significantly lower than that recorded with typical agents. These results, along with numerous case reports on the effects of CLZ in patients with polydipsia and water intoxication, point to a safe or even positive profile of CLZ on electrolytic regulation.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antipsychotic Agents; Cardiomyopathies; Clozapine; Cross-Sectional Studies; Female; Humans; Hyponatremia; Male; Middle Aged; Venezuela; Young Adult

Polydipsia is the intake of more than 3-4 litres of fluids per day. Primary polydipsia (PP) occurs when excessive fluid intake cannot be explained by an identified medical condition. PP has a prevalence varying between 6% and 20% in the population of chronically hospitalized psychiatric patients. Hyponatraemia--sometimes with severe somatic consequences--developing in 25-86% of these patients. We discuss the case of a schizophrenic patient who had polydipsia, polyuria and hyponatremia without any known medical conditions in the etiological background of these symptoms. In accordance with data of literature, clozapine medication was effective in the treatment of this severe condition.

Topics: Adult; Antipsychotic Agents; Clozapine; Drinking Behavior; Humans; Hyponatremia; Male; Osmolar Concentration; Polyuria; Schizophrenia; Treatment Outcome

A 54-year-old woman with schizophrenia presented to hospital with unconsciousness, fever and marked muscle rigidity. She had been given fluphenazine decanoete 20 mg intramuscularly 15 days before the admission and she had continued taking haloperidol 20 mg daily and oral biperiden 2-4 mg. She was extremely rigid and unresponsive. On laboratory investigations revealed: serum sodium 120 mEq/l, creatinine phosphokinase 12,980 IU/l (normal up to 170), lactate dehydrogenase 1544 IU/l (150-500), free trioidothyronine < 1.00 pg/ml (1.5-4.5), free throxyine 0.76 ng/dl (0.8-1.9), thyroid stimulating hormone 1.14 microU/ml (0.4-4), cortisol (at 8.00 a.m.) 9 microg/dl (5-25). Antipsychotic drugs were withdrawn after admission. A diagnosis of secondary adrenal insufficiency and secondary hypothyroidism was made. Hormonal substitution with hydrocortisone and levothyroxine and correction of hyponatremia with intravenous hypertonic saline solution resulted in rapid improvement of symptoms and signs. It seems that the symptoms and signs of hypothyroidism and hyponatremia were attributed to acute psychosis in this patient. As a conclusion failure to recognize the endocrinopathy may not only produce recovery difficulties but also psychiatric and endocrine repercussions if psychotropic medications are given in such masked cases.

Topics: Adrenal Insufficiency; Antipsychotic Agents; Body Temperature; Clozapine; Female; Haloperidol; Humans; Hyponatremia; Hypothyroidism; Middle Aged; Muscle Rigidity; Neuroleptic Malignant Syndrome; Schizophrenia

Topics: Antidiuretic Agents; Antipsychotic Agents; Clozapine; Deamino Arginine Vasopressin; Enuresis; Glasgow Coma Scale; Humans; Hyponatremia; Male; Middle Aged; Schizophrenia; Severity of Illness Index; Sodium

This is a retrospective review of the author's experience with polydipsia in a long-term unit for treatment refractory patients at a US psychiatric state hospital during a 5-year period [1996-2000]. Sixty-one patients were admitted to this long-term unit, comprising approximately 1 % of the hospital admissions. Polydipsic patients were followed with diurnal weight changes and other biological measures. This longitudinal study of 61 chronic inpatients suggests that polydipsia is no doubt present in at least 20 % of chronic psychiatric inpatients and hyponatremia in more than 10 %. Two polydipsic patients worsened when switched from clozapine to other atypical antipsychotics. Polydipsia in severe mentally ill patients continues to be a neglected subject and a challenge for psychiatrists. Polydipsic patients should not be switched to other atypical antipsychotics, unless new prospective studies prove that they are as effective as clozapine for polydipsia.

Topics: Adult; Antipsychotic Agents; Clozapine; Drinking; Female; Hospitals, Psychiatric; Humans; Hyponatremia; Kentucky; Length of Stay; Long-Term Care; Male; Retrospective Studies; Schizophrenia; Treatment Outcome; Water Intoxication

Polydipsia-hyponatremia is a poorly understood disorder that causes considerable mortality and morbidity. Hyponatremia in polydipsia-hyponatremia has been attributed to disturbances in antidiuretic hormone (ADH) function. Improvements in polydipsia-hyponatremia during clozapine treatment offered the chance to see if levels of ADH and other hormones associated with osmoregulation changed with improvement in biochemical and clinical measures of polydipsia-hyponatremia.. In this preliminary, longitudinal study, we studied 2 male schizophrenic patients (DSM-III-R) who had polydipsia-hyponatremia. Measures were (1) biochemical and clinical: serum sodium and osmolality, urine osmolality and specific gravity, normalized diurnal weight gain, and estimated urine volume and (2) endocrine: ADH, angiotensin II, atrial natriuretic peptide, and prolactin. Measures were collected during 2 months of baseline (typical neuroleptic) and 6 months of clozapine treatment.. Single-case statistical procedures showed significant changes in sodium levels (a.m. and p.m.), estimated urine volume, and a.m. urine specific gravity in both patients and significantly decreased diurnal weight gain in 1 patient. Both serum and urine osmolality showed improvement, but values did not reach statistical significance. Low baseline ADH levels persisted through 6 months of clozapine treatment and showed no changes in the context of improvements in serum sodium and osmolality. No significant changes were seen in levels of angiotensin II and atrial natriuretic peptide.. Given the limitations of this study, there is some evidence to suggest that the improvements in serum sodium and osmolality during clozapine treatment of polydipsia-hyponatremia may not be related to serum levels of ADH, although altered ADH receptor function cannot be ruled out. These data need to be extended in larger samples.

Topics: Adult; Angiotensin II; Atrial Natriuretic Factor; Circadian Rhythm; Clozapine; Humans; Hyponatremia; Longitudinal Studies; Male; Middle Aged; Osmolar Concentration; Prolactin; Schizophrenia; Sodium; Urine; Vasopressins; Water Intoxication

To report a case of rhabdomyolysis related to rapid correction of hyponatremia attributable to compulsive drinking of water, possible complicated by clozapine use.. A 42-year-old white man treated with clozapine for schizophrenia was admitted for a generalized seizure. Marked hyponatremia due to psychogenic polydipsia was present. He developed a marked elevation of creatine kinase concentrations after correction of hyponatremia with hyperosmolar sodium solution, without clinical signs of rhabdomyolysis.. Rhabdomyolysis associated with hyponatremia due to water intoxication has been reported in 17 patients to date. A possible explanation may lie within the framework of the calcium-sodium exchange across the skeletal muscle cell membrane. By increasing muscle cell permeability, clozapine treatment may possibly enhance the destruction of muscle cells.. Hyponatremia due to water intoxication and concurrent use of clozapine should be considered in the differential diagnosis of rhabdomyolysis, especially in the severely psychiatrically disabled population.

Topics: Adult; Antipsychotic Agents; Clozapine; Drinking Behavior; Humans; Hyponatremia; Male; Rhabdomyolysis; Schizophrenia, Paranoid; Schizophrenic Psychology; Sodium Chloride

Topics: Adult; Clozapine; Drinking; Humans; Hyponatremia; Male; Schizophrenia; Schizophrenic Psychology; Water Intoxication

Recent case reports indicate that clozapine treatment diminishes excessive diurnal weight gain and alleviates hyponatremia observed in some chronically psychotic patients. We examined the influence of clozapine on sodium metabolism and water regulation across a group of patients with the syndrome of polydipsia and intermittent hyponatremia.. Eleven patients with treatment-resistant DSM-III-R schizophrenia or schizoaffective disorder were studied. Each had a history of repeated diurnal weight gains of greater than 10% with at least one documented bout of hyponatremia in the 6 months before clozapine treatment. We utilized a target weight protocol and serial laboratory measures to compare changes in sodium metabolism and water regulation during 26 weeks of standard antipsychotic medication and 26 weeks of clozapine treatment.. Across patients, we found significant improvement in routinely monitored 6 a.m. and 4 p.m. serum sodium, reflecting normalization of sodium metabolism. We also found that the frequency (as reflected by diurnal weight gain), severity (lowest serum sodium), and estimated quantity (calculated urine volume) of polydipsia improved across patients. Improvement in polydipsia and hyponatremia was associated with decreased necessity for monitoring and restrictive interventions, and tended to be associated with psychiatric improvement.. We found a corrective and stabilizing effect of clozapine on polydipsia and intermittent hyponatremia. Future studies need to examine the relationship of psychiatric improvement and alterations in the regulation of sodium and water physiology to our findings.

Topics: Adult; Circadian Rhythm; Clozapine; Drinking; Female; Humans; Hyponatremia; Male; Middle Aged; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology; Sodium; Thirst; Water Intoxication; Water-Electrolyte Balance; Weight Gain

Topics: Adult; Antidepressive Agents, Tricyclic; Antipsychotic Agents; Clomipramine; Clozapine; Drug Monitoring; Electrolytes; Female; Humans; Hyponatremia; Male; Perphenazine

Polydipsia can be defined as an impulsive behavior leading to absorption of large amounts of water (4 to 20 litres a day), without any underlying organic disease. Its prevalence in a population of chronic psychiatric patients can be as high as 6 to 17%. Schizophrenia represents 80% of cases reported. Some patients with polydipsia may develop hyponatremia, leading to a PIP syndrome (Polydipsia intermittent hyponatremia and psychosis). Hyponatremia or water intoxication appears when three conditions are present: an abnormal regulation of thirst, an inappropriate ADH secretion and/or an excessive renal sensitivity to ADH, with an increased sensitivity of the central nervous system to hyponatremia. The clinician must first identify patients at risk to develop water intoxication and start treatment before any severe physical complication occurs. Pharmacological treatments aiming at an increase of renal free-water excretion--do not show a constant efficacy in the correction of hyponatremia, they have no action on polydipsia. The new atypical neuroleptics such as clozapine and risperidone seem to open new perspectives in the treatment of polydipsia. Controlled studies should be performed in this field.

Topics: Adult; Antipsychotic Agents; Clozapine; Humans; Hyponatremia; Male; Schizophrenia; Schizophrenic Psychology; Water Intoxication

Polydipsia occurs frequently in chronic schizophrenic patients, some of whom develop intermittent hyponatremia. Most therapeutic efforts have tried to control the hyponatremia. Four schizophrenic patients, followed for more than one year, showed improvement on clozapine. Case 1 was an outpatient without history of hyponatremia who improved from polydipsia and psychosis. The last three were inpatients with polydipsia, intermittent hyponatremia, and psychosis who showed minimal improvement of psychosis but significant decrease in polydipsia and water intoxication. Case 2 relapsed to polydipsia when clozapine was discontinued on two occasions. Case 3 demonstrated polyuria during 39% of days before clozapine and in 0% of days after two weeks of clozapine. In case 4, most baseline sodium levels were abnormal, but all became normal after clozapine. A time-series analysis for intervention effects showed a significant effect of clozapine (p = .017). The limited information provided by these case reports suggest the need for controlled studies of the clozapine effect on polydipsic patients.

Topics: Adult; Ambulatory Care; Clozapine; Drinking; Female; Follow-Up Studies; Hospitalization; Humans; Hyponatremia; Male; Schizophrenia; Schizophrenic Psychology; Treatment Outcome; Water Intoxication

A patient with refractory chronic schizophrenia having severe polydipsia and hyponatremia was treated with clozapine. There followed a dramatic improvement in the polydipsia and correction of the hyponatremia. This improvement has been sustained throughout a 6-month follow-up.

Topics: Adult; Chronic Disease; Clozapine; Compulsive Behavior; Dose-Response Relationship, Drug; Drinking; Drug Administration Schedule; Humans; Hyponatremia; Male; Mental Status Schedule; Schizophrenia, Disorganized; Water-Electrolyte Balance

Topics: Adult; Chronic Disease; Clozapine; Female; Humans; Hyponatremia; Male; Middle Aged; Schizophrenia; Water Intoxication

Topics: Adult; Clozapine; Drinking; Humans; Hyponatremia; Male; Middle Aged; Schizophrenia; Schizophrenia, Paranoid; Schizophrenic Psychology; Water Intoxication

Topics: Adult; Adverse Drug Reaction Reporting Systems; Clozapine; Female; Humans; Hyponatremia; Middle Aged; Schizophrenia

The mechanism by which clonidine suppresses renin release was investigated in conscious rats. This suppression was studied by means of selected autonomic interventions in conjunction with changes in sodium balance. Serum renin activity and direct arterial pressure were monitored. Clonidine administration suppressed basal (by 68-85%), diuretic-induced (by 89%), and sympathetic nervous system-mediated (by 75-100%) renin release. Cholinergic, ganglionic, and peripheral sympathetic neuronal blockade did not prevent this inhibitory effect of clonidine. These results indicate a peripheral site of action for suppression of renin release by clonidine. The alpha-adrenergic blocking drug phentolamine prevented clonidine suppression of renin release in sodium-depleted rats and was partially effective in normal rats. Phentolamine blocked the decrease in renin caused by clonidine in ganglion-blocked rats. Clozapine, a new neuroleptic agent with alpha-adrenergic blocking activity, or phenoxybenzamine blocked the effect of clonidine on renin release in both sodium-depleted and normal rats. After ganglionic blockade in sodium-depleted rats, clonidine caused a significantly greater suppression of renin release than did an equipressor dose of methoxamine. These data, combined with hemodynamic correlates, suggest that clonidine inhibits renin release by activation of an intrarenal alpha-adrenergic receptor.

Topics: Adrenergic alpha-Antagonists; Animals; Blood Pressure; Chlorisondamine; Clonidine; Clozapine; Hyponatremia; Juxtaglomerular Apparatus; Male; Methoxamine; Phenoxybenzamine; Phentolamine; Propranolol; Rats; Receptors, Adrenergic; Renin; Sympathetic Nervous System