Dr. McDaniel is a psychiatrist at the Mental Health Clinic at the Hampton VA Medical Center in Virginia and associate clinical professor of the Community Faculty in the Department of Psychiatry and Behavioral Science at Eastern Virginia Medical School in Norfolk. Dr. Spiegel is associate clinical professor in the Department of Psychiatry and Behavioral Science at Eastern Virginia Medical School.
Disclosures: Dr. McDaniel reports no affiliation with or financial interest in any organization that may pose a conflict of interest. Dr. Spiegel is on the speaker’s bureaus of AstraZeneca, Janssen, Merck, and Pfizer.
Off-label disclosure: This article contains discussion of uapproved treatments for catatonia, including minocycline and amantadine.
Please direct all correspondence to: William W. McDaniel, MD, MS, Psychiatrist, Mental Health Clinic, Hampton VA Medical Center, 100 Emancipation Dr, Hampton, VA 23667; Tel: 757-722-9961; Fax: 757-728-3174; E-mail: firstname.lastname@example.org.
Four cases are presented in whom psychotic illness was associated with both catatonia and hyponatremia with polydipsia and concentrated urine. Furthermore, one of the patients ingested foreign objects during the same episode of illness. The presence of concentrated urine in these and many reported cases suggests a role for vasopressin in generating the abnormal excessive ingestion of water, producing hyponatremia with concentrated urine (and perhaps ingestion of foreign objects, as in one case). It may be that hyponatremia in psychosis, and abnormal ingestion of either water or foreign objects, should be regarded as potential signs of catatonia
• Hyponatremia may be associated with catatonia.
• Hyponatremia associated with catatonia may share an underlying mechanism, rather than causing the alteration in mental state.
• Hyponatremia in catatonia is often associated with psychogenic polydipsia, which as a repeated, stereotyped, self-injurious behavior may represent a stereotypy, and thus a sign of the catatonic state.
• Hyponatremia associated with catatonia is likely to be associated with concentrated urine, or increased urine sodium, and thus the syndrome of inappropriate antidiuretic hormone.
Hyponatremia has been reported in association with catatonia, in a case in which it appeared that the electrolyte abnormality might have caused the catatonic state.1 The authors of this article report four cases in which there seemed to be evidence that the hyponatremia and associated excessive water intake (and in one case, eating foreign objects) did not cause catatonia, but were produced by the same underlying process that generated the catatonic state. It may be that excessive water drinking and hyponatremia can be manifestations of catatonia, and understood and treated as such.
Catatonia is a relatively common syndrome of psychomotor dysregulation characterized by symptoms such as mutism, immobility, negativity, or, alternately, extreme agitation, often with echolalia or echopraxias. Signs such as catalepsy or “waxy” rigidity (limbs will hold a position after being passively positioned), are commonly associated with mutism and immobility. Other signs such as gegenhalten (German, literally “going and stopping”, in which patients initially permit passive movement, but then resist) may be noted with either presentation. Catatonia may be associated with bipolar disorder, depression, or schizophrenia, and may be the presenting sign of medical problems including infectious, metabolic, neoplastic, autoimmune, and toxic disorders.2-7
Patients were encountered in inpatient units, on the consultation service, and in the course of outpatient care. As they improved to their baseline, permission was obtained to report their course of illness, with the promise to conceal their identities. All subjects signed consent. Records were reviewed, and features of the episodes of illness were recorded and tabulated, with special attention to the presence and interaction of signs of catatonia with the behaviors of ingesting excess fluids or foreign objects. The Bush-Francis Catatonia Rating Scale (BFCRS)8 was used to rate the severity of symptoms of catatonia in each patient during the episode of illness described, based on the recorded signs and symptoms. Measures of osmolality were not available for any of the cases. Plasma and urine osmolality were assumed to be low when sodium levels were low. This assumption is not always true, but was thought to be true in these cases because of the association with excessive water drinking behavior.
“A” was a 30-year-old male diagnosed as suffering from schizoaffective disorder and cocaine dependence, who presented in two different hospitalizations within 2 weeks with exacerbations of psychosis due to cessation of his medications (divalproex 1,500 mg/day and risperidone 4 mg qHS), and abuse of crack cocaine. During one case, he demonstrated euphoria and rapid, pressured speech intermittently, alternating with periods of mute immobility, frequently in uncomfortable positions (such as squatting to sit on a sofa, but having come to rest about two inches above the cushions, for several hours). BFCRS score was 33. During the first day of each hospitalization, he seized paper clips from the nursing station desk and swallowed them. Despite being put on watch to prevent another ingestion, he worked a steel bracket and its screw loose from the wall, and swallowed them. He never seemed to suffer from these foreign object ingestions, but allowed the authors to obtain abdominal x-rays to catalog his ingestions and to obtain a surgical consultation in case he developed an acute abdomen. The x-ray films demonstrated the presence of several paper clips, the bracket and screw, the cap and wires used to secure the cork stopper of a champagne bottle, and a couple of pieces of metal the authors could not identify. The surgeon prescribed a high-fiber diet in hope that surgical intervention would not be necessary. It was not, as the patient passed all of the objects in his stool over the next few days. He never permitted the drawing of laboratory studies during that hospitalization. During a second hospital stay 1 week later, the patient demonstrated mute, immobile catatonia only on the first day, after which treatment with lorazepam (he required 2 mg 3–4 times daily) allowed him to move and respond more normally (BFCRS score was 33). The authors took precautions against further ingestion of metal objects, but initially did not notice how much water he was drinking. On the second hospital day, the rounding team took note of the collection of 17 Styrofoam cups on his bedside table. He explained he had drunk that many cups of water since admission, which was about 26 hours. His admission laboratory studies were remarkable for serum sodium of 124 mEQ/L. The patient’s psychosis and agitation resolved fairly quickly after initiation of lorazepam therapy and reinstatement of his usual divalproex and risperidone. Internal medicine consultation was obtained, and a urine sodium was obtained (the result was 40 mEq/L), which was thought consistent with the syndrome of inappropriate antidiuretic hormone (SIADH) rather than psychogenic polydipsia. The patient was treated with demeclocycline by the consultant, who reasoned the patient might leave the hospital against advice again. This resulted in resolution of hyponatremia and the excessive water intake was treated with fluid restriction. Mania remitted with resumption of valproate and risperidone therapy, as did signs of catatonia and excessive water drinking.
“B” was a 65-year-old female treated with citalopram for a recurrence of depression. A previous episode of depression after a death in the family at ~30 years of age was associated with catatonia with muteness and immobility, and with auditory and visual hallucinations of the deceased. None of these psychotic symptoms presented at first, and she was initially treated with citalopram alone. After ~3 weeks, depression was reported to be lifting, but shortly thereafter the patient developed a severe degree of anxiety and agitation. The patient was hospitalized medically for chest pain, and developed rapid, pressured speech during that hospital stay. Plasma sodium level at that time was 129 mEq/L, with urine sodium 88 mEq/L. Divalproex therapy was begun with initial success, and citalopram was discontinued. Plasma sodium then normalized to 143 mEq/L. Anxiety and agitation recurred and were treated with lorazepam until the patient demonstrated abuse of the drug and suffered a motor vehicle accident under its influence. A brief hospitalization permitted adjustment of divalproex therapy so that the patient returned home in a normal mood state. However, she unilaterally discontinued the medication and over the next 2 months became sleepless, agitated, and anxious. She was nearly immobile and was thought to be weak by loved ones who brought her to the hospital. She ambulated with an odd gait that appeared to be tremulous, and she had a tremor. Testing of muscle tone did not reveal a paratonia, however, but gegenhalten were observed. BFCRS score was 24. Laboratory studies revealed she was hyponatremic with serum sodium of 125 mEq/L. Urine sodium was 51 mEq/L. Urinary tract infection (UTI) was detected incidentally, and was treated with minocycline in hope of providing some relief of catatonia as well. Divalproex therapy was maintained, and the UTI was treated with minocycline, in hopes of further benefitting her catatonic symptoms. The catatonia remitted, but serum sodium was re-tested at 125 mEq/L. Because catatonic agitation appeared to be relapsing, divalproex therapy was augmented with amantadine 100 mg BID. Further worsening of catatonic, mood, and psychotic symptoms finally prompted treatment with electroconvulsive therapy, which resulted in full remission after 12 treatments with right unilateral electrode placement.
“C” was a 58-year-old female with bipolar disorder and alcohol dependence. She had several hospitalizations under the authors’ care for agitated, psychotic states with paranoid delusions and auditory hallucinations, following periods of manic agitation and heavy alcohol abuse. Her mood disorder was responsive to divalproex, which was reinstated, with lorazepam for alcohol detoxification and for catatonic agitation. She was uniformly agitated at the time of admission. She retained normal orientation. During two admissions, she was agitatedly catatonic, with hyperkinetic state, constant meaningless activity, verbigeration, echolalia and echopraxia. During both of those hospital admissions (and several when she did not show signs of catatonia), she was hyponatremic, and was treated with either fluid restriction or demeclocycline by the consulting internist. Hyponatremia during the episodes associated with catatonic agitation was once associated with dilute urine one time (serum sodium was 123 mEq/L with urine sodium of 18 mEq/L), and with concentrated urine during another admission (serum sodium 121 mEq/L, urine sodium 40 mEq/L). The BFCRS was 23 during the first episode, and 28 during the second. The patient was never able to explain her excessive thirst and drinking, and resisted advice to restrict fluid intake. She was treated for SIADH with demeclocycline 300 mg BID with successful remission of hyponatremia. Fluid restriction was still required to prevent recurrence. Her mood disorder was treated with valproic acid 1,500 mg/day, with apparently complete remission of mood and catatonic symptoms. Excessive water intake ceased about the time mania remitted.
“D” was a 54-year-old female with a 30-year history of bipolar disorder, with several episodes of mania associated with psychosis, and one mixed state during which she was psychotic with increased energy, simultaneously felt depressed, and attempted suicide. She had been stable and had not required hospitalization for 25 years since starting lithium therapy. She did well with lithium 900 mg/day, sustaining plasma levels of lithium between 0.8–1.3 mEq/L. She also took fluphenazine 5 mg/day, fluoxetine 60 mg/day and lorazepam 1 mg TID. Attempts to withdraw or taper fluoxetine uniformly resulted in relapsing depression. She was quite thirsty, and drank a good deal of water, a habit of many years, pre-dating lithium and fluoxetine therapy; she said it had begun during her last hospitalization 25 years earlier. She had been diagnosed as suffering from psychogenic polydipsia at that time, and she regarded it as a chronic condition, which she attempted to deal with by consciously resisting the urge to drink more. She was most successful when her mood state was most normal, and consistently began to drink more whenever her mood started to become more depressed or more hypomanic. Serum electrolytes were followed regularly, and were in normal range until an exacerbation occurred, as follows. A recent episode of depressed and labile mood, hallucinations, and circumscribed paranoid delusions was accompanied by greatly increased fluid intake, and catatonic symptoms comprising motor excitement, interspersed with periods of brief muteness and staring, perseveration, and verbigeration. She demonstrated odd mannerisms, including saluting people and always ending and beginning conversations with a “hearty handshake” (announced out loud), and stereotypical repeated motions, mostly with her hands and feet. The BFCRS was just 15. Serum electrolytes were evaluated as soon as her increased fluid intake was ascertained. The results were remarkable for sodium of 123 mEq/L. Her urine was concentrated with urine sodium of 40 mEq/L. Her lithium level was below therapeutic level, due to missed doses. Resuming regular doses of lithium restored a therapeutic level, and her agitation, including catatonic symptoms, improved within 2 days of increasing lorazepam dose. She was able to resume her voluntary fluid restriction, and was helped by purchasing a 1-liter polycarbonate bottle that she filled with water once per day, using that to limit herself to that much water daily.
Severity of catatonia as expressed by the BFCRS was not significantly correlated to the serum or urine sodium, nor to the ratio between the serum and urine sodium levels (Pearson’s Coefficient of Correlation=10.2, P>.05).
Hyponatremia was observed during catatonia of both types (mute/immobile and hyperkinetic/agitated). Concentrated urine was associated with it during catatonia of both types, and one patient demonstrated dilute urine during one episode, and concentrated urine during another episode. The eating of foreign objects was observed in one patient experiencing an episode of illness during which he was mute and immobile at some times, and agitated and hyperkinetic at others. That patient was hyponatremic during that illness (the two admissions ~1 week apart) and had concentrated urine.
There are two recognized forms of catatonic agitation: the mute-immobile form that is familiar to most practitioners, and the agitated, hyperkinetic form. The patients described above all demonstrated catatonia of varying degrees of severity, and during the same episode of illness, hyponatremia, excessive water drinking, and in the first case described, eating foreign objects.
Hyponatremia and psychogenic polydipsia are well described among psychotic patients, though only a single case was associated with diagnosed catatonia.1 In the cases of “B” and “D”, there were some signs of catatonia present before hyponatremia or polydipsia were observed, and, in fact, when normal sodium levels were documented. If this is not a simply accidental finding, it may mean either that polydipsia and hyponatremia were caused by the catatonia in those cases, or that hyponatremia, polydipsia, and catatonia share common underlying mechanisms. The authors’ knowledge of some pathophysiology of both catatonia and hyponatremia as it occurs in psychotic illness may permit making useful inferences about each and about their association.
These patients all shared common features of an agitated impulse to drink water (and in one case also to eat metal objects), responded with verbigeration when they asked to be allowed to do what they wished, but did not seem more anxious or agitated when this was not allowed. All of them demonstrated signs of catatonia during the same episode of illness. The authors suggest that perhaps the act of “ritualistic” water drinking (psychogenic polydipsia) could be considered a stereotypy, meeting the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-Text Revision,9 criteria as repetitive, nonfunctional behaviors present for at least 4 weeks, that markedly interfere with normal activities or possibly cause self-injuries. The behaviors also share features with the category of bizarre mannerisms, in the sense of repeatedly wanting or doing things that one should not. They may be a perseveration at a normal behavior (drinking or eating), or may in part reflect autonomic changes, other kinds of which are well-described in catatonic patients.2,6 When associated with catatonia, psychogenic polydipsia and ingesting foreign objects may be part of part of the same process in the brain. How might this work?
There are many reported cases of psychotic patients developing hyponatremia, sometimes so severe that osmotic cellular swelling occurs, disrupting brain function and causing confusion, headache, nausea, vomiting, and death. In such cases, hyponatremia is often associated with concentrated urine, which may be inferred from elevated urine sodium, the threshold for which there is some disagreement between 20 mEqL and 40 mEq/L. Concentrated urine in the presence of hyponatremia with hypo-osmolar plasma is abnormal, and is termed SIADH.10-14 There appear to be several mechanisms by which antidiuretic hormone (vasopressin [AVP]) function can be altered to produce the syndrome of hyponatremia in psychotic patients, including excess AVP release.10,11 Other mechanisms are more subtle, and produce a syndrome of excessive water drinking, hyponatremia, and concentrated urine with normal blood levels of AVP.11-13 None of the authors’ patients had yet developed symptoms of the hypo-osmolar delirium, but a recent case that had progressed to death after discharge had prompted a higher degree of caution than usual in approaching hyponatremia. The authors suggest that the evidence for SIADH (hyponatremia with concentrated urine or elevated urine sodium) in many reported cases besides theirs suggests a role for AVP in the genesis of hyponatremia, and its link with catatonia.
Catatonia involves hyperdopaminergic, hyperglutamatergic, and hypo-g-aminobutyric acid (GABA)-ergic signaling.15 The evident possible role of AVP in hyponatremia and the behavior of psychogenic polydipsia may be the clue to the association with catatonia. AVP is one of several peptide neurohormones that also serve as neurotransmitters. AVP is known to function as a neurotransmitter in several areas in the brain. The paraventricular nucleus (PVN) in the hypothalamus is an important site for autonomic and endocrine homeostasis,16 including fluid and electrolyte homeostasis. The magnocellular neurosecretory cells in the supraoptic nuclei (SON) and PVN secrete AVP (and oxytocin) into the circulation. There is increasing evidence that glutamate acts as a transmitter in the neuronal control of release of AVP and oxytocin from the neurohypophysis. These cells express two types of ionic glutamate receptors characterized by the synthetic agonists a-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA) and N-methyl-d-aspartic acid (NMDA). Immunochemical and ultrastructural studies demonstrate glutamatergic axon terminals in the SON and PVN in synaptic contact with cells secreting both AVP and oxytocin.17 Additionally, in rats under ethanol anesthesia in which a diuresis was maintained by a constant fluid load, the intracerebroventricular injection of glutamate and synthetic agonists of AMPA and NMDA receptors produced an antidiuretic response which was abolished by an AVP antagonist.17 Furthermore, in the same rat model, secretion of AVP and oxytocin was inhibited by injection of GABA or its agonist muscimol.18
Pathophysiologically, motor stereotypy is a common component of several developmental, genetic, and neuropsychiatric disorders. In animals, these behaviors can be induced or attenuated via pharmacologic manipulation of specific neural loci comprising cortico-basal ganglia-cortical feedback circuits, including the striatum. Some findings support a role of the striatal glutamatergic system in the mediation of spontaneous stereotypic behavior and suggest a potential neuronal mechanism by which transition to stereotypy occurs in these mice.
If this pre-clinical evidence is accurate, then in a hyper-glutamatergic state, ie, catatonia, glutamate can theoretically not only result in secretion of AVP, resulting in hyponatremia, but also motor stereotypies, such as “water drinking.” The authors recognize that the ultimate development of “repetitive water drinking” cannot be simply ascribed as above, but that the etiology of repetitive water drinking is multi-factorial; they propose this hyper-glutamatergic pathogenesis as a possible putative mechanism, which has not been evaluated in humans.19
AVP has been shown to interact specifically with hypocretin/orexin neurons in a manner that increases locomotor activity.20 If AVP has a role in catatonia, it would imply that the agitated, hyperkinetic form of catatonia might be more often associated with hyponatremia. The prevalence was equal in the authors’ cases.
AVP interacts with the cells that secrete it by feedback through auto-receptors, and indirectly as well, by the consequences of its secretion in excess. The magnocellular neurons that release AVP (and oxytocin) into the circulation from the hypothalamus are adversely affected by chronic hyponatremia.21
The effect of demeclocycline in reversing hyponatremia in SIADH is thought to be at the renal tubules, where aquaporin molecules within the tubule epithelial cell membrane initiate pinocytosis of water in response to AVP.10-13 Minocycline has not been reported to have this effect, and one of the authors’ patients whose mute, immobile catatonia responded to minocycline, continued to demonstrate low sodium and concentrated urine. There are several reports of minocycline exerting beneficial effects on psychotic or catatonic states.22-25 The postulated mechanism, which remains to be proven, has been minocycline inhibition of caspase, and resultant neuroprotection. A second neuroprotective mechanism is inhibition of mitochondrial poly-(adenosine diphosphate-ribose)-polymerase-1. This is an effect minocycline shares with doxycycline, demeclocycline, and chlortetracycline, in descending order of potency.26
AVP injected into the anterior hypothalamus elicits aggressive behavior, manifested as biting in rodents. There is evidence that AVP functions normally as a neurotransmitter in that brain region, controlling aggression via a tension with serotonin release.27 It thus may not be too great a leap to suppose that excess AVP transmission may be related to abnormal water drinking, or perhaps ingestion of foreign objects during psychotic states.
It is less certain to infer a role for AVP in the behavior of ingesting foreign objects. The majority of cases reported of adults ingesting foreign objects are among prison inmates who hope to manipulate their environment, or other malingering. It is associated with severe personality disorders (possibly as a self-destructive behavior) and with bulimia (sometimes inadvertent swallowing of an object one hopes will induce vomiting), as well as with psychosis.28 Psychotic patients ingesting foreign objects may be responding to delusions, such as a man who believed he was a machine in need of spare parts. When this behavior occurs in the setting of catatonia, the authors suggest it may, just as excessive drinking, represent a stereotypy, and may thus be a sign of the catatonic state.
The authors’ study depends on a very small number of patients, constituting a case series. Any study with such a small number of subjects is vulnerable to sampling error. Any study of a phenomenon as common as hyponatremia in psychiatric patients may also be vulnerable to finding accidental associations that are without meaning. The authors believe their cases may indicate a true and significant association. Their hypothesis regarding that association has some theoretical support from recent developments in the neuroscience of AVP. It would be very valuable to examine this question prospectively across a large number of catatonic patients and a large number of hyponatremic patients.
The association of catatonia with abnormal ingestion of water or non-food objects may be more common than has been appreciated, and may be linked by changes or abnormalities in AVP neurotransmission. the authors suggest that hyponatremia in a psychotic patient may be regarded potentially as an autonomic sign of catatonia, and the behavior of abnormal water ingestion may constitute a class of stereotypy that should be regarded as a possible sign of catatonia. The physiologic link, suggested in the presented cases by concentrated urine in the face of hyponatremia, may be abnormal vasopressin transmission and secretion. PP
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