Hemodialysis as a treatment for schizophrenia

JAVIER I. ESCOBAR, M.D., M.S.

Hemodialysis as a treatment for schizophrenia ABSTRACT: The author reviews available reports on the effects of renal dialysis on schizophrenia and offers critiques of these studies and their conclusions. He also addresses the possible mechanisms of action for hemodialysis on the psychoses, along with the risks inherent in dialysis research.

The reported therapeutic action of hemodialysis on a few schizophrenic patients· and the finding of endorphins in their dialysates2 have recently revitalized old theories on schizophrenic "humors." These provocative reports rapidly reached the news media and raised unrealistic hopes in the general public for this method of dealing with unremitting psychiatric syndromes. Consequently, hemodialysis is now actively sought as a panacea by many who have grown weary of standard treatments and their lack of results. The dialysis studies Hemodialysis is not at all a new idea as a treatment for schizophre-

nia (Table). A report in 1960 claimed remission of acute catatonia in three of five patients after one to two IO-hour hemodialyses.) The investigators in this study tested the hypothesis of Kielholz in Basel, who believed endotoxins to be the cause of catatonia and proposed blood exchange transfusions as a therapy.) Some 17 years passed before we heard again of this heroic treatment modality. This time, Florida nephrologist Robert Cade noted symptomatic improvement of a schizophrenic patient who was undergoing dialysis for renal failure. He teamed up with psychiatrist Herbert Wagemaker and pursued clinical observations. The prelimi-

Dr. Escobar is associate prOfessor ofpsychiatry at the University of California, Los A ngeles, and director of the Veterans Administration Neighborhood Center in East Los Angeles. Reprint requests to him, 915 Bonnie Beach Place, East Los Angeles, CA 90063. JUNE 1980· VOL 21 • NO 6

nary results of these studies were quite optimistic concerning symptom relief and subsequent social adjustment of schizophrenic patients dialyzed an average of 16 times. 1 Following Wagemaker and Cade's report, a number of anecdotes and retrospective observations were published.4-6 These reports failed to support therapeutic actions of dialysis in schizophrenia; unlike Wagemaker and Cade's experiment, these reports were based on schizophrenic patients in renal failure. Major problems with most published reports on hemodialysis and schizophrenia are their anecdotal quality, lack of diagnostic criteria, and absence of adequate and objective measurements. Only four reports had a formal research design and made attempts to measure clinical changes.6-9 Wagemaker and Cade utilized Brief Psychiatric Rating Scale (BPRS) ratings and more rigid diagnostic criteria for their later series. Analysis of BPRS total scores revealed that five of six 503

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jective rating of "maximum improvement" revealed that 16% of this sample improved while on dialysis. This percentage compared with Kraepelin's spontaneous remission figure of 12.6% and was taken to suggest that dialysis did not have any effect on schizophrenic symptoms.b Our group' reported a transient improvement in a schizophrenic

schizophrenic patients had a significant decrease in psychopathology after 16 weeks of hemodialysis. x A retrospective study utilized responses to a questionnaire from dialysis units at several Veterans Administration hospitals. Fifty-three patients with an established diagnosis of schizophrenia and kidney failure requiring maintenance hemodialysis were identified. A sub-

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patient with normal kidneys undergoing weekly dialysis treatments. Later, however, his condition worsened despite continuing dialysis, and treatment had to be discontinued after II weeks. A more recent report also failed to demonstrate any effect of dialysis on symptoms of three schizophrenic subjects who were each dialyzed 12 times.~

-StudI.. of Hemodlal, I and Schizophrenia P.............

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5 catatonic patients

1 to 2 hemodialyses

3/5 patients Improved

Cade,1977

Anecdotal

1 schizophrenic patient with hypertension

Maintenance hemodialysis

Psychotic symptoms cleared

Wlgemaker

Open

4 schizophrenic patlents with normal kIdney function

Hemodialysis once weekly until symptoms cleared

3/4 patients had symptomatic remissions

Anecdotal

1 schizophrenic patient in renal failure

24 hemodialyses over

No change in symptoms

andCadel

weddington"

8 weeks

~

Anecdotal

3 schizophrenic patients in renal failure

Maintenance hemodialysis

No change in symptoms

Ferris"

Anecdotal

1 schizoid patient in renal failure

Maintenance hemodialysis

No change In symptoms

W8gemaker and Cade8

Open

6 schizophrenics (SChneider criteria) with normal kidneys

16 hemodialyses (one per week)/BPRS,. CGI'

5/6 patients had complete remissions; BPRS scores decreased significantly

Kroll et a15

Anecdotal

2 schizophrenic patients in renal failure

Maintenance hemodialysis

No change in symptoms

Port.t~

VA hasp survey (retro-

50 schizophrenic petlents (by psychiatric consultation) in renal failure

Maintenance hemodialysis

16% got better while on dialysis

Open

1 schizophrenic patient (Feighner; WHO; DSM III criteria) with normal kidneys

II hemodialyses/BPRS·

Moderate decrease in BPRS scores

Open

3 unremitting schizophrenic patients (with florid symptoms)

12 hemodialyses I BPRS,· NOSIEI

No improvement in any of the scales

pecth,. study) 8t

Emrich et al9 • 8nef Plycllla1,oc RMlng

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InpMoenl E\Ialua1ions

PSYCHOSOMATICS

Hemodialysis

Risks of hemodialysis Although the unknown etiology and prevailing therapeutic hopelessness regarding schizophrenia are thought to justify even heroic procedures, it is important to remember that hemodialysis, aside from being quite intricate and expensive, poses a number of physical and psychological risks. First, surgical intervention for formation of an arteriovenous fistula has inherent risks. Then, cutting out the AV fistula may be a problem: since the fistula is superficially located for easy access, a psychotic patient or one with suicidal tendencies may be in grave danger of self-inflicted harm. In addition, thrombosis of the AV fistula is rather common in patients in kidney failure; theoretically, at least, the incidence of thrombosis should be even higher in the patient with normal kidney function because of normal coagulation mechanisms. Dialysis may also induce a number of physiologic changes such as neutropenia and a decrease in calcium levels as well as such functional complications as hypovolemia, hypotension, and the grave "disequilibrium syndrome."10 A hypotonic mixture may accidentaIly precipitate severe electrolyte disturbances or even renal shutdown.s Other complications cause further risks. The procedure may induce symptoms such as headache and severe anxiety resulting from psychological distress, which is capable of also reactivating psychotic processes. 1O And viral hepatitis remains an important complication of hemodialysis. 1O The risks outlined above apply primarily to patients in renal failure undergoing long-term hemodialysis. However, two of the reports

on dialysis treatment of schizophrenia have already described some complications.3.8 How might dialysis work? In attempts to identify potential mechanisms through which dialysis could modify schizophrenic symptoms, three possibilities have been suggested: (1) removal of pathogenic substances; (2) induction of a physiologic shock; and (3) a placebo effect. The first proposition, that dialysis removes toxic substances from blood, substances that would otherwise be reabsorbed by the kidney tubules, foIlowed Wagemaker and

Hemodialysis, aside from being quite intricate and expensive, poses a number ofphysical and psychological risks. Cade's original therapeutic claim and its apparent link to the removal of a variant endorphin with a leucin-enkephalin moiety by means of dialysis. 5 A number of objections have been raised against this thesis, based on the available knowledge of mechanisms of hemodialysis. 6 Since the filter of the dialysis machine is in general less permeable than the glomerular membrane, the only advantage of the dialysis filter over the glomerulus would be that it retained those smaIl molecules normaIly reabsorbed by the kidney. This applies to most amino acids and such substances as phosphates and organic acids. However, the overaIl capacity of hemodialysis to eliminate larger molecules (middle molecules) with

molecular weights between 300 and 5000 daltons-such as is the weight class of endorphins and enkephalins-is less than that of the normal kidney.1O Obviously, dialysis would not help for those toxins that are proteins or protein-bound, as would be those speculated to playa role in schizophrenia. Thus, basic facts of renal physiology and of hemodialysis seem to refute the endorphin-retention mechanisms. The original reports of increased endorphins in biologic fluids (CSF and dialysates) of schizophrenic patients2. 11.12 stimulated us to assay weekly plasma ultrajiltrates of a schizophrenic patient dialyzed II times. Opiate activity from the ultrafiltrates was determined by a radioreceptor assay.13 Material eluting near the ~-en­ dorphin area was the major component of ultrafiltrates. And the amounts of this material were lower in dialysates of this schizophrenic patient as compared with a control patient in kidney failure undergoing his first dialysis. 7 However, levels of this uncharacterized endogenous opiate in our schizophrenic subject had wide weekly variations, did not decrease with dialysis, and did not correlate with measures of psychosis. Nonetheless, most interesting was the significant correlation we found between levels of this material and BPRS indices of psychomotor activation-that is, tension, anxiety, and excitement. This suggests some connection to stress, which is borne out by studies linking other variables to stress. Reports of simultaneous ACTH-endorphin release during stress,14 the endorphin increases seen in such stress-loaded conditions as the first dialysis,27 and acute psychotic decompensation 2. 11 . 12 and their dePSYCHOSOMATICS

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crease following symptomatic improvement or adjustment to hemodialysis are all consonant with a nonspecific stress theory. Recent work utilizing more sophisticated assays for opiates has failed to measure Met- and Leuendorphin in dialysates of schizophrenic l5 . 16 and control subjects. 16 Moreover, even though J1-endorphin has been consistently measured in blood,16.17 levels of the peptide did not differ between schizophrenic patients and controls. '6 This strongly argues against the endorphin hypotheses of schizophrenia. The second concept as to how hemodialysis would work is the induction ofa physiologic shock. 10 It is speculated that a physiologic shock may result from the various physicochemical alterations induced by dialysis. Such nonspecific mechanisms are reminiscent of those believed to playa role in such occurrences as insulin coma, sleep deprivation, and even electroconvulsive therapy-all of which are capable of producing symptomatic changes in the functional psychoses. A third possibility is a placebo effect. It is undeniable that a placebo effect plays an important role in treatment outcome of psychiatric patients. Schizophrenic patients display a keen sensitivity to environmental contingencies in both positive and negative directions

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and undergo unexplained remIssions at times. Hemodialysis is an elaborate procedure with an almost magical connotation. In addition, patients receive lavish attention from various medical specialists during investigational projects. Together these factors could generate a strong placebo effect. Indeed, so powerful can this effect be, that it is important to establish control measures for placebo effect in any study of hemodialysis and schizophrenia. Unfortunately, none of the studies reviewed in this paper has controlled for this variable. In the absence of such controls, other conclusions are unwarranted. Summary This review has shown that there is no convincing theoretical or empirical argument to favor treating schizophrenics with dialysis. Unexpectedly, this treatment modality has spread in an uncontrolled fashion, possibly due to wide news media coverage. The task of separating fact from fantasy relies, then, on well-designed, double-blind, placebo-controlled clinical trials done on large homogeneous samples. A number of these studies are presently under way. 0

REFERENCES 1. Wagemaker H. Cade R: The use of hemodial· ysis on chronic schizophrenia. Am J Psychiatry 134:684-685, 1977.

2. Palmour RM: Characterization of a peptide from the serum of psychiatric patients. in Usdin E. Bunney WE (eds): Endorphins in Mental Illness. London, Macmillan Publishers Ltd. 1978. 3. Feer H. Thoelen H, Massini MA, et al: Hemodialysis in schizophrenia. Compr Psychiatry 1:338-344.1960. 4. Weddington WW, Ferris GN. Levy NB: Can dialysis help the chronic schizophrenic?, let· ters to editor. Am J Psychiatry 134:13101311,1977. 5, Kroll PO, Port FK, Silk FR: Hemodialysis and schizophrenia: A negative report. J Nerv Men' Dis 166:291-293, 1978. 6, Port FK, Kroll PO, Swartz RD: The effect of hemodialysis on schizophrenia: A survey of patients with renal failure. Am J Psychiatry 135: 743-744, 1978. 7. Escobar JI, Codd EE. Acchiardo S, et al: Dialysis, endorphins, and schizophrenia: Pre· liminary findings. Proceedings of the Seventh Latin American Congress of Pharmacology. sao Paulo. Brazil, December 1978. 8. Wagemaker H, Cade R: Hemodialysis in chronic schizophrenia. South Med J 71: 1463. t978. 9. Emrich HM, Kissling W. Fischler M. et al: Hemodialysis in schizophrenia: Three failures with chronic patients. Am J Psychiatry 136:1095, 1979. 10. Czazkes JW, Kaplan de Nour A: Chronic Hemodialysis as a Way of Life. New York, Brunner IMazel, 1978. 11. Terenius L, Wahlstrom A, Lindstrom L, et al: Increased CSF levels of endorphin in chronic psychosis. Neuroscience Letters 3: 157-162, 1976. 12. Domschke W. Dickschas A. Mitznegg P: CSF p·endorphin in schizophrenia. Lancet 1:1024,1979. 13. Codd EE, Santos NN. King CD, ef al: En· dorphin partial purification and demonstration of multiple components. Prog Neuro-psycho· pharmaco/1:259-264, 1977, 14. Guillemin R. Vargo T. Rossier J. et al: p-endorphin and adrenocorticotrophin are secreted concomitantly by the pituitary gland. Science 197:1367-1369.1977. 15. Lewis RV, Gerber LD, Stein S, et al: On PH·Leu 5.endorphin and schizophrenia. Arch Gen Psychiatry 36:237-239, 1979. 16. Ross M, Berger PA, Goldstein A: Plasma p-endorphin immunoreactivity in schizophre· nia. Science 205:1163-1164. 1979. 17. Nakao K, Nakai Y. Oki S, et al: Presence of immunoreactive p·endorphin in human plasma. J Clin Invest 62: 1395-1398. 1978.

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