c A s E R E p o R T s

Delusions in a patient treatedwith histamine H

2receptor antagonists

IRA M. LESSER, M.D.• BRUCE L. MILLER, M.D. • KYLE BOONE, Ph.D. • CARYN LOWE, M.S.w.

In recent years, histamine H, receptor antagonists have beenthe mainstay for treating peptic ulcer disease. Both cimeti­dine hydrochloride and more recently ranitidine hydrochlo­ride have been prescribed with great frequency. It has be­come increasingly clear that cimetidine can have multipleand varied neuropsychiatric side effects,l.' including toxicpsychoses and, rarely, a depressive state.' Reports of simi­lar side effects with ranitidine have been much fewer (thedrug also has been available for a shorter period of time),with confusional states noted in two patients." To ourknowledge, psychotic symptoms, ie, delusions in the ab­sence of a concomitant confusional state, have not been de­scribed.

We now report the case of a previously healthy womanwho, after being placed on cimetidine, developed multipledelusions associated with a clear sensorium. The delusionscontinued after the cimetidine was discontinued and shestarted taking ranitidine. They cleared only after the raniti­dine was stopped.

I Case reportThis 63-year-old, married, unemployed woman with aneighth-grade education had no history of psychiatric ill­ness prior to the current referral by her gastroenterolo­gist. Four months before our examination, she had beenadmitted to the hospital for recurrent abdominal pain. Aduodenal ulcer and gallstones were discovered, and shewas begun on antacids and cimetidine (300 mg I.V.) ev­ery six hours. She also had been taking metoprolol forstable hypertension of approximately two years duration.She was discharged on cimetidine (300 mg tid), contin­ued this dosage for about 15 weeks, and experienced

Dr Lesser is adjunctassociateprofessor ofpsychiatry, Dr Miller is assistantprofessor ofneurology, and Dr Boone is clinical assistant professor ofpsy­chiatry, all at Harbor/UCLA Medical Center, Torrance, Catif At the time ofthis case, Ms Lowe was agraduate student at the UCLA School of SocialWelfare. Reprint requests to Dr. Lesser, Department ofPsychiatry. Bldg. 0-5.Harbor/UCLA Medical Center, tOOO W Carson St., Torrance, CA 90509.

SEPTEMBER 1987' VOL 28' NO 9

complete relief of her abdominal symptoms.Two weeks prior to the psychiatric evaluation, the pa­

tient complained to her physician that she had a "crawl­ing sensation on her skin." At this time. the cimetidinewas stopped and ranitidine (150 mg bid) substituted. Be­cause of the physician's concern that her new com­plaints might have a psychiatric basis, she was referredfor psychiatric consultation. Upon initial psychiatric eval­uation, her presenting complaint was, "Since they putthat I.V. [cimetidine] in me, these things have been visit­ing me, getting on my bed, ruffling the covers and myclothes. They crawled into my stomach and between mylegs. When I left the hospital. they came home with me."The patient had continued to have this delusion afterleaving the hospital but never shared this with her physi­cians until two weeks before our examination.

Other delusional beliefs were that she delivered alarge fetus that "they" had implanted into her, and thatthe fetus had "sort of breast-fed on me." She had visualdisturbances, which she described as fleeting glimpsesof the "creatures" penetrating her skin; they related tomoving clothes or ripples on her skin. She denied anyauditory hallucinations. ideas of reference, thought inser­tion or thought broadcasting, feelings of being con­trolled. or persecutory ideas. She denied being de­pressed and did not appear so. She was fully oriented,and her Mini-Mental State Examination" score was 28.(She performed incorrectly only the serial sevens sub­traction, having never learned more than very simplearithmetic.)

Careful questioning of both the patient and a closefriend revealed no history of affective symptomatology,psychotic thinking, confusional episodes, or alcohol or il­licit drug abuse. The patient was living with her husbandof 35 years in a chaotic relationship; their marital difficul­ties had been long-standing, and no change had oc­curred in this or other recent stresses. Despite the delu­sions, daily functioning was not impaired.

The patient underwent a full neurologic examination,with entirely normal results. The score on a Hachinskitest' was 4, providing evidence against a diagnosis ofmulti-infarct dementia. An extensive neuropsychological

501

c A s E R E p o R T s

Delusions in a patient treatedwith histamine H

2receptor antagonists

IRA M. LESSER, M.D.• BRUCE L. MILLER, M.D. • KYLE BOONE, Ph.D. • CARYN LOWE, M.S.w.

In recent years, histamine H, receptor antagonists have beenthe mainstay for treating peptic ulcer disease. Both cimeti­dine hydrochloride and more recently ranitidine hydrochlo­ride have been prescribed with great frequency. It has be­come increasingly clear that cimetidine can have multipleand varied neuropsychiatric side effects,l.' including toxicpsychoses and, rarely, a depressive state.' Reports of simi­lar side effects with ranitidine have been much fewer (thedrug also has been available for a shorter period of time),with confusional states noted in two patients." To ourknowledge, psychotic symptoms, ie, delusions in the ab­sence of a concomitant confusional state, have not been de­scribed.

We now report the case of a previously healthy womanwho, after being placed on cimetidine, developed multipledelusions associated with a clear sensorium. The delusionscontinued after the cimetidine was discontinued and shestarted taking ranitidine. They cleared only after the raniti­dine was stopped.

I Case reportThis 63-year-old, married, unemployed woman with aneighth-grade education had no history of psychiatric ill­ness prior to the current referral by her gastroenterolo­gist. Four months before our examination, she had beenadmitted to the hospital for recurrent abdominal pain. Aduodenal ulcer and gallstones were discovered, and shewas begun on antacids and cimetidine (300 mg I.V.) ev­ery six hours. She also had been taking metoprolol forstable hypertension of approximately two years duration.She was discharged on cimetidine (300 mg tid), contin­ued this dosage for about 15 weeks, and experienced

Dr Lesser is adjunctassociateprofessor ofpsychiatry, Dr Miller is assistantprofessor ofneurology, and Dr Boone is clinical assistant professor ofpsy­chiatry, all at Harbor/UCLA Medical Center, Torrance, Catif At the time ofthis case, Ms Lowe was agraduate student at the UCLA School of SocialWelfare. Reprint requests to Dr. Lesser, Department ofPsychiatry. Bldg. 0-5.Harbor/UCLA Medical Center, tOOO W Carson St., Torrance, CA 90509.

SEPTEMBER 1987' VOL 28' NO 9

complete relief of her abdominal symptoms.Two weeks prior to the psychiatric evaluation, the pa­

tient complained to her physician that she had a "crawl­ing sensation on her skin." At this time. the cimetidinewas stopped and ranitidine (150 mg bid) substituted. Be­cause of the physician's concern that her new com­plaints might have a psychiatric basis, she was referredfor psychiatric consultation. Upon initial psychiatric eval­uation, her presenting complaint was, "Since they putthat I.V. [cimetidine] in me, these things have been visit­ing me, getting on my bed, ruffling the covers and myclothes. They crawled into my stomach and between mylegs. When I left the hospital. they came home with me."The patient had continued to have this delusion afterleaving the hospital but never shared this with her physi­cians until two weeks before our examination.

Other delusional beliefs were that she delivered alarge fetus that "they" had implanted into her, and thatthe fetus had "sort of breast-fed on me." She had visualdisturbances, which she described as fleeting glimpsesof the "creatures" penetrating her skin; they related tomoving clothes or ripples on her skin. She denied anyauditory hallucinations. ideas of reference, thought inser­tion or thought broadcasting, feelings of being con­trolled. or persecutory ideas. She denied being de­pressed and did not appear so. She was fully oriented,and her Mini-Mental State Examination" score was 28.(She performed incorrectly only the serial sevens sub­traction, having never learned more than very simplearithmetic.)

Careful questioning of both the patient and a closefriend revealed no history of affective symptomatology,psychotic thinking, confusional episodes, or alcohol or il­licit drug abuse. The patient was living with her husbandof 35 years in a chaotic relationship; their marital difficul­ties had been long-standing, and no change had oc­curred in this or other recent stresses. Despite the delu­sions, daily functioning was not impaired.

The patient underwent a full neurologic examination,with entirely normal results. The score on a Hachinskitest' was 4, providing evidence against a diagnosis ofmulti-infarct dementia. An extensive neuropsychological

501

c A s E R E p o R T sbattery of 11 tests of memory, frontal lobe function, andgeneral intelligence was administered. She performedwell on tests of attention and concentration. The results,interpreted in the context of her limited educational level,did not indicate any cognitive impairment nor a confu­sional state.

An EEG produced normal recordings. An attempt wasmade to perform a magnetic resonance scan, but owingto obesity the patient could not fit in the machine. Theranitidine was discontinued, and within one week the de­lusions were no longer present. In retrospect, she saidthat, although she had held her belief strongly at thetime, she now recognized that "my mind was playingtricks on me because of the medication."

I DiscussionThis case adds to the growing literature regarding the psy­chiatric complications of histamine H, receptor antagonists.Most case reports have stressed the confusional or toxic na­ture of the patient's presentation, with psychotic symptomsas part of this picture.'" Adler and associates' reported thecase ofa man who had initial confusion with a predominant­ly paranoid psychosis and both auditory and visual halluci­nations. Other reports"" document depressive symptom­atology as being temporally related to cimetidine use.

Several features of this patient's presentation are uniquein regard to these previous reports: She had no previous psy­chiatric or neurologic symptoms; her general physicalhealth was good; there was no hepatic or renal impairment;there were no signs of a confusional or toxic state; and shedid not have an affective syndrome. She displayed only so­matic delusions, in the presence of a clear sensorium andwith preservation of daily functioning.

In the absence of any concomitant drug use, the patient'sdiagnosis would be atypical psychosis. However, because

REFERENCES1 Weddington WW. Muelling AE, Moosa HH: Adverse neuropsychiatric re­

actions to cimetidine. Psychosomatics 23:49-53, 1982.2. Freston JW: Cimetidine. II. Adverse reactions and panerns of use Ann In­

tern Med97:728-734. 1982.3. Crowder MK, Pate JK: A case report of cimetidine-induced depressive

syndrome. AmJ Psychiatry 137:1451,1980.4. Goff DC. Garber HJ, Jenike MA: Partial resolution of ranitidine-associated

delirium with physostigmine: Case report. J Clin Psychiatry 46:400-401,1985

5. Hughes JD. Reed WD. Serjeant CS: Mental confusion associated with ra­nitidine, letter MedJ Aust2:12. 1983

soz

of the clear temporal association with both cimetidine andranitidine, organic delusional syndrome is the most appro­priate diagnosis. In the older patient with an acute onset of a"functional-appearing" psychosis, organic factors must beconsidered. In addition to medication-induced psychosis,the sudden onset of a delusional state has been described' inelderly patients following stroke. Since a vascular etiologyseemed unlikely and the results of other laboratory andphysical examinations were normal, we conclude that themedication was the cause ofthis patient's psychosis.

We must qualify the above by pointing out that we did nothave the opportunity to interview the patient at the onset ofher psychiatric symptoms. However, she has no recollec­tion of any confusion, and review of her medical chart re­veals no indication of any mental status changes. Thus, al­though we cannot say with absolute certainty that she neverexperienced a confusional state, during this episode lastingseveral months, the extensive neuropsychological testingand EEG results precluded this diagnosis at that time. How­ever, at the same time she was quite delusional.

The mechanism by which histamine H, receptor antago­nists cause psychotic symptoms is not clear. Although thesecompounds initially were thought not to cross the blood­brain barrier, subsequent data'O suggest that they do enterthe CNS and are found in the CSF. To what degree raniti­dine enters the CNS remains to be tested objectively. Onehypothesis is that these drugs interfere with histamine re­ceptors in the CNS, disrupting histamine's role as a neuro­transmitter. Whether this or some hitherto unknown mecha­nism of action leads to psychiatric symptoms is unclear atthis time. 0

This research was partially supported by a State ofCalifornia De­partment of Mental Health grant (85-76263) and by a PublicHealth Service grant (AGOO284-02) to Dr. Miller.

6. FOlstein MF. Folstein SE. McHugh PR: 'Mini-Mental State': A practicalmethod for grading the cognitive state of patients for the clinician. J Psy­chiatrRes 12:185-198, 1975.

7. Hachinski VC, Lassen NA, Marshall J: Multi-infarct dementia: A cause ofmental deterioration in the elderly. Lancet 2:207-210, 1974.

8. Adler LE, Sadja L. Wilets G: Cimetidine toxicity manifested as paranoiaand hallucinations AmJ Psychiatry 137:1112·1113. 1980

9. Miller BL. Benson DF, Cummings JL. et al: Late-life paraphrenia: An or­ganic delusional syndrome. J Clin Psychiatry 47:204-207, 1986

10. Berg MJ, Schentag JJ: Cimetidine distribution in human serum, tissue,and cerebrospinal fluid. Clin Pharmacol Ther 25:214, 1979.

PSYCHOSOMATICS

c A s E R E p o R T sbattery of 11 tests of memory, frontal lobe function, andgeneral intelligence was administered. She performedwell on tests of attention and concentration. The results,interpreted in the context of her limited educational level,did not indicate any cognitive impairment nor a confu­sional state.

An EEG produced normal recordings. An attempt wasmade to perform a magnetic resonance scan, but owingto obesity the patient could not fit in the machine. Theranitidine was discontinued, and within one week the de­lusions were no longer present. In retrospect, she saidthat, although she had held her belief strongly at thetime, she now recognized that "my mind was playingtricks on me because of the medication."

I DiscussionThis case adds to the growing literature regarding the psy­chiatric complications of histamine H, receptor antagonists.Most case reports have stressed the confusional or toxic na­ture of the patient's presentation, with psychotic symptomsas part of this picture.'" Adler and associates' reported thecase ofa man who had initial confusion with a predominant­ly paranoid psychosis and both auditory and visual halluci­nations. Other reports"" document depressive symptom­atology as being temporally related to cimetidine use.

Several features of this patient's presentation are uniquein regard to these previous reports: She had no previous psy­chiatric or neurologic symptoms; her general physicalhealth was good; there was no hepatic or renal impairment;there were no signs of a confusional or toxic state; and shedid not have an affective syndrome. She displayed only so­matic delusions, in the presence of a clear sensorium andwith preservation of daily functioning.

In the absence of any concomitant drug use, the patient'sdiagnosis would be atypical psychosis. However, because

REFERENCES1 Weddington WW. Muelling AE, Moosa HH: Adverse neuropsychiatric re­

actions to cimetidine. Psychosomatics 23:49-53, 1982.2. Freston JW: Cimetidine. II. Adverse reactions and panerns of use Ann In­

tern Med97:728-734. 1982.3. Crowder MK, Pate JK: A case report of cimetidine-induced depressive

syndrome. AmJ Psychiatry 137:1451,1980.4. Goff DC. Garber HJ, Jenike MA: Partial resolution of ranitidine-associated

delirium with physostigmine: Case report. J Clin Psychiatry 46:400-401,1985

5. Hughes JD. Reed WD. Serjeant CS: Mental confusion associated with ra­nitidine, letter MedJ Aust2:12. 1983

soz

of the clear temporal association with both cimetidine andranitidine, organic delusional syndrome is the most appro­priate diagnosis. In the older patient with an acute onset of a"functional-appearing" psychosis, organic factors must beconsidered. In addition to medication-induced psychosis,the sudden onset of a delusional state has been described' inelderly patients following stroke. Since a vascular etiologyseemed unlikely and the results of other laboratory andphysical examinations were normal, we conclude that themedication was the cause ofthis patient's psychosis.

We must qualify the above by pointing out that we did nothave the opportunity to interview the patient at the onset ofher psychiatric symptoms. However, she has no recollec­tion of any confusion, and review of her medical chart re­veals no indication of any mental status changes. Thus, al­though we cannot say with absolute certainty that she neverexperienced a confusional state, during this episode lastingseveral months, the extensive neuropsychological testingand EEG results precluded this diagnosis at that time. How­ever, at the same time she was quite delusional.

The mechanism by which histamine H, receptor antago­nists cause psychotic symptoms is not clear. Although thesecompounds initially were thought not to cross the blood­brain barrier, subsequent data'O suggest that they do enterthe CNS and are found in the CSF. To what degree raniti­dine enters the CNS remains to be tested objectively. Onehypothesis is that these drugs interfere with histamine re­ceptors in the CNS, disrupting histamine's role as a neuro­transmitter. Whether this or some hitherto unknown mecha­nism of action leads to psychiatric symptoms is unclear atthis time. 0

This research was partially supported by a State ofCalifornia De­partment of Mental Health grant (85-76263) and by a PublicHealth Service grant (AGOO284-02) to Dr. Miller.

6. FOlstein MF. Folstein SE. McHugh PR: 'Mini-Mental State': A practicalmethod for grading the cognitive state of patients for the clinician. J Psy­chiatrRes 12:185-198, 1975.

7. Hachinski VC, Lassen NA, Marshall J: Multi-infarct dementia: A cause ofmental deterioration in the elderly. Lancet 2:207-210, 1974.

8. Adler LE, Sadja L. Wilets G: Cimetidine toxicity manifested as paranoiaand hallucinations AmJ Psychiatry 137:1112·1113. 1980

9. Miller BL. Benson DF, Cummings JL. et al: Late-life paraphrenia: An or­ganic delusional syndrome. J Clin Psychiatry 47:204-207, 1986

10. Berg MJ, Schentag JJ: Cimetidine distribution in human serum, tissue,and cerebrospinal fluid. Clin Pharmacol Ther 25:214, 1979.

PSYCHOSOMATICS