- Email: [email protected]
Famotidine: a supplemental drug for the treatment of schizophrenia
F.ur Ps)'chiotry 1997; 12:263-264 EJ!\Cvier. Pari~
o
Rapld communication
Famotidine: a supplemental drug for the treatment of schizophrenia PN Dannen, E Lcpkifkcr 0, I Iancu, R Ziv, N Horcsh, M Kotler Divtsion of Psychiatry, Chaim Sh~ba M~Jical Center, T~/'''aSlto,"rr !l2ti2/, Isra~1 Summary - In an open-label study, famotidine waa added In the regular neuroleplie regimen of II achlzuphrcnic: pal lenl. f", ~ w«.... r:.ach palienl was scored weekly with SAPS, SANS, COl Dnd HAM-I)· 17 Kille • . The re.ull. lunelllhlll famuCidtne II indeed effecuve al an adjunclive drug 10 neuroleptics in the treatment nf ~chiZllphren i8 . r.molld1ne ' " z·receplor an"~onl~lJ , schlzophrenla , nrurolrplla
INTRODUCTION Schizophrenia is considered to be one of the most severe psychiatric disorders. The available therapies demonstrate a relatively good efficacy on positive symptoms, whereas their effect on deficit symptoms is limited (Carpenter and Buchanan. 199.J). Mood stabilizers, benzodiazepines, antidepressant drugs and electroconvulsive therapy have been used as additional therapies, with limited success (Rifkin, 1993), Famotidine is a potent selective 11 2 -receptor antagonist. widely used in gastroenterology. It has a negligible effect on muscarinic. nicotinic, adrenergic and III receptors. Common side effects include headaches. dizziness. nausea. itching and "kin rashes (Rifkin. 1993). Very rarely. famotidine has been found to cause hepatitis (Chcrmos, 19R6) or central nervous system toxicity in patients with renal failure (Yoshimoto et al, 1994), In the human brain, several areas are rich in 11 2 receptors. including the cerebral cortex. the caudate nucleus. the putamen, the hypocarnpal formation of the amygdala and the thalamus (Kaminsky et al, 1989). These areas play an important role in the physiopathology of schizophrenia (Carpenter and Buchanan. I 99.J). In animals, 11 2 receptors transmit primarily inhibitory signals when stimulated, and decrease • Car"sf'lHk/tn('~ and "prints.
their spontaneous activity and exploratory behaviour. Overactive 11 2 receptors could contribute to the deficit symptoms of schizophrenia (Hough, 19RR; White and Rumbold, 1988). Kaminsky et al (19K9) reported a dramatic improvement after famotidine Wll.'l adminisrcred to a ~6..year-old patient with schizophrenia. On the basis of this report. Deutsch et LlI (11)1))) ndminislered famotidlnc in an open trial to ten ~hi1.Ophrenic ur schizoaffective patients. After stabililation with standard neuroleptic" for I week. these patient'l were shifted to farnotidine 20 018 bd fur J weeks, then maintained without medication fur another week . The researchers reported notable improvement with significantly lower scores of the Brief Psychiatric Ruring Scale (l)PRS) lind the Clinical G1nhal Impression" scale CeCil) lind n trend toward lower scores on the Scale for the Assessment of Negative Symptoms (SANS) during the "tudy period. A recent open-label study hi~hlilthtC'd Ihe subjective improvement in hoth positive and negative symptoms. as well as a "i~nificnnt reduction uf BPRS and SANS scores, which were temporally related tn the addition of furnotidinc (J(X) Inj% pd) to n stable neuroleptic regimen In I K patients wilh schizophrenia or schizoalfective disorder (RnsliC c. al, 19(16). In the present report, the efrlc:u:y (If fnmotidinc in IiC'hi70phrenia was lIJ,sellset1 1l!O II "upplcmcmal drug to neumlepucs.
264
I'N I>annun et al SUBJECTS ANI> METHOD
Eleven patients admitted to our ward between December 1993 and June 1994 participated in this preliminary study. The inclusion criteria were a DSM-IV diagnosis of chronic schizophrenia, disorganized, undifferentiated or residual type; age between 18 to 65 years: partial response to adequate doses of a high-potency neuroleptic; more than 2 months on the same neuroleptic treatment; and evidence of both negativeand positive symptoms. Patients were excluded if they were pregnant. had a history of renal failure, were allergic to Iarnotidine or had a history of substance abuse. Of the II patients accepted into the study, there were ten males and one female. The mean age WIIS 39.1 ± 12.7, and the mean duration of illness 17.1 ± S.H years. Ten of the patients had no history or signs of somatic illness. The remaining patient suffered from insulin-dependent diabetes mellitus, and had been successfully treated with insulin for more than 20 years. During the famotidine treatment, all of this patient's laboratory tests remained within normal limits. Elich patient had received a neuroleptic (either haloperidol, fluphenazine or perphcnazme) at a constant dosage for a period of at least 3 months (4.2 ± 1.2 months) prior to initiation of furnotidine, and the slime regimen was maintained throughout the study. Fumoridinc was added at bedtime at the dosage of 40 mg in the first week and 60 mg for the remaining 3 weeks, in accordance with the study design. Response to treatment was assessed separately every week by two of the authors (II and I'ND) using the Scale for the Assessment of Positive Symptoms (SAPS), SANS, COl, 17-ilcm Ilamiiton Rating Scale Depression for OIAM-D-17). The inter-rater reliability was 0.94. RESULTS As indicated in table I, a significant improvement was found on all measures of outcome during famotidinc supplemental treatment. Moreover, ?ccording to ANOVA with repeated measures, the Improvement was already noticeable during the 2nd week of treatment mSCUSSION TIIC results of our observations show that farnotidine may be an effective supplemental drug to neuroleptics in the treatment of schizophrenia. All the patients who were treated with famotidine would he regarded us refractory, or partial responders 10 conventional antipsychotic medications. Some of our patients derived more benefit from this treatment than others, but all reported a subjec-
Table I. Outcome of famotidine supplementation.
cm
SANS SAPS IIAMD-11
WukO
Wed 4
t-test
47.63 %10.72 29.36%7.03 29.()l) %5.87 14.72 %4.21
32.27 %6.16 19.09%4.01 17.27%4.51 4.72 ± 2.31
P
tive improvement. However, our uncontrolled design limits the applicability of the results. Further studies would be needed before a conclusion could be drawn as to whether the improvements observed in the patients resulted from the natural course of the disorder, nonspecific effects, ongoing neuroleptic therapy or indeed from famotidine itself. In our study, we found statistically significant changes on all the scales used. Of note, most of the patients were reluctant to discontinue famotidine after the termination of the study because of their feeling of improvement. Four patients stopped the medication after their discharge, and, within 2 months, three of them required rehospitalization due to an exacerbation of their illnesses. In conclusion, farnotidine seems to be effective in at least some treatment-resistant schizophrenics and could be of value as a supplemental drug in the treatment of schizophrenia. However, doubleblind placebo control studies are necessary to confinn these results. REFERENCES Carpenter W. Buchanan R. Schizophrenia (A Review). N Engl J Med 1994 ;330:681-8 Chermos AN. Pharmacodynamics of famotidine in humans. Am J Med J986;84(suppI4B):3-7
Deutsch 51. Rosse RD. Kendrick KA. Fay-McCl1lthy M et al. Pamotidine adjunctive pharmacotherapy for schizophrenia: preliminary data. CUn Neuropharmacol J 993 ; 16: 518-24 Hough LB. Cellular localization and possible functions for brain histamine: recent progress. Prall Neurobiol 1988 ;30: 469-505 Kaminsky R, Moriarty TM. Bodine J. Wolf DE, Davidson M. Effect of farnotidine on deficit symptoms of schizophrenia. Lancet 1989;335:1351-2
Rifkin A. Pharmacological strategies in thetreatment of schizophrenia. Psych Clin of North America 1993; 16:351 ~2 Rosse RD. Kendrick K. Fay-MeCwthy M. Prell GO et al. An open-label study of the therapeutic efficacy of high-dose fumotidine adjuvant pharmllCothcrapy in schizophrenia: preliminary evidence for treatment efficacy. Clin Neuropharmacol 1996; 19:341-11
White JM, Rumbold GR. Behavioral effects of histamine and itsantagonists: a review. Psychapharmacology 1988;95:1-4 Yoshimoto K, Suima S, Echi7cn II. Nakamura Y et al. Famoridine-associated CNS reactions and plasma and CS drug concentrations in neurosurgical patients with renal failure. Clin Phurmacol Ther 1994;5S:()93-700
o
Rapld communication
Famotidine: a supplemental drug for the treatment of schizophrenia PN Dannen, E Lcpkifkcr 0, I Iancu, R Ziv, N Horcsh, M Kotler Divtsion of Psychiatry, Chaim Sh~ba M~Jical Center, T~/'''aSlto,"rr !l2ti2/, Isra~1 Summary - In an open-label study, famotidine waa added In the regular neuroleplie regimen of II achlzuphrcnic: pal lenl. f", ~ w«.... r:.ach palienl was scored weekly with SAPS, SANS, COl Dnd HAM-I)· 17 Kille • . The re.ull. lunelllhlll famuCidtne II indeed effecuve al an adjunclive drug 10 neuroleptics in the treatment nf ~chiZllphren i8 . r.molld1ne ' " z·receplor an"~onl~lJ , schlzophrenla , nrurolrplla
INTRODUCTION Schizophrenia is considered to be one of the most severe psychiatric disorders. The available therapies demonstrate a relatively good efficacy on positive symptoms, whereas their effect on deficit symptoms is limited (Carpenter and Buchanan. 199.J). Mood stabilizers, benzodiazepines, antidepressant drugs and electroconvulsive therapy have been used as additional therapies, with limited success (Rifkin, 1993), Famotidine is a potent selective 11 2 -receptor antagonist. widely used in gastroenterology. It has a negligible effect on muscarinic. nicotinic, adrenergic and III receptors. Common side effects include headaches. dizziness. nausea. itching and "kin rashes (Rifkin. 1993). Very rarely. famotidine has been found to cause hepatitis (Chcrmos, 19R6) or central nervous system toxicity in patients with renal failure (Yoshimoto et al, 1994), In the human brain, several areas are rich in 11 2 receptors. including the cerebral cortex. the caudate nucleus. the putamen, the hypocarnpal formation of the amygdala and the thalamus (Kaminsky et al, 1989). These areas play an important role in the physiopathology of schizophrenia (Carpenter and Buchanan. I 99.J). In animals, 11 2 receptors transmit primarily inhibitory signals when stimulated, and decrease • Car"sf'lHk/tn('~ and "prints.
their spontaneous activity and exploratory behaviour. Overactive 11 2 receptors could contribute to the deficit symptoms of schizophrenia (Hough, 19RR; White and Rumbold, 1988). Kaminsky et al (19K9) reported a dramatic improvement after famotidine Wll.'l adminisrcred to a ~6..year-old patient with schizophrenia. On the basis of this report. Deutsch et LlI (11)1))) ndminislered famotidlnc in an open trial to ten ~hi1.Ophrenic ur schizoaffective patients. After stabililation with standard neuroleptic" for I week. these patient'l were shifted to farnotidine 20 018 bd fur J weeks, then maintained without medication fur another week . The researchers reported notable improvement with significantly lower scores of the Brief Psychiatric Ruring Scale (l)PRS) lind the Clinical G1nhal Impression" scale CeCil) lind n trend toward lower scores on the Scale for the Assessment of Negative Symptoms (SANS) during the "tudy period. A recent open-label study hi~hlilthtC'd Ihe subjective improvement in hoth positive and negative symptoms. as well as a "i~nificnnt reduction uf BPRS and SANS scores, which were temporally related tn the addition of furnotidinc (J(X) Inj% pd) to n stable neuroleptic regimen In I K patients wilh schizophrenia or schizoalfective disorder (RnsliC c. al, 19(16). In the present report, the efrlc:u:y (If fnmotidinc in IiC'hi70phrenia was lIJ,sellset1 1l!O II "upplcmcmal drug to neumlepucs.
264
I'N I>annun et al SUBJECTS ANI> METHOD
Eleven patients admitted to our ward between December 1993 and June 1994 participated in this preliminary study. The inclusion criteria were a DSM-IV diagnosis of chronic schizophrenia, disorganized, undifferentiated or residual type; age between 18 to 65 years: partial response to adequate doses of a high-potency neuroleptic; more than 2 months on the same neuroleptic treatment; and evidence of both negativeand positive symptoms. Patients were excluded if they were pregnant. had a history of renal failure, were allergic to Iarnotidine or had a history of substance abuse. Of the II patients accepted into the study, there were ten males and one female. The mean age WIIS 39.1 ± 12.7, and the mean duration of illness 17.1 ± S.H years. Ten of the patients had no history or signs of somatic illness. The remaining patient suffered from insulin-dependent diabetes mellitus, and had been successfully treated with insulin for more than 20 years. During the famotidine treatment, all of this patient's laboratory tests remained within normal limits. Elich patient had received a neuroleptic (either haloperidol, fluphenazine or perphcnazme) at a constant dosage for a period of at least 3 months (4.2 ± 1.2 months) prior to initiation of furnotidine, and the slime regimen was maintained throughout the study. Fumoridinc was added at bedtime at the dosage of 40 mg in the first week and 60 mg for the remaining 3 weeks, in accordance with the study design. Response to treatment was assessed separately every week by two of the authors (II and I'ND) using the Scale for the Assessment of Positive Symptoms (SAPS), SANS, COl, 17-ilcm Ilamiiton Rating Scale Depression for OIAM-D-17). The inter-rater reliability was 0.94. RESULTS As indicated in table I, a significant improvement was found on all measures of outcome during famotidinc supplemental treatment. Moreover, ?ccording to ANOVA with repeated measures, the Improvement was already noticeable during the 2nd week of treatment mSCUSSION TIIC results of our observations show that farnotidine may be an effective supplemental drug to neuroleptics in the treatment of schizophrenia. All the patients who were treated with famotidine would he regarded us refractory, or partial responders 10 conventional antipsychotic medications. Some of our patients derived more benefit from this treatment than others, but all reported a subjec-
Table I. Outcome of famotidine supplementation.
cm
SANS SAPS IIAMD-11
WukO
Wed 4
t-test
47.63 %10.72 29.36%7.03 29.()l) %5.87 14.72 %4.21
32.27 %6.16 19.09%4.01 17.27%4.51 4.72 ± 2.31
P
tive improvement. However, our uncontrolled design limits the applicability of the results. Further studies would be needed before a conclusion could be drawn as to whether the improvements observed in the patients resulted from the natural course of the disorder, nonspecific effects, ongoing neuroleptic therapy or indeed from famotidine itself. In our study, we found statistically significant changes on all the scales used. Of note, most of the patients were reluctant to discontinue famotidine after the termination of the study because of their feeling of improvement. Four patients stopped the medication after their discharge, and, within 2 months, three of them required rehospitalization due to an exacerbation of their illnesses. In conclusion, farnotidine seems to be effective in at least some treatment-resistant schizophrenics and could be of value as a supplemental drug in the treatment of schizophrenia. However, doubleblind placebo control studies are necessary to confinn these results. REFERENCES Carpenter W. Buchanan R. Schizophrenia (A Review). N Engl J Med 1994 ;330:681-8 Chermos AN. Pharmacodynamics of famotidine in humans. Am J Med J986;84(suppI4B):3-7
Deutsch 51. Rosse RD. Kendrick KA. Fay-McCl1lthy M et al. Pamotidine adjunctive pharmacotherapy for schizophrenia: preliminary data. CUn Neuropharmacol J 993 ; 16: 518-24 Hough LB. Cellular localization and possible functions for brain histamine: recent progress. Prall Neurobiol 1988 ;30: 469-505 Kaminsky R, Moriarty TM. Bodine J. Wolf DE, Davidson M. Effect of farnotidine on deficit symptoms of schizophrenia. Lancet 1989;335:1351-2
Rifkin A. Pharmacological strategies in thetreatment of schizophrenia. Psych Clin of North America 1993; 16:351 ~2 Rosse RD. Kendrick K. Fay-MeCwthy M. Prell GO et al. An open-label study of the therapeutic efficacy of high-dose fumotidine adjuvant pharmllCothcrapy in schizophrenia: preliminary evidence for treatment efficacy. Clin Neuropharmacol 1996; 19:341-11
White JM, Rumbold GR. Behavioral effects of histamine and itsantagonists: a review. Psychapharmacology 1988;95:1-4 Yoshimoto K, Suima S, Echi7cn II. Nakamura Y et al. Famoridine-associated CNS reactions and plasma and CS drug concentrations in neurosurgical patients with renal failure. Clin Phurmacol Ther 1994;5S:()93-700