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Intranasal oxytocin in obsessive-compulsive disorder
Intranasal Oxytocin in Obsessive-Compulsive Disorder C. Neill Epperson, Christopher J. McDougle, and Lawrence H. Price K e y W o r d s : O b s e s s i v e - c o m p u l s i v e disorder, oxytocin, neuropeptide, obsessions, compulsions, intranasal BIOL PSYCHIATRY 1996;40:547-549
Introduction Oxytocin is a neurosecretory nonapeptide which is synthesized by hypothalamic cells and distributed to the central nervous system (CNS), as well as the neurohypophysis. Although oxytocin's roles in milk ejection and uterine contraction have been well-characterized, it is only in the past decade that the scope and complexity of its effects in the CNS have been appreciated. Oxytocin has been implicated in the expression of a number of grooming, cognitive, affiliative, sexual, and reproductive behaviors in animals (Insel 1992). There is growing evidence to suggest that oxytocin may play a role in the pathogenesis of some forms of obsessive-compulsive disorder (OCD). For example, administration of oxytocin can increase autogrooming of the head and anogenital regions in rats (Kaltwasser and Crawley 1987). It has been suggested that such behaviors may be similar to the repetitive handwashing and cleaning present in many patients with OCD (Leckman et al 1994a). Oxytocin is critically involved in the initiation of maternal behavior in animals (Pedersen and Prange 1979), and cerebrospinal fluid (CSF) levels of oxytocin are elevated during the third trimester of pregnancy and the early puerperium. We recently reported that 18.6% and 55.9% of women presenting to an OCD clinic reported onset and worsening, respectively, of obsessive-
From the Yale University Department of Psychiatry, New Haven, Connecticut, USA. Address reprint requests to C. Neill Epperson, Yale University Department of Psychiatry, 34 Park Street, New Haven, CT 06519. Received October 18, 1995; revised February 21, 1996.
© 1996 Society of Biological Psychiatry
compulsive (OC) symptoms during pregnancy or the puerperium (Epperson et al 1995). Obsessions regarding the safety of others and dirt and germs, as well as compulsions such as checking and cleaning might be seen as pathological correlates of normal maternal behavior. Importantly, oxytocin has been reported to be elevated in the CSF of patients with OCD compared with ageand sex-matched normal control subjects and patients with Tourette's syndrome (Leckman et al 1994b). It has been hypothesized that there may be abnormalities in memory processing systems in some patients with OCD. Oxytocin, which has been referred to as the "amnestic" neuropeptide, can attenuate memory consolidation and retrieval (Bohus et al 1978). In addition, oxytocin is elevated in the hippocampus and temporal cortex of postmortem Alzbeimer brains compared with normal control brains (Mazurek et al 1987). There have been previous reports of oxytocin administration in patients with OCD. Ansseau et al (1987) reported symptomatic improvement in 1 man treated with intranasal oxytocin 8.4-16.8 IU per day for 4 weeks. This individual showed the most improvement within the first 2 weeks of treatment, but subsequently developed memory loss, psychosis, and a decrease in plasma sodium and osmolality. Den Boer and Westenberg (1992) randomized 12 patients with OCD to placebo or intranasal oxytocin 17.6 IU/day for 6 weeks. Two additional patients received a threefold higher dosage. No significant changes in OC symptoms occurred and side effects were minimal. Additionally, Salzberg and Swedo (1992) found that a one-time dose of intranasal oxytocin 8 IU had no appreciable affects on OC symptoms in 3 patients. Charles et al (1989) also found no effect of oxytocin administration in 2 cases. One explanation for these negative results is that peripherally administered oxytocin does 0006-3223/96/$15.00 PII S0006-3223(96)00120-5
548
BIOL PSYCHIATRY 1996;40:547-549
not cross the blood-brain barrier in sufficient quantities to affect CNS processes (Insel 1992). The purpose of the present study was to further investigate the effects of oxytoein on OC symptoms using significantly higher doses of intranasal oxytocin. It was hypothesized that higher dosages might enable a sufficient amount of oxytoein to cross the blood-brain barrier and have behavioral effects.
Methods Three women and 4 men, aged 46.3 -- 12.4 years (mean _+ SD), gave voluntary written informed consent to participate. All 7 met
Diagnostic and Statistical Manual Of Mental Disorders, 4th ed (DSM-IV) (American Psychiatric Association, 1994) criteria for OCD with baseline Yale-Brown Obsessive Compulsive Scale (Y-BOC$) scores of 27.3 • 6.3. Mean age of onset of OC symptoms was 18.7 +- 3.7 yeats. Contamination obsessions and cleaning rituals were primary symptoms reported by the women. One man was a hoarder, while the others' primary symptoms involved obsessions of harm coming to others, the need to check, and repeating rituals. All 7 patients presented with comorbid major depression, 1 with dependent personality disorder, and 1 with Tourette's syndrome. Three patients had received multiple serotonin uptake inhibitors (SUB), whereas 3 had never had treatment with these agents. All patients were medication-free for at least 5 weeks prior to starting the study and were without significant medical illness, hi a randomized, double-blind, placebo-controlled crossover design, patients received intranasal oxytucin (Syntocinon®) 40 IU/mL for 1 week and saline placebo for 1 week. Patients underwent a 7-day washout between treatment phases. Five of the 7 patients received oxytoein 160 IU (68 nasal instffflations) divided in four daily doses. Two patients received twice this dosage (320 IU/day) by doubling the number of insufflations. Each hlsufflation administered approximately 0.06 mL of solution and 2.4 IU of oxytocin. During active and placebo administration phases, patients were rated for 0(2, mood, and anxiety symptoms and memory at baseline and after acute administration (10 rain after the first insufflation on the fast day). After each 7-day administration phase, patients were rated again in an identical manner. OC, depressive, and anxiety symptoms were assessed with the Y-BOCS, the Hamilton Depression Rating Scale, the Beck Depression Inventory (BDI), the Hamilton Anxiety Scale, the Patient-Rated Anxiety Scale, and patient-rated analog scales (Table 1). Effects on memory were determined using a digit span test.
Results Paired t tests revealed no significant differences between active and placebo administration phases on any of the patient or clinician ratings for OC or anxiety symptoms or memory. There was a statistically, but not clinically, significant decrease in BDI scores (from 16.0 to 14.5) after acute administration in the active group (p < ,045). After a preliminary analysis, 2 patients were given double doses of oxytocin because no effect was seen in the first 5 patients who had received the original dosage of oxytocin 160
Brief Reports
Table 1. Oxytocin Administration in OCD Patients (Mean _.+ SD) Rating BDI
Active/ placebo
Active Placebo Y-BOCS Active Placebo VAS Obsessions Active Placebo VAS Compulsions Active Placebo
Baseline
Acute
Chronic
16.0 - 2.82 20.0 -+ 2.96 25.67-+ 3.34 25.67 -+ 3.35 7.75 -+ 2.05 6.58± 1.93 7.25 --- 2.03 6.50- 1.88
14.5-- 2.64 18.0-+ 2.24 N/A N/A 7.25 -+ 1.87 5.33 + 1.50 6.75 - 1.82 4.50 - 1.65
15.33 -+ 2.46 21.83 --- 3.2 25.83 "4-3.63 27.67 -+ 2.26 6.67 -+ 1.63 8.25 -- 1.81 6.17 + 1.7 7.08 _ 2.08
N/A, not applicable;VAS,VisualAnalogScale, IU/day. These 2 patients also showed no significant changes on any of the rating scales. No significant changes in blood pressure, pulse, or serum osmolality occurred and side effects were minimal.
Discussion The results of this double-blind, placebo-controlled study indicate that maximal doses of intranasal oxytocin do not effect OC symptoms. None of the patients showed a significant change in OC symptoms during oxytocin or placebo administration. These results are consistent with those of Den Boer and Westenberg (1992), but in contrast to Ansseau et al (1987), who reported improvement in 1 patient who received intranasal oxytocin 14.4 IU/day over 4 weeks; however, this patient had an atypical case of OCD due to the late age (50 years) of symptom onset, and the authors acknowledge that OC symptoms may have been masked by the psychosis and memory disturbance that developed during oxytocin administration. Patients in the present study were administered significantly higher dosages of intranasal oxytocin (160 IU and 320 IU per day), than those administered previously (18 IU and 54 IU per day) (Den Boer and Westenberg 1992); however, even at dosages 6 - 8 times higher, intranasal oxytoein failed to have a discernable effect on OC symptoms. One potential limitation of this study is the relatively short period (1 week) of oxytocin administration. It can take up to 10 weeks for serotonin reuptake inhibitors to have an effect on OC behavior (Goodman et al 1990). It is conceivable that, even at high doses, a week of intranasal oxytocin administration does not sufficiently effect the CNS to result in a change in behavior. Given the robust CSF findings linking oxytucin with some forms of OCD (Leckman et al 1994b), it will be critical to develop better methods to investigate central oxytocin function in this disorder. This work was supported by a National Alliance for the Research on schizophrenia and Depression Young Investigator Award (Drs. Epperson and McDougle), the Stanley Foundation (Dr. Price), the State of Connecticut Department of Mental Health, and the National Institutes of Health grants PO1 MH25642 and T32 MH 18268. The authors wish to thank Sandoz Pharmaceuticals, East Hanover, New Jersey for providing the bottles for the study, Suzanne Wasylink RNc and Donna Fasnla RN, BSN for their valuable assistance, and Elizabeth Kyle for preparing the manuscript.
Brief Reports
BIOLPSYCHIATRY 1996;40:547-549
549
References American Psychiatric Association, Committee on Nomenclature and Statistics (1994): Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington, DC: American Psychiatric Press. Ansseau M, Legros JJ, Mormont C, et al (1987): Intranasal oxytocin in obsessive compulsive disorder. Psychoneuroendocrinology 12:231-236. Bohus B, Kovacs GL, De Wied D (1978): Oxytocin, vasopressin and memory. Opposite effects on consolidation and retrieval processes. Brain Res 157:414-417. Charles G, Guillanme R, Schittecatte M, Pholien P, Van Wettere JP, Wilmotte J (1989): Oxytocin in the treatment of obsessive-compulsive disorder: A report on two cases. Psychiatry Psychobiol 4:111-115. Den Boer JA, Westenberg HGM (1992): Oxytocin in obsessive compulsive disorder. Peptides 13:1083-1085. Epperson CN, McDougle CJ, Brown RM, Price LH (1995): Obsessive compulsive disorder during pregnancy and the puerpedum. New Research Poster Session, APA Annual Meeting, American Psychiatric Association New Re,arch Abstract #NRl12 May 22, p 84. Goodman WK, Price LH, Delgado PL, et al (1990): Specificity of serotonin reuptake inhibitors in the treatment of obsessivecompulsive disorder. Arch Gen Psychiatry 47:577-585.
Insel TR (1992): Oxytocin--A neuropeptide for affiliation: Evidence from behavioral, receptor autoradiographic and comparative studies. Psychoneuroendocrinology 17:3-35. Kaltwasser TM, Crawley JN (1987): Oxytocin and cholecystoldnin induce grooming behavior in the ventral tegmentum of the rat. Brain Res 426:1-7. Leckman JF, Goodman WK, North WC, et al (1994a): The role of central oxytocin in obsessive compulsive disorder and related normal behavior. Psychoneuroendocrinology 19:723749. Leckman JF, Goodman WK, North WC, et al (1994b): Elevated cerebrospinal fluid levels of oxytocin in obsessive-compulsive disorder: Comparison with Tourette's syndrome and healthy controls. Arch Gen Psychiatry 51:782-792. Mazurek MF, Beal MF, Bird El), Matin JB (1987): Oxytocin in alzbeimer's disease: Postmortem brain levels. Neurology 37:1001-1003. Pedersen CA, Prange AJ (1979): Induction of mammal behaviour in virgin rats after intracerebroventricular administration of oxytocin. Proc Natl Acad Sci USA 76:6661-6665. Salzberg AD, Swedo SE (1992): Oxytocin and vasopressin in obsessive-compulsive disorder. Am J Psychiatry 149:713714.
Introduction Oxytocin is a neurosecretory nonapeptide which is synthesized by hypothalamic cells and distributed to the central nervous system (CNS), as well as the neurohypophysis. Although oxytocin's roles in milk ejection and uterine contraction have been well-characterized, it is only in the past decade that the scope and complexity of its effects in the CNS have been appreciated. Oxytocin has been implicated in the expression of a number of grooming, cognitive, affiliative, sexual, and reproductive behaviors in animals (Insel 1992). There is growing evidence to suggest that oxytocin may play a role in the pathogenesis of some forms of obsessive-compulsive disorder (OCD). For example, administration of oxytocin can increase autogrooming of the head and anogenital regions in rats (Kaltwasser and Crawley 1987). It has been suggested that such behaviors may be similar to the repetitive handwashing and cleaning present in many patients with OCD (Leckman et al 1994a). Oxytocin is critically involved in the initiation of maternal behavior in animals (Pedersen and Prange 1979), and cerebrospinal fluid (CSF) levels of oxytocin are elevated during the third trimester of pregnancy and the early puerperium. We recently reported that 18.6% and 55.9% of women presenting to an OCD clinic reported onset and worsening, respectively, of obsessive-
From the Yale University Department of Psychiatry, New Haven, Connecticut, USA. Address reprint requests to C. Neill Epperson, Yale University Department of Psychiatry, 34 Park Street, New Haven, CT 06519. Received October 18, 1995; revised February 21, 1996.
© 1996 Society of Biological Psychiatry
compulsive (OC) symptoms during pregnancy or the puerperium (Epperson et al 1995). Obsessions regarding the safety of others and dirt and germs, as well as compulsions such as checking and cleaning might be seen as pathological correlates of normal maternal behavior. Importantly, oxytocin has been reported to be elevated in the CSF of patients with OCD compared with ageand sex-matched normal control subjects and patients with Tourette's syndrome (Leckman et al 1994b). It has been hypothesized that there may be abnormalities in memory processing systems in some patients with OCD. Oxytocin, which has been referred to as the "amnestic" neuropeptide, can attenuate memory consolidation and retrieval (Bohus et al 1978). In addition, oxytocin is elevated in the hippocampus and temporal cortex of postmortem Alzbeimer brains compared with normal control brains (Mazurek et al 1987). There have been previous reports of oxytocin administration in patients with OCD. Ansseau et al (1987) reported symptomatic improvement in 1 man treated with intranasal oxytocin 8.4-16.8 IU per day for 4 weeks. This individual showed the most improvement within the first 2 weeks of treatment, but subsequently developed memory loss, psychosis, and a decrease in plasma sodium and osmolality. Den Boer and Westenberg (1992) randomized 12 patients with OCD to placebo or intranasal oxytocin 17.6 IU/day for 6 weeks. Two additional patients received a threefold higher dosage. No significant changes in OC symptoms occurred and side effects were minimal. Additionally, Salzberg and Swedo (1992) found that a one-time dose of intranasal oxytocin 8 IU had no appreciable affects on OC symptoms in 3 patients. Charles et al (1989) also found no effect of oxytocin administration in 2 cases. One explanation for these negative results is that peripherally administered oxytocin does 0006-3223/96/$15.00 PII S0006-3223(96)00120-5
548
BIOL PSYCHIATRY 1996;40:547-549
not cross the blood-brain barrier in sufficient quantities to affect CNS processes (Insel 1992). The purpose of the present study was to further investigate the effects of oxytoein on OC symptoms using significantly higher doses of intranasal oxytocin. It was hypothesized that higher dosages might enable a sufficient amount of oxytoein to cross the blood-brain barrier and have behavioral effects.
Methods Three women and 4 men, aged 46.3 -- 12.4 years (mean _+ SD), gave voluntary written informed consent to participate. All 7 met
Diagnostic and Statistical Manual Of Mental Disorders, 4th ed (DSM-IV) (American Psychiatric Association, 1994) criteria for OCD with baseline Yale-Brown Obsessive Compulsive Scale (Y-BOC$) scores of 27.3 • 6.3. Mean age of onset of OC symptoms was 18.7 +- 3.7 yeats. Contamination obsessions and cleaning rituals were primary symptoms reported by the women. One man was a hoarder, while the others' primary symptoms involved obsessions of harm coming to others, the need to check, and repeating rituals. All 7 patients presented with comorbid major depression, 1 with dependent personality disorder, and 1 with Tourette's syndrome. Three patients had received multiple serotonin uptake inhibitors (SUB), whereas 3 had never had treatment with these agents. All patients were medication-free for at least 5 weeks prior to starting the study and were without significant medical illness, hi a randomized, double-blind, placebo-controlled crossover design, patients received intranasal oxytucin (Syntocinon®) 40 IU/mL for 1 week and saline placebo for 1 week. Patients underwent a 7-day washout between treatment phases. Five of the 7 patients received oxytoein 160 IU (68 nasal instffflations) divided in four daily doses. Two patients received twice this dosage (320 IU/day) by doubling the number of insufflations. Each hlsufflation administered approximately 0.06 mL of solution and 2.4 IU of oxytocin. During active and placebo administration phases, patients were rated for 0(2, mood, and anxiety symptoms and memory at baseline and after acute administration (10 rain after the first insufflation on the fast day). After each 7-day administration phase, patients were rated again in an identical manner. OC, depressive, and anxiety symptoms were assessed with the Y-BOCS, the Hamilton Depression Rating Scale, the Beck Depression Inventory (BDI), the Hamilton Anxiety Scale, the Patient-Rated Anxiety Scale, and patient-rated analog scales (Table 1). Effects on memory were determined using a digit span test.
Results Paired t tests revealed no significant differences between active and placebo administration phases on any of the patient or clinician ratings for OC or anxiety symptoms or memory. There was a statistically, but not clinically, significant decrease in BDI scores (from 16.0 to 14.5) after acute administration in the active group (p < ,045). After a preliminary analysis, 2 patients were given double doses of oxytocin because no effect was seen in the first 5 patients who had received the original dosage of oxytocin 160
Brief Reports
Table 1. Oxytocin Administration in OCD Patients (Mean _.+ SD) Rating BDI
Active/ placebo
Active Placebo Y-BOCS Active Placebo VAS Obsessions Active Placebo VAS Compulsions Active Placebo
Baseline
Acute
Chronic
16.0 - 2.82 20.0 -+ 2.96 25.67-+ 3.34 25.67 -+ 3.35 7.75 -+ 2.05 6.58± 1.93 7.25 --- 2.03 6.50- 1.88
14.5-- 2.64 18.0-+ 2.24 N/A N/A 7.25 -+ 1.87 5.33 + 1.50 6.75 - 1.82 4.50 - 1.65
15.33 -+ 2.46 21.83 --- 3.2 25.83 "4-3.63 27.67 -+ 2.26 6.67 -+ 1.63 8.25 -- 1.81 6.17 + 1.7 7.08 _ 2.08
N/A, not applicable;VAS,VisualAnalogScale, IU/day. These 2 patients also showed no significant changes on any of the rating scales. No significant changes in blood pressure, pulse, or serum osmolality occurred and side effects were minimal.
Discussion The results of this double-blind, placebo-controlled study indicate that maximal doses of intranasal oxytocin do not effect OC symptoms. None of the patients showed a significant change in OC symptoms during oxytocin or placebo administration. These results are consistent with those of Den Boer and Westenberg (1992), but in contrast to Ansseau et al (1987), who reported improvement in 1 patient who received intranasal oxytocin 14.4 IU/day over 4 weeks; however, this patient had an atypical case of OCD due to the late age (50 years) of symptom onset, and the authors acknowledge that OC symptoms may have been masked by the psychosis and memory disturbance that developed during oxytocin administration. Patients in the present study were administered significantly higher dosages of intranasal oxytocin (160 IU and 320 IU per day), than those administered previously (18 IU and 54 IU per day) (Den Boer and Westenberg 1992); however, even at dosages 6 - 8 times higher, intranasal oxytoein failed to have a discernable effect on OC symptoms. One potential limitation of this study is the relatively short period (1 week) of oxytocin administration. It can take up to 10 weeks for serotonin reuptake inhibitors to have an effect on OC behavior (Goodman et al 1990). It is conceivable that, even at high doses, a week of intranasal oxytocin administration does not sufficiently effect the CNS to result in a change in behavior. Given the robust CSF findings linking oxytucin with some forms of OCD (Leckman et al 1994b), it will be critical to develop better methods to investigate central oxytocin function in this disorder. This work was supported by a National Alliance for the Research on schizophrenia and Depression Young Investigator Award (Drs. Epperson and McDougle), the Stanley Foundation (Dr. Price), the State of Connecticut Department of Mental Health, and the National Institutes of Health grants PO1 MH25642 and T32 MH 18268. The authors wish to thank Sandoz Pharmaceuticals, East Hanover, New Jersey for providing the bottles for the study, Suzanne Wasylink RNc and Donna Fasnla RN, BSN for their valuable assistance, and Elizabeth Kyle for preparing the manuscript.
Brief Reports
BIOLPSYCHIATRY 1996;40:547-549
549
References American Psychiatric Association, Committee on Nomenclature and Statistics (1994): Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington, DC: American Psychiatric Press. Ansseau M, Legros JJ, Mormont C, et al (1987): Intranasal oxytocin in obsessive compulsive disorder. Psychoneuroendocrinology 12:231-236. Bohus B, Kovacs GL, De Wied D (1978): Oxytocin, vasopressin and memory. Opposite effects on consolidation and retrieval processes. Brain Res 157:414-417. Charles G, Guillanme R, Schittecatte M, Pholien P, Van Wettere JP, Wilmotte J (1989): Oxytocin in the treatment of obsessive-compulsive disorder: A report on two cases. Psychiatry Psychobiol 4:111-115. Den Boer JA, Westenberg HGM (1992): Oxytocin in obsessive compulsive disorder. Peptides 13:1083-1085. Epperson CN, McDougle CJ, Brown RM, Price LH (1995): Obsessive compulsive disorder during pregnancy and the puerpedum. New Research Poster Session, APA Annual Meeting, American Psychiatric Association New Re,arch Abstract #NRl12 May 22, p 84. Goodman WK, Price LH, Delgado PL, et al (1990): Specificity of serotonin reuptake inhibitors in the treatment of obsessivecompulsive disorder. Arch Gen Psychiatry 47:577-585.
Insel TR (1992): Oxytocin--A neuropeptide for affiliation: Evidence from behavioral, receptor autoradiographic and comparative studies. Psychoneuroendocrinology 17:3-35. Kaltwasser TM, Crawley JN (1987): Oxytocin and cholecystoldnin induce grooming behavior in the ventral tegmentum of the rat. Brain Res 426:1-7. Leckman JF, Goodman WK, North WC, et al (1994a): The role of central oxytocin in obsessive compulsive disorder and related normal behavior. Psychoneuroendocrinology 19:723749. Leckman JF, Goodman WK, North WC, et al (1994b): Elevated cerebrospinal fluid levels of oxytocin in obsessive-compulsive disorder: Comparison with Tourette's syndrome and healthy controls. Arch Gen Psychiatry 51:782-792. Mazurek MF, Beal MF, Bird El), Matin JB (1987): Oxytocin in alzbeimer's disease: Postmortem brain levels. Neurology 37:1001-1003. Pedersen CA, Prange AJ (1979): Induction of mammal behaviour in virgin rats after intracerebroventricular administration of oxytocin. Proc Natl Acad Sci USA 76:6661-6665. Salzberg AD, Swedo SE (1992): Oxytocin and vasopressin in obsessive-compulsive disorder. Am J Psychiatry 149:713714.