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ADJUNCTIVE INTRANASAL OXYTOCINTO IMPROVE SOCIAL COGNITION AND FUNCTIONING IN SCHIZOPHRENIA
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Abstracts of the 3rd Biennial Schizophrenia International Research Conference / Schizophrenia Research 136, Supplement 1 (2012) S1–S375
stable doses of antipsychotic medication (n=15). A separate team of investigators at the University of North Carolina lead by Dr. Pedersen conducted a 14 day parallel arm, study of daily intranasal oxytocin (24 IU BID, n=14) versus placebo (n=11) given adjunctive to stable regimes of antipsychotic medication in schizophrenia patients. We found that intranasal oxytocin significantly reduced positive and negative symptoms compared to placebo. Dr. Pederson’s team found within groups that oxytocin recipients had significantly greater declines in PANSS total, positive, negative and general subscale scores while the placebo group had no significant changes in these variables. ANCOVAs controlling for baseline measures showed that total PANSS scores declined significantly more in the OT compared to the placebo group. Intranasal oxytocin was well tolerated in both studies. Both studies also found oxytocin produced improvement in highly relevant secondary measures beyond positive and negative symptoms (see Pedersen et al abstract in this symposium). Together these preclinical and clinical findings suggest that there is an exciting opportunity to develop novel treatments for schizophrenia targeting oxytocin receptors. However, larger studies addressing several parametric issues are needed to both replicate these exciting initial findings and to inform possible drug development efforts.
OXYTOCIN TREATMENT IMPROVES SOCIAL COGNITION, PANSS SOCIAL ITEM SCORES AND VERBAL LEARNING IN SCHIZOPHRENIA Cort Pedersen University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA Social dysfunction is a major cause of disability in schizophrenia and responds poorly to current antipsychotic medications. Social impairment is strongly linked to deficits in social cognition (mental abilities that facilitate social decisions and behavior) and less robustly associated with neurocognitive deficits. Decades of animal research have established that oxytocin (OT) has many pro-social effects. In recent human studies, acute intranasal OT administration increased interpersonal trust, eye contact, face emotion recognition and Theory of Mind. We hypothesized that more prolonged intranasal OT treatment would improve social cognition and possibly neurocognition in schizophrenia. The first randomized, double blind, placebo-controlled study was conducted in subjects with schizophrenia for >1 yr and baseline PANSS total scores >60. The effects of 14 days of intranasal OT (24 IU/BID, N=14) vs. placebo (N=11) were compared on a battery of social cognition tests and on social behavior-related items on the PANSS. Symptoms and psychotropic medication regimens were stable for >1 month prior to the treatment trial and medication doses remained unchanged during the study period. In a second RCT (N=15), patients received intranasal OT (40 IU/BID) or placebo for 3 wks in a crossover design with a 1 week washout period. The California Verbal Leaning Test (CVLT) and the Letter Sequence Test (LST) were administered before and after each 3-wk segment of the trial. In the first study, demographic data, psychiatric history and baseline measures did not differ between treatment groups. The OT group had significant reductions from baseline to treatment day 14 in accurate identification in the Brüne Theory of Mind Test of 3rd order false belief (t=-2.19, p=0.048). The mean scores on PANSS social items improved more than any other variable (t=5.08, p=0.0003). In addition, OT recipients showed trends on the Brüne Test toward significant improvement on accurate identification of 2nd order false belief (t=-2.11, p=0.055) and deception (t=-1.88, p=0.082) as well as rating untrustworthy faces (faces rated by a normative sample as untrustworthy) as less untrustworthy (t=-1.96, p=0.072). None of these measures changed significantly in the placebo group. ANCOVAs controlling for baseline revealed that the OT compared to the placebo group trended weakly toward significantly greater decreases in mean PANSS social item scores (F=3.15, p=0.090). In the second study, CVLT scores improved significantly in the OT compared to the placebo group on Total Recall (t= -2.47. p=0.027), Short Delay Free Recall (t=-2.38, p=0.032), Short Delay Cued Recall (t=-2.33, p=0.035), Total Repetitions (t=-2.69, p=0.018) and Total Recall Discriminability (t=-2.63, p=0.018). Performance on the LST did not differ between treatment groups. These are the first studies to demonstrate in patients with schizophrenia that sustained OT treatment may improve aspects of social cognition (Theory of Mind measures, trustworthiness perception) and neurocognition (verbal learning). Our results raise important questions for future studies. 1) Will longer periods of OT treatment further improve social cognition, neu-
rocognition and social functioning? 2) Would combining OT treatment with social cognition/skill training have additive or even synergistic beneficial effects on social functioning?
SEX-SPECIFIC ASSOCIATIONS BETWEEN PERIPHERAL OXYTOCIN, SYMPTOMS, AND EMOTION PERCEPTION IN SCHIZOPHRENIA Leah Rubin University of Illinois at Chicago, Chicago, Illinois, USA Sex hormones are implicated in the pathogenesis of schizophrenia. Low levels of estrogen and oxytocin, hormones that may act as neuromodulators, are common in women with schizophrenia, and variations in these hormones affect cognitive functions (including social cognition) that are impaired in the disease. Emerging evidence from clinical trials suggests that oral estrogen and intranasal oxytocin might reduce symptom severity in schizophrenia. Additionally, treatment with intranasal oxytocin may also improve social cognition in schizophrenia. Here we investigated the influence of sex, sex steroid hormone fluctuations, and peripheral oxytocin levels on clinical symptoms and emotional processing in men and women with schizophrenia. Fifty women (30 healthy and 20 patients) completed assessments at two distinct phases of their menstrual cycle, and 54 men (27 healthy and 27 patients) completed testing at comparable intervals to the women. Assessments included the Positive and Negative Syndrome Scale (PANSS) and the PENN Emotion Acuity Test (PEAT), a facial emotion recognition and perception task. We obtained plasma hormone assays of estrogen, progesterone, testosterone, and oxytocin. Female patients showed less severe symptoms during the midluteal versus early follicular phase. Oxytocin did not fluctuate across phases, but in female patients, higher oxytocin levels were associated with less severe positive, general, and overall psychopathology. In both sexes, higher oxytocin levels were associated with more prosocial behavior. Higher oxytocin levels also related to perceiving faces as happier in both female patients and controls but not in men. Individual differences in oxytocin levels differentially predict clinical symptoms and emotion processing in men and women with schizophrenia. These findings suggest the hypothesis that endogenous oxytocin may impact the clinical manifestation of schizophrenia. Future trials of oxytocin in patients with schizophrenia should include measures of social cognition to evaluate whether exogenous oxytocin also makes patients view faces as “happier” and explore the functional correlates of this benefit. Additionally, it may be important to consider sex when evaluating oxytocin in the management of schizophrenia.
ADJUNCTIVE INTRANASAL OXYTOCINTO IMPROVE SOCIAL COGNITION AND FUNCTIONING IN SCHIZOPHRENIA Mary Lee National Institute on Drug Abuse, Baltimore, Maryland, USA Social cognition includes emotion perception, social perception, theory of mind (social intelligence), and attributional style and has been shown to be deficient in people with schizophrenia. Social cognition does not appear to be remediated by antipsychotic medications or psychosocial interventions and is related but distinct from neurocognition, positive and negative symptoms. Further, it is associated with functional outcome, including community functioning. Oxytocin (OT) has improved aspects of social cognition in humans such as social bonding/positive interaction, trust, empathy, and emotional perception/memory as well as stress reduction. Two published studies, (by authors presenting in this symposium) using repeated dosing of intranasal OT, report improvements in some domains of social cognition and psychiatric symptoms. We sought to investigate the effect of adjunctive treatment with intranasal OT (20 IU/BID) in schizophrenia on multiple domains of social cognition including an objective measure of social functioning as well as measures of social and emotional perception, theory of mind, attributional style as well as on a range of clinical symptoms in a 3 week placebo controlled double blind clinical trial. Subjects had a DSM-IV diagnosis of schizophrenia or schizoaffective disorder and were on a stable medication regimen for 6 weeks. Our primary measure of social cognition is the Mayer-Salovay Caruso Emotional Intelligence Test (MSCEIT): understanding and managing emotions components that have been shown to be
Abstracts of the 3rd Biennial Schizophrenia International Research Conference / Schizophrenia Research 136, Supplement 1 (2012) S1–S375
sensitive to social cognition deficits in schizophrenia and sensitive to measuring the effect of therapeutic interventions. Importantly, we also employ an objective measure of social functioning, The Maryland Assessment of Social Competence (MASC) that is designed to assess, objectively, the ability to resolve interpersonal problems through conversation. The MASC has been shown to have good discriminatory power for assessing overall social skill deficits among people with schizophrenia. The MSCEIT and MASC are administered at baseline and at the end of the study drug administration phase (under the acute effect of OT). In addition to primary and secondary outcome measure side effects and symptoms are measured weekly. Serum OT and vasopressin levels are measured by radioimmunoassay at baseline and before last dose of study medication. The study population enrolled to date is 19 patients (N=9 placebo; N=10 oxytocin) with an expected enroll-
S71
ment of 30. There are no significant differences noted between treatment groups in age, educational level, gender, race or marital status. At baseline total BPRS scores in the placebo group are 35.00±12.78 and 39.40±6.69 in the OT group (p=NS). Baseline MSCEIT and MASC scores to date demonstrate moderate levels of impairment in social cognition and social function and the final presentation will include treatment X time interactions controlling for any baseline differences. We will also examine the relationship of baseline and change in OT and vasopressin levels to severity and change in primary measures of social cognition and social functioning. This most recent randomized double blind clinical trial results will be compared and contrasted to the two other clinical studies in the symposium and will add additional information to the existing literature and body of evidence with OT with respect to these primary outcome measures.
Abstracts of the 3rd Biennial Schizophrenia International Research Conference / Schizophrenia Research 136, Supplement 1 (2012) S1–S375
stable doses of antipsychotic medication (n=15). A separate team of investigators at the University of North Carolina lead by Dr. Pedersen conducted a 14 day parallel arm, study of daily intranasal oxytocin (24 IU BID, n=14) versus placebo (n=11) given adjunctive to stable regimes of antipsychotic medication in schizophrenia patients. We found that intranasal oxytocin significantly reduced positive and negative symptoms compared to placebo. Dr. Pederson’s team found within groups that oxytocin recipients had significantly greater declines in PANSS total, positive, negative and general subscale scores while the placebo group had no significant changes in these variables. ANCOVAs controlling for baseline measures showed that total PANSS scores declined significantly more in the OT compared to the placebo group. Intranasal oxytocin was well tolerated in both studies. Both studies also found oxytocin produced improvement in highly relevant secondary measures beyond positive and negative symptoms (see Pedersen et al abstract in this symposium). Together these preclinical and clinical findings suggest that there is an exciting opportunity to develop novel treatments for schizophrenia targeting oxytocin receptors. However, larger studies addressing several parametric issues are needed to both replicate these exciting initial findings and to inform possible drug development efforts.
OXYTOCIN TREATMENT IMPROVES SOCIAL COGNITION, PANSS SOCIAL ITEM SCORES AND VERBAL LEARNING IN SCHIZOPHRENIA Cort Pedersen University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA Social dysfunction is a major cause of disability in schizophrenia and responds poorly to current antipsychotic medications. Social impairment is strongly linked to deficits in social cognition (mental abilities that facilitate social decisions and behavior) and less robustly associated with neurocognitive deficits. Decades of animal research have established that oxytocin (OT) has many pro-social effects. In recent human studies, acute intranasal OT administration increased interpersonal trust, eye contact, face emotion recognition and Theory of Mind. We hypothesized that more prolonged intranasal OT treatment would improve social cognition and possibly neurocognition in schizophrenia. The first randomized, double blind, placebo-controlled study was conducted in subjects with schizophrenia for >1 yr and baseline PANSS total scores >60. The effects of 14 days of intranasal OT (24 IU/BID, N=14) vs. placebo (N=11) were compared on a battery of social cognition tests and on social behavior-related items on the PANSS. Symptoms and psychotropic medication regimens were stable for >1 month prior to the treatment trial and medication doses remained unchanged during the study period. In a second RCT (N=15), patients received intranasal OT (40 IU/BID) or placebo for 3 wks in a crossover design with a 1 week washout period. The California Verbal Leaning Test (CVLT) and the Letter Sequence Test (LST) were administered before and after each 3-wk segment of the trial. In the first study, demographic data, psychiatric history and baseline measures did not differ between treatment groups. The OT group had significant reductions from baseline to treatment day 14 in accurate identification in the Brüne Theory of Mind Test of 3rd order false belief (t=-2.19, p=0.048). The mean scores on PANSS social items improved more than any other variable (t=5.08, p=0.0003). In addition, OT recipients showed trends on the Brüne Test toward significant improvement on accurate identification of 2nd order false belief (t=-2.11, p=0.055) and deception (t=-1.88, p=0.082) as well as rating untrustworthy faces (faces rated by a normative sample as untrustworthy) as less untrustworthy (t=-1.96, p=0.072). None of these measures changed significantly in the placebo group. ANCOVAs controlling for baseline revealed that the OT compared to the placebo group trended weakly toward significantly greater decreases in mean PANSS social item scores (F=3.15, p=0.090). In the second study, CVLT scores improved significantly in the OT compared to the placebo group on Total Recall (t= -2.47. p=0.027), Short Delay Free Recall (t=-2.38, p=0.032), Short Delay Cued Recall (t=-2.33, p=0.035), Total Repetitions (t=-2.69, p=0.018) and Total Recall Discriminability (t=-2.63, p=0.018). Performance on the LST did not differ between treatment groups. These are the first studies to demonstrate in patients with schizophrenia that sustained OT treatment may improve aspects of social cognition (Theory of Mind measures, trustworthiness perception) and neurocognition (verbal learning). Our results raise important questions for future studies. 1) Will longer periods of OT treatment further improve social cognition, neu-
rocognition and social functioning? 2) Would combining OT treatment with social cognition/skill training have additive or even synergistic beneficial effects on social functioning?
SEX-SPECIFIC ASSOCIATIONS BETWEEN PERIPHERAL OXYTOCIN, SYMPTOMS, AND EMOTION PERCEPTION IN SCHIZOPHRENIA Leah Rubin University of Illinois at Chicago, Chicago, Illinois, USA Sex hormones are implicated in the pathogenesis of schizophrenia. Low levels of estrogen and oxytocin, hormones that may act as neuromodulators, are common in women with schizophrenia, and variations in these hormones affect cognitive functions (including social cognition) that are impaired in the disease. Emerging evidence from clinical trials suggests that oral estrogen and intranasal oxytocin might reduce symptom severity in schizophrenia. Additionally, treatment with intranasal oxytocin may also improve social cognition in schizophrenia. Here we investigated the influence of sex, sex steroid hormone fluctuations, and peripheral oxytocin levels on clinical symptoms and emotional processing in men and women with schizophrenia. Fifty women (30 healthy and 20 patients) completed assessments at two distinct phases of their menstrual cycle, and 54 men (27 healthy and 27 patients) completed testing at comparable intervals to the women. Assessments included the Positive and Negative Syndrome Scale (PANSS) and the PENN Emotion Acuity Test (PEAT), a facial emotion recognition and perception task. We obtained plasma hormone assays of estrogen, progesterone, testosterone, and oxytocin. Female patients showed less severe symptoms during the midluteal versus early follicular phase. Oxytocin did not fluctuate across phases, but in female patients, higher oxytocin levels were associated with less severe positive, general, and overall psychopathology. In both sexes, higher oxytocin levels were associated with more prosocial behavior. Higher oxytocin levels also related to perceiving faces as happier in both female patients and controls but not in men. Individual differences in oxytocin levels differentially predict clinical symptoms and emotion processing in men and women with schizophrenia. These findings suggest the hypothesis that endogenous oxytocin may impact the clinical manifestation of schizophrenia. Future trials of oxytocin in patients with schizophrenia should include measures of social cognition to evaluate whether exogenous oxytocin also makes patients view faces as “happier” and explore the functional correlates of this benefit. Additionally, it may be important to consider sex when evaluating oxytocin in the management of schizophrenia.
ADJUNCTIVE INTRANASAL OXYTOCINTO IMPROVE SOCIAL COGNITION AND FUNCTIONING IN SCHIZOPHRENIA Mary Lee National Institute on Drug Abuse, Baltimore, Maryland, USA Social cognition includes emotion perception, social perception, theory of mind (social intelligence), and attributional style and has been shown to be deficient in people with schizophrenia. Social cognition does not appear to be remediated by antipsychotic medications or psychosocial interventions and is related but distinct from neurocognition, positive and negative symptoms. Further, it is associated with functional outcome, including community functioning. Oxytocin (OT) has improved aspects of social cognition in humans such as social bonding/positive interaction, trust, empathy, and emotional perception/memory as well as stress reduction. Two published studies, (by authors presenting in this symposium) using repeated dosing of intranasal OT, report improvements in some domains of social cognition and psychiatric symptoms. We sought to investigate the effect of adjunctive treatment with intranasal OT (20 IU/BID) in schizophrenia on multiple domains of social cognition including an objective measure of social functioning as well as measures of social and emotional perception, theory of mind, attributional style as well as on a range of clinical symptoms in a 3 week placebo controlled double blind clinical trial. Subjects had a DSM-IV diagnosis of schizophrenia or schizoaffective disorder and were on a stable medication regimen for 6 weeks. Our primary measure of social cognition is the Mayer-Salovay Caruso Emotional Intelligence Test (MSCEIT): understanding and managing emotions components that have been shown to be
Abstracts of the 3rd Biennial Schizophrenia International Research Conference / Schizophrenia Research 136, Supplement 1 (2012) S1–S375
sensitive to social cognition deficits in schizophrenia and sensitive to measuring the effect of therapeutic interventions. Importantly, we also employ an objective measure of social functioning, The Maryland Assessment of Social Competence (MASC) that is designed to assess, objectively, the ability to resolve interpersonal problems through conversation. The MASC has been shown to have good discriminatory power for assessing overall social skill deficits among people with schizophrenia. The MSCEIT and MASC are administered at baseline and at the end of the study drug administration phase (under the acute effect of OT). In addition to primary and secondary outcome measure side effects and symptoms are measured weekly. Serum OT and vasopressin levels are measured by radioimmunoassay at baseline and before last dose of study medication. The study population enrolled to date is 19 patients (N=9 placebo; N=10 oxytocin) with an expected enroll-
S71
ment of 30. There are no significant differences noted between treatment groups in age, educational level, gender, race or marital status. At baseline total BPRS scores in the placebo group are 35.00±12.78 and 39.40±6.69 in the OT group (p=NS). Baseline MSCEIT and MASC scores to date demonstrate moderate levels of impairment in social cognition and social function and the final presentation will include treatment X time interactions controlling for any baseline differences. We will also examine the relationship of baseline and change in OT and vasopressin levels to severity and change in primary measures of social cognition and social functioning. This most recent randomized double blind clinical trial results will be compared and contrasted to the two other clinical studies in the symposium and will add additional information to the existing literature and body of evidence with OT with respect to these primary outcome measures.