S82 Abstracts of the 4th Biennial Schizophrenia International Research Conference / Schizophrenia Research 153, Supplement 1 (2014) S1–S384

INFANT MOTOR DEVELOPMENT PREDICTS DECLINE IN EXECUTIVE

FUNCTION IN ADULT SCHIZOPHRENIA IN THE NORTHERN FINLAND 1966

BIRTH COHORT STUDY

Graham Murray1, Hiroyuki Kobayashi2,3, Matti Isohanni4,

Erika Jääskeläinen4, Jouko Miettunen4, Marjo Riitta Järvelin5,6,

Marianne Haapea4, Peter Jones2, Jouko Miettunen4

1University of Cambridge; 2Department of Psychiatry, University of Cambridge,

Cambridge, United Kingdom; 3Department of Neuropsychiatry, School of

Medicine, Toho University, Tokyo, Japan; 4Department of Psychiatry,

University of Oulu, Oulu, Finland; 5Department of Epidemiology and

Biostatistics, MRC-HPA Centre for Environment and Health, Imperial College

London, London, United Kingdom; 6Institute of Health Sciences, University of

Oulu, Oulu, Finland

Neurodevelopmental and neurodegenerative theories are traditionally

viewed as incompatible accounts that compete to explain the pathogenesis

of schizophrenia. However, it is possible that neurodevelopmental and

neurodegenerative processes could both reflect common underlying causal

mechanisms. We hypothesized that cognitive dysfunction would gradually

deteriorate over time in schizophrenia and the degree of this deterioration

in adulthood would be predicted by an infant measure of neurodevelop-

ment (age of learning to stand without support). We aimed to examine the

association between age of learning to stand in infancy and deterioration

of cognitive function in adulthood. Participants were non-psychotic control

subjects (n=71) and participants with schizophrenia (n=34) drawn from the

Northern Finland 1966 Birth Cohort study. Participants were assessed at

age 34 and 43 on the following cognitive measures: verbal learning with

the California Verbal Learning Test, visual learning with the Visual Object

Learning Test, and abstraction and abstraction with memory from the

Abstraction, Inhibition and Working Memory Test. The schizophrenia group

showed greater deterioration in abstraction with memory than controls,

but there were no differences between schizophrenia and controls in rate

of change of other cognitive measures. Age of learning to stand in infancy

significantly inversely predicted later deterioration of abstraction with

memory in adult schizophrenia (later infant development linked to greater

subsequent cognitive deterioration during adulthood), possibly suggest-

ing a link between abnormal neurodevelopmental and neurodegenerative

processes in schizophrenia.

Symposium

OXYTOCIN, SOCIAL COGNITION, AND SCHIZOPHRENIA

Chairperson: Robert W. Buchanan

Discussant: Shitij Kapur

Wednesday, 9 April 2014 1:30 PM – 3:30 PM

Overall Abstract: People with schizophrenia are characterized by marked

impairments in social function. These impairments may reflect disturbances

in basic social cognitive processes, including emotion recognition and per-

ception (i.e., the ability to infer emotional information from facial and

other non-verbal and verbal expressions); social perception (i.e., the ability

perceive social cues from the context of the observed behavior); theory of

mind (i.e., the ability to make inferences about the intentions and beliefs

of others, and attributional style (i.e., how a person tends to explain the

causes of events in their lives). The development of therapeutic approaches

to enhance social cognition is a major area of treatment development. In

this regard, a potentially promising approach is the use of oxytocin to

improve social cognitive processes, which would be hypothesized to lead

to improved social function. Oxytocin has been shown in animals to play a

critical role in the regulation of social and emotional behaviors, including

social affiliation, pair bonding, maternal behavior, and social memory. In

normal healthy controls, studies have demonstrated that intranasal oxy-

tocin: 1) increases the amount of time spent gazing at the eye region; 2)

improves the ability to infer the internal mental state of another person

through processing affective eye expressions, with this effect potentially

more pronounced in those who have difficulty in identifying their own

emotions; 3) enhances the ability to recognize facial expressions, with a

differential effect observed for rapidly presented happy facial expressions;

4) increases the perception of attractiveness and trustworthiness in the

faces of others; 5) reduces arousal ratings to negative or threatening human

visual stimuli; and 6) decreases the likelihood that positive or neutral facial

emotions will be misclassified as negative emotions. In the past 5 years,

there have been several challenge studies and clinical trials of oxytocin in

people with schizophrenia, which suggest that oxytocin may have mixed

effects on social cognition and symptoms. The proposed Symposium is

designed to provide an update from preclinical to clinical studies on the

relationship among oxytocin, social cognition, and schizophrenia. James

Koenig, Ph.D. will present preclinical findings on the relationship between

oxytocin and social function from the subchronic phencyclidine (PCP) and

prenatal stress animal models of schizophrenia. Gregory Strauss, Ph.D. will

present data from a cross-sectional study, which examines the relation-

ship between oxytocin levels and various aspects of facial and emotion

processing in healthy controls and people with schizophrenia; Andrea

Meyer-Lindenberg, M.D. will present data on the effect of acute oxytocin

and vasopressin challenge studies on neural circuits involved in emotion

processing and the impact of genetic variations of vasopressin and oxytocin

receptors on these effects; and Stephen Marder, M.D. will present results

from a recently completed 6-week, placebo-controlled, randomized clinical

trial designed to examine the effect of oxytocin administration on social

cognition and function in people with schizophrenia. Shitij Kapur. M.D.,

Ph.D. will serve as the Discussant.

PRECLINICAL ASSESSMENT OF OXYTOCIN’S ABILITY TO MODULATE

SOCIAL BEHAVIOR

James Koenig

National Institute of Neurological Diseases and Stroke, Rockville, USA

The hypothalamic peptide, oxytocin, was originally found to be an essential

regulator of female reproductive behaviors, including maternal behavior

and lactation. However, in the late 1980’s and early 1990’s publications

from a number of laboratories began to reveal a role for oxytocin in

non-reproductive social behaviors in male rodents. Seminal reports by

Witt, Insel, Popik and vanRee, to name a few, sparked great interest in

the biology of oxytocin beyond its role in reproductive functions. The

importance of oxytocin in social behaviors was further confirmed through

the use of genetically manipulated mouse models around 2000. Several

neuropsychiatric disorders, including schizophrenia and autism, share the

symptom of asociality and an argument has been made for oxytocin as a

novel target for further prosocial drug development. However, current un-

derstanding of how and where oxytocin acts in the brain to elicit improved

social functioning is still somewhat obscure. To that end, gaining further

insights into the ability of oxytocin to modulate social behavior relevant to

schizophrenia has been an important focus of research. In a series of studies,

we have demonstrated that brain oxytocin levels in both the subchronic

phencyclidine (PCP) and prenatal stress animal models of schizophrenia

were reduced in animals showing increased social withdrawal. Moreover,

our studies demonstrated that administration of the peptide could improve

social liabilities present in both models. Interestingly, the ability of oxytocin

to improve social functioning resulted when the peptide was administered

directly into the central nucleus of the amygdala, which has been shown

to receive a direct oxytocinergic neural projection from the paraventricular

nucleus of the hypothalamus (PVN), the home of the brain’s oxytocin cell

bodies. Furthermore, we showed that gestational environmental insults,

such as stress, compromise the expression of a key transcriptional reg-

ulator for oxytocin in the PVN of animals with social deficits. However,

because oxytocin is a small peptide, it has a restricted ability to pene-

trate the brain after systemic administration, which potentially limits the

use of this peptide as a therapeutic agent. An alternative pathway that

overcomes this obstacle is to identify mechanisms to pharmacologically

activate brain neurons that produce oxytocin and bolster the release of

the endogenous peptide in brain centers regulating social function. Recent

findings from my laboratory demonstrated the feasibility of using this ap-

proach in a neurodevelopmental animal model of schizophrenia. Together

evidence from preclinical and clinical studies identified oxytocin as an im-

portant component of the neurocircuit engaged during social activity and

that oxytocin-related mechanisms are impaired in psychiatric disorders

having a social withdrawal component. The ability to use oxytocin as a

prosocial therapeutic will require further investigation but the appropriate

groundwork now appears to be in place to justify studies with this goal.