S36 Abstracts of the 4th Biennial Schizophrenia International Research Conference / Schizophrenia Research 153, Supplement 1 (2014) S1–S384

in complex neuropsychiatric disease versus health, however, have remained

unclear. We tested sera of 2817 subjects (1325 healthy, 1081 schizophrenic,

263 Parkinson and 148 affective-disorder subjects) for presence of NMDAR-

AB, conducted a genome-wide genetic association study (GWAS), comparing

AB-carriers versus non-carriers, and assessed their influenza AB status. For

mechanistic insight and documentation of AB functionality, in vivo ex-

periments involving mice with deficient blood-brain-barrier (ApoE−/−) and

in vitro endocytosis assays in primary cortical neurons were performed.

In 10.5% of subjects, NMDAR-AB (NR1 subunit) of any immunoglobulin

isotype were detected, with no difference in seroprevalence, titer, or in

vitro functionality between patients and healthy controls. Administration

of extracted human serum to mice influenced basal and MK-801 induced

activity in the open field only in ApoE−/− mice injected with NMDAR-AB

positive serum but not in respective controls. Seropositive schizophrenic

patients with a history of neurotrauma or birth complications, indicating

an at least temporarily compromised blood-brain-barrier, had more neuro-

logical abnormalities than seronegative patients with comparable history.

A common genetic variant (rs524991, p=6.15E-08) as well as past influenza

A (p=0.024) or B (p=0.006) infection were identified as predisposing fac-

tors for NMDAR-AB seropositivity. The >10% overall seroprevalence of

NMDAR-AB of both healthy individuals and patients is unexpectedly high.

Clinical significance, however, apparently depends on association with past

or present perturbations of blood-brain-barrier function.

Symposium

RELAPSE – RISK AND PREVENTION

Chairpersons: Robert Zipursky and Robin Emsley

Discussant: S. Charles Schulz

Monday, 7 April 2014 4:15 PM – 6:15 PM

Overall Abstract: The treatment of schizophrenia can now be expected to

result in a remission of symptoms for a majority of people with schizophre-

nia. Relapses, however, are very common and are often considered to be

an expected characteristic of the natural course of the illness. The risk of

relapse and the extent to which they may be preventable has been the

subject of much ongoing research. This symposium will focus on research

that has addressed key questions about the risk of relapse, the causes and

predictors of relapse, as well as methodological and ethical considerations

in studying relapse. Relapses may occur for a myriad of reasons. Some may

be a manifestation of the underlying biology of schizophrenia while others

may be better understood as a reflection of factors indirectly associated

with illness such as non-adherence to treatment and concurrent substance

abuse. Making the distinction between primary and secondary causes of

relapse has important implications for understanding and preventing re-

lapses. While maintenance treatment with antipsychotic medication has

been considered to be a mainstay for relapse prevention, little is known

about how much medication is required and how often it needs to be

administered to be effective. In a recent meta-analysis, relapse rates have

been estimated to be lower in patients receiving maintenance antipsychotic

treatment (27%) in comparison with those receiving placebo (64%). The

extent to which these estimates are affected by the degree of improvement

and the level of treatment adherence remains to be determined. A sys-

tematic review of antipsychotic discontinuation in stable remitted patients

who were treated for a first episode of non-affective psychosis will be pre-

sented. The estimated rate of symptom recurrence was found to be much

higher than previously described for those who discontinued medication

and much lower for those who continued treatment. The implications of

this finding for clinical care and for the design of future research will be

discussed. The high risk of relapse associated with the use of placebo in

medication discontinuation studies raises important ethical considerations

for future research. Little is known about either the short-term or long-term

consequences of relapse. The distress experienced by those affected directly

and indirectly may be considerable. The possibility that discontinuation

studies involving placebo assignment may result in long-term harm cannot

yet be excluded. The design of future studies will need to be informed by

this consideration. The identification of valid predictors of relapse would

be valuable in minimizing the risks associated with relapse in clinical

care and in the research setting. Research addressing this issue will be

described. Future studies of relapse, including its predictors, consequences

and prevention, will need to incorporate design features that ensure that

this research can be carried out in ways that are both safe and informative.

CAN THE ONGOING USE OF PLACEBO IN RELAPSE-PREVENTION CLINICAL

TRIALS IN SCHIZOPHRENIA BE JUSTIFIED?

Robin Emsley1, Wolfgang W. Wolfgang Fleischhacker2

1Stellenbosch University; 2Department of Biological Psychiatry, Innsbruck

University Clinics, Austria

Background: Placebo-controlled randomised controlled trials (RCTs) con-

tinue to be required or strongly recommended by regulatory authorities

for the licensing of new drugs for schizophrenia, despite concerns of risks

to trial participants. The risk is likely to be greatest in relapse-prevention

RCTs where patients are stabilized and then switched to placebo. Active

treatment is sometimes withheld for considerable periods, and substantial

numbers of relapse events need to occur before a treatment effect can be

statistically demonstrated.

Methods: In this presentation we systematically review the relapse-

prevention RCTs with second-generation antipsychotics (SGAs) in

schizophrenia and examine the risks of harm associated with exposure

to placebo in such trials. Results are interpreted in the context of ethical

and scientific pros and cons and current regulatory guidelines.

Results: We identified 12 studies involving 2842 participants of which 968

received placebo. Relapse rates were 56% for placebo and 17.4% for active

treatment groups. Only one of the studies investigated the consequences

of relapse, in a post-hoc analysis. There is a lack of well-designed longi-

tudinal studies investigating the psychosocial and biological consequences

of exposure to placebo, to treatment discontinuation and to relapse in

schizophrenia.

Discussion: In the absence of such studies it is risky to assume that patients

experiencing relapses are not at risk of significant distress or lasting harm,

and it is difficult to justify the on-going use of placebo in relapse-prevention

trials in schizophrenia, particularly in view of the difficulties in identify-

ing early warning signs and the ineffectualness of rescue medication in

preventing full-blown relapse.

ARE THERE CLINICALLY USEFUL PREDICTORS AND EARLY WARNING

SIGNS FOR RELAPSE IN SCHIZOPHRENIA?

Wolfgang Gaebel

Heinrich-Heine-University Duesseldorf, Dept. of Psychiatry and Psychotherapy

Background: Despite the availability of effective long-term treatment

strategies in schizophrenia, relapse is still common. Relapse prevention is

one of the major treatment objectives, because relapse represents burden

and costs for patients, their environment, and society and seems to in-

crease illness progression at the biological level. Valid predictors for relapse

are urgently needed to enable more individualized recommendations and

treatment decisions to be made.

Methods: Mainly recent evidence regarding predictors and early warning

signs of relapse in schizophrenia will be reviewed. In addition, data from the

first-episode (long-term) study (FES; Gaebel et al. 2007, 2011) performed

within the German Research Network on Schizophrenia will be presented.

Results: On the basis of FES data, premorbid adjustment, residual symptoms

and some side effects are significant predictors. Although a broad spectrum

of potential parameters have been investigated in several other studies,

only a few and rather general valid predictors were identified consistently.

Data of the FES also indicated that predictive power could be enhanced

by considering interacting factors, as suggested by the vulnerability-stress-

coping model. Respective studies, however, are rare. In addition, prodromal

symptoms as course-related characteristics likewise investigated in the FES

add substantially to early recognition of relapse and may serve as early

warning signs, but prediction nevertheless remains a challenge.

Discussion: Comprehensive and well-designed studies are needed to iden-

tify and confirm valid predictors for relapse in schizophrenia. In this respect,

broadly accepted and specifically defined criteria for relapse would greatly

facilitate comparison of results across studies.

References:[1] Gaebel et al. (2007) Maintenance treatment with risperidone or low-dose

Abstracts of the 4th Biennial Schizophrenia International Research Conference / Schizophrenia Research 153, Supplement 1 (2014) S1–S384 S37

haloperidol in first-episode schizophrenia. One-year results of a randomized con-

trolled trial within the German Research Network on Schizophrenia. J. Clin. Psy-

chiatry. 68, 11, 1763-1774.

[2] Gaebel et al. (2011). Relapse prevention in first-episode schizophrenia: Mainte-

nance vs. intermittent drug treatment with prodrome-based early intervention.

Results of a randomized controlled trial within the German Research Network on

Schizophrenia. J. Clin. Psychiatry. 72, 205-18.

[3] Gaebel & Riesbeck (2013). Are there clinically useful predictors and early warning

signs for pending relapse? Schizophr Res [Epub ahead of print].

PATTERNS OF RESPONSE AND THE NEUROBIOLOGY OF RELAPSE IN

SCHIZOPHRENIA

Ofer Agid1, Cynthia Siu2, Gary Remington3,4

1University of Toronto; 2Data Power (DP), Inc; 3Department of Psychiatry,

Univerity of Toronto; 4Centre for Addiction and Mental Health, Toronto, ON,

Canada

Background: Dopamine’s proposed role in psychosis provides a starting

point for our understanding of the neurobiology of relapse in schizophrenia.

While perturbations in dopamine have been proposed as the final common

pathway in psychosis, it is evident that relapse, like response, cannot be

conceptualized as a singular process. Similarly, the relationship between

response and relapse appears to be multidimensional, with patterns of

response defining relapse, and trajectories of response translating to dif-

ferent trajectories of relapse. Relapse can be defined as either primary (i.e.

idiopathic) or secondary (e.g. substance abuse, medication non-adherence).

Primary relapse occurs in the absence of clear precipitants and thus may

better reflect the biology that underlies schizophrenia. Evidence suggests,

however, that secondary relapse is more common and may be associated

with a more attenuated response to antipsychotics than found in the

treatment of the initial episode of psychosis.

Methods: Antipsychotic-naïve individuals diagnosed with first-episode

schizophrenia were treated following an algorithm that involved treat-

ment with risperidone or olanzapine. Each trial consisted of 3 stages (low,

full, or high-dose) lasting up to 4 weeks at each level and adjusted according

to response and tolerability. Clinical response was defined as resulting in

a Clinical Global Impression Inventory - Improvement (CGI-I) of “much” or

“very much improved”, or a Brief Psychiatric Rating Scale (BPRS) Thought

Disorder subscale of <6. Clinical data was collected on a monthly basis

over a period of 6 months. In the case of relapse due to non-adherence,

the same medication and dose where response was previously noted was

offered again for the second episode. Results A total of 38 individuals (82%

male; average age=22) reached that point following treatment with the

first antipsychotic where they met criteria for response. Over a period of 2

years, each of these individuals relapsed due to non-adherence and went

through a second trial with the same treatment. We observed that the BPRS

(total/core psychosis scale) improvement was significantly greater for the

first episode compared to the second episode at every time point over the

first 6 months of treatment. The shape of trajectory was, however, similar

for both first and second episodes.

Discussion: Reinitiating antipsychotic treatment for a second episode of

psychosis was found to be associated with an attenuated response to

antipsychotic medication. This finding raises questions about the nature of

changes that may be taking place in the dopamine system in patients who

have relapsed after discontinuing their antipsychotic medication. Whether

this observation reflects the progression of biological changes associated

schizophrenia or the impact of previous treatment or its withdrawal is not

yet understood. The doses of antipsychotic medication and the frequency

of administration required to prevent relapse also remains to be elucidated.

In a recent 6-month placebo-controlled trial, we found that administering

antipsychotic medication on alternating days was not associated with an

increased risk of relapse. These lines of evidence raise a number of impor-

tant questions about the prevention and treatment of psychotic relapses.

Our results challenge the assumption that sustained D2 antagonism is the

singular requirement for preventing relapse and the expectation that rein-

stituting the previous level of D2 antagonism is likely to result in a return

to a remitted state. Taken together, these findings indicate that response

and relapse must be viewed as multidimensional and are likely mediated

by distinct mechanisms.

RISK OF SYMPTOM RECURRENCE WITH MEDICATION DISCONTINUATION

IN FIRST-EPISODE PSYCHOSIS: A SYSTEMATIC REVIEW

Robert Zipursky, Natasja M. Menezes, David L. Streiner

Department of Psychiatry and Behavioural Neurosciences, McMaster University

Background: The large majority of individuals with a first episode of

schizophrenia will experience a remission of symptoms within their first

year of treatment. It is not clear how long treatment with antipsychotic

medications should be continued in this situation. The possibility that a

percentage of patients may not require ongoing treatment and may be

unnecessarily exposed to the long-term risks of antipsychotic medications

has led to the development of a number of studies to address this question.

Methods: We carried out a systematic review to determine the risk

of experiencing a recurrence of psychotic symptoms in individuals who

have discontinued antipsychotic medications after achieving symptomatic

remission from a first episode of non-affective psychosis (FEP).

Results: Six studies were identified that met our criteria and these reported

a weighted mean one-year recurrence rate of 77% following discontinuation

of antipsychotic medication. By two years, the risk of recurrence had in-

creased to over 90%. By comparison, we estimated the one-year recurrence

rate for patients who continued antipsychotic medication to be 3%.

Discussion: These findings suggest that in the absence of uncertainty about

the diagnosis or concerns about the contribution of medication side effects

to problems with health or functioning, a trial off of antipsychotic medica-

tions is associated with a very high risk of symptom recurrence and should

thus not be recommended.

Symposium

REWARD PROCESSING, COGNITION AND PERCEPTION DURING

ADOLESCENT BRAIN DEVELOPMENT AND VULNERABILITY FOR

PSYCHOSIS

Chairpersons: Richard S.E. Keefe and Bita Moghaddam

Discussant: Philip McGuire

Monday, 7 April 2014 4:15 PM – 6:15 PM

Overall Abstract: Adolescence is a stage in which many neural processes

are still maturing. Brain networks involved in context-based perception

and reward processing are in frequent transition during this critical devel-

opmental stage. Although psychosis does not usually emerge until young

adulthood, subtle neurobiological changes and the cognitive and behavioral

manifestations of these changes may be present during adolescence. It

is thus important to determine to what extent an abnormal maturation

of reward networks contributes to these conditions. Social interaction,

development of perceptual systems, and processing of rewarding infor-

mation may have a strong impact on sculpting these circuits during

adolescence. Cortical inhibitory processes that are essential for response

selection and error detection may not be mature during adolescence. Al-

terations in the maturation of these processes may lead to vulnerability

for psychosis. Bita Moghaddam will present single unit and local field

potential data suggesting that during value processing and reinforcement

expectation tasks, adolescent rats had local field potentials demonstrating

that adolescent phasic neural activity is less inhibited and more vari-

able during motivated/reward-driven behaviors. Specifically, diminished

inhibitory response of orbitofrontal cortex neurons to salient events and

the accompanying detrimental impact on coordinated large-scale activity

may lead to reduced efficiency in the processing of cortical neural activity

and related behaviors in adolescents. Alison Adcock will present fMRI data

from young healthy subjects and ultra high risk participants suggesting

a directional prefrontal influence on dopaminergic regions during reward

anticipation. These data suggest a model in which the dlPFC integrates and

transmits representations of reward to the mesolimbic and mesocortical

dopamine systems, thereby initiating motivated behavior. Hypoactivation

in the high-risk group during reward anticipation may be explained by fail-

ures in prefrontal regulation of mesolimbic systems. Markus Leweke will

present data suggesting that the failures of these neural systems may be

evident in basic measures of perceptual integration assessed with binocular

depth inversion methodology. These perceptual-cognitive measures may

be impaired very early in the disease process in individuals who will later