Extracting spurious messages from noise and risk of schizophrenia-spectrum disorders in a prodromal population

Atendency to extract spurious, message-like meaning from meaninglessnoise was assessed as a risk factor leading to shizophrenia-spectrumdisorders by assessing word length of speech illusions elicitedby multispeaker babble in 43 people with prodromal symptoms.These individuals were randomised to olanzapine v. placebogroups during year 1 followed by no pharmacological treatmentfor those with no disorder conversion during year 2. A time-dependentCox regression analysis of conversion to schizophrenia-spectrumdisorder revealed a significant interaction between condition(olanzapine v. no drug) and length of speech illusion, with the latter strongly predicting subsequent conversion duringmedication-free intervals but not during olanzapine treatment.

INTRODUCTION

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INTRODUCTION

Assessments of prodromal symptoms that identify individualsat high risk of conversion to psychosis – namely 25–35%within 1 year – have been reported (McGorry et al, 2002;McGlashan et al, 2006). Factors prompting conversion to schizophrenia-spectrum disorders within this group remain poorly understood, however.

A speech perception study comparing patients with schizophrenia-spectrum disorder with and without auditory hallucinations and normalcontrols (Hoffman et al, 1999) included a task requestingparticipants to report any words or phrases ‘heard’in response to multispeaker babble. This task did not producedifferences between those who experienced hallucinations v. those who did not, as predicted. However, more extended, multiwordspeech illusions emerged in patients with early-phase, schizophreniformpsychosis compared with both normal controls and patients withestablished schizophrenia (further details available from theauthors). We consequently developed the hypothesis that extendedspeech illusions detected in response to multispeaker babblereflect a general tendency to extract spurious, message-likemeaning in response to objectively meaningless sensory information,which, over time, can produce a ‘matrix of unreality’,prompting the initial psychotic phase of schizophrenia-spectrumdisorders.

METHOD

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METHOD

Our hypothesis was tested prospectively using data collectedfor the multisite North America Prevention Through Risk Identification,Management and Education (PRIME) clinical trial (McGlashan et al, 2006).This trial enrolled people with operationally defined syndromesprodromal for psychosis consisting of attenuated positive symptoms,or genetic risk plus deterioration (schizotypal personalitydisorder and/or first-degree relative with psychosis, plus recent loss of social and/or work capacity with a drop of 30 percentagepoints on the Global Assessment of Functioning sustained forat least 1 month). Participants, who had no prior lifetimehistory of a psychosis or schizophrenia diagnosis, were randomlyallocated to receive either olanzapine (5–15 mg per day)or placebo for 1 year during the double-blind phase of thestudy. Those whose disorder did not convert to psychosis wereinvited to remain in the study for a second year with no pharmacologicaltreatment. Those whose disorder converted to sustained psychosiswere switched to a 6-month ‘rescue’ arm using open-labelolanzapine. All participants provided written informed consent.

We focused on conversion to schizophrenia-spectrum disorder(schizophrenia or schizophreniform disorder) rather than onpsychosis broadly defined, given our expectation that specificrisk factors would be more likely to cluster within this moreuniformly defined and stable diagnostic group (Correll et al, 2005). Diagnosis was determined using the Comprehensive Assessmentof Symptoms and History (CASH; Andreasen, 1987). Out of 60patients with prodromal symptoms enrolled in the trial, 44were assessed using the ‘babble’ task, because some study sites did not administer the task. This subgroup includedone patient exhibiting a psychotic decompensation who was notassessed diagnostically and whose data were consequently droppedfrom this conversion analysis. Among the remaining 43 patients,10 experienced conversion to a schizophrenia-spectrum disorderduring year 1, and 2 patients’ condition converted duringyear 2 to a schizophrenia-spectrum disorder following drugor placebo discontinuation.

The babble stimulus derived from overlapping recordings of sixspeakers (three women, three men) reading neutral texts. Twodifferent speech segments from each speaker were mixed, yielding12 simultaneous streams of speech heard binaurally using headphones.This verbal stimulus was designed to produce a high densityof phonetic information rendering corresponding words virtually undetectable. Stimulus duration was 2 min 33 s. Participantswere instructed to repeat any words or phrases that they ‘heard’while listening to the babble. Only four words (‘increase’, ‘children’, ‘A–OK’, and ‘Republican’)were consistently reproduced across participants in this task.Tape-recordings of responses were transcribed for analysis.The longest phrase generated (counted as the number of words)constituted the length of speech illusion (LSI) score. Interraterreliability for this measure was high (R_I=0.98). Examples ofresponses are given below:

‘another...the children’ (LSI 2; placebo group member,no conversion);
‘bombing...the administration...seemto be having trouble...the ball...the republicans...it’simportant to...the ball...practice dancing...’ (LSI=5;placebo group member, conversion).

The babble task was administered as part of a neuropsychologicalbattery administered at baseline, 6 months and 1 year. Analysesof other neuropsychological test data were exploratory andhypothesis-generating. Patients also received serial clinicalassessments using the Positive and Negative Syndrome Scale(PANSS; Kay et al, 1987).

RESULTS

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RESULTS

In order to undertake a time-dependent assessment of conversionrisk, data for the year 1 placebo and year 2 drug discontinuationphases of the study were analysed together as a single ‘nodrug’ condition that was compared with the olanzapinecondition using a Cox regression analysis. Overall, the associationbetween LSI and subsequent conversion risk was nonsignificant(hazard ratio (HR) 1.28, 95% CI 0.93–1.75, P=0.13). However,the interaction between LSI and condition was statisticallysignificant (HR=0.51, 95% CI 0.27–0.95, P=0.035). Forthe no-drug condition alone, LSI was robustly associated withsubsequent conversion (HR=1.78, 95% CI 1.26–2.53, P=0.0011),whereas for the olanzapine condition this association was absent(HR=0.92, 95% CI 0.55–1.55, P=0.75). An identical time-dependenceanalysis of concurrent composite PANSS positive, negative andgeneral psychopathology symptoms revealed no significant associationwith subsequent conversion (HR range 1.05–1.12, P range0.09–0.38), including when analysing data for the no-drugcondition alone (HR range 1.03–1.07, P range 0.30–0.51).

The capacity of LSI scores to predict subsequent conversionto schizophrenia-spectrum disorder during the no-drug conditionwas considered. Optimal classification accuracy was obtainedusing a cut-off of 4 or above for the maximum LSI score observedat the onset of and during no-drug periods to predict subsequentconversion. Overall classification accuracy was high (Fig. 1;Fisher’s exact test, P=0.0001; positive predictive value0.80, negative predictive value 0.94).

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Fig. 1 Maximum length of speech illusion (LSI) during ‘no drug’ intervals (placebo in year 1 or no pharmacological treatment in year 2) grouped according to those whose condition converted to a schizophrenia-spectrum disorder during these intervals and those who did not. The dashed line shows the optimum cut-off point for predicting conversion.

DISCUSSION

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DISCUSSION

Elevated LSI scores signalled subsequent increased risk of schizophrenia-spectrumdisorders when participants were not receiving olanzapine.In this condition, each unit increase in LSI score predictedan amplification of conversion risk of 78%. In contrast, concurrentcomposite symptoms measures did not signal subsequent riskof conversion when examined using the same analysis. Thesedata suggest that elevated LSI scores during the prodrome signalleda covert conversion risk unexpressed by concurrent symptoms.Elevated LSI scores observed in this study might have been causedby excessive top-down processing of phonetic inputs, distortedperceptual processing or misinterpretation of percepts. Extractingspurious messages from meaningless input by patients at riskmay extend beyond speech processing per se, as suggested bythe Nobel prizewinner John Nash, whose schizophrenic illnessemerged subsequent to his detecting ‘encrypted messages’embedded in letter patterns appearing in the New York Times,which he attributed to space aliens or foreign governments (Nasar, 1998).

The significant interaction between condition and LSI scoresreflected in the Cox regression analysis of conversion suggeststhat early administration of olanzapine reduced risk associatedwith elevated LSI scores.

The relatively small pool of prodromal patients reported hereunderscores the need for further studies of spurious message-likemeaning induced by babble as a predictor of conversion to schizophrenia-spectrumdisorders. Confirmation that LSI predicts risk of conversion– and that antipsychotic drugs reduce this risk –would be an important advance insofar as serial LSI assessmentsmight then be used to identify the patients with prodromalsymptoms most likely to benefit from preventive drug therapy.

REFERENCES

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