Brain volume changes in the first year of illness and 5-year outcome of schizophrenia

Progressive brain volume changes have been reported in first-episode schizophrenia, but their relationship to the disease processor to other factors remains unclear. We examined such changesin the first year of illness, and related them to 5-year outcome.Progressive brain volume changes, in particular of grey matter,during the first year of illness were found to be significantlyassociated with clinical and functional outcome 5 years after the first episode. These findings suggest that early dynamicbrain volume changes are related to the disease process andpredict the longer-term outcome of schizophrenia.

INTRODUCTION

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INTRODUCTION

Through cross-sectional magnetic resonance imaging studies,it is now well established that brain volume reductions arepresent in schizophrenia (Wright et al, 2000). Were thesereductions to reflect the disease process, one would expectthem to mimic the clinical course and to be related to outcome.A cross-sectional magnetic resonance imaging study (van Haren et al, 2003)examined brain volume change as a predictor of outcome in recent-onsetschizophrenia, but did not find any associations between thestatic baseline brain volume measurements and clinical and functionaloutcomes after 2 years. As brain volume reductions have beenshown to be progressive (Cahn et al, 2002; Lieberman et al, 2005;Woods et al, 2005), dynamic brain volume changes, using twomagnetic resonance measurements, might be more informativein relation to clinical and functional outcome. In a similarstudy, we examined 34 people with first-episode schizophreniaat baseline and after 1 year and compared them with 36 healthy people. An accelerated decline in total brain volume and ingrey matter volume and an increase in lateral ventricle volumewere found in patients compared with healthy individuals (Cahn et al, 2002).These progressive changes were not associated with symptoms,but did predict functional outcome 2 years after the initial assessment. Thus, in contrast to static brain volumes, dynamicbrain measurements could be more useful in predicting outcomein schizophrenia. As the clinical course of schizophrenia reachesa plateau after about 5 years following the initial treatment(Davidson & McGlashan, 1997), the present study clinicallyreexamined the same individuals 5 years after the initial evaluation,using various outcome measures. It was hypothesised that earlybrain volume changes in schizophrenia predict the longer-termoutcome of the illness.

METHOD

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METHOD

Our initial study included 34 people with first-episode schizophrenia. After a mean follow-up period of 5.3 years (s.d.=0.8), threepatients refused further participation. The present study includedthe remaining 31 participants (27 men and 4 women), with amean age of 25.74 years (s.d.=4.88). Before inclusion, participantshad used no or little antipsychotic medication: mean lifetimedose 163.85 mg (s.d.=72.26) haloperidol equivalents. All participantsreceived a DSM–IV (American Psychiatric Association, 1994)diagnosis of schizophrenia (26) or schizoaffective disorder (5) and provided written informed consent.

Magnetic resonance images were acquired on a 1.5 Philips NTscanner and obtained at inclusion (T0) and after 1 year (T1).In-house developed software was used to measure mean (s.d.):total brain volume T0=1321.22 ml (108.57) and T1=1306.84 ml(113.66); grey matter T0=687.36 ml (50.29) and T1=668.91 ml (57.20); white matter T0=473.87 ml (64.06) and T1=476.06 ml(60.61); cerebellar T0=145.79 ml (11.99) and T1=147.04 ml (7.70);frontal lobe T0=291.86 ml (28.70) and T1=288.05 ml (23.11);lateral T0=14.84 ml (6.64) and T1=15.89 ml (7.70); and thirdventricle T0=0.84 ml (0.39) and T1=0.88 ml (0.37). Images werechecked and corrected manually if necessary. For a descriptionof procedure and segmentation, see Hulshoff Pol et al (2002).

Patients were assessed with the Positive and Negative SyndromeScale (PANSS; Kay et al, 1987), mean (s.d.) at: T0 positivesymptoms 18.24 (5.77) and negative symptoms 18.90 (6.55); T1positive symptoms 12.93 (4.61) and negative symptoms 15.40(5.20); and T5 (5 years) positive symptoms 14.13 (5.71) and negative symptoms 15.38 (7.13). The Camberwell Assessment ofNeed (CAN; Phelan et al, 1995) mean (s.d.) was obtained after2 years of follow up (T2): number of met and unmet needs 5.97(3.77); and at T5: number of met and unmet needs 9.48 (6.61). In addition, Global Assessment of Functioning (GAF; American Psychiatric Association, 1994)mean (s.d.) 53.61 (21.57); and the assessment whether patientslived independently or not: (yes=17; no=14); were obtained atT5. Negative and positive PANSS symptom scores at T5 were usedas measures of clinical outcome. Scores on the CAN, GAF andthe assessment whether patients lived independently or notwere used as measures of functional outcome.

To assess whether dynamic brain volume changes in the firstyear predict the 5-year clinical and functional outcome, linearregression analyses were performed with the unstandardisedregression coefficient (ß) representing the outcomescore per millilitre volume change. Brain volume change (T0to T1) of the various brain structures entered the analysesas predictor variables, with age and intracranial volume ascovariates. As progressive brain volume change might have commencedbefore T0, baseline measures of the brain structures also enteredthe analyses as covariates. The various clinical and functionaloutcome scores obtained at T5 entered the analyses as dependent variables separately. Since clinical outcome might be variableinitially but could stabilise over time, the same analyseswere done with changes in PANSS scores (T1 to T5) as dependentvariables. To assess whether clinical decline is progressive,paired-sample t-tests were performed with PANSS scores (T1to T5) and CAN scores (T2 to T5) as paired variables.

RESULTS

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RESULTS

A greater total brain volume decrease in the first year predicteda higher negative symptom score on PANSS (ß=–0.1,t=–2.51, P=0.02) and a lesser likelihood of living independently (ß=–0.01, t= –2.29, P=0.03) at 5-year follow up.

A greater grey matter volume decrease in the first year predicteda higher positive symptom score (ß=–0.09, t=–2.29, P= –0.03), a higher negative symptom score (ß=–0.16, t=–3.38, P=0.002) (Fig. 1a), a lower GAF score (ß=0.40,t=2.79, P= 0.01) and a lesser likelihood of living independently(ß=–0.01, t=–3.94, P=0.001) (Fig. 1b)at T5.

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Fig. 1 Progressive brain volume changes in the first year predict 5-year outcome in schizophrenia. T0, baseline, T1, follow up at 1 year, T5, follow up 5 years. (a) Change in grey matter (T0–T1) and negative symptoms as measured with the Positive and Negative Syndrome Scale (T5). (b) Change in grey matter (T0–T1) and living independently (T5). (c) Change in lateral ventricle volume (T0–T1) and need of care measured with the Camberwell Assessment of Need (T5).

A greater white matter volume increase in the first year predictedhigher positive symptom score (ß=0.09, t=2.29, P=0.03)at T5.

A greater lateral ventricle volume increase in the first yearpredicted a greater number of met and unmet needs (ß=1.47,t=2.82, P=0.009) (Fig. 1c) as measured with the CAN and alesser likelihood to live independently (ß=–1.0,t=–2.31, P=0.03) at T5. A greater cerebellar volume decreasein the first year predicted a higher negative symptom score(ß=–0.79, t= –2.24, P=0.03) at T5.

Frontal lobe and third ventricle volume change did not predictoutcome. A greater grey matter (ß=–0.12, t=–2.8, P=0.009) and cerebellar (ß–0.68, t=–2.43, P=0.02) volume decrease in the first year predicted a greater increase in the negative symptom score of the PANSS (T1 toT5). A greater white matter increase (ß=0.19, t=3.12,P=0.004) predicted a greater increase in the positive symptomscore of the PANSS. There was no significant increase in symptomsas measured with PANSS between T1 and T5, but total CAN scoressignificantly increased (t=3.24, d.f.=27, P=0.003) betweenT2 and T5.

DISCUSSION

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DISCUSSION

This study found that early progressive brain volume changesin the first year can predict the 5-year outcome of schizophrenia.Those patients who had the largest decrease in grey matterin the first year had the highest negative symptom scores andwere less likely to live independently 5 years after the firstevaluation. Thus, it appears that early dynamic brain changesare not only associated with symptomatic outcome but also withfunctional outcome. Furthermore, these findings suggest thatbrain changes in the early stages of schizophrenia are relatedto the disease process and are clinically relevant in determiningprognosis, and they emphasise the importance of early interventionin the treatment of schizophrenia, aiming to slow down or stop progressive brain volume loss.

This view is strengthened by another longitudinal magnetic resonancestudy that examined dynamic brain volume changes in peopleat very high risk of developing schizophrenia (Pantelis et al, 2003).This study reported progressive grey matter decrease in very-high-riskindividuals who developed a psychotic illness within 12 months.None the less, whether these early progressive brain volume changes in prodromal and first-episode schizophrenia are causedby the disease itself or are a consequence of the disease (andits treatment) still remains unanswered. The treatment of schizophreniashould focus on slowing this early progressive brain loss,with the goal of affecting the clinical course favourably.

REFERENCES

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