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Negative symptoms and functioning during the first year after a recent onset of schizophrenia and 8 years later

Schizophrenia Research, 2-3, 161, pages 407 - 413

Abstract

Background

Understanding the longitudinal course of negative symptoms, especially in relationship to functioning, in the early phase of schizophrenia is crucial to developing intervention approaches. The course of negative symptoms and daily functioning was examined over a 1-year period following a recent onset of schizophrenia and at an 8-year follow-up point.

Methods

The study included 149 recent-onset schizophrenia patients who had a mean age of 23.7 (SD = 4.4) years and mean education of 12.9 (SD = 2.2) years. Negative symptom (BPRS and SANS) and functional outcome (SCORS) assessments were conducted frequently by trained raters.

Results

After antipsychotic medication stabilization, negative symptoms during the first outpatient year were moderately stable (BPRS ICC = 0.64 and SANS ICC = 0.66). Despite this overall moderate stability, 24% of patients experienced at least one period of negative symptoms exacerbation. Furthermore, entry level of negative symptoms was significantly associated with poor social functioning (r = − .34,p < .01) and work/school functioning (r = − .25,p < .05) at 12 months, and with negative symptoms at the 8-year follow-up (r = .29,p < .05).

Discussion

Early negative symptoms are fairly stable during the first outpatient year, are predictors of daily functioning at 12 months, and predict negative symptoms 8 years later. Despite the high levels of stability, negative symptoms did fluctuate in a subsample of patients. These findings suggest that negative symptoms may be an important early course target for intervention aimed at promoting recovery.

Keywords: Schizophrenia, Negative symptoms, Long-term follow-up, Functional outcome, Symptom exacerbation, Intraclass correlation coefficient, BPRS, SANS.

1. Introduction

Recently, there has been a rather large resurgence of interest in virtually all aspects of negative symptoms, most likely fueled by the robust and consistent finding that negative symptoms are linked to a variety of central features of schizophrenia. Specifically, the current direction of findings in early course patients parallels findings in chronic patients that negative symptoms are prevalent (57% had at least one), persistent, and have an adverse impact on functioning ( Bobes et al., 2010 ). The evidence is mounting that, even in first episode patients, negative symptoms are often a core feature. Like cognitive deficits, negative symptoms have prognostic importance, are associated with poor functioning, and have been shown to have their onset prior to the emergence of positive symptoms ( Harvey et al., 2006 ). Despite their central role in the illness, negative symptoms have proven to be resistant to psychopharmalogical treatment with currently available medications. In fact, treating negative symptoms in schizophrenia patients with the aim of achieving sustained periods of remission can very challenging ( Levine and Leucht, 2013 ). There is an interest in knowing more about the nature and impact of negative symptoms because such findings may inform the search for new drugs and the development of psychosocial interventions. Knowing early prevalence rates, including the percentage of patients with clinically significant negative symptoms at baseline and persisting at various follow-up points, would help provide general benchmarks for identifying negative symptom severity.

Follow-up studies of early course patients, although few in number, found that negative symptoms are present at baseline, tend to be stable and persistent, but can fluctuate in severity. The negative symptom assessments for most of those studies have been cross-sectional in nature, covering about a 1-week to 1-month period. The percentages of patients with clinically significant negative symptoms at baseline ranged from substantial to very substantial: 25.8%, 33%, and 71% (Chang et al, 2011, Evensen et al, 2012, and Galderisi et al, 2013), respectively. Prevalence rates of negative symptoms at 1-year and 3-year follow-up varied: 6.7%, 23.7%, 27% (Chang et al, 2011, Galderisi et al, 2013, and Hovington et al, 2012). These studies also suggest that early negative symptoms can persist, as they are present at subsequent follow-up points for up to 10 years ( Evensen et al., 2012 ) and might become more prevalent over time ( Chang et al., 2011 ). Differing definitions of negative symptoms and the cross-sectional assessment methodology used in most studies may have impacted these rates. Interestingly, a persisting negative symptom of rate of 20% has been reported in the same patients at baseline and then again at 1-year ( Galderisi et al., 2013 ). However, baseline levels of negative symptoms can change ( Subotnik et al., 1998 ). When patients were followed for up to 10 years and flat affect was measured at various follow-up time points, symptoms were found to change from remitted to present, or, conversely, from present to remitted ( Evensen et al., 2012 ). The authors concluded that flat affect can fluctuate in as high as 40% of patients. However, fewer follow-through studies have been conducted in which relatively frequent assessments of negative symptoms were conducted.

Important predictive links have been found in the early course of schizophrenia, mostly indicating that higher negative symptom severity is associated with poor daily functioning and worse long-term outcomes (Chang et al, 2013, Evensen et al, 2012, Hovington et al, 2012, and White et al, 2009). Because cognition is a robust predictor of functioning, some studies have examined the differential impact of cognition and negative symptoms on outcome. Interestingly, negative symptoms can make a separate, non-overlapping contribution to the prediction of functioning, beyond the joint contribution with cognition (Henry et al, 2007, Milev, 2005, and Peña et al, 2012). In addition, a meta-analysis that focused primarily on studies of chronic patients indicated that negative symptoms mediated the relationship between neurocognition and functional outcome ( Ventura et al., 2009a ). This relationship has recently been observed in first episode patients cross sectionally and in a 5-year follow-up study, confirming the influence of negative symptoms on functioning (González-Ortega et al, 2012 and Lin et al, 2013). Further, the presence of negative symptoms at baseline has been proposed as a risk factor that contributes to the failure to achieve functional recovery (Albert et al, 2011, Leslie et al, 2004, and Siegel et al, 2006). Studies of first episode psychosis (FEP) concurred with previous studies indicating that negative symptoms are a rate limiting factor that often accounts for absence of functional recovery in schizophrenia patients (Leslie et al, 2004, Savla et al, 2013, and Ventura et al, 2011). There is very strong support for the importance of negative symptoms in the early course of schizophrenia in that negative symptoms, whether they were present at baseline, were stable or persisting, or acted as a mediator, have a broad influence on functional outcome. However, most of the studies used a follow-up design, rather than a design in which patients were continuously treated, assessed, and then followed-up.

We aimed to examine the following in recent-onset schizophrenia patients: (1) the prevalence rates of negative symptoms at baseline, (2) the stability of negative symptoms in a first follow-through year and at 8-year follow-up point, (3) the percentage of patients who show a remitting and relapsing negative symptom course similar to positive symptoms, and (4) the relationships between negative symptoms and daily functioning.

2. Methods

2.1. Subjects

The sample involved 149 schizophrenia patients who had an initial onset of psychosis within 2 years prior to study entry, 82% of whom were experiencing a first episode. Subsamples were used to address some questions, as the number of subjects varied with available data of a given type. All subjects were participants in Samples 1 and 2 of the Developmental Processes in Schizophrenic Disorders Project and were followed clinically in the UCLA Aftercare Research Program, which specializes in the treatment of recent-onset schizophrenia patients. The demographic and diagnostic characteristics of the combined sample as well as medication dose in chlorpromazine equivalents ( Andreasen et al., 2010 ) are provided in Table 1 .

Table 1 Sample characteristics at study entry for recent-onset schizophrenia patients.

  Sample 1 at baseline (n = 102) Sample 2 at baseline (n = 47) Difference Samples 1 and 2 combined (n = 149)
Mean age (SD) 23.4 (4.4) 25.0 (5.3) F(1,148) = 3.92, p = .05 23.7 (4.45)
Mean education (SD) 12.4 (2.1) 13.5 (2.1) F(1,147) = 8.2, p < .01 12.91 (2.2)
Gender 84 (82%) 33 (70%) χ2(1) = 2.7, p = .10 117 (78%)
Marital status        
 Single 93 (91%) 41 (87%) χ2(3) = 5.81, p = .181 134 (90%)
 Married 4 (4%) 4 (8%) 8 (5%)
 Divorced 1 (1) 2 (4%) 3 (2%)
 Separated 4 (4%) 0 4 (3%)
Race        
 Caucasian 95 (93%) 23 (50%) χ2(3) = 53.8, p < .01 118 (79%)
 Asian 3 (3%) 5 (11%) 8 (5%)
 Native American/Pacific 0 0 0
 Islander      
 African American 0 13 (28%) 13 (9%)
 Other 4 (4%) 6 (13%) 10 (3%)
Diagnosis        
 Schizophrenia 61 (59%) 35 (74%) χ2(3) = 11.2, p < .01 95 (64%)
 Schizoaffective 8 (8%) 6 (13% 14 (10%)
 Schizophreniform 33 (33%) 5 (11%) 38 (26%)
 Other psychotic disorder   1 (2%) 1 (1%)
Number of months (mean, SD) since psychosis onset, including prodrome, at study entry 6.8 (7.1) 8.0 (6.8) F(1,143) = 1.0, p = .32 9.08 (8.63)
Chlorpromazine equivalent dosage, mg (mean, SD) 137.4 (110.1) 275.6 (126.9) F(1,94) = 23.4, p < .01 166.22 (126.38)

The patient characteristics and research protocols for Samples 1 and 2 are described in detail elsewhere and hence will only be briefly reviewed in this study (Nuechterlein et al, 1992 and Nuechterlein et al, 2011). For both samples, diagnostic, demographic, psychiatric, and social history data were collected at study entry, usually immediately following a psychiatric hospitalization. All raters were trained to criterion levels of interrater reliability and administered either an expanded version of the Present State Exam ( Wing et al. 1974 ) or the Structured Diagnostic Interview for DSM-IV (SCID) to determine the diagnosis ( First et al., 1996 ). After discharge from the index hospitalization, the patients were treated during their first outpatient year by a team of psychiatrists, psychologists, and social workers. Outpatient medication stabilization (but not necessarily clinical remission) was established on average 3 months after hospital discharge. All patients completed an informed consent process and signed UCLA IRB-approved informed consent documents.

2.2. Procedures

2.2.1. Treatment protocols
2.2.1.1. Sample 1

Sample 1 (n = 102) included patients who received individual and group therapy conducted by a case manager focusing on social skills and psychoeducation while working within the context of a treatment team. Patients were initially seen weekly by their case manager and psychiatrist and then at 2-week intervals. Family members were provided with psychoeducation. Medication treatment for all patients involved the administration of a standard starting dosage of injectable maintenance antipsychotic medication, 12.5 mg fluphenazine decanoate every 2 weeks, with adjustments within the 6.25 mg to 12.5 mg range if intolerable side effects developed. Dosages above 12.5 mg were given if clinically necessary to control psychotic symptoms. Of the 102 patients in Sample 1, 53 were reassessed at a follow-up point 8 years later ( Table 2 ), an attrition rate of 48%. Patients successfully assessed after 8 years were generally demographically similar to those who could not be located and assessed at 8 years, except that those assessed were somewhat more likely to be single at baseline.

Table 2 Sample characteristics at study entry for recent-onset schizophrenia patients who were assessed 8 years later (n = 53).

  Baseline characteristics for patients who were assessed at follow-up (n = 53) Baseline characteristics for patients who were not assessed (n = 49) Difference
Mean age (SD) 23.2 (3.6) 23.6 (5.2) F(1,103) = .32, p = .75
Mean education (SD) 12.8 (2.0) 12.0 (2.2) F(1,103) = − 1.76. p = .08
Gender 44 (83 %) Male 38 (81%) Male χ2(1) = .08, p = .78
Marital status      
 Single 51 (96%) 40 (85%) χ2(3) = 8.9, p = .03
 Married 0 4 (9%)
 Divorced 1 (2%) 0
 Separated 1 (2%) 3 (6%)
Race      
 Caucasian 47 (89%) 39 (83%) χ2(3) = 3.1, p = .38
 Latino 2 (4%) 5 (11%)
 Asian 1 (2%) 2 (4%)
 Other 3 (6%) 1 (2%)
Diagnosis      
 Schizophrenia 33 (63%) 26 (55%) χ2(2) = .535, p = .53
 Schizoaffective 5 (9%) 3 (6%)
 Schizophreniform 15 (28%) 18 (38%)
Number of months (mean, SD) since psychosis onset, including prodrome, at study entry 8.2 (9.8) 8.0 (9.1) F(1, 101) = .35, p = .73
2.2.1.2. Sample 2

The research protocol, including entry criteria, assessment measures and procedures, and psychosocial treatments, etc., for Sample 2 (n = 48) was very similar to that of Sample 1. However, oral risperidone was used as the standardized initial antipsychotic medication. Dosage was set by the treating psychiatrist during the initial stabilization phase to optimize clinical response. Changes in antipsychotic medication could be made for lack of a therapeutic response or if intolerable side effects occurred. There was no attempt for follow-up at 8 years with the patients from Sample 2.

In both samples ( Table 1 ), we did not use specific work or school training or vocational rehabilitation interventions, such as individual placement and support ( Becker and Drake, 2003 ). Rather, patients were encouraged to use the Los Angeles County Vocational Rehabilitation Service after a period of convalescence.

2.2.2. Assessment protocol

Symptom assessments were conducted by trained raters during the index hospitalization and immediately after discharge, as well as from the initial point of outpatient medication stabilization. Raters were trained to conduct symptom assessments to a criterion ICC = .80 or greater and were entered into a quality assurance program to prevent rater drift ( Ventura et al., 1993a ). Symptoms were assessed every 2 weeks during the first outpatient year and once at the 8-year follow-up using the Brief Psychiatric Rating Scale ( Ventura et al., 1993b ). The full Schedule for Assessment of Negative Symptoms ( Andreasen, 1984 ) was added in the latter part of this study and was administered every 3 months to provide an assessment of a more complete range of negative symptoms. Functional assessments with the Strauss-Carpenter Outcome Scale ( Strauss and Carpenter, 1972 ) were completed at the outpatient stabilization baseline point, at 3 months, 6 months, 9 months, and 12 months and at an 8-year follow-up point.

2.2.3. Assessment measures
2.2.3.1. Psychiatric and social history schedule

Demographic information and premorbid history data were collected at intake using a structured form. Data included age, gender, patient level of education, first appearance of psychotic and prodromal symptoms, and prior psychiatric treatments including antipsychotic medications and hospitalizations.

2.2.4. Symptom assessment
2.2.4.1. Brief Psychiatric Rating Scale (BPRS)

Each BPRS rater achieved a median intraclass correlation coefficient (ICC) of .80 or higher across all items compared with the criterion ratings, and participated in a quality assurance program ( Ventura et al., 1993a ). Each patient was rated by a trained rater on an expanded version of the BPRS ( Lukoff et al., 1986 ) at the point of outpatient medication stabilization and every 2 weeks during the first post-hospitalization year.

2.2.4.2. Scale for the Assessment of Negative Symptoms (SANS)

Each month, trained raters administered the SANS, which is widely used to assess two negative symptom domains: (1) expressive symptoms, which consists of affective flatting (blunted affect) and alogia, and (2) experiential symptoms, which consists of avolition/apathy and asociality/anhedonia. The global ratings for each of these negative symptom domains were combined to create the SANS composite. The attention subscale was not included in these analyses due to the strong correlational relationship to cognitive functioning ( Andreasen et al., 2005 ).

2.2.5. Functional assessment
2.2.5.1. Strauss–Carpenter Outcome Rating Scale (SCORS)

This scale contains four discrete dimensions of outcome ( Strauss and Carpenter, 1972 ). Two were relevant to functional outcome: the frequency of social contacts and the amount of school or useful work participation. The SCORS was administered at the point of outpatient medication stabilization, every 3 months during the first out-patient year, and at the 8-year follow-up point. The assessment covered the period three-months prior to assessment.

2.2.6. Data analysis

For prediction of negative symptom stability and functional outcome at the 8-year point, we calculated negative symptom levels for each of three time periods during the first outpatient year: study entry (period immediately after an episode), medication stabilization (the period of initial medication stabilization on average 3 months post-hospitalization), and the 1-year average of negative symptoms across the first outpatient year after medication stabilization (months 0 to 12).

We calculated the stability of BPRS and SANS-rated negative symptoms obtained during the first outpatient year by using an ICC statistic from the statistical software program R. The ICC has advantages over a zero-order correlation coefficient in that it is adjusts for the effects of variability in scale measurement. The ICCs in this study were calculated following the methods of Bliese and Halverson (1998) , allowing for an unequal number of observations for the different subjects. From the BPRS, we examined a negative symptom factor that was composed of three symptoms: blunted affect, emotional withdrawal, and motor retardation. The results of most factor analyses of the BPRS show that these three items form a negative symptom factor ( Ventura et al., 2000 ). From the SANS, we used (1) expressive symptoms, (2) experiential symptoms, and (3) the SANS total score (without the attention domain).

Using the same BPRS ratings, another approach was used to examine the possible occurrence of periods of negative symptom exacerbation in the first outpatient year. We adapted a classification system developed for positive symptom episodes in order to identify periods of significant exacerbation, remission, and persisting negative symptoms ( Nuechterlein et al., 2006 ). This categorization involves explicit criteria for identifying significant fluctuations in symptoms over time, distinguishes among different types of relapsing outcomes, identifies individuals with gradual improvement of symptoms, and continuous remissions. It provides high interrater agreement.

To examine the domains of functional outcome, social functioning and employment/school functioning, we used ratings that were made for the period of 9–12 months and at the 8-year follow-up point. Hierarchical logistic regression was used to determine if the three negative symptom periods predicted the level of functional outcome at 9–12 months and at the 8-year follow-up point.

3. Results

3.1. Stability of negative symptoms during the first outpatient year

Negative symptoms assessed with the BPRS every 2 weeks from the point of outpatient stability to the 1-year point during the first outpatient year were moderately stable (ICC = .64; Table 3 ), as were the three negative symptoms that were included in the negative symptom factor. This analysis includedn = 119 patients who had between 11 and 53 BPRS assessments (M = 24.9; SD = 6.6) that covered between 284 and 432 outpatient days (M = 365; SD = 20.4). The total number of BPRS observations was 2,975.

Table 3 Stability of negative symptoms in the early course of schizophrenia over 1 year (n = 119).

Negative symptom assessment ICC statistic
BPRS Negative Symptom Factor .64
 Blunted affect .61
 Emotional withdrawal .53
 Motor retardation .63
SANS Negative Symptom Clusters .66
 Expressive negative symptoms .64
 Experiential negative symptoms .60

The pattern of stability for the SANS assessments was similar to the negative symptoms measured using the BPRS. We found that the three SANS negative symptom scores were stable: SANS negative symptom total score (ICC = .66), the expressive score (ICC = .64), and the SANS experiential score (ICC = .60).

3.2. Classifying periods of negative symptom exacerbation

Beyond the overall moderate stability of negative symptoms in the early course of schizophrenia, 24% of patients (36/149) had at least one period of negative symptom exacerbation that met criteria for one of the following: (1) remission followed by relapse, (2) remission followed by significant exacerbation, or (3) persisting symptoms followed by significant exacerbation. Of those 36 patients with a negative symptom exacerbation, 5% (7/149) of patients had two periods of negative symptom exacerbations within the first outpatient year. Thus, although negative symptoms appear to be moderately stable over time, a substantial subgroup of patients have periods of negative symptom exacerbations.

3.3. Relationship of negative symptoms to functional outcome rated during the first outpatient year

We note that the level of BPRS negative symptoms at study entry moderately predicted social functioning (r = − .34,p < .01) and work/school functioning (r = − .25,p < .05) at the 9- to 12-month follow-up point ( Table 4 ). Analyses with the SANS total score at study entry and medication stabilization suggest that negative symptoms predict work/school functioning (r = − .53,p < .01,r = − .62,p < .01, respectively) and, to a lesser extent, social functioning (r = − .23,p < .05) ( Table 4 ). However, these findings are based on a subsample of patients for whom the SANS was collected later in the study.

Table 4 Correlation from baseline negative symptoms to functional outcome at the 12-month point (n = 65).

Functional domains
Time period for negative symptoms Social functioning Work/school functioning
BPRS study entry − .34 lowastlowast − .25 lowast
BPRS medication stabilization − .38 lowastlowast − .13
BPRS 1-year average − .40 lowastlowast − .25 lowast
SANS study entry (n = 24) − .08 − .53 lowastlowast
SANS medication stabilization (n = 24) − .28 − .62 lowastlowast
SANS 1-year average (n = 24) − .23 lowast − .44 lowastlowast

lowast p < .05.

lowastlowast p < .01.

Note: Negative symptoms are rated from the BPRS and SANS; social functioning and work/school functioning are rated from the SCORS

3.4. Relationship of negative symptom severity during the first outpatient year to negative symptoms and functioning at the 8-year follow-up

The BPRS study entry and 1-year average negative symptom levels (M(SD) = 2.10(0.99) andM(SD) = 2.13(0.90), respectively) were significantly higher than the BPRS negative symptom levels at the 8-year follow-up point [M(SD) = 1.77(1.00) (n = 53),p = .05 andp = .02, respectively]. However, BPRS negative symptoms at the medication stabilization [M(SD) = 2.10 (1.60)] were not significantly different from negative symptom levels at the 8-year follow-up [M(SD) = 1.80(1.03) (n = 51),p = .10)]. For the SANS, negative symptom levels study entry [M(SD) = 2.58 (1.11) vs. 1.78 (1.13),F(1,18) = 2.49,p = .02], medication stabilization [M(SD) = 2.65 (0.81) vs. 1.90 (1.13),F(1,17) = 3.25,p = .01], and 1-year average [M(SD) = 2.20 (0.86),n = 23 vs. 1.71 (1.10),F(1,22) = 2.53,p = .02] were all significantly higher compared to the 8-year follow-up point.

The BPRS study entry level of negative symptoms was significantly predictive of the level of negative symptoms rated at the 8-year follow-up (r = .29,p = .02; Table 5 ). In addition, BPRS negative symptoms rated at medication stabilization and the 1-year average were both correlated at about the same magnitude with negative symptoms rated 8 years later, indicating that this relationship is moderately stable despite the long intervening interval ( Table 5 ). Although BPRS negative symptoms in the first year showed relationships to social and work/school functioning at 8 years that were in the expected direction, the correlations were not strong enough to reach statistical significance.

Table 5 Correlations between negative symptoms assessed during baseline and negative symptoms, social functioning, and work/school functioning at the 8-year follow-up point (n = 53).

Symptom and functional domains
Time period for negative symptoms BPRS negative symptoms SANS negative symptoms Social functioning Work/school functioning
BPRS study entry .29 lowast − .26 − .04
BPRS medication stabilization .31 lowast − .23 .10
BPRS 1-year average .32 lowast − .21 .04
SANS study entry (n = 19) .21 − .47 lowast − .12
SANS medication stabilization (n = 18) .54 lowast − .24 .08
SANS 1-year average (n = 24) .54 lowastlowast − .18 .06

lowast p < .05.

lowastlowast p < .01.

Note: Social functioning and work/school functioning were rated from the SCORS

Additional evidence for stability was found in that SANS negative symptom levels at medication stabilization (r = .54) and the 1-year average (r = .54) yielded somewhat higher correlations (than the BPRS) with negative symptoms 8 years later ( Table 5 ). However, the SANS involved a smaller sample size. Also, negative symptoms at study entry were significantly related to social functioning 8 years later (r = − .47).

3.5. Cross-sectional relationships between negative symptoms and functioning at the 8-year follow-up point

Cross-sectional relationships at the 8-year follow-up indicated moderate associations between BPRS negative symptoms and work/school functioning ( Table 6 ). There were no other statistically significant cross-sectional relationships between symptoms and functioning. However, cross-sectional relationships between SANS negative symptoms were stronger in magnitude than for the BPRS with both social functioning, and work/school functioning ( Table 6 ).

Table 6 Cross-sectional correlations between negative symptoms, social functioning, work/school functioning at the 8-year follow-up point (n = 53).

Functional domains
  Social functioning Work/school functioning
BPRS negative symptoms − .12 − .31 lowast
SANS negative symptoms (n = 35) − .35 lowast − .60 lowastlowast
Social functioning (n = 37) .12

lowast p < .05.

lowastlowast p < .01.

Note: Social functioning and work/school functioning were rated from the SCORS

3.6. BPRS negative symptom severity and medication dosage

We conducted an analysis of negative symptoms, including motor retardation, and mediation dose. Correlations were near zero between medication dose in chlorpromazine equivalents ( Andreasen et al., 2010 ) for the BPRS negative symptom factor (r = .00,p = .95) and for the BPRS item Motor Retardation (r = .08,p = .37), a BPRS symptom that has been linked to medication side effects. Similar results were found for medication dose and SANS Expressive (r = − .13,p = .39), SANS Experiential (r = − .26,p = .09), and SANS total (r = − .22,p = .15) symptoms, indicating that there were no statistically significant relationships with negative symptom severity.

4. Discussion

This is one of the few follow-through studies that evaluated the longitudinal stability of negative symptoms assessed regularly using two symptom measures (BPRS, SANS) administered to recent-onset schizophrenia patients during their first outpatient year. Analyses of BPRS and SANS ratings demonstrated that there was generally moderate stability of negative symptoms over the first outpatient year. When negative symptoms are present, they tend to remain present in patients, even when assessed frequently. In both the cross-sectional and longitudinal analyses, the severity of negative symptoms rated at baseline was moderately predictive of poor social and employment/school functioning during the first outpatient year. A significant level of negative symptom stability extended to the 8-year follow-up period, where despite the number of intervening years, negative symptom severity levels in the first year were correlated with negative symptom severity 8 years later. The implication of this observation is that negative symptoms do not appear to remit spontaneously. Although the impairments associated with negative symptoms identified in this study have previously been found in first-episode patients, this study is among the first to systematically examine longitudinal patterns of stability with follow-through assessments and to document marked fluctuations of negative symptoms.

Although negative symptoms are generally stable, to determine whether negative symptoms sometimes do show fluctuations similar to episodes of positive symptoms, we used a system that was previously developed for classifying positive symptom episodes. We found that a substantial subgroup of patients (24%) had periods of negative symptom change that were similar to positive symptom episodes. Interestingly, the percentage of early course patients (21%) that showed positive symptom exacerbations ( Nuechterlein et al., 2006 ) is very similar to the percentage that show negative symptom exacerbations (24%). This similarity, as well as the fluctuating nature of negative symptoms, suggests that attempts to determine triggers of these exacerbations might prove fruitful. There are several possibilities to explore, such as stressful life events ( Ventura et al., 1989 ), periods of medication non-compliance ( Subotnik et al., 2011 ), or exacerbations of positive symptoms ( Ventura et al., 2004 ). Considering that this is a rather newly observed phenomenon, additional research is needed to determine likelihood and relevance of these possible contributors to negative symptom exacerbations.

In the first outpatient year, we found that negative symptom level was significantly correlated with social functioning, which is consistent with prior studies showing that even early in the course, negative symptoms adversely impact functioning ( Evensen et al., 2012 ). In addition, we found that negative symptom severity was associated with poor employment and school functioning. Perhaps the lack of motivation (avolition) and social withdrawal that is associated with negative symptoms contributes to poor work functioning and school performance. This is consistent with a large literature in chronic schizophrenia indicating the strong association between negative symptoms and functioning ( Ventura et al., 2009b ). For the 8-year follow-up, cross-sectional relationships between negative symptoms and work/school functioning were similar to those rated during the first outpatient year. Current levels of negative symptoms at the 8-year follow-up point are likely to be a determinant of their current level of employment and school functioning. However, we did not find statistically significant evidence that negative symptoms rated at the 8-year follow-up were associated with current levels of social functioning.

These findings indicate that negative symptom severity rated during the first year is related to negative symptom severity rated 8 years later, showing moderate stability even over long time periods. The stability of negative symptoms was found despite the fact that during the intervening years the patients may have gone through periods of psychotic symptom remission, exacerbation, relapse, or even rehospitalization (Subotnik et al, 2011, Ventura et al, 2004, and Ventura et al, 2011). Considering all of the factors that could have intervened, the finding of moderate stability of negative symptoms is remarkable. We did not find evidence that negative symptoms rated during the first year significantly predicted social functioning or employment and school status at the 8-year point. Given longer durations of follow-up, the predictive value of negative symptoms on subsequent functional outcome might decrease due to a variety of factors such as treatment with antipsychotic agents, availability of comprehensive psychosocial rehabilitation programs, and the accumulation of environmental factors during the course of illness. On the other hand, this lack of 8-year predictive significance for functional outcome may be due to limited sample size.

One limitation of this study is that the predictive relationships between negative symptoms and functioning are not proof of causation as they are correlational in nature. Also, correlations found in this study among the variables we examined might be due to third variables that influence both correlated variables, such as premorbid adjustment, duration of untreated psychosis, etc. In addition, the sample size for the 8-year follow-up was only moderate.

These converging cross-sectional and longitudinal results indicate the significance of developing interventions that decrease negative symptoms to maximize long-term recovery for FEP. Such interventions are needed to actively prevent negative symptoms in the first outpatient year from persisting into the chronic period of illness (Crespo-Facorro et al, 2013 and González-Ortega et al, 2012). Following a recovery model, these results provide support for intervening and treating negative symptoms early in the hope that this may prevent those symptoms from disrupting both short-term and long-term work and school functioning.

Role of funding source

The funding source did not play a role in the study design, implementation, interpretation of results, preparation of drafts, or the publication of this paper.

Contributors

Drs. Keith Nuechterlein and Michael Gitlin conceived of the study design and obtained funding to conduct the study. Drs. Ventura and Nuechterlein trained and supervised research staff on the data collection process and the daily operations of the clinical staff. Dr. Ventura selected the variables of interest, participated in data analysis, and prepared the manuscript. All authors read and commented on initial drafts and approved the final manuscript. Dr. Hellemann conducted the data analysis and drafted portions of the results. Ms. Ered complied the raw data, coded data, created data bases used for data analysis, performed literature searches, and created tables.

Conflict of interest

Joseph Ventura, PhD, has received funding from Janssen Scientific Affairs, LLC, Posit Science, Inc., and Genentech, Inc. He has served as a consultant to Posit Science, Inc., and Boehringer-Ingelheim, GmbH.

Kenneth L. Subotnik, PhD, has received research funding from Janssen Scientific Affairs, LLC, and Genentech, Inc., through grants to Drs. Nuechterlein and Ventura. He is a consultant to Otsuka America Pharmaceutical, Inc.

Michael J. Gitlin, MD, has received funding from or been a consultant to Eli Lilly and Company, AstraZeneca, Bristol-Myers Squibb, and Otsuka America Pharmaceutical, Inc.

Kathleen F. Villa was an employee of Genentech, Inc. at the time that this work was completed and is now an employee of Jazz Pharmaceuticals, plc.

Denise Gretchen-Doorly, PhD, Gerhard S. Hellemann, PhD, and Arielle Ered., have no financial conflicts of interest to disclose.

Keith H. Nuechterlein, PhD, has received funding from Janssen Scientific Affairs, LLC, Posit Science, Inc., and Genentech, Inc. He has served as a consultant to Genentech, Inc. and Otsuka America Pharmaceutical, Inc.

Acknowledgment

This research was supported in part by the National Institute of Mental Health Grants MH37705 (PI: Keith H. Nuechterlein, PhD), MH30911 (PI: R.P. Liberman, MD), P50 MH066286 (PI: Keith H. Nuechterlein, PhD), and a grant from Genentech, Inc (PI: J. Ventura, PhD).

The authors would like to thank the following research associates who assisted with data collection, collating data, and data coding: Craig Childress, M.A., Rhonda Daily, and Rachel C. Wood, M.A.

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Footnotes

a UCLA Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, Los Angeles, CA, USA

b UCLA Department of Psychology, Los Angeles, CA, USA

c Genentech, Inc., South San Francisco, CA, USA

lowast Corresponding author at: UCLA Department of Psychiatry, 300 Medical Plaza, Room 2243, Los Angeles, CA 90095-6968. Tel.: + 1 310 206 5225; fax: + 1 310 206 3651.