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Characterization of premorbid functioning during childhood in patients with deficit vs. non-deficit schizophrenia and in their healthy siblings

Schizophrenia Research, Volume 174, Issue 1-3, July 2016, Pages 172 - 176

Abstract

Impaired premorbid adjustment has been reported in patients with schizophrenia, generally in association with unfavorable aspects of the illness (e.g., poor outcome and severe negative symptoms). Several studies attempted to define the domains of premorbid dysfunction associated with negative symptoms and poor outcome; however, most of them assessed broadly defined negative symptoms. The present study was aimed to characterize premorbid functioning in a group of patients with deficit schizophrenia (DS), characterized by the presence of at least two primary and persistent negative symptoms (PPNS), and one of patients with a diagnosis of schizophrenia who did not meet criteria for DS (NDS).

The presence of emotional/behavioral problems during childhood was investigated using the Childhood Behavior Checklist (CBCL) in both patient groups and in their respective healthy siblings. The Premorbid Adjustment Scale (PAS) was also used to assess premorbid functioning during childhood in the two patient groups. PPNS were also treated as a continuous variable and correlated with the indices of premorbid functioning regardless the DS/NDS categorization.

DS patients, as compared to NDS, showed higher scores on the CBCL subscale “Withdrawn”. Both DS and NDS patients showed, as compared to their healthy siblings, a greater impairment on almost all CBCL subscales. PAS findings revealed that DS patients had poorer premorbid adjustment than NDS. No significant correlation between premorbid functioning and PPNS was observed.

These findings support the hypothesis that DS has a different developmental trajectory with respect to NDS, and that premorbid adjustment is one of the essential aspects of its characterization.

Keywords: Schizophrenia, Primary negative symptoms, Childhood behavior, Premorbid functioning.

1. Introduction

In patients with schizophrenia, an impairment of premorbid adjustment involving several areas of functioning has been widely reported (Hans et al, 1992, Addington and Addington, 1993, Cannon et al, 2001, and Reichenberg et al, 2002). Such an impairment is not found in all patients, as a proportion of them present an abrupt onset with a relatively good premorbid functioning (Neumann et al, 1995 and McGlashan, 2008). Moreover, when present, the impairment may vary in its age of onset and course over time, degree of severity, and functional domains involved (Neumann et al., 1995). Many authors reported associations between impaired premorbid functioning and some unfavorable aspects of schizophrenia, including a chronic clinical course, a poor outcome and a higher severity of negative symptoms (Kelley et al, 1992, Haim et al, 2006, Rabinowitz et al, 2002, Rabinowitz et al, 2006, Galderisi et al, 2002, Galderisi et al, 2013, and Ayesa-Arriola et al, 2013). Several studies attempted to define the domains of premorbid dysfunction associated with negative symptoms and poor outcome. Most of them used the Premorbid Adjustment Scale (PAS, Cannon-Spoor et al., 1982), extracting two distinct functional subdomains, i.e. a social and an academic one, and found that the impairment of the social domain was more strongly related to the severity of negative symptoms than the impairment of the academic domain (McClellan et al, 2003, Monte et al, 2008, Chang et al, 2013, and Strauss et al, 2012).

In these studies, broadly defined negative symptoms were considered, notwithstanding the largely acknowledged heterogeneity within this psychopathological dimension, including negative symptoms that are inherent to the disease (generally referred to as primary) and negative symptoms caused by factors other than the core disease process (generally referred to as secondary negative symptoms, and due to medication side-effects, concurrent depression, and limited social stimulation). Primary negative symptoms are usually enduring and resistant to pharmacological and non-pharmacological interventions, contrary to secondary negative symptoms that are related to identifiable sources, are generally not enduring and are often modifiable with adequate treatment interventions addressing their causes.

Primary and persistent negative symptoms (PPNS) are considered as the main clinical aspect of deficit schizophrenia, a diagnosis requiring the presence during the 12 months preceding the diagnosis of at least two primary negative symptoms.

A poor premorbid adjustment, in conjunction with an insidious onset and a poor response to treatment with antipsychotic drugs, has been reported among the characteristics of deficit schizophrenia (DS) (Carpenter et al, 1988, Kirkpatrick et al, 1996, Fenton and McGlashan, 1994, Galderisi et al, 2002, Kirkpatrick and Galderisi, 2008, and Galderisi and Maj, 2009).

Two investigations (Strous et al, 2004 and Strauss et al, 2012) focused on PPNS so far. In the former one, the criteria proposed by Mayerhoff et al. (1994) to assess the deficit state in first-episode schizophrenia were used, while in the latter one the Schedule for the Deficit Syndrome was administered to assess PPNS. The two PAS subdomains (i.e., Social and Academic) were analyzed only in the study by Strauss et al. (2012): a greater deterioration of academic than social premorbid functioning was observed in NDS patients, while DS showed comparable deterioration in both premorbid domains, as well as a poorer social premorbid adjustment as compared to NDS.

Two studies (Baum and Walker, 1995 and Rossi et al, 2000) explored the relationships between negative symptoms and premorbid adjustment assessed by the Childhood Behavioral Checklist (CBCL; Achenbach, 1991), an instrument evaluating several behavioral and emotional aspects in five age periods in patients as compared to their siblings. Baum and Walker (1995) found that the negative psychopathological dimension was associated with withdrawn behavior, while Rossi et al. (2000) found that patients showing a higher level of behavioral abnormalities during childhood and adolescence had more severe negative symptoms. Neither study assessed PPNS.

The present study was aimed to characterize premorbid functioning in patients with PPNS. In particular, here we tested the hypothesis that patients with DS, as compared to those with NDS, have poorer premorbid functioning since childhood, and that aspects relevant to the negative dimensions (i.e., withdrawal) are also found in healthy siblings of subjects with DS, due to their high genetic load (Smyrnis et al, 2007, Pelayo-Terán et al, 2011, and Li et al, 2012). To this aim, the presence of emotional/behavioral problems during childhood was investigated by means of the CBCL in both DS and NDS patients, as well as in their respective healthy siblings; the assessment of premorbid functioning during childhood was also carried out by means of the PAS in the two patient groups. Moreover, since PPNS can still be present in patients with NDS, we also treated them as a continuous quantitative variable and investigated their correlations with the indices of premorbid functioning regardless the DS/NDS categorization.

2. Methods

2.1. Subjects

Subjects were recruited in four university departments of psychiatry (Naples, L'Aquila, Milan and Pisa) within a multicenter project aimed at characterizing historical, clinical, neuropsychological and neuroradiological aspects of DS (Galderisi et al., 2013).

Before entering the study, patients participated in a 1-h clinical interview to verify their conformity to the following inclusion criteria: 1) a DSM-IV diagnosis of schizophrenia, confirmed by the Structured Clinical Interview for DSM-IV (SCID); 2) age between 16 and 55 years; 3) no history of severe mental retardation, alcoholism, or drug abuse or dependence in the last 12 months and no previous ECT; 4) no significant changes in the clinical state or in drug treatment during the preceding 3 months; and 5) willingness to participate in the study procedures, expressed by providing written informed consent after complete description of the study.

Patients meeting these criteria were then classified as having either DS or NDS after being interviewed with the Schedule for the Deficit Syndrome (SDS, Kirkpatrick et al., 1989). According to this instrument, patients are classified as having DS when meeting the following criteria: 1) presence of at least two negative symptoms among the following: restricted affect, diminished emotional range, poverty of speech, curbing of interests, diminished sense of purpose, diminished social drive; 2) some combination of two or more of the negative symptoms listed above are persistent, i.e., have been present for the preceding 12 months and always present during periods of clinical stability; 3) the abovementioned negative symptoms must be primary or idiopathic, i.e., not secondary to factors other than the disease process, such as anxiety, drug effect, suspiciousness or other psychotic symptoms, mental retardation or depression.

2.2. Clinical assessment

Psychopathological evaluation was carried out by the Scale for the Assessment of Negative Symptoms (SANS; Andreasen, 1981) and the Scale for the Assessment of Positive Symptoms (SAPS; Andreasen, 1984). Measures from the SANS and SAPS were grouped into three dimensions (Liddle, 1987, Liddle and Barnes, 1990, Peralta et al, 1992, and Galderisi et al, 1999): 1) negative symptoms (sum of global scores on the alogia, anhedonia, affective flattening, and avolition subscales of the SANS); 2) reality distortion (sum of global scores on the hallucinations and delusions subscales of the SAPS); and 3) disorganization (sum of global scores on the formal thought disorder and bizarre behavior subscales of the SAPS).

2.3. Assessment of premorbid characteristics

In all patients with at least one sibling and whose mother (or father) was available for the interview, premorbid functioning was assessed by Baum and Walker's (1995) modified version of the CBCL. In this version of the instrument, the 124 CBCL items were changed to the past tense to evaluate five age periods (0–3 years, 4–7 years, 8–11 years, 12–15 years, 16–18 years). The CBCL items measure a broad range of emotional/behavioral problems. For each item, at each time period, one of the parents (usually the mother, when available) rates the patient and the sibling closest in age on a three point scale (0 = not true; 1 = somewhat or sometimes true; 2 = very true or often true).

Scores obtained on the 124 items were converted by means of the Assessment Data Manager (ADM) software into the composite scores for the eight CBCL subscales suggested by Achenbach (1991): “Withdrawn”, “Somatic Complaints”, “Anxious/depressed”, “Social Problems”, “Thought Problems”, “Attention Problems”, “Delinquent Behaviour”, “Aggressive Behavior”, plus a residual category called “Other”. The age periods 12–15 and 16–18 years were excluded from the analysis in order to minimize possible contamination with early prodromal and psychotic symptoms of the illness, since for some recruited patients the age at onset was 14 years. Outlier values, identified as those with a z-score ≥ 3, were replaced by the mean of the group.

A further assessment of patients' premorbid functioning was carried out by using the PAS. Similarly to the CBCL, only the age period ≤ 11 years (childhood) was included in the analysis. The PAS assesses five psychosocial domains, i.e. sociability and withdrawal, peer relationships, scholastic performance, adaptation to school, and social-sexual functioning. Ratings are made on a 0 to 6 point Likert scale, with 0 indicating normal adjustment and 6 indicating severe impairment. To gather information about the premorbid period, a semi-structured interview was utilized with the participant and her/his family members. According to the procedure followed in previous studies (Allen et al, 2005 and Strauss et al, 2012), separate scores were calculated for social and academic premorbid domains of functioning at each age level, by averaging the items sociability, withdrawal, peer relationships and social-sexual functioning for the Social domain and the items scholastic performance and adaptation to school for the Academic domain.

2.4. Data analysis

Cronbach's alpha coefficients, both general and for each time period, were calculated to verify the internal consistency of each subscale. When Cronbach's alpha was < 0.7, the subscale was not included in the analysis.

Independent one-way analyses of variance (ANOVAs) were used to test group differences between DS and NDS patients on demographic variables, age of onset, duration of illness and Full Scale Intelligence Quotient (FSIQ) of the Wechsler Adult Intelligence Scale-Revised (WAIS-R).

Multivariate analyses of variance (MANOVAs) were run to investigate differences on psychopathological dimensions between DS and NDS patients, differences on CBCL subscales between siblings and patients in the two groups (DS/NDS) in the three considered age periods, as well as differences in social and academic PAS factors between the two patient groups during childhood. The Fisher's Least Significant Difference Test was used for post-hoc comparisons only when a significant main effect of or interaction with syndrome was found in the analyses.

Correlations of PPNS with CBCL and PAS indices in the whole group of patients were investigated by means of the Pearson's test. In order to reduce the number of tests, we investigated only correlations with CBCL and PAS indices showing significant differences between DS and NDS patients.

3. Results

3.1. Subject characteristics

The initial sample consisted of 51 patients with DS and 44 patients with NDS, recruited within a multicenter study on the historical, clinical, neuropsychological and neuroradiological aspects of DS (Galderisi et al., 2013). From that sample, 43 patients with DS (31 males, 12 females) and 41 with NDS (31 males, 10 females) were included in the present study, since they had at least one sibling and their mother (or father) available for the interview. No difference was observed between the recruited DS and NDS patients on gender distribution, age, education level, age of onset, duration of illness and FSIQ (Table 1). Gender distribution was comparable also between siblings of DS patients (21 males and 22 females) and those of NDS patients (23 males and 18 females).

Table 1

Demographic and clinical characteristics of the study sample.

 

Subjects with deficit schizophrenia (n = 43) Subjects with nondeficit schizophrenia (n = 41)
Age 35.14 ± 7.30 34.87 ± 7.60
Education 11.53 ± 3.11 11.48 ± 3.02
WAIS-R Full-scale IQ 76.53 ± 10.78 81.54 ± 16.26
Age at onset 21.64 ± 4.59 21.49 ± 4.29
Duration of illness 13.50 ± 7.09 13.39 ± 6.61
Negative symptoms 12.53 ± 3.10⁎⁎ 9.76 ± 3.45
Reality distortion 3.26 ± 2.71 4.68 ± 2.80
Disorganization 2.67 ± 2.16 2.95 ± 1.95

Significant group difference: p < 0.01.

⁎⁎Significant group difference: p < 0.000005.

WAIS-R = Wechsler Adult Intelligence Scale-Revised; IQ = Intelligence Quotient;

MANOVA on SANS/SAPS dimensions revealed a significant syndrome-by-dimension interaction (F2,164 = 15.92; p = 0.000001) due to the presence in patients with DS, with respect to those with NDS, of higher scores for the negative dimension (p = .00001) and lower scores for the reality distortion dimension (p = .01). Mean values of the psychopathological dimensions in the two groups are shown in Table 1.

3.2. Group comparisons on CBCL subscales

Cronbach's alpha coefficients were ≥ 0.7 for all CBCL subscales, with the exception of “Somatic Complaints” and “Other”, that were excluded from the analysis. Outlier values, which were replaced by the mean of the group, were 43/3.528 (1.21%).

The general MANOVA on the seven analyzed CBCL subscales showed a significant effect of syndrome (F21,144 = 1.77; p = 0.03) and sibling group (F21,144 = 4.19; p = 0.00001), as well as a significant syndrome-by-sibling group interaction (F21,144 = 1.96; p = 0.01). Post-hoc analyses showed that premorbid abnormalities were greater in both DS and NDS patients as compared to their siblings (p = 0.000001 and p = .0004, respectively). The within-subjects multivariate tests showed a significant syndrome-by-subscale interaction (F6,159 = 2.58; p = 0.02) that, according to post-hoc analyses, was due to a significantly greater withdrawal in DS with respect to NDS (p = .04). Significant interactions subscale-by-syndrome-by-sibling group and subscale-by-time-by-syndrome-by-sibling group were also observed (F6,159 = 2.58; p = 0.02 and F12,153 = 1.85; p = 0.04, respectively). Post-hoc analyses showed that both DS and NDS patients were more impaired than their respective siblings on all subscales, with the exception of “thought problems”, that were greater in NDS but not in DS patients as compared to their siblings, in the age periods 4–7 and 8–11 years, and “delinquent behavior”, that was greater in DS but not in NDS patients as compared to their siblings at age 8–11 years (Table 2).

Table 2

Child Behavior Checklist subscales (mean ± SD) in the two groups of patients and in their healthy siblings.

 

Deficit schizophrenia group Non-deficit schizophrenia group
Healthy siblings (N = 43) Patients (N = 43) Healthy siblings (N = 41) Patients(N = 41)
Withdrawn 0–3 years 0.56 ± 1.28 3.12 ± 3.25⁎⁎⁎# 0.45 ± 0.77 2.24 ± 2.71⁎⁎⁎
Withdrawn 4–7 years 0.79 ± 1.42 4.14 ± 3.75⁎⁎⁎# 0.54 ± 0.83 3.12 ± 3.45⁎⁎⁎
Withdrawn 8–11 years 0.84 ± 1.43 4.63 ± 3.88⁎⁎⁎# 0.77 ± 1.06 3.63 ± 3.87⁎⁎⁎
Thought problems 0–3 years 0.05 ± 0.21 0.51 ± 0.98 0.00 ± 0.00 0.71 ± 1.23
Thought problems 4–7 years 0.07 ± 0.34 0.36 ± 0.78 0.10 ± 0.30 0.78 ± 1.41
Thought problems 8–11 years 0.02 ± 0.15 0.41 ± 0.79 0.00 ± 0.00 0.80 ± 1.31
Anxious/depressed 0–3 years 0.93 ± 1.58 3.56 ± 3.59⁎⁎⁎ 0.55 ± 1.16 3.24 ± 3.41⁎⁎⁎
Anxious/depressed 4–7 years 0.43 ± 0.85 2.19 ± 2.27⁎⁎⁎ 0.16 ± 0.42 2.44 ± 2.58⁎⁎⁎
Anxious/depressed 8–11 years 0.43 ± 0.69 2.60 ± 2.40⁎⁎⁎ 0.47 ± 0.77 3.17 ± 3.37⁎⁎⁎
Social problems 0–3 years 0.00 ± 0.00 0.26 ± 0.62 0.00 ± 0.00 0.15 ± 0.36
Social problems 4–7 years 0.30 ± 0.64 1.33 ± 1.71 0.27 ± 0.63 1.00 ± 1.32
Social problems 8–11 years 0.28 ± 0.59 1.31 ± 1.65 0.27 ± 0.63 0.88 ± 1.14
Attention problems 0–3 years 0.44 ± 0.76 1.47 ± 2.15 0.60 ± 0.83 1.24 ± 1.62
Attention problems 4–7 years 0.62 ± 1.21 2.79 ± 3.78⁎⁎⁎ 0.82 ± 1.02 2.39 ± 2.91⁎⁎⁎
Attention problems 8–11 years 0.55 ± 1.20 3.09 ± 3.83⁎⁎⁎ 0.92 ± 1.01 2.54 ± 3.03⁎⁎⁎
Aggressive behavior 0–3 years 0.47 ± 1.08 1.00 ± 1.69 0.78 ± 1.19 1.44 ± 2.17
Aggressive behavior 4–7 years 0.47 ± 0.93 2.19 ± 3.82⁎⁎⁎ 1.05 ± 1.52 1.90 ± 2.57⁎⁎
Aggressive behavior 8–11 years 0.51 ± 0.83 2.37 ± 3.94⁎⁎⁎ 1.02 ± 1.27 1.95 ± 2.65⁎⁎
Delinquent behavior 0–3 years 0.05 ± 0.31 0.42 ± 0.85 0.00 ± 0.01 0.37 ± 0.73
Delinquent behavior 4–7 years 0.05 ± 0.30 0.60 ± 1.20 0.08 ± 0.26 0.44 ± 0.90
Delinquent behavior 8–11 years 0.05 ± 0.30 0.98 ± 1.50⁎⁎ 0.18 ± 0.49 0.49 ± 0.87

#Significant difference between DS and NDS patients: p ≤ 0.01.

⁎⁎⁎Significant difference between patients and healthy siblings: p ≤ 0.000005.

⁎⁎Significant difference between patients and healthy siblings: p ≤ 0.001.

Significant difference between patients and healthy siblings: p ≤ 0.04.

Group comparisons on CBCL subscales showed a significantly greater withdrawal in DS with respect to NDS patients in all the considered age periods. “Thought problems”, resulted significantly more severe only in NDS patients as compared to their siblings, and “delinquent behavior” resulted significantly more severe only in DS patients as compared to their siblings.

3.3. Group comparisons on PAS dimensions

MANOVAs on PAS domains (Social and Academic) showed a significant effect of syndrome (F1,82 = 13.08; p = 0.0005), due to a poorer premorbid functioning in DS with respect to NDS regardless of the domain (Table 3), as well as a significant effect of domain (F1,82 = 19.95; p = 0.00002) due to a poorer premorbid academic compared to social functioning regardless of the syndrome.

Table 3

Premorbid Adjustment Scale domains (mean ± SD) in the two groups of patients.

 

Deficit schizophrenia patients (DS) (N = 43) Non-deficit schizophrenia patients (NDS) (N = 41)
Social domain 1.97 ± 1.75 0.83 ± 1.11
Academic domain 2.43 ± 1.23 1.83 ± 1.10
Mean total score 2.20 ± 1.28# 1.33 ± 0.89

#Significant difference between DS and NDS patients: p ≤ 0.0001.

Group comparisons on PAS domains showed a significant effect of syndrome, due to a poorer premorbid functioning in DS with respect to NDS regardless of the domain.

3.4. Correlation analyses

Each PPNS was present in a number of NDS patients ranging from 2 to 5. On the whole, the number of patients included in the correlation analyses ranged from 34 to 41, depending on the considered symptom.

No significant correlation was observed between any PPNS and the CBCL subscale “Withdrawal” nor the PAS domains.

4. Discussion

A first prominent finding of this study is that DS patients, as compared to NDS, show higher scores on the CBCL subscale “Withdrawn” over the three considered age periods (0–3, 8–7 and 4–11 years). This subscale is composed by items such as “would rather be alone than with others”, “secretive, keep things to self”, “refused to talk” and “withdrawn, didn't get involved with others”, i.e. aspects that probably interfere since childhood with the socialization processes of the child.

The presence of these aspects since childhood in patients with DS would support the hypothesis that they represent a schizophrenia endophenotype (Fanous and Kendler, 2005 and Wessman et al, 2009), i.e. a heritable quantitative trait, that co-segregates with the illness, is state independent and might contribute to elucidate relationships between genetic variations and complex illness phenotypes.

In the light of a previous study reporting social withdrawal in non-psychotic relatives of probands with DS but not with NDS (Kirkpatrick et al., 2000), we predicted the presence of aspects relevant to the negative dimension in the group of healthy siblings of DS patients. We did not find this difference, but cannot exclude a bias related to the tendency of mothers to minimize behavioral problems in the healthy sibling. Such a bias did probably not affect the DS/NDS differences, since mothers were unaware of this categorization and its implications.

PAS findings also highlighted a worse adjustment since childhood in patients with DS, as compared to those with NDS, regardless of the PAS domain (social or academic). As previously reported by Strauss et al. (2012), the gap between academic and social functioning was much larger in NDS than in DS patients, though this finding was not statistically significant in our sample.

The lack of correlations of PPNS with the CBCL subscale “Withdrawn” and with the PAS domains may be related to the low variance in the degree of severity of PPNS among subjects (only a few NDS subjects had PPNS of reduced severity).

Both DS and NDS patients showed, as compared to their healthy siblings, a greater impairment on almost all CBCL subscales over the three considered age periods. This is in line with previous studies carried out in patients with schizophrenia, reporting a broad range of childhood behavioral problems in pre-schizophrenia children with respect to their siblings (Baum and Walker, 1995, Neumann et al, 1995, and Rossi et al, 2000) or peers (Schenkel and Silverstein, 2004 and Tarbox and Pogue-Geile, 2008).

Only the CBCL subscales “Thought problems” and “Delinquent behavior” showed a diverse pattern of differences with respect to siblings in the two patients groups. Only NDS patients were significantly more impaired than their siblings on “Thought Problems”, while only DS patients showed significantly more “Delinquent behavior” than their siblings. It is not surprising that the subscale “Thought problems” (including items such as “couldn't get his/her minds off certain thoughts; obsessions”, “had strange ideas”, “heard sounds or voices that weren't there”, “saw things that weren't there”) indicates an impairment during childhood in patients in which reality distortion is more represented during adulthood. As to the finding concerning “Delinquent behavior” it was quite unexpected and was never reported previously. In fact, people with DS generally are not offenders and do not have other characteristics of patients with antisocial personality disorders (e.g. frequent drug abuse). The possibility might be considered that some “antisocial” aspects observed during childhood in individuals later diagnosed as DS are actually an epiphenomenon of low IQ and social abilities, frequently reported in these subjects (Galderisi et al, 2002, Wang et al, 2008, and Kirkpatrick and Galderisi, 2008), and that greater withdrawal than observed in other schizophrenia patients prevents them from engaging in delinquent behaviors from early adolescence onwards.

In conclusion, our CBCL data indicate a more severe withdrawal in DS than in NDS patients since early life epochs, and our PAS data highlight a greater impairment since childhood of both social and academic functioning in DS versus NDS patients. We found an impairment of childhood adjustment involving a broad range of functional domains in patients with schizophrenia, as compared to their siblings. Mothers' unawareness of the DS/NDS categorization and its implications, together with the consistency between the CBCL and PAS results, argue in favor of the validity of these findings, which provide further support to the hypothesis that DS has a different developmental trajectory with respect to NDS, and suggest that premorbid adjustment is one of the essential aspects of its characterization.

Conflicts of interest

AM received fees from the following companies, for the described activities: Amgen Dompè for advisory board and Janssen-Cilag for educational activity.

SG received honoraria from the following companies, for the described activities: Janssen-Cilag and Eli-Lilly for lectures; Amgen-Dompé and Gedeon-Richter for Advisory boards.

AR has received funding for advisory board membership and sponsored lectures from: Astra Zeneca, Bristol-Meyers Squibb, Eli Lilly, Janssen-Cilag, Lundbeck, Pfizer, Stroder.

AV has received funding for research, advisory board membership and sponsored lectures from: Astra Zeneca, Bristol-Meyers Squibb, Eli Lilly, Glaxo SmithKline, Janssen-Cilag, Lundbeck, Otsuka, Pfizer, Sanofi, Servier, Stroder.

All other authors have declared no conflict of interest.

As these financial relationships have not influenced the content of this article, all authors have declared that there are no conflicts of interest in relation to the subject of this article.

Contributors

MM, SG, AV, AR and SP contributed to the conception and design of the study. GP coordinated data collection. MN and PB analyzed the data. SG, AM and PB interpreted the data and drafted the manuscript. All Authors participated in the critical revision of the manuscript and provided the final approval of the version to be published.

Role of the funding source

None.

Acknowledgments

The present multicenter study was supported by grant 2003064871 from the Italian Ministry of University and Scientific Research.

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Footnotes

a Department of Psychiatry, University of Naples SUN, Italy

b Eugenio Medea Scientific Institute, Child Psychiatry Department, Bosisio Parini, LC, Italy

c Department of Clinical and Experimental Medicine, Psychiatric Clinic, University of Pisa, Italy

d Institute of Experimental Medicine-Section of Psychiatry, University of L'Aquila, Italy

e Department of Clinical and Experimental Sciences, University of Brescia, Italy

Corresponding author at: Department of Psychiatry, University of Naples SUN, Largo Madonna delle Grazie, 80138 Naples, Italy.