1. Introduction
Social functioning is severely damaged by schizophrenia Reference Harvey and Bellack[1], which is detrimental for both patients and their families Reference Bellack, Green, Cook, Fenton, Harvey and Heaton[2]. Improving social functioning is recognized as an important treatment goal, beyond the alleviation of psychotic symptoms [Reference Falkai, Wobrock, Lieberman, Glenthoj, Gattaz and Möller3, Reference Harvey, Green, Keefe and Velligan4] and also ranked as important by patients and their families Reference Karow, Naber, Lambert and Moritz[5].
The major impact of antipsychotics is the reduction of symptoms, not necessarily correlated with the improvement of social functioning [Reference Lambert, Naber, Schacht, Wagner, Hundemer and Karow6–Reference Priebe, McCabe, Bullenkamp, Hansson, Lauber and Martinez-Leal8]. However, this clinical improvement may be difficult to acknowledge for patients. Usually patients are more interested in, and more able to assess, functional improvement. But the level of functional activity is a complex entity, with many instruments Reference Figueira and Brissos[9], no clear consensus on which scale to use Reference Brissos, Molodynski, Dias and Figueira[10], poor agreement between care givers Reference Karow, Naber, Lambert and Moritz[5], and many psychometric difficulties (for example between-gender or inter-cultural differences) Reference Bromley and Brekke[11]. The lack of standardized assessment methods impacts treatment and subsequently patient outcomes [Reference Figueira and Brissos9, Reference Gorwood and Peuskens12, Reference Valencia, Fresán, Barak, Juárez, Escamilla and Saracco13]. Furthermore, none of these instruments was specifically designed to capture the benefice on functional activities of continuing the treatment when treatment response is observed and clinical remission is obtained. Moreover, they usually are not sensitive to the length of clinical remission and they are either too crude, either too detailed, making the functional assessment difficult for both clinicians and patients.
Developing such an instrument could have several advantages. First, it would help clinicians to have an accurate idea of the level of functioning of their patients, giving opportunity to have a window on the lives of patients out of their office, and potentially to adapt treatment strategies. Second, it would increase the quality of the assessment of each treatment strategy, potentially showing immediate benefit on symptoms reduction but also later benefit in everyday life. Third, such an instrument could be used to modify the message given to patients about the impact of their treatment, not only relying on symptoms, but with more obvious assessments of the improvement of functional activities of their everyday life.
Although rarely assessed, the functionality of patients seems paramount when considering recovery as an outcome Reference Leucht and Lasser[14]. Evidence exists that social functioning can predict long-term outcomes in patients with schizophrenia: changes in psychosocial factors are strong predictors of subjective quality of life at 10-year follow-up Reference Ritsner, Arbitman, Lisker and Ponizovsky[15]; baseline impairments in social functioning is predictive of psychosis in Clinical High-Risk patients Reference Cornblatt, Carrión, Addington, Seidman, Walker and Cannon[16], higher social functioning score is predictive of remission at 1-year follow-up Reference Schennach, Riedel, Obermeier, Jäger, Schmauss and Laux[17] and greater improvement in functioning over 1 year rehabilitation programs Reference Brekke, Hoe, Long and Green[18]. Still, there has not been adequate development of convenient and effective instruments for measuring functional improvement in drug treatment trials for these indications according to a NIMH workshop devoted to the assessment of Community Functioning in People With Schizophrenia Reference Bellack, Green, Cook, Fenton, Harvey and Heaton[2].
The aim of the present research is to propose a short list of items assessing important domains of psychosocial functioning, reflecting as much as possible the length of clinical remission and to study its correlations with functionality scores from other established tools. This instrument could be used in different countries, with different types of patients and treatment settings, and could constitute a tool, able to quickly capture the benefit of long term compliance.
2. Subjects and methods
With the above mentioned aims, we used two sets of data: the first national one to depict the minimal number of items of the first version of our instrument FROGS Reference Llorca, Lançon, Lancrenon, Bayle, Caci and Rouillon[19], and a second one, mostly European, for replication on an independent sample, more specifically testing validity of the scale in different cultural backgrounds and treatment settings Reference Peuskens and Gorwood[20].
2.1. Study 1 (FROGS)
This was a national observational multicenter survey, involving 15 psychiatric departments across France as already described Reference Llorca, Lançon, Lancrenon, Bayle, Caci and Rouillon[19]. Inclusion criteria included: being older than 18 years, schizophrenia diagnosed Reference American Psychiatric Association[21] and having the symptomatic remission criteria Reference Andreasen, Carpenter, Kane, Lasser, Marder and Weinberger[22] for at least 6 months using the Positive and Negative Syndrome Scale (PANSS) Reference Kay, Fiszbein and Opler[23]. Patients who had been hospitalized full-time or were unable to provide informed consent were not included in the first evaluation. The assessment of patients included the FROGS and the Global Assessment of Functioning (GAF) Reference Endicott, Spitzer, Fleiss and Cohen[24]. A second assessment took place 12 to 18 months after Reference Lançon, Baylé, Llorca, Rouillon, Caci and Lancrenon[25], allowing prospective approaches, including the analysis of the “quantitative” impact of an additional year of remission on the mini-FROGS, and the “qualitative damage” of a clinical relapse during this follow-up.
2.2. Study 2 (EGOFORS)
The EGOFORS initiative was an international observational multicenter survey, initiated by a group of experts (the European Group On Functional Outcomes and Remission in Schizophrenia, EGOFORS) and well-described in Peuskens et al. Reference Peuskens and Gorwood[20]. Overall 11 centers across Europe were involved: two from France and Italy, and one from Belgium, England, Germany, Israel, Spain, Turkey and Sweden. This sample offered the opportunity to compare various questionnaires devoted to psychosocial functioning in different countries, therefore with variable patients, treatment settings, and cultural backgrounds. The inclusion criteria required the DSM-IV diagnosis of schizophrenia, with around half of the patients being in clinical remission for at least 6 months, according to Andreasen's criteria Reference Andreasen, Carpenter, Kane, Lasser, Marder and Weinberger[22]. All patients were assessed with the PANSS, the GAF Reference Endicott, Spitzer, Fleiss and Cohen[24], and at least three instruments out of the Personal and Social Performance (PSP) scale Reference Morosini, Magliano, Brambilla, Ugolini and Pioli[26], the Quality of Life Scale (QLS) Reference Heinrichs, Hanlon and Carpenter[27], the FROGS Reference Llorca, Lançon, Lancrenon, Bayle, Caci and Rouillon[19], the UPSA-B (brief version of the UCSD Performances-based Skills Assessment [UPSA])Reference Mausbach, Harvey, Goldman, Jeste and Patterson[28], the Psycho-Social Remission in Schizophrenia scale (PSRS) Reference Barak, Bleich and Aizenberg[29] and the shortened “Subjective Well-being under Neuroleptic” (SWN) scale [Reference Brissos, Molodynski, Dias and Figueira30, Reference Bromley and Brekke31]. This open choice of instruments was proposed as a compromise, facilitating reliable assessments (as groups having expertise with specific instruments could choose them) and allowing comparisons (for more information, refer to Reference Peuskens and Gorwood[20]).
2.3. Ethical concerns
The assessment protocol was approved by the relevant ethical review board for each study and all patients provided informed consents to participate.
2.4. Instruments
The FROGS was developed using expert consensus Reference Helmer[32], and comprises 19 items, as described previously Reference Llorca, Lançon, Lancrenon, Bayle, Caci and Rouillon[19]. Five domains are assessed (daily life, social activities, social functioning, quality of rehabilitation and general health and treatment) and three factors were observed (social functioning, daily life and treatment). The GAF was mandatory in the two studies, as the most well-known functional assessment [Reference Peuskens and Gorwood20, Reference Endicott, Spitzer, Fleiss and Cohen24]. The PSRS requires assessing impairment in 8 domains and was filled-in for 274 patients (93% of the EGOFORS Study), representing the only functional scale devoted to schizophrenia apart from the FROGS Reference Barak, Bleich and Aizenberg[29]. The PSP scale Reference Morosini, Magliano, Brambilla, Ugolini and Pioli[26] was developed from the social functioning component of the DSM-IV, assessing four domains and was used in 76% of centers of the second sample (n = 223). The QLS Reference Heinrichs, Hanlon and Carpenter[27] is a 21-items clinician-rated interview containing 4 domains, evaluating mostly quality of life but also providing information on symptoms or functioning. The shortened-SWN scale is a 20-item self-rating scale reflecting the subjective experience of well-being Reference Naber, Moritz, Lambert, Pajonk, Holzbach and Mass[31]. This scale suggests that five dimensions contribute to subjective well-being: emotional regulation, self-control, mental functioning, social integration and physical functioning. The UPSA-B Reference Mausbach, Harvey, Goldman, Jeste and Patterson[28] was developed to assess the capacity of patients to perform in daily functioning and consists of two tasks evaluating financial and communication skills (role play situations).
2.5. Statistical analyses
The variable « duration of remission », from the Study 1, was the variable we used to shortlist the FROGS. The “duration of remission” is here considered as the time being in remission for each patient. First, Spearman correlation coefficients were used to measure the link between this non-parametric variable and each item of the FROGS.
Table 1 Study 1 – Characteristics of 443 patients with schizophrenia in clinical remission.
We then performed multiple regression analyses to study the relationship between the variable to explain “duration of remission” (after rank transformation) and each of the 19 items of the FROGS (explicative variables). Two different regression methods were used: the stepwise method that adds or removes explicative variables based solely on the t-statistics of their estimated coefficients (significance levels for adding and removing effects fixed at 0.05). The second method was the R2 selection method, which allows identifying the best explicative variables group to predict the “duration of remission”.
Student's t-test and Mann-Whitney U were used to compare results between groups (depending on the distribution of the data). Pairwise comparisons of mean changes over time were analyzed by a non-parametric Wilcoxon test for matched samples.
Pearson or spearman correlation coefficients (depending on the distribution of the data) were also used to measure the relationships between the different scales.
Two-tailed tests with a significance level of 0.05 were performed and normality was tested by Shapiro-Wilk test.
Statistical analyses were performed using SAS 9.2 software.
3. Results
3.1. Design of the mini-FROGS (Study 1)
3.1.1. Patient characteristics
Table 1 presents patients’ characteristics. 443 patients in clinical remission were included. Average duration of remission was 3.2 years ± 3.7.
3.1.2. Study population
Among the 531 evaluated patients in the validation of FROGS scale Reference Llorca, Lançon, Lancrenon, Bayle, Caci and Rouillon[19], 443 patients presented available data for the identification of items that were most related to the length of present remission. Twenty-two patients did not fulfil the clinical remission criteria (Remission for less than 6 months, according to Andreasen et al. Reference Andreasen, Carpenter, Kane, Lasser, Marder and Weinberger[22]) and were therefore used to “qualitatively” distinguish patients with versus without the former criteria (Fig. 1).
FROGS data were available for 163 patients for the second wave of the assessment (from the initial sample of 443) Reference Lançon, Baylé, Llorca, Rouillon, Caci and Lancrenon[25], with 140 still having the criteria for clinical remission and 23 who relapsed between the two assessments (Fig. 1).
3.1.3. Mini-FROGS scale: selection of items
Measures of the correlations between each item of the FROGS and the duration of remission are presented in Table 2.
In a stepwise multiple regression, four items emerged from the analysis to explain the duration of remission: “Management of illness and treatment”, “Housekeeping”, “Travel and communication”, and “Self-esteem and sense of independence”. The multiple regressions by R2 method also identified this subset of four items as the best selection to explain the duration of remission (R2 = 0.07) (Model 1 Table 3). However, because of the selection of “Housekeeping”, the relationship between the gender and the 4 items score was studied and found to be significant (P = 0.04) (Table 4). To overcome this difficulty, we selected the second best selection of 4 items identified in the multiple R2 regression (R2 = 0.07). The item “Respect for biological rhythms” was selected instead of “Housekeeping” (Model 2 Table 3). The R2 being relatively small, these regression models indicate that the mini-FROGS items explain only a small degree of variability of length of clinical remission.
Fig. 1 Study 1 – Distribution of patients.
3.1.4. Mini-FROGS scale: psychometric properties
Among the initial sample of 443 patients in remission, the correlation of the mini-FROGS score with total FROGS score was very high (rho = 0.88, P < 0.001), as expected.
The mean score of the Mini-FROGS for the 22 patients excluded from the first assessment due to a too short time of remission was also significantly lower 13.7 ± 3 than for the 443 included patients 15.3 ± 3 (P=0.005).
Among the 140 patients in remission at both assessments, the mean of the Mini-FROGS total score was 15.9 ± 2.5 at the first evaluation and 16.7 ± 2.4 at the second, showing a significant improvement (+0.81, P < 0.001) between the two evaluations.
In addition, the 23 patients showing a relapse between the first and second assessments showed a decrease of their mini-FROGS score of − 0.96 ± 2.5 (versus an increase of +0.81 ± 1.4 for the 140 patients still in remission [P < 0.001]).
Table 2 Study 1 – Spearman correlation coefficient between each item of the FROGS scale and duration of remission (non parametric).
a Non-parametric test.
Table 3 Study 1 – Summary of stepwise multiple regressions.
a Model 2 was obtained by deleting the item “Housekeeping” from the model 1 and by changing the significance level at 6%.
3.2. Informativity of the mini-FROGS in comparison to different functioning scales in different European treatment centers (Study 2)
3.2.1. Study population and patient characteristics
Overall, 295 patients were consecutively included in European and Turkish centres. Table 5 presents patients’ characteristics: 44.7% were female, with a mean age of 42.7 years old ( ± 16.2 years old). All patients were currently treated with antipsychotics (100% adherence). Among the patients, 33% were considered in clinical remission according to the Andreassen criteria and 10% in clinical remission for less than 6 months.
3.2.2. Study of the relationships between the mini-FROGS and other scales
As in study 1, the mini-FROGS score was highly correlated with the total FROGS score (rho = 0.93). Table 6 shows that the other scales also have good positive correlations with the mini-FROGS score: the QLS total score (rho = 0.78), the GAF (rho = 0.78), the UPSA-B (rho = 0.45), the PSP (rho = 0.44) and the SWN (rho = 0.31). As the PSRS assesses functional impairment, its total score showed a negative correlation with the mini-FROGS (rho = −0.75).
4. Discussion
The mini-FROGS was designed to measure functional remission in schizophrenia, with only four items, assessing important domains of psychosocial functioning, namely (1) management of illness and treatment, (2) biological rhythms, (3) travel and communication and (4) self-esteem and sense of independence. This abridged 4-item FROGS scale reflects presence and length of clinical remission, and showed satisfying cultural and gender consistency. Consequently, it can be used in different countries, with different types of patients and treatment settings, and constitutes a tool able to quickly capture the benefit of long-term clinical remission. Doing so, such tool could be used by clinicians as an indirect way to reinforce the benefit of good compliance, as potentially increasing the awareness of patients on the associated functional improvement.
Table 4 Study 1 – Effect of gender over the mini-FROGS scores.
Table 5 Study 2 – Characteristics of 295 European schizophrenia patients (EGOFORS study).
a According to the Andreassen's criteria
Table 6 Study 2–Spearman correlation coefficient between the mini-FROGS score and other scales.
The FROGS proposed five relevant domains to define functional remission in schizophrenia: daily life activity, relationship, quality of rehabilitation, health and treatment. But the factor analysis of the 19 items of the FROGS finally distinguished 3 factors of clinical relevance: “Social functioning”, “Daily life” and “Treatment”. These factors are interestingly also present in the mini-FROGS, with 2 items for factor 1 (“travel and communication”, “self-esteem and sense of independence”), 1 item for factor 2 (“Respect for biological rhythms”) and 1 item for factor 3 (“Management of illness and treatment”).
The homogeneity of the tested samples in terms of symptomatology, presence of clinical remission including the duration criterion Reference Andreasen, Carpenter, Kane, Lasser, Marder and Weinberger[22], is a specific feature of our study, in comparison with various studies designed for the validation of scales with nearby purposes [Reference Morosini, Magliano, Brambilla, Ugolini and Pioli26, Reference Jaeger, Berns and Czobor33–Reference Saraswat, Rao, Subbakrishna and Gangadhar35]. Particularly, few brief versions are developed and able to capture functional remission as clinically defined. The UPSA-B is not specific to schizophrenia and evaluates functional capacity (a person's potential to perform) whereas the mini-FROGS evaluates real-world functioning according to the clinician (how the patient actually performs) [Reference Green, Kern, Braff and Mintz36–Reference Helldin, Kane, Karilampi, Norlander and Archer38]. Lastly, the PSRS measures psychosocial remission in schizophrenia, which is only a part of functional remission Reference Valencia, Fresán, Barak, Juárez, Escamilla and Saracco[13] and includes items overlapping symptomatology (such as “energy” and “interest”). Thus the mini-FROGS is to our knowledge the first brief questionnaire specifically devoted to assess functional remission in schizophrenia.
More importantly, the mini-FROGS captures the benefit on functional activities to continue treatment when clinical remission is obtained, being sensitive to the length of clinical remission. Studies reported that achieving symptomatic remission was associated with better functioning [Reference Cannavò, Minutolo, Battaglia and Aguglia39–Reference Chang, Chan, Chen, Hui, Wong and Chan43] and that this latter outcome was correlated with length of remission [Reference Chang, Chan, Chen, Hui, Wong and Chan40, Reference Jaracz, Górna, Kiejda, Grabowska-Fudala, Jaracz and Suwalska43, Reference Jordan, Lutgens, Joober, Lepage, Iyer and Malla44]. In routine care, the use of the mini-FROGS may help patients to understand the impact of adherence in everyday life.
This study has several limits. First, the Mini-FROGS is a clinician-rated scale and its inter-reliability has yet not been tested. Second, the evaluations were made by experienced psychiatrists. However, the mini-FROGS is easy to use as the rating instructions are simple, and has already been efficiently used by nurses to demonstrate the functional benefit of psychosocial skill training Reference Uzdil and Tanrıverdi[45]. Third, the impact of the severity of clinical symptoms on the mini-FROGS remains to be explored. The sample size of patients with clinical relapse is too small (n = 23) to draw any definite conclusions. Fourth, the length of illness duration in these two studies could be a possible bias for the results (respectively 14.5 years ± 9.8 for the first sample and 18.8 years ± 14.5 for the EGOFORS Study). One can speculate that young persons in their first psychosis period might value their social network and contacts with friends more important than being able to travel and communicate. Further studies should explore the mini-FROGS properties in young adults with recent schizophrenia onset. Lastly, further studies should determine the correlations between the mini-FROGS and cognitive functions. The links between cognition, functional remission and functional capacity is indeed considered as important but irresolute. The relationships with other broader aspects of remission, such as quality of life, should also be elucidated. Finally, by looking at functionality items that best predict symptom remission, we considered that symptoms improvement and functional outcome are strongly related. While this may be so in most cases [Reference Chang, Chan, Chen, Hui, Wong and Chan39–Reference Heering, Janssens, Boyette and van Haren44], some patients may have good functionality without achieving symptomatic remission. Thus, there may be components of functionality that are clinically relevant but less closely related to symptom improvement and that have not been included in this short-listed version of the FROGS.
5. Conclusion
The mini-FROGS is a short version of the FROGS with good psychometric properties, highly linked to other scales assessing the psychosocial functioning. It gives a new and easy assessment of social functioning, qualitatively distinguishing patients with relapse and quantitatively reflecting the length of remission. A shortened time of administration increases its applicability across studies, especially when functional remission is not the primary outcome.
Role of funding source
This study was financially supported by an educational grant by Janssen-Cilag France.
Contributors
Philip Gorwood and Jasmina Mallet wrote the draft of the final manuscript and did the Medline review. Sylvie Lancrenon was responsible for the statistical analyses. Christophe Lançon and Franck-Jean Bayle contributed as clinical investigators. Pierre-Michel Llorca contributed as a clinical investigator and coordinated the analyses. Philip Gorwood contributed as a clinical investigator, participated in the analyses, wrote the first draft and organized the submission of the final manuscript.
Disclosure of interest
Consultancies, honoraria, paid expertise and grants were obtained by authors according to the list below, with no stock ownership or shares, nor patent application neither registration.
Jasmina Mallet, Sylvie Lancrenon and Christophe Lançon declare no conflicts of interest.
Pierre-Michel Llorca has received consulting fees from Astra-Zeneca, Bristol-Myers Squibb, Eli Lilly, Euthérapie, Lundbeck, and Sanofi.
Franck Baylé has received consulting fees within the last 4 years from Servier, Lundbeck, Eli Lilly, Bristol-Myers Squibb, and Janssen.
Philip Gorwood received research grants from Eli Lilly and Servier; honoraria for presentations in congresses from AstraZeneca, Bristol-Myers Squibb, Janssen, Lundbeck, and Servier; participated on advisory board of AstraZeneca, Janssen, Roche, and Servier.
Acknowledgments
The EGOFORS initiative is relying on the work performed by Yoram Barak (Israel), Roberto Cavallaro (Italy), Silvana Galderisi (Italy), Philip Gorwood (France), Lars Helldin (Sweden), Robert Hunter (England), Pierre Michel Llorca (France), Dieter Naber (Germany), Joseph Peuskens (Belgium), Luis San (Spain) and Alp Uçok (Turkey).
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