Validation of a specific measure to assess health-related quality of life in patients with schizophrenia and bipolar disorder: the 'Tolerability and quality of life' (TOOL) questionnaire

Schizophrenia and bipolar disorder are worldwide prevalent and severe mental diseases [1, 2]. Newer antipsychotic treatments have proven useful in reducing both relapses and the severity of symptoms [3]. However, weight gain, extrapyramidal symptoms, sexual dysfunction, or sedation are quite common side effects among patients under antipsychotic treatment [4]. The occurrence of these symptoms may affect patient adherence to medication, leading to discontinuation, limiting treatment effectiveness, and increasing both personal and social costs [5, 6]. Therefore, when comparing alternative therapies, side effects and their impact on patient health-related quality of life (HRQoL) could be of great importance in order to define the most efficient antipsychotic drug treatment [3, 7].

The systematic assessment of patient perspective may provide valuable information that could be lost when relying only on clinical evaluation. In chronic conditions such as schizophrenia and bipolar disorder, there are advantages in using patient-reported measures to understand complex needs and improve alliances between patients and clinicians [8]. The importance of involving patients in their own healthcare, and of patient-reported assessments, is increasingly recognised [9].

Many efforts have been made to develop or validate specific instruments to assess patient affectation within different domains [10‐13]. Regarding side effects, the most widely used and specific measure is the Udvalg for Kliniske Undersøgelser (UKU) side effects scale [14]. This questionnaire, filled out by clinicians or patients, comprises 56 items that refer to psychic, neurological, autonomical and others effects. Despite this scale, more specific tools in terms of HRQoL are still needed to afford greater insight in describing and grading the impact of side effects associated to antipsychotic drugs [15, 16]. A brief instrument is preferred for use in clinical practice and in investigations such as clinical management studies or clinical trials comparing the effectiveness of treatments.

A specific measure to assess HRQoL impairment related to adverse events of antipsychotic drugs has been previously developed and validated in Sweden: the 'TOlerability and quality Of Life' (TOOL) questionnaire [17]. This self-rated measure reflects the subjective perception of side effects in patients treated with antipsychotic medication. It comprises eight attributes and has four levels per domain (Likert scale: 1 = minimum to 4 = maximum impact). These domains are mood (worry-upset), function capabilities, and several adverse events frequently associated with antipsychotic treatment (fatigue-weakness, weight gain, stiffness-tremor, physical restlessness, sexual dysfunction, and dizziness-nausea). In contrast to the Drug Attitude Inventory [10] or the Subjective Well-being under Neuroleptic scale [11], the TOOL questionnaire was specifically designed to identify from the patient perspective the most common adverse events of both typical and atypical antipsychotic drugs [4, 18].

The aim of the present study was to evaluate the linguistic adaptation and psychometric validation into Spanish of the TOOL questionnaire for the assessment of side effects in patients treated with antipsychotic medication and their impact on health-related quality of life.

This trial was registered under no. NCT00692133.

A total of 242 patients were included in the study. For the validation analysis, 238 (121 with a diagnosis of schizophrenia and 117 with bipolar disorder) were studied. The mean age of the sample was 41.9 years (SD 10.9), and 63% were males (n = 151). Sociodemographic and clinical characteristics of the sample are shown in Tables 1 and 2.

The percentage of missing values in each of the items contained in the questionnaire was less than 5%. The mean completion time was 4.91 min (SD 4.48). A ceiling effect was found for the following items: stiffness-tremor and dizziness-nausea (more than 50% of all patients reported not being bothered at all by any of these symptoms).

ITC scores were above 0.2 in all items, and body weight was the only item with a discrimination index below 0.3: ITC worry-upset = 0.581; function capabilities = 0.598; fatigue-weakness = 0.633; weight = 0.284; stiffness-tremor = 0.401; physical restlessness = 0.505; sexual dysfunction = 0.360; dizziness-nausea = 0.345. Exploratory factorial analysis reflected a unidimensional structure of the TOOL questionnaire (eigenvalue = 3.331) (Table 3). This dimension explained 39.1% of the variance. The component matrix is shown in Table 2. Furthermore, the reliability of this structure in terms of internal consistency was found to be adequate (Cronbach α = 0.757). When test-retest reliability was examined, the results showed fairly appropriate stability in the evaluations of patient involvement when no changes in clinical status were detected by the clinicians (ICC = 0.90). Since unidimensionality had been proven, it was possible to calculate a global score summarising the patient level in each of the eight domains. A range of scores between 8 (minimum impact) to 32 (maximum impact) was obtained. This total score was also analysed with respect to generic and specific measures to test convergent and criterion validity.

Correlations between the TOOL and generic measures of HRQoL were highly-moderately negative and significant (Table 4). These results were also observed when the TOOL scores of bipolar and schizophrenic patients were compared separately (Table 4). Negative values in r_s responded to the inverse scoring of the measures. In addition, the associations between the TOOL items and the generic measures of HRQoL (Table 4) were negative, significant and mild to high. With respect to specific measures, the TOOL questionnaire correlated moderately-highly and significantly with the MADRS. Moreover, regarding CGI-S, correlation was not only moderate and significant but also higher than the one found between these scales and the HRQoL generic measures (Table 5). Correlations between specific domains of TOOL and related UKU subscales were positive, significant and mild or moderate (Table 6).

Agents involved in health technology research have incorporated other important aspects to the basic aims of granting new treatments efficacy and safety, such as those related to patient subjective perception [9, 26]. There is published evidence on the appropriateness and accuracy of self-assessments or self-report evaluations in patients suffering from mental chronic illness [27‐29]. Despite this, however, recently published studies have focused on the side effects of antipsychotic drugs and their relationship with HRQoL by following mainly clinician criterion [30]. Few studies have tried to develop specific instruments to comprehensively quantify the impact of side effects on HRQoL based on the patient perspective. This objective should be of primary importance, taking into account the high prevalence of side effects in patients undergoing antipsychotic treatments and their relationship with adherence to treatment [5].

Our results show that the TOOL questionnaire presents adequate psychometric characteristics for use in patients with schizophrenia and bipolar disorder. The completion time of the questionnaire was low (<5 min) compared with longer questionnaires such as the UKU scale. Moderate-high correlations were found in both bipolar and schizophrenic patients between the TOOL and specific clinician-rated measures as the MADRS, PANSS, and YMRS, as well as a negative relationship with generic quality of life instruments (EQ-5 D and SF-6D), thus highlighting the convergent validity of this instrument. These correlations were also similar to those found in other studies analysing the association between generic and specific measures [31]. Criterion and discriminative validity were proven by the significant differences found in the TOOL between those patients with mild involvement and patients with moderate-severe symptoms. Thus, patients suffering a worse health status according to the CGI-S obtained higher scores in the TOOL, which indicates a more severe impact on their HRQoL, as has been previously underscored [32, 33].

The one-dimensional construct of the TOOL, along with its internal consistency and test-retest reliability, have been proven, thus allowing clinicians to obtain a simple and global score (ranging from 8 to 32) with the same interpretation in terms of severity as the generalised UKU scale.

Despite these results, this study presents some limitations that should be considered. A ceiling effect was observed in two items: stiffness-tremor and dizziness-nausea. This may be due to the idiosyncrasy of the population sample collected in the present study: clinically stable patients under drug treatment, based mainly on atypical antipsychotic agents. Although similar ceiling effects have been reported in other studies [31, 32], these items should be tested in further investigations with schizophrenic and bipolar patients showing a worse health status in order to test discriminative power. The characteristics of the sample may limit the scope of use of this measure. Therefore, it may be arguable whether patients with greater involvement (that is, patients with severe negative symptoms or patients suffering a maniac episode) could provide reliable reports when completing the questionnaire. Although there is evidence supporting the accuracy of such measurement, as has been commented above, the questionnaire should be applied within such populations to test its psychometrical properties. Secondly, it is necessary to analyse the sensitivity of the TOOL in detecting changes in longitudinal studies.

The Spanish validation of the TOOL questionnaire shows appropriate feasibility, reliability, and discriminative performance as a patient-reported outcome to be used for the assessment of the impact of side effects on patient health-related quality of life. This information could be very important to improve therapeutic alliances and treatment adherence among patients with schizophrenia and bipolar disorder.