Seren Roberts

Enhancing rigour in the validation of patient reported outcome measures (PROMs): bridging linguistic and psychometric testing

BackgroundA strong consensus exists for a systematic approach to linguistic validation of patient reported outcome measures (PROMs) and discrete methods for assessing their psychometric properties. Despite the need for robust evidence of the appropriateness of measures, transition from linguistic to psychometric validation is poorly documented or evidenced. This paper demonstrates the importance of linking linguistic and psychometric testing through a purposeful stage which bridges the gap between translation and large-scale validation.FindingsEvidence is drawn from a study to develop a Welsh language version of the Beck Depression Inventory-II (BDI-II) and investigate its psychometric properties. The BDI-II was translated into Welsh then administered to Welsh-speaking university students (n = 115) and patients with depression (n = 37) concurrent with the English BDI-II, and alongside other established depression and quality of life measures. A Welsh version of the BDI-II was produced that, on administration, showed conceptual equivalence with the original measure; high internal consistency reliability (Cronbach’s alpha = 0.90; 0.96); item homogeneity; adequate correlation with the English BDI-II (r = 0.96; 0.94) and additional measures; and a two-factor structure with one overriding dimension. Nevertheless, in the student sample, the Welsh version showed a significantly lower overall mean than the English (p = 0.002); and significant differences in six mean item scores. This prompted a review and refinement of the translated measure.ConclusionsExploring potential sources of bias in translated measures represents a critical step in the translation-validation process, which until now has been largely underutilised. This paper offers important findings that inform advanced methods of cross-cultural validation of PROMs.

Half-baked? B vitamins and depression

The study by Skarupski et al (1) in this issue of the Journal has made an important contribution to a long-running fascination with the associations between B vitamins and depression. Epidemiologic, observational, and case-control studies dating back to the 1960s have indicated a strong association between functional or absolute folate deficiency and depressive symptoms, symptom severity, and treatment outcomes in adults and the older adult population (2–6). Patients with depression are reported to have lower concentrations of folate than patients with other psychiatric disorders and nonpsychiatric comparison groups. Low folate concentrations are also associated with poor antidepressant response. These findings together with robust evidence of the role of folate in other disease areas, particularly in the prevention of neural tube defects, have prompted large-scale public health interventions, such as folate enrichment of flour in the United States and other countries. Yet, these interventions do not have an entirely benign risk-benefit profile and have led to criticism and concerns that they may be exposing the public to other potential health risks. Given the large-scale and high-profile public health interventions that flow from the interest in the role of B vitamins in mental health and other health areas, it is important to acknowledge that these associations are not clear cut. Up to now there has been less evidence available for the role of other B vitamins in depression. Vitamin B-12 has been shown to be associated with depression, with higher concentrations of vitamin B-12 reported to result in better treatment outcomes (7). Indeed, it has been proposed that vitamin B-12 has a stronger causal relation to depression than does folate (8), although, interestingly, low folate but not low vitamin B-12 significantly delays time to onset of clinical improvement in patients with depression compared with depressed patients with normal folate concentrations (9). There is limited evidence in relation to dietary intake of B vitamins, with much of the research focus placed on supplementation. Higher dietary intakes of folate but not of other B vitamins [including vitamins B-12, B-6, and B-2 (riboflavin)] and higher serum folate concentrations have been shown to be associated with a lower prevalence of depressive symptoms in men (10, 11). However, low folate status (12) and low vitamin B-12 intake (13) have also been associated with depressive symptoms in women. Vitamin B-12 deficiency is reported to increase the risk of severe depression in older women (14), but in one study, B vitamin supplementation had no effect on depression in women (15). Evidence suggests, however, that the older population in particular may benefit from B vitamin supplementation (16) because of the prevalence of disorders that reduce folate and vitamin B-12 and B-6 absorption. The current study by Skarupski et al (1) enhances our existing evidence base by presenting longitudinal findings of the association of B vitamin intake, through both diet and supplementation, with depressive symptoms in older adults. Importantly, the study findings do not support the association of folate intake either by supplementation or diet alone with depressive symptoms in this population. Neither do they report differences between sexes. However, the study provides compelling evidence of the protective effects of dietary intake and supplementation of vitamin B-12 against depression. The study also shows that vitamin B-6 intake through supplementation, but not through diet, may also have this protective effect. This contrasts with the limited available evidence on vitamin B-6 in depression (10, 14, 17). There is still much to be gleaned about the role of these vitamins in the pathogenesis and treatment of depression and indeed more generally in maintaining mental health. First, the role of dietary intake of these vitamins needs further exploration, even though the Skarupski et al study and others (1, 11, 13) come some way to this end. Second, the long-term mental health benefit of supplementation needs further investigation. The Skarupski et al study (1) has provided intriguing insights into this area with the older population, but this type of longitudinal research needs extending to the adult population. Third, the relative benefits of supplementation with naturally occurring vitamins compared with synthetic forms needs to be better understood in relation to depression, with very little evidence currently available in this area. There is still uncertainty as to thresholds to classify deficiency of these vitamins, with observations pointing to large individual differences in the metabolism of vitamins such as folate. There is also uncertainty about the best measurement of these vitamins with, for example, methylmalonic acid and red cell folate reported to be better markers of vitamin B-12 and folate status, respectively, but many studies fail to report these measures. Finally, the extent to which pretreatment folate

Higher dose L-methylfolate may be an effective adjunctive therapy for adults with major depression who have inadequate response to SSRIs

ED FROM Papakostas GI, Shelton RC, Zajecka JM, et al. (L)-methylfolate as adjunctive therapy for SSRI-resistant major depression: results of two randomized, double-blind, parallel-sequential trials. Am J Psychiatry 2012;169:1267–74. Correspondence to: Dr Papakostas,gpapakostas@partners.org Sources of funding: Both trials were funded by Pamlab. OM M EN TRY Folate is a B vitamin with an essential role in the biosynthesis of neurotransmitters, and implicated in the pathogenesis and treatment of depression. Low folate is associated with depression and a poorer response to antidepressants. Although evidence suggests sufficient folate protects against depressive symptoms, there is limited evidence to support folate alone as an effective treatment. Thus, the focus has been on folate as an adjunct to antidepressant treatments. With up to 50% of patients failing to respond adequately to antidepressants, folate is a potentially appealing means to enhance antidepressant efficacy. Papakostas and colleagues add to the growing body of evidence in favour of adjuvant folate and antidepressant therapy, particularly for treatment-resistant depression, although one relatively robust study showed no benefit of folic acid and other B vitamins in depression. Like previous studies, there are methodological limitations to this study, including a relatively small sample size, short treatment period and short duration of follow-up. Use of high doses of folate is also noteworthy given concerns that exposure to high doses accelerates tumour growth in people with a history of colorectal cancer. A strength of this study is the use of L-methylfolate instead of synthetic folic acid. On balance, one must be cautious in recommending adjunctive antidepressant treatment with folate as they have yet to be fully established: (a) any long-term risks and benefits of exposure to high doses, (b) a dose-response relationship, or (c) the optimal duration of treatment required. The evidence base needs large, pragmatic clinical trials to replicate promising results from small-sized and medium-sized studies. These must also measure the important individual differences in folate metabolism to determine if there are clinical subgroups who respond to folate augmentation and how to identify them. There is still much research to be carried out before we can safely recommend widespread adjuvant prescribing for depression. Seren H Roberts, Richard Tranter Institute of Medical and Social Care Research, Bangor University, Wrexham, UK; Kawai Clinic, Nelson Hospital, Nelson Marlborough DHB, Nelson, New Zealand Correspondence to Seren H Roberts, Institute of Medical and Social Care Research, Bangor University, Cambrian House, Archimedes Centre, Wrexham Technology Park, Wrexham, LL13 7YP, UK; seren. roberts@bangor.ac.uk Competing interests SHR and RTare principal investigators on a large NIHR HTA funded trial of folic acid augmentation of antidepressants (FolATED). REFERENCES 1. Ford AH, Flicker L, Thomas J, et al. Vitamins B12, B6, and folic acid for onset of depressive symptoms in older men: results from a 2-year placebo-controlled randomized trial. J Clin Psych 2008;69:1203–9. 2. Cole BF, Baron JA, Sandler RS, et al. Folic acid for the prevention of colorectal adenomas: a randomized clinical trial. JAMA 2007;297:2351–9. Evid Based Mental Health August 2013 Vol 16 No 3 75 Therapeutics