Title: Association between vitamin B12 levels and melancholic depressive symptoms. A Finnish population-based study

Transcription

1 Author's response to reviews Title: Association between vitamin B12 levels and melancholic depressive symptoms. A Finnish population-based study Authors: Jussi Seppala (jussi.seppala@esshp.fi) Hannu Koponen (hannu.koponen@kuh.fi) Hannu Kautiainen (hannu.kautiainen@medcare.fi) Johan G Eriksson (johan.eriksson@helsinki.fi) Olli Kampman (olli.kampman@uta.fi) Jaana Leiviskä (jaana.leiviska@thl.fi) Satu Männistö (satu.mannisto@thl.fi) Pekka Mäntyselkä (pekka.mantyselka@uef.fi) Heikki Oksa (heikki.oksa@pshp.fi) Yrjö Ovaskainen (yrjo.ovaskainen@kolumbus.fi) Merja Viikki (merja.viikki@uta.fi) Mauno Vanhala (mauno.vanhala@ksshp.fi) Version: 3 Date: 10 May 2013 Author's response to reviews: see over

2 BMC Psychiatry Kuopio May To the Editor Thank you for the opportunity to re-revise and improve our manuscript entitled ASSOCIATION BETWEEN VITAMIN B 12 LEVELS AND MELANCHOLIC DEPRESSIVE SYMPTOMS. A FINNISH POPULATION-BASED STUDY by Jussi Seppälä et al. Please find enclosed all the alterations and clarifications that we have made based on the reviewers`comments. You can check them also in the revised manuscript by track changes. Reviewer's report Title: Association between vitamin B12 levels and melancholic depressive symptoms. A Finnish population-based study Version: 2 Date: 2 March 2013 Reviewer: Henning Tiemeier Reviewer's report: Major compulsory revisions The effect seems to be only in the group with moderate depressive symptoms, not in those with more severe symptoms. Am I misinterpreting the figure or why did the authors not comment on this observation? The following text is added in the results section; please see page number 8: The vitamin B 12 levels were significantly lower in the sub-group of melancholic depressive symptoms scoring in the BDI. The finding is further discussed in the end of second paragraph of discussion; please see page number 9: In addition, the severity of DS is also relevant as the difference was significant only in the sub-group of mild to moderate depression i.e points in the BDI. Statistical reasons, such as a low

3 number of subjects, or a large variety of vitamin B 12 levels in the sub-group having BDI-scores 15 may have affected the significance of the result. The rationale for the selection of melancholic symptoms is not really sufficient despite the discussion. I would like to see some sensitivity analyses here and Reference to papers from other than the own Finnish research group.. Please see discussion;, paragraph numbers 5 and 6, and methods section. The available evidence suggest some clinical utility and some validity for the concept of melancholic features[44]. Depression with melancholic or nonmelancholic features can be established by using diagnostic interviews [45-46]. Instead,we used a summary score of melancholic symptoms in the BDI based on the DSM-IV- defined criteria for melancholic depression in order to examine the effect of the subtype of DS [33]. The way of dividing the DS into melancholic or non-melancholic DS has been applied in several previous studies as well [29,34-36]. Unfortunately, we were not able to present sensitivity analysis due to a dicotomous, and not a continuous method established in dividing DS into melancholic and non-melancholic DS. When using this method the subject had to score 2 or 3 points in each chosen item in order to have a positive item (a melancholic or a non-melancholic item). Factor analysis was not used because symtom composition of the resultant factors may be dependant of the types of samples being studied [33]. Furthermore, due to population-based design of the study the amount of subjects having lower scores in the BDI was high. A direct comparison of the melancholic and non-melancholic group is still lacking, see figure 1 A, can this be quantified? The following is added in results section, please see page number 8: The adjusted difference of vitamin B 12 levels between the nonmelancholic and the melancholic group was 33 pmol/l (95%CI 8 to 57, p = 0.008). My other points were addressed sufficiently.

4 One more point: Could the authors present continuous analyses of depressive symptoms? I guess the data is too skewed for an analyses over the whole range, but if it cannot be normalized perhaps this analyses can be conducted in a subgroup? This has been done; please see Figure 1C that shows non-linear quadric model of the vitamin B12 levels versus BDI score. Model adjusted using age, sex, use of antidepressive medication and chronic diseases. The gray band gives the 95% confidence intervals. Reviewer's report Title: Association between vitamin B12 levels and melancholic depressive symptoms. A Finnish population-based study Version: 2 Date: 25 March 2013 Reviewer: Martin Alda Reviewer's report: While the authors added one analysis that showed the vitamin B12 levels in relation to the "melancholic" symptoms and the overall severity of depression measured by BDI, they have not not addressed the comments about arbitrariness of their chosen cut-off points for the severity of depression. Pease see the following text in the discussion section (page 9).. In addition, the severity of DS is also relevant as the difference was significant only in the sub-group of mild to moderate depression i.e points in the BDI. The cut-off points for BDI tertiles were selected according to previous studies suggesting BDI-score of 10 [25,26 ] or 14 as proper cut of values [38,39].

5 A scatter plot and/or analyzing the data as continuous variables might be more illustrative (or at least testing different cut-off points to test the sensitivity of the results to these arbitrary decisions. Similarly, the B12 levels if analyzed as a categorical variable should take into account if they are low (abnormal) versus normal. Likewise, the authors have not dealt with the definition of "melancholic" - again based on dichotomous split. This has been done; please see Figure 1C that shows non-linear quadric model of the vitamin B12 levels versus BDI score. Model adjusted using age, sex, use of antidepressive medication and chronic diseases. The gray band gives the 95% confidence intervals. Please see also discussion, paragraph numbers 5 and 6, and methods section. The available evidence suggest some clinical utility and some validity for the concept of melancholic features[44]. Depression with melancholic or nonmelancholic features can be established by using diagnostic interviews [45,46]. Instead,we used a summary score of melancholic symptoms in the BDI based on the DSM-IV- defined criteria for melancholic depression in order to examine the effect of the subtype of DS[33]. The way of dividing the DS into melancholic or non-melancholic DS has been applied in several previous studies as well [29,34-36]. Unfortunately, we were not able to present sensitivity analysis due to a dicotomous, and not a continuous method established in dividing DS into melancholic and non-melancholic DS. When using this method the subject had to score 2 or 3 points in each chosen item in order to have a positive item (a melancholic or a non-melancholic item). Factor analysis was not used because symtom composition of the resultant factors may be dependant of the types of samples being studied [33]. Furthermore, due to population-based design of the study the amount of subjects having lower scores in the BDI was high.

6 Finally, the list of refrerences was updated. We hope that the revised manuscript could be considered for publication in the BMC Psychiatry. Sinc. Jussi Seppälä M.D., Ph.D. South-Savo Hospital District Tel Fax