Author's response to reviews Title: Prevalence and sociodemographic associations of common mental disorders in a nationally representative sample of the general population of Greece Authors: Petros Skapinakis (p.skapinakis@gmail.com) Stefanos Bellos (bellos.stefanos@gmail.com) Sotirios Koupidis (sotirioskoupidis@yahoo.gr) Ilias Grammatikopoulos (ilias17grams@gmail.com) Pavlos N Theodorakis (theodorakispavlos@gmail.com) Venetsanos Mavreas (vmavreas@cc.uoi.gr) Version: 3 Date: 22 April 2013 Author's response to reviews: see over
Response to reviewers and list of changes regarding MS #7831633818871049: Prevalence and sociodemographic associations of common mental disorders in Greece: Cross-sectional study in a nationally representative sample of the general population by Skapinakis et al., submitted to BMC Psychiatry. We would like to thank both reviewers and the editor for reading and commenting on our paper. In the next paragraphs we give details on how we responded to their comments. Please note that changes to the manuscript have been highlighted with yellow. Reviewer #1: Professor Rachel Jenkins Minor Essential Revisions Point 1: The authors say full detail of the sampling procedures and sampling distribution in each regional health authority are available from the detailed technical reports submitted to the Ministry of Health and are available by the authors on request. But more information does need to go into this paper, as is usual for the reporting of epidemiological surveys. 1a: What was the projected sample size? 1b: Eg What was the sampling fraction for stage 1? 1c: What were the building blocks referred to in this sentence At the first stage a random sample of building blocks was selected proportionally to size based on the 2001population census. 1d: What was the sampling fraction for stage 2? 1e: At the second stage, households within the selected blocks were selected using systematic sampling, and how did the systematic sampling vary from random sampling? Response 1: Thank you very much for this comment. Sampling methodology was designed and implemented by MRB Hellas. This a leading market, social and political research agency in Greece. It is a founder member of the Association of Greek Market & Opinion Research Companies and has 1
substantial experience in conducting nationwide surveys of social or political issues, including public opinion polls of voting intentions using representative samples of the general adult population of Greece. More specifically, regarding the sampling methodology: the primary sampling units (PSUs) were the enumerator areas (one or more unified city blocks) based on the 2001 census survey, the secondary sampling units selected in each primary unit were the households and the ultimate sampling units were the individuals, selected from eligible members of the sampled households. The primary sampling units were first stratified by allocating the Municipalities and Communes included in each Region according to the degree of urbanization. Except for the two Major City Agglomerations (Athens and Thessaloniki), the produced strata according to the degree of urbanization were: Stratum 1: Urban areas defined as municipalities with 10,000 inhabitants or more. Stratum 2: Semi-urban areas defined as municipalities and communes with 2,000 to 9,999 inhabitants. Stratum 3: Rural areas, defined as communes with up to 1,999 inhabitants. Stratification for Athens and Thessaloniki were different: The Greater Athens Area was divided into 31 strata of about equal size (equal number of households) on the basis of the lists of city blocks of the Municipality of Athens. Similarly, the Greater Thessaloniki Area was divided into 9 equally sized strata. The national population size for households and individuals aged 18-70 (based on 2001 population census and excluding Crete which was not sampled) was approximately: Households: 3,168,000 private households Individuals: 7,200,000 individuals aged 18 70. Sampling frame: The sampling frame of the primary units (enumerator areas) was based on the data from the last population census of the year 2001. 2
The sampling frame containing the secondary units (households) in the selected sampling primary units was a list of households updated before the selection of households. Sampling fraction and sample size: The projected sample size n of individuals was defined by applying the following formula: n= [((1-p)/p)/cv 2 (p) + 1/N*((1-p)/p)] * deff where p= the proportion of a subgroup population (p=0.02) cv(p) = the coefficient of variation of p (cv(p)=0.1) N: the population size (N=7,200,000) deff: the design effect (deff = 2) This was estimated to approximately 9800 individuals. Given an expected participation rate of approximately 40% (including immediate refusals, dropouts etc) we anticipated a final sample size of 5900 (which was smaller given the lower response rate) The sampling fraction 1/λ was 0.085% for individuals and 0.19% for households. The sampling fraction of households in each stratum was considered constant and equal to 1/λ. Multistage sampling: 1 st stage: In this stage, from any ultimate stratum (crossing of region with the degree of urbanization), say stratum h, n h primary units were drawn. The number of draws was approximately proportional to the population size X h of the stratum (number of households in 2001 census). Each area unit (primary unit) of the stratum has a probability of being selected proportional to its size. The total number of primary sampling units selected were approximately 400 enumerator areas. 2 nd stage: In this stage from each selected area (PSU) the sample of secondary units (households) was selected. Actually, in the second stage we drew a random systematic sample of dwellings (however, in most cases, one household corresponds to each dwelling). Systematic sampling is a statistical method involving the selection of elements from an ordered sampling frame. The sampling starts by selecting an element from the list at random and then every kth element in the frame is selected, where k, the sampling interval. Let M hi be the number of households during the survey period in the i selected area of the stratum h. Out of them a systematic sample of m hi households was selected with equal probabilities. Each of m hi households had a 3
known and same probability to be included in the survey, equal to m hi / M hi. This makes systematic sampling functionally similar to simple random sampling. In any selected primary unit, the sample size m hi was determined from the sampling interval δhi = M hi / m hi which was calculated using data from the 1 st stage. For the random starting point, maps of the selected enumerator areas were used. 3 d stage: At this stage one member (aged 18-70) of the sampling household was selected using simple random sampling (table of random numbers). In response to this point, in the revised manuscript we have made the following changes regarding the description of the sampling procedure: Sampling methodology was designed and implemented by a research agency in Greece with substantial experience in conducting nationwide surveys of social or political issues using representative samples of the general adult population of Greece. According to the latest Population Census (2001) the survey population consisted of approximately 7,200,000 individuals. A three-stage sampling design was used with enumerator areas (one or more unified city blocks) based on the 2001 census survey selected at the first stage, households within the selected areas at the second stage and individuals within the households at the third stage. The primary sampling units (enumerator areas) were first stratified by allocating the Municipalities and Communes included in each Region according to the degree of urbanization (stratum 1: urban areas; stratum 2: semi-urban; stratum 3: rural areas). The stratification for the two major cities, Athens and Thessaloniki, were different (Athens was divided into 31 strata of equal size and Thessaloniki into 9 strata). The projected sample size for the whole survey was 9,800 individuals with a sampling fraction 1/λ for each stratum considered constant and equal to 0.085%. At the first stage of the sampling procedure primary sampling units (enumerator areas) had a probability of being selected proportional to their size (number of households according to the 2001 census). At the second stage. from each 4
selected area (primary sampling unit) the sample of secondary units (households) was selected. Actually, in the second stage a random systematic sample of households was drawn. Systematic sampling is functionally similar to random sampling because each element (household) had a known and equal probability to be selected. Systematic sampling starts by selecting a random starting point (using maps of the enumerator areas) and then every kth element in the sampling frame is selected, where k is the sampling interval. In any selected primary unit, the sample size was determined from the sampling interval which was calculated using data from the 1st stage. At the third stage one eligible member (aged 18-70 years) of the household was selected using simple random sampling. Point 2: Results - there are some sentences here which are not clear 2a: Cannabis use during the past month was less common at 2.06% (95% CI: 1.66 2.46) and it was also more common in men. This is a confusing sentence suggest delete less common at OR say less common than alcohol consumption Response: Thank you. This sentence was changed to: The prevalence of cannabis use during the past month was 2.06% (95% CI: 1.66 2.46) 2b: For depression, female gender, being divorced/separated or widowed and being unemployed were associated with an increased prevalence, while having a better education with a lower (p=0.024 for the linear trend in education). This is also confusing. Suggest add prevalence after lower to ease understanding. Response: We added the term prevalence after the lower. 2c: Presence of a chronic severe medical condition was also strongly associated with both depression or anxiety disorders but not harmful alcohol use. Suggest add With to harmful alcohol use Response: Thank you. We added with as suggested by the reviewer. 5
2d: this creates a plasmatic association between older age and depression or anxiety that is due to the confounding effect What does plasmatic mean?? Perhaps use another word Response: Apologies for using the nice ancient Greek word plasmatic ( plasmatikon ) which means spurious or fictitious (but it is perhaps one of the few that have not been borrowed yet by the international scientific language!). This word was first used in the context of mathematics by Diophantus of Alexandria, sometimes called the father of Algebra, in his treatise: Arithmetica (for more details, please look at the Meaning of plasmatikon in Diophantus Arithmetica, by Fabio Acerbi (2009). Archive for History of Exact Sciences 2009; 63:5-31 available at: http://hal.archives-ouvertes.fr/docs/00/34/61/21/pdf/plasmatikonacerbifinal.pdf). In the revised manuscript this sentence now reads: this creates a spurious association between older age and depression or anxiety that is due to the confounding effect 2e: The Greek health system is still physician-centred and autonomy or involvement in care of other health professionals including nurses is not yet encouraged This sentence is not clear. Could say still physician centred rather than multidisciplinary?? Response: Thank you for your suggestion, we changed the sentence accordingly. 2f: The Russian example during the 90s is quite didactic with an increase in mortality due to vascular diseases and harmful alcohol use This sentence is not clear, and the word didactic would not seem t be appropriate Response: we changed the word didactic to informative and we also rewrote the sentence that now reads: The Russian example during the 90 s is quite informative: the mortality fluctuations observed there during the 90 s were mainly due to changes in mortality from vascular diseases and harmful alcohol use. Reviewer #2: Dr Yuan-Pang Wang 6
Major Compulsory Revisions Point 1. The report could be shortened to answer the main objectives, by presenting directly the core findings. Similarly, the discussion (9 out of 20 pages of text) should highlight only the main results in contrast with previous literature and related studies. Therefore, the Discussion should be reduced. Response 1: We agree that the discussion could be shortened. On the other hand, it should be noted that this is the first nationwide survey of common mental disorders in Greece using a fully-structured psychiatric interview. Due to the recent financial crisis there is an interest for health data from Greece and we thought we should give some more details on how are results differ from previously published studies in Greece and also to put our findings into their wider context in Europe and the World. BMC Psychiatry, is a digital-only archive and contrary to the printed Journals, space may not be thus important. In any case, we shortened the discussion by 15% by reducing material which we felt was not necessary (word count for the discussion was approximately 2700 in the first version, and this was reduced by 15% to 2300). We have also omitted some figures as suggested (see below in discretionary revision). The authors would like to thank in advance the reviewer for his understanding. Point 2. I missed the ethical statements for this report. Response: We had included the ethical statement in the Description of the Sample and Data Collection Sub-section of the Methods section: Ethical approval for the study was provided from the Ministry of Health. All participants provided verbal informed consent for their inclusion in the study. B. Minor Essential revisions Point 3: Table 1, was the prevalence rates weighted? Response 3: Yes they were, in the revised version we have indicated that prevalence rates are weighted. Point 4: Inform the p-value for men vs. women comparison for Table 1; and Health status for Table 2. 7
Response 4: Thank you for your suggestion, we have now included this information in both tables. In Table 1, we have added a separate column showing all p-values. In Table 3 we have indicated all p-values<0.05 for EQ-5D (for the comparison between pure and comorbid disorders) and for the use of mental health services (for the comparison between pure and comorbid diagnosis). Due to the complexity of this table we did not add a separate column but we indicated p-values in the footnote, at the bottom of the table. Point 5: Also, improve the multivariate regression models to control for the effect of confusion (e.g., page 11, Figure 3, 3a, 3b), with further discussion. Response: Please note, that all odds ratios of the multivariate regression model presented in Table 3 are fully adjusted for all other variables of the table. Therefore, we have taken into account the effect of chronic physical disorders in older age or the effect of all other variables of the table. For comparison, we have also presented the crude odds ratios in the supplement. In a footnote at the bottom of Table 3, we have indicated that all odds ratios are adjusted for all other variable of the table, so we hope there is no confusion to the reader any more. - Minor Essential Revisions Point 1. Title: Suggest shorten the title. Cross-sectional study is unnecessary, as prevalence already indicates the study design. Response: Thank you for your suggestion. The title has now been revised to: Prevalence and sociodemographic associations of common mental disorders in a nationally representative sample of the general population of Greece Point 2. Abstract: 2a Do report prevalence of smoking and cannabis use in the Results. Response: we have added this information: Regular smoking was reported by 39.60% of the population (38.22, 40.97) while cannabis use (at least once during the past month) by 2.06% (1.66, 2.46). 2b Harmful alcohol use s confidence interval replace 13,62 by 13.62. Response: Thank you! We have corrected this. 8
2c. Suggest keep all prevalence rates in the first part of the Results, and then report socio-demographic associations. Response: we re-arranged the results section of the abstract accordingly 14% of the population (Male: 11%, Female: 17%) was found to have clinically significant psychiatric morbidity according to the scores on the CIS-R. The prevalence (past seven days) of specific common mental disorders was as follows: Generalized Anxiety Disorder: 4.10 % (95% CI: 3.54, 4.65); Depression: 2.90 % (2.43, 3.37); Panic Disorder: 1.88 % (1.50, 2.26); Obsessive-Compulsive Disorder: 1.69 % (1.33, 2.05); All Phobias: 2.79 % (2.33, 3.26); Mixed anxiety-depression: 2.67 % (2.22, 3.12). Harmful alcohol use was reported by 12.69 % of the population (11.75, 13.62). Regular smoking was reported by 39.60% of the population (38.22, 40.97) while cannabis use (at least once during the past month) by 2.06% (1.66, 2.46). Clinically significant psychiatric morbidity was positively associated with the following variables: female gender, divorced or widowed family status, low educational status and unemployment. Use of all substances was more common in men compared to women. Common mental disorders were often comorbid, undertreated, and associated with a lower quality of life. Point 3. Background: 3a. Suggest include a more recent publication on the burden of disease, e.g., Vos et al. Lancet (2013) Vos T, Flaxman AD, Naghavi M, Lozano R, Michaud C, Ezzati M, Shibuya K, Salomon JA, Abdalla S, Aboyans V et al: Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2013; 380(9859): 2163-2196. Response: Thank you very much for this suggestion. We have added the more recent citation in our list. 3b. Suggest collapsing the first two paragraphs of Background in a more straightforward manner. Response: Thank you for the suggestion, we merged the two paragraphs into one. 9
3c. Please also mention the ESEMeD/MHEDEA consortium survey than relying on Wittchen s review. Response: Thanks for the suggestion. We have also cited the WMH survey (Kessler et al. 2009) earlier in the manuscript at number 6 just after the Wittchen review. 3d. After enumerating the gap of epidemiological surveys in Greece, the authors may want list the aims in a separated paragraph, for clarity purpose. Response: the aims are now in a separate paragraph. Point 4. Methods: 4a. page 5 is a long paragraph on the sampling and data collection. Splitting this description in 2 or 3 paragraphs can improve the readability of the procedure. Response: We have re-organized this section adding subheadings, as one of the reviewers also asked for some more detail of the sampling procedure. We think that readability is now quite improved. 4b. Page 5. The instruments were computerized, but have the participants selfreported all the answers directly in a laptop screen? Please clarify. Response: If you noticed, just below this line we wrote that Approximately 35% of the participants entered their data into the laptop without any further assistance from the interviewer after the first guidance. The remaining 65% required some help from the interviewer. We hope this clarifies your point. Participants that were not very familiar with PCs read the questions through the computer monitor and asked the interviewer to select from the menu the appropriate answer. 4c. Page 6, paragraph 2: typing error for Post-sratification weights. The weighting procedure should be moved to statistical analysis section. Response: done 4d. Provide additional description on the questions on smoking and cannabis use. Response: We have now added this information in the relevant section Assessment of Substance Use subsection of the Methods section: 10
Regarding smoking, participants were asked to report the average number of cigarettes they smoked per day during the past month. A second question asked the participants to classify themselves into one of the following smoking history categories: never-smoker, ex-smoker, occasional / light smoker, moderate smoker, heavy smoker. We combined those two questions to define a binary variable of regular smoker in the past 30 days (all those who were at least moderate smokers OR reported more than 2 cigarettes per day on average during the past month). Regarding cannabis, we asked two questions, the first for lifetime use (five categories: never, 1-2 times, 3-10 times, >10 times / regular use, do not wish to reply) and the second for past 30 days use ( have you used cannabis during the past 30 days? with three possible answers: Yes, No, do not wish to reply). We classified participants as users of cannabis during the past 30 days if they replied yes to the second question OR reported regular use to the first. 4e. Do inform the cutoff of adopted EQ-5D and/or psychometric properties. This is important to aid the reader in the interpretation of the results. Response: Please note that we have not used any cutoff values for EQ-5D, we just reported the mean values (and standard deviation) of the EQ index in the different groups of disorders and in healthy individuals. Therefore, all the information necessary to interpret the results is shown in Table 2. The mean value (SD) of the EQ- 5D was very similar to the values reported in the Greek validation study (Kontodimopoulos et al. 2008): 0.82 (0.23) in the present study vs. 0.80 (0.27) in the validation study. As it is evident in table 2, the EQ index discriminated well between healthy and non-healthy individuals. Alpha values for the five items was 0.54 but excluding the mental health item (anxiety/depression) this increased to 0.63. The spearman correlation coefficient between the EQ index and the EQ visual analogue scale was 0.48 (p<0.001). Spearman correlation between the mental health item and the total score on the CIS-R score was 0.50 (p<0.001). 4f. Page 7: I missed the description of how the psychopathology was classified into mild or severe. This criterion is important to understand the Figure 1b. Response: Thank you for pointing this out. We have added this information in the relevant subsection of the Methods section: 11
For the dimensional assessment, we have defined four groups of severity based on previous work with the UK and Greek samples [8, 9, 15]: no/minimal symptoms (CIS-R score=0-5), subthreshold symptoms (CIS-R score=6-11), mild symptoms (CIS-R score=12-17) and severe symptoms (CIS-R score >=18). A score on the CIS-R 12 (by combining the last two groups into one) is usually considered as the cut-off for clinically significant psychiatric morbidity [8, 9, 15]. 5. Results: 5a. Sample: The authors indicated that as expected the participants were married and employed. The expectation was based on a previous census? Response: Yes, based on the previous census. However, we agree that this expression is not informative and therefore in the revision we omitted it. 5b. The rate of 40% of participants who were not currently employed is very high for an adult population; did it include either unemployed or inactive population (page 8)? On Table S1, what does mean other economically inactive? Clarify this point in the text. Response: It can be seen from table 3 that those who were not employed were grouped into four groups: looking after the house, the retired, the unemployed and other economically inactive. These four groups accounted for approximately 40% of the population. The most common categories were those looking after the house (~ 14% of the total population) and the retired (~ 12% of the total population). The unemployed were approximately 4%. From the remaining 10% (referred to in the table as other economically inactive ) the majority (~6%) were either students or doing their military service (this is mandatory for all young male in Greece). Approximately 1.5% reported that they were living with parents or not living on their own, 0.5% reported that they were unable to work due to disability, illness or other reason and 0.5% that they were living on income from other sources (e.g. rents, shares etc). The remaining did not select any specific reason for their economic inactivity. In response to this point we have added the following text in the relevant subsection of the Methods section: 12
Regarding employment status, we distinguished between unemployment (i.e. the participant did not do any paid work but looked for any kind of paid work in the past 4 weeks) and economic inactivity (the participant did not do any paid work but did not look for any paid work in the past 4 weeks; additional questions clarified the reason for not seeking any work: a) looking after the house, b) retired, and c) a residual category of other economically inactive (including students, persons doing their mandatory military service, those living with parents, those unable to work, living on other income such as rents or shares and other non-specific reasons). 5c. Table 1: As informed in the legend, the last row CIS-R 12 the superscript 1 should be 2? Response: Thank you for pointing this out. We have corrected the superscript from 1 to 2. 6. The Discussion is long and digressive. Should address the main findings and compare with similar studies. Bearing in mind the main objectives, after summarizing the core findings, start to discuss the convergent and divergent results with the literature, as well as the reason why the authors reached to the conclusions. Response: We have dealt with this comment in our response to your first point. In summary, we have shortened the discussion by 15% by reducing material which we felt was not necessary (word count for the discussion was approximately 2700 in the first version, and this was reduced by 15% to 2300). We have also omitted two figures as suggested (see below in discretionary revision). 7. Some additional limitations should be noted for this survey: (a) there is no formal assessment of health-related disability, unless the authors assume the health status EQ-5D as proxy-assessment of disability; Response: We think that EQ-5D is a proxy of disability. However, please note that the main psychiatric interview (CIS-R) has three questions in the end to assess impairment in functioning due to the reported symptoms. These are: Now I would like to ask you how all of these things that you have told me about have affected you overall. 13
1. In the past week, has the way you have been feeling ever actually stopped you from getting on with things you used to do or would like to do? 2. In the past week, has the way you have been feeling stopped you doing things once or more than once? 3. Has the way you have been feeling made things more difficult even though you have got everything done? Therefore, we have taken this into account in the diagnostic criteria. In the Measurement of Psychiatric Morbidity subsection of the Methods section, we have added that: Additional questions, including questions assessing the impairment of functioning, enable the diagnosis of six common mental disorders (b) use of non-formal health services, e.g., folk-healer, social workers, nursing service, religious advisors etc seemed to be disregarded in the survey; Response: Please note that we have asked about non-formal services. However, we noted in the discussion that: An analysis of the correlates of service use is beyond the scope of the current paper and it will be explored in more detail in future reports.. Therefore, we will explore these issues in a future, more detailed paper, that is under preparation. (c) The self-reported chronic physical illness is of concern, as well as the retrospective report of chronicity of the disorders, that would be prone to recall bias (e.g., Figure 5). Response: Your point is correct, we have added this limitation in the revision: Chronic physical illnesses were assessed crudely by self-report and this will be inaccurate. In addition, the duration of psychiatric symptoms was retrospectively assessed and there is a risk for recall bias which could lead to overestimation depending on the severity of the current episode of illness. - Discretionary Revisions 1. Results: It is usual for publications in the field presenting the results in Tables, with respective SE and/or 95%CI. The Tables are important sources for further comparison with similar articles. I think that the numerical Tables of OR and 95%CI are more 14
informative than Figures. Probably the figures can be considered supplementary material. Anyhow, it is interesting indicate significant difference in the histogram by an asterisks (*). Response: In the revised version we have omitted some figures that we thought less interesting or important and we have moved them to the supplement. Regarding asterisks, it is our choice not to indicate significant differences in figures, because these are crude, unadjusted, differences and sometimes they transfer the wrong message, especially in the case of gender differences. We prefer to report point estimates and 95% CIs in the tables rather than p-values for the same reason. Thank you for your understanding. 15