Life is pain: Fibromyalgia as a nexus of multiple liability distributions.

Fibromyalgia is a complex disease of unclear etiology that is complicated by difficulties in diagnosis, treatment, and clinical heterogeneity. To clarify this etiology, healthcare-based data are leveraged to assess the influences on fibromyalgia in several domains. Prevalence is less than 1% of females in our population register data, and about 1/10th that in males. Fibromyalgia often presents with co-occurring conditions including back pain, rheumatoid arthritis, and anxiety. More comorbidities are identified with hospital-associated biobank data, falling into three broad categories of pain-related, autoimmune, and psychiatric disorders. Selecting representative phenotypes with published genome-wide association results for polygenic scoring, we confirm genetic predispositions to psychiatric, pain sensitivity, and autoimmune conditions show associations with fibromyalgia, although these may differ by ancestry group. We conduct a genome-wide association analysis of fibromyalgia in biobank samples, which did not result in any genome-wide significant loci; further studies with increased sample size are necessary to identify specific genetic effects on fibromyalgia. Overall, fibromyalgia appears to have strong clinical and likely genetic links to several disease categories, and could usefully be understood as a composite manifestation of these etiological sources.

Sibling alcohol use disorder is associated with increased risk for suicide attempt.

The association between having a sibling diagnosed with alcohol use disorder (AUD) and risk for suicide attempt may be attributable to shared genetic liability between AUD and suicidal behavior, effects of environmental exposure to a sibling's AUD, or both. To distinguish between these alternatives, we conducted a series of Cox regression models using data derived from Swedish population-based registers with national coverage. Among full sibling pairs (656,807 males and 607,096 females), we found that proband risk for suicide attempt was significantly elevated when their sibling was affected by AUD, even after accounting for the proband's AUD status. Further, risk for proband suicide attempt was consistently higher when the sibling's AUD registration had occurred more recently. Our findings provide evidence for exposure to sibling AUD as an environmental risk factor for suicide attempt and suggest that clinical outreach may be warranted following a sibling's diagnosis with AUD.

Oral contraceptive use and risk of suicidal behavior among young women.

BACKGROUND: Oral contraceptive use has been previously associated with an increased risk of suicidal behavior in some, but not all, samples. The use of large, representative, longitudinally-assessed samples may clarify the nature of this potential association. METHODS: We used Swedish national registries to identify women born between 1991 and 1995 (N = 216 702) and determine whether they retrieved prescriptions for oral contraceptives. We used Cox proportional hazards models to test the association between contraceptive use and first observed suicidal event (suicide attempt or death) from age 15 until the end of follow-up in 2014 (maximum age 22.4). We adjusted for covariates, including mental illness and parental history of suicide. RESULTS: In a crude model, use of combination or progestin-only oral contraceptives was positively associated with suicidal behavior, with hazard ratios (HRs) of 1.73-2.78 after 1 month of use, and 1.25-1.82 after 1 year of use. Accounting for sociodemographic, parental, and psychiatric variables attenuated these associations, and risks declined with increasing duration of use: adjusted HRs ranged from 1.56 to 2.13 1 month beyond the initiation of use, and from 1.19 to 1.48 1 year after initiation of use. HRs were higher among women who ceased use during the observation period. CONCLUSIONS: Young women using oral contraceptives may be at increased risk of suicidal behavior, but risk declines with increased duration of use. Analysis of former users suggests that women susceptible to depression/anxiety are more likely to cease hormonal contraceptive use. Additional studies are necessary to determine whether the observed association is attributable to a causal mechanism.

Does Neighborhood Alcohol Availability Moderate the Impact of Familial Liability and Marital Status on Risk for Alcohol Use Disorders? A Swedish National Study.

OBJECTIVE: The purpose of this study was to determine whether ease of access to alcohol at the neighborhood level moderates the impact of familial liability and marital status on risk for alcohol use disorder (AUD). METHOD: Individuals in Sweden were divided into those residing in a neighborhood with (n = 14.1%) versus without (n = 85.9%) an alcohol outlet (bars/nightclubs or government stores). AUD was detected through national medical, legal, and pharmacy registries. Using an additive model predicting AUD registration over 5 years in 1,624,814 individuals, we tested for interactions between the presence of outlets in the individuals' neighborhoods and familial risk for externalizing syndromes and marital status. RESULTS: In both males and females, we found positive and significant interactions in the prediction of AUD between the presence versus absence of a nearby alcohol outlet with (a) familial risk and (b) single and divorced versus married status. Similar but nonsignificant interactions were seen between nearby outlets and widowed versus married status. These results changed little when all cases with prior AUD were removed from the sample. For males, most of the interaction arose from the proximity of bars/nightclubs, whereas for females the results varied across different kinds of outlets. CONCLUSIONS: Environments that provide easy access to alcohol augment the impact of a range of risk factors for AUD, especially familial vulnerability and the reduced social constraints associated with single, divorced, and widowed marital status.

Modeling Etiology of Smoking During Pregnancy in Swedish Twins, Full-, and Half-Siblings, Reared Together and Apart.

INTRODUCTION: Using Swedish nationwide registry data, we investigated the contribution of genetic and environmental risk factors to the etiology of smoking status across stages of pregnancy with increasing degrees of social and psychological pressure to reduce or quit smoking, by twin and sibling modeling. AIMS AND METHODS: Smoking status was available before, and during early and late pregnancy from the Medical Birth Register. Twin, full-, and half-sibling pairs, both reared together and apart, born between 1960 and 1990 were obtained from national twin and genealogical registers. Genetic structural equation modeling in OpenMx was applied to the population-based data to estimate shared genetic and/or environmental covariance across stages of pregnancy, accounting for maternal birth cohort and age at pregnancy. RESULTS: Analyses of paired data on 258 749 individuals suggested that risk factors for smoking status changed across stages of pregnancy. Results predicted substantial heritability (60-70%) and moderate contributions of shared environmental factors (10-15%) for smoking status. Whilst the same shared environmental factors were amplified from before pregnancy to late pregnancy, new primarily unique environmental factors explained ~10% of the variance during early pregnancy which was carried forward to late pregnancy. CONCLUSIONS: Using registry data on women across pregnancy, we replicated that smoking status is highly heritable. Furthermore, we found support for increased impact of shared environmental factors during pregnancy of factors already present prior to pregnancy, and an independent set of mostly new unique environmental factors that may be triggered by increased social pressure to reduce or quit smoking during pregnancy. IMPLICATIONS: As new factors partially explain smoking status during pregnancy and the effects of familial factors increase across pregnancy, efforts to prevent or reduce smoking during pregnancy should receive continued attention, with a focus on both the individual and the family unit.

Accumulated neighbourhood deprivation and coronary heart disease: a nationwide cohort study from Sweden.

OBJECTIVE: Neighbourhood deprivation is a recognised predictor of coronary heart disease (CHD). The overall aim was to investigate if accumulated exposure to neighbourhood deprivation resulted in higher odds of CHD. DESIGN: This is a longitudinal cohort study. Models based on repeated assessments of neighbourhood deprivation as well as single-point-in-time assessments were compared. SETTING: Sweden. PARTICIPANTS: 3 140 657 Swedish men and women without a history of CHD and who had neighbourhood deprivation exposure data over the past 15 years. PRIMARY OUTCOME MEASURES: CHD within 5 years' follow-up. RESULTS: The results suggested a gradient of stronger association with CHD risk by longer cumulative exposures to neighbourhood deprivation, particularly in the younger age cohorts. Neighbourhood deprivation was also highly correlated over time, especially in older age cohorts. CONCLUSIONS: The effect of neighbourhood deprivation on CHD might depend on age. Accounting for individuals' baseline age may therefore be important for understanding neighbourhood environmental effects on the development of CHD over time. However, because of high correlation of neighbourhood deprivation over time, single-point-in-time assessments may be adequate for CHD risk prediction especially in older adults.

Is familial risk for depression confounded by individual and familial socioeconomic factors and neighborhood environmental factors? A 7-year follow-up study in Sweden.

Family history of depression is an important risk factor for depression. The aim of this study was to examine whether the effect of family history of depression is confounded by individual and familial socioeconomic factors (i.e., country of origin, educational attainment, family income and mobility) and neighborhood environmental factors (i.e., neighborhood deprivation and neighborhood social capital). The study population comprised 188,907 individuals aged 20-44 years from a nationwide sample of primary care centers in Sweden. Among these individuals, 22,014 with a first event of depression (6,486 men and 15,528 women) were identified during the 7-year follow-up period. Family history of depression was defined as depression in at least one parent. Cross-classified multilevel logistic regression models were used to calculate odds ratios with 95% credible intervals. Increased familial odds were observed after adjustment for individual and familial socioeconomic factors and neighborhood environmental factors for both men and women. Our results suggest that family history of depression is an independent risk factor for depression. Offspring of parents with depression are important targets for disease prevention, regardless of individual and familial socioeconomic factors and neighborhood environmental factors.

The Origin of Spousal Resemblance for Alcohol Use Disorder.

Importance: Although spouses strongly resemble one another in their risk for alcohol use disorder (AUD), the causes of this association remain unclear. Objectives: To examine longitudinally, in first marriages, the association of a first registration for AUD in one spouse with risk of registration in his or her partner and to explore changes in the risk for AUD registration in individuals with multiple marriages as they transition from a spouse with AUD to one without or vice versa. Design, Setting, and Participants: Population-wide Swedish registries were used to identify individuals born in Sweden between 1960 and 1990 who were married before the end of study follow-up on December 31, 2013. The study included 8562 marital pairs with no history of AUD registration prior to their first marriage and an AUD registration in 1 spouse during marriage and 4891 individuals with multiple marriages whose first spouse had no AUD registration and second spouse did or vice versa. Final statistical analyses were conducted from August 15 to September 1, 2017. Exposures: A spousal onset or history of AUD registration. Main Outcomes and Measures: Alcohol use disorder registration in national medical, criminal, or pharmacy registries. Results: Among the 8562 marital pairs (5883 female probands and 2679 male probands; mean [SD] age at marriage, 29.2 [5.7] years) in first marriages, the hazard ratio of AUD registration in wives immediately after the first AUD registration in their husbands was 13.82, which decreased 2 years later to 3.75. The hazard ratio of AUD registration in husbands after the first AUD registration in their wives was 9.21, which decreased 2 years later to 3.09. Among the 4891 individuals with multiple marriages (1439 women and 3452 men; mean [SD] age at first marriage, 25.5 [4.2] years), when individuals transitioned from a first marriage to a spouse with AUD to a second marriage to a spouse without AUD, the hazard ratio for AUD registration was 0.50 (95% CI, 0.42-0.59) in women and 0.51 (95% CI, 0.44-0.59) in men. After a first marriage to a spouse without AUD, the hazard ratio for AUD with a second marriage to a spouse with AUD was 7.02 (95% CI, 5.34-9.23) in women and 9.06 (95% CI, 7.55-10.86) in men. These patterns were modestly attenuated when moving from second to third marriages. Controlling for AUD registration prior to first marriage or between first and second marriages produced minimal changes in risk. Conclusions and Relevance: The increase in risk for AUD registration in a married individual following a first AUD registration in the spouse is large and rapid. When an individual with serial spouses is married, in either order, to partners with vs without an AUD registration, the risk for AUD registration is substantially increased when the partner has an AUD registration and decreased when the partner does not have an AUD registration. These results suggest that a married individual's risk for AUD is directly and causally affected by the presence of AUD in his or her spouse.

Divorce and the Onset of Alcohol Use Disorder: A Swedish Population-Based Longitudinal Cohort and Co-Relative Study.

OBJECTIVE: The purpose of this study was to clarify the magnitude and nature of the relationship between divorce and risk for alcohol use disorder (AUD). METHOD: In a population-based Swedish sample of married individuals (N=942,366), the authors examined the association between divorce or widowhood and risk for first registration for AUD. AUD was assessed using medical, criminal, and pharmacy registries. RESULTS: Divorce was strongly associated with risk for first AUD onset in both men (hazard ratio=5.98, 95% CI=5.65-6.33) and women (hazard ratio=7.29, 95% CI=6.72-7.91). The hazard ratio was estimated for AUD onset given divorce among discordant monozygotic twins to equal 3.45 and 3.62 in men and women, respectively. Divorce was also associated with an AUD recurrence in those with AUD registrations before marriage. Furthermore, widowhood increased risk for AUD in men (hazard ratio=3.85, 95% CI=2.81-5.28) and women (hazard ratio=4.10, 95% CI=2.98-5.64). Among divorced individuals, remarriage was associated with a large decline in AUD in both sexes (men: hazard ratio=0.56, 95% CI=0.52-0.64; women: hazard ratio=0.61, 95% CI=0.55-0.69). Divorce produced a greater increase in first AUD onset in those with a family history of AUD or with prior externalizing behaviors. CONCLUSIONS: Spousal loss through divorce or bereavement is associated with a large enduring increased AUD risk. This association likely reflects both causal and noncausal processes. That the AUD status of the spouse alters this association highlights the importance of spouse characteristics for the behavioral health consequences of spousal loss. The pronounced elevation in AUD risk following divorce or widowhood, and the protective effect of remarriage against subsequent AUD, speaks to the profound impact of marriage on problematic alcohol use.

Criminal offending and the family environment: Swedish national high-risk home-reared and adopted-away co-sibling control study.

BACKGROUND: Criminal offending is strongly transmitted across generations. AIMS: To clarify the contribution of rearing environment to cross-generational transmission of crime. METHOD: Using Swedish national registries, we identified 1176 full-sibling and 3085 half-sibling sets from high-risk families where at least one sibling was adopted and the other raised by the biological parents. RESULTS: Risk for criminal conviction was substantially lower in the full- and half-siblings who were adopted v. home-reared (hazard ratios (HR) = 0.56, 95% CI 0.50-0.64 and 0.60, 95% CI 0.56-0.65, respectively). The protective effect of adoption was significantly stronger in sibships with two v. one high-risk parent. CONCLUSIONS: Using matched high-risk full- and half-siblings, we found replicated evidence that (a) rearing environment has a strong impact on risk for criminal conviction, (b) high-quality rearing environments have especially strong effects in those at high familial risk for criminal offending and (c) the protective effects of adoption are stronger for more severe crimes and for repeated offending.

Effect of Marriage on Risk for Onset of Alcohol Use Disorder: A Longitudinal and Co-Relative Analysis in a Swedish National Sample.

OBJECTIVE: The authors sought to clarify the relationship between marriage and risk for alcohol use disorder. METHOD: The association between marital status and risk for first registration for alcohol use disorder in medical, criminal, and pharmacy registries was assessed in a population-based Swedish cohort (N=3,220,628) using longitudinal time-dependent survival and co-relative designs. RESULTS: First marriage was associated with a substantial decline in risk for onset of alcohol use disorder in men (hazard ratio=0.41, 95% CI=0.40-0.42) and women (hazard ratio=0.27, 95% CI=0.26-0.28). This association was slightly stronger when the spouse had no lifetime alcohol use disorder, while marriage to a spouse with lifetime alcohol use disorder increased risk for subsequent alcohol use disorder registration in both men (hazard ratio=1.29, 95% CI=1.16-1.43) and women (hazard ratio=1.18, 95% CI=1.06-1.30). In both sexes, the protective effect of marriage was significantly stronger in those with than those without a family history of alcohol use disorder. In both men and women, the associations between marriage and risk for alcohol use disorder in cousins, half siblings, full siblings, and monozygotic twins discordant for marital status were as strong as that seen in the general population. CONCLUSIONS: First marriage to a spouse with no lifetime alcohol use disorder is associated with a large reduction in risk for alcohol use disorder. This association cannot be explained by standard covariates or, as indicated by co-relative analyses, familial genetic or shared environmental confounders. These results are consistent with the hypothesis that the psychological and social aspects of marriage, and in particular health-monitoring spousal interactions, strongly protect against the development of alcohol use disorder. The protective effects of marriage on risk for alcohol use disorder are increased in those at high familial risk for alcoholism.

A Swedish Population-Based Multivariate Twin Study of Externalizing Disorders.

In epidemiological and twin populations, prior interview studies have identified an externalizing spectrum of disorders. Could this be detected utilizing objective registry data? In 20,603 twin pairs from the Swedish Twin Registry, we obtained information from national medical, criminal and pharmacy records on drug abuse (DA), criminal behavior (CB) and alcohol use disorders (AUD). Multivariate twin modeling was performed with the OpenMx package. A common pathway model with quantitative but not qualitative sex effects fit best with twin resemblance for the latent liability to externalizing syndromes due to both genetic and shared environmental factors. Heritability of the liability was higher in females (76 vs. 62%) while shared environmental influences were considerably stronger in males (23 vs. 3%). In both sexes, this latent liability was most strongly indexed by DA and least by CB. All three syndromes had specific genetic influences (especially CB and AUD in males, and CB in females) and specific shared environmental effects (especially DA and CB in males, and AUD in females). For DA, CB and AUD in men, and DA and AUD in women, at least 75% of the genetic risk arose through the common factor. The best fit model assumed that genetic and environmental influences on these externalizing syndromes in males and females were the same. We identified, in registry data, a highly heritable externalizing spectrum. DA, CB and AUD share substantial genetic and modest to moderate shared environmental influences. The nature of the externalizing spectrum differed meaningfully between the sexes.

Smoking and schizophrenia in population cohorts of Swedish women and men: a prospective co-relative control study.

OBJECTIVE: The purpose of this study was to clarify the causes of the smoking-schizophrenia association. METHOD: Using Cox proportional hazard and co-relative control models, the authors predicted future risk for a diagnosis of schizophrenia or nonaffective psychosis from the smoking status of 1,413,849 women and 233,879 men from, respectively, the Swedish birth and conscript registries. RESULTS: Smoking was assessed in women at a mean age of 27 and in men at a mean age of 18. The mean age at end of follow-up was 46 for women and 26 for men. Hazard ratios for first-onset schizophrenia were elevated both for light smoking (2.21 [95% CI=1.90-2.56] for women and 2.15 [95% CI=1.25-3.44] for men) and heavy smoking (3.45 [95% CI=2.95-4.03] for women and 3.80 [95% CI=1.19-6.60] for men). These associations did not decline when schizophrenia onsets 3-5 years after smoking assessment were censored. When age, socioeconomic status, and drug abuse were controlled for, hazard ratios declined only modestly in both samples. Women who smoked into late pregnancy had a much higher risk for schizophrenia than those who quit early. Hazard ratios predicting nonaffective psychosis in the general population, in cousins, in half siblings, and in full siblings discordant for heavy smoking were, respectively, 2.67, 2.71, 2.54, and 2.18. A model utilizing all relative pairs predicted a hazard ratio of 1.69 (95% CI=1.17-2.44) for nonaffective psychosis in the heavy-smoking member of discordant monozygotic twin pairs. CONCLUSIONS: Smoking prospectively predicts risk for schizophrenia. This association does not arise from smoking onset during a schizophrenic prodrome and demonstrates a clear dose-response relationship. While little of this association is explained by epidemiological confounders, a portion arises from common familial/genetic risk factors. However, in full siblings and especially monozygotic twins discordant for smoking, risk for nonaffective psychosis is appreciably higher in the smoking member. These results can help in evaluating the plausibility of various etiological hypotheses for the smoking-schizophrenia association.

A national Swedish longitudinal twin-sibling study of criminal convictions from adolescence through early adulthood.

BACKGROUND: Prior twin and adoption studies have demonstrated the importance of both genetic and shared environmental factors in the etiology of criminal behavior (CB). However, despite substantial interest in life-course theories of CB, few genetically informative studies have examined CB in a developmental context. METHOD: In 69,767 male-male twin pairs and full-sibling pairs with ≤ 2 years' difference in age, born 1958-1976 and ascertained from the Swedish Twin and Population Registries, we obtained information on all criminal convictions from 1973 to 2011 from the Swedish Crime Register. We fitted a Cholesky structural model, using the OpenMx package, to CB in these pairs over three age periods: 15-19, 20-24, and 25-29. RESULTS: The Cholesky model had two main genetic factors. The first began at ages 15-19 and declined in importance over development. The second started at ages 20-24 and was stable over time. Only one major shared environmental factor was seen, beginning at ages 15-19. Heritability for CB declined from ages 15-29, as did shared environmental effects, although at a slower rate. CONCLUSIONS: Genetic risk factors for CB in males are developmentally dynamic, demonstrating both innovation and attenuation. These results are consistent with theories of adolescent-limited and life-course persistent CB subtypes. Heritability for CB did not increase over time as might be predicted from active gene-environmental correlation. However, consistent with expectation, the proportion of variability explained by shared environmental effects declined slightly as individuals aged and moved away from their original homes and neighborhoods.

Depression, stroke and gender: evidence of a stronger association in men.

BACKGROUND/AIMS: Depression is associated with an increased risk for stroke. The aim of this study was to examine whether demographic and socioeconomic factors modify this association. METHODS: This follow-up study comprised 137 305 men and 188 924 women aged ≥30 years from a nationwide sample of primary healthcare centres in Sweden. We identified 4718 first-ever stroke cases (2217 men and 2501 women) during the follow-up period (2005-2007). Multilevel logistic regression models were used to calculate ORs and examine interactions in order to determine whether the association between depression and stroke differs by demographic or socioeconomic factors. RESULTS: Depression was associated with significantly greater odds of stroke after adjustment for potential confounding factors (OR=1.22, 95% CI 1.08 to 1.38). Interaction tests showed that the effect of depression on stroke was higher in men compared with women (the difference in OR between men and women was 1.30, 95% CI 1.01 to 1.68), that is, the association between depression and stroke was modified by gender. CONCLUSIONS: Our findings suggest that the depression-stroke association is modified by gender. Further studies are required to examine the underlying mechanisms in men and women.

Swedish hunters' safety behaviour and experience of firearm incidents.

Since any firearm injury is potentially lethal, it is of great interest to prevent firearm incidents. This study investigated such incidents during hunting and Swedish hunters' safety behaviour. A 48-item questionnaire was posted to a random sample of 1000 members of the Swedish Association for Hunting and Wildlife Management. The questions considered demographics, hunting experience/hunting habits/safety behaviour/attitudes and experience of careless weapon handling, hunters' weapons and safety behaviour relating to weapons, health status, firearm incidents and their preventability, and personal comments on the questionnaire. The response rate was almost 50%. The mean age of the responders was 54 years; 5% were females. Almost none (1%) reported hunting under the influence of alcohol. Young age and male sex were positively associated with risk behaviour, although the presence of multiple risk behaviours in the same responder was not common. A very high degree of compliance with Swedish laws regarding weapon storage was reported. One-quarter of the responders had witnessed a firearm incident caused by another hunter, which in most situations did not result in human injury or death. An unsafetied weapon was the most common reported "cause" of these incidents. Experience of a firearm incident was not uncommon and the majority of the responders considered the incident in question to be preventable. This study provides a picture of the possible risk behaviour among hunters and the results suggest that future prevention work should target safer weapon handling.

Neighborhood walkability, income, and hour-by-hour physical activity patterns.

PURPOSE: This study aimed to investigate both the mean daily physical activity and the hour-by-hour physical activity patterns across the day using accelerometry and how they are associated with neighborhood walkability and individual income. METHODS: Moderate physical activity (MPA) was assessed by accelerometry in 2252 adults in the city of Stockholm, Sweden. Neighborhood walkability (residential density, street connectivity, and land use mix) was objectively assessed within 1000m network buffers around the participants' residence and individual income was self-reported. RESULTS: Living in a high walkability neighborhood was associated with more mean daily MPA compared with living in a low walkability neighborhood on weekdays and weekend days. Hour-by-hour analyses showed that this association appeared mainly in the afternoon/early evening during weekdays, whereas it appeared across the middle of the day during weekend days. Individual income was associated with mean daily MPA on weekend days. On weekdays, the hour-by-hour analyses showed that high income was associated with more MPA around noon and in late afternoon/early evening, whereas low income was associated with more MPA at the hours before noon and in the early afternoon. During the weekend, high income was more consistently associated with higher MPA. CONCLUSIONS: Hour-by-hour accelerometry physical activity patterns provides a more comprehensive picture of the associations between neighborhood walkability and individual income and physical activity and the variability of these associations across the day.

Satisfaction with medication is correlated with outcome but not persistence in patients treated with placebo, escitalopram, or serotonin-norepinephrine reuptake inhibitors: a post hoc analysis.

OBJECTIVE: To test whether satisfaction with taking medication, assessed using item 15 of the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q), is associated with clinical outcome and persistence with treatment. METHOD: In this post hoc analysis, data were analyzed from 4 randomized placebo-controlled studies of patients with major depressive disorder treated with escitalopram (650 patients taking escitalopram and 534 taking placebo), together with data from 2 randomized trials of escitalopram versus venlafaxine or duloxetine (235 patients taking escitalopram and 233 taking a serotonin-norepinephrine reuptake inhibitor). The studies were published between 2002 and 2007. Instruments included the Q-LES-Q, which was assessed at baseline and week 8, and the Montgomery-Asberg Depression Rating Scale (MADRS), which was assessed at baseline and weeks 1, 2, 4, 6, and 8. RESULTS: At baseline, the mean ± SD MADRS total score was 30.0 ± 4.6, and the mean Q-LES-Q item 15 score was 2.9 ± 0.9. At week 8, the MADRS response rates of placebo-treated patients with a low, moderate, or high satisfaction with medication at baseline were 30%, 37%, and 46%, respectively (mixed model repeated measures [MMRM]). The corresponding MADRS response rates for escitalopram-treated patients with a low, moderate, or high satisfaction at baseline were 56%, 60%, and 67%, respectively (MMRM). Baseline satisfaction with medication was not significantly correlated with time to withdrawal (all reasons). The change in satisfaction with medication from baseline to endpoint was significantly correlated with symptomatic improvement on the MADRS (P < .001). CONCLUSIONS: Baseline satisfaction with medication after 1 week of placebo run-in is a moderator of treatment outcome but not of persistence of treatment in the acute treatment phase of depressed outpatients. Patient attitude toward medication should be taken into account before treatment is initiated.

Escitalopram versus serotonin noradrenaline reuptake inhibitors as second step treatment for patients with major depressive disorder: a pooled analysis.

The objective of this study was to evaluate the efficacy and tolerability of escitalopram versus serotonin and noradrenaline reuptake inhibitors (SNRIs) as second step treatment (defined operationally as poor response or intolerability to an antidepressant) for major depressive disorder (MDD). Results from all eligible head-to-head clinical trials of MDD (which excluded patients who earlier failed two or more antidepressants) sponsored by Lundbeck or Forest comparing escitalopram and SNRIs (venlafaxine and duloxetine) were pooled. A second step treatment subgroup was identified, defined as patients treated earlier with any antidepressant in the 6-month period before baseline. Data from three clinical trials were included in the analysis; 132 patients were identified in the second step treatment subgroup (66 in each of the escitalopram and SNRI groups). The primary efficacy analysis showed that the patients subsequently treated with escitalopram had significantly lower Montgomery Asberg Depression Rating Scale total scores after 8 weeks compared with those subsequently treated with SNRIs (difference = -6.4, P<0.0001). Escitalopram treatment was also associated with higher clinical response (73 vs. 44%, P=0.0004) and remission rates (62 vs. 41%, P=0.0083) compared with subsequent treatment with SNRIs. Escitalopram showed a better tolerability profile with lower all-cause withdrawals from study (9 vs. 23%, P<0.04) and lower withdrawals because of adverse events (2 vs. 17%, P<0.003). In conclusion, escitalopram is associated with a better efficacy and tolerability profile than SNRIs (duloxetine and venlafaxine) when used as a second step treatment in patients with MDD. These results should be confirmed in prospective randomized clinical trials.