Antidepressant prescription patterns and CNS polypharmacy with antidepressants among children, adolescents, and young adults: a population-based study in Sweden.

This study examines trends in antidepressant drug dispensations among young people aged 0-24 years in Sweden during the period 2006-2013, as well as prescription patterns and central nervous system (CNS) polypharmacy with antidepressants. Using linkage of Swedish national registers, we identified all Swedish residents aged 0-24 years that collected at least one antidepressant prescription (here defined as antidepressant users) between 1 January 2006 and 31 December 2013 (n = 174,237), and categorized them as children (0-11 years), adolescents (12-17 years), and young adults (18-24 years). Prevalence of antidepressant dispensation rose from 1.4 to 2.1% between 2006 and 2013, with the greatest relative increase in adolescents [by 97.8% in males (from 0.6 to 1.3%) and by 86.3% in females (from 1.1 to 2.1%)]. Most individuals across age categories were prescribed selective serotonin reuptake inhibitors, received their prescriptions from psychiatric specialist care, and had treatment periods of over 12 months. Prevalence of CNS polypharmacy (dispensation of other CNS drug classes in addition to antidepressants) increased across age categories, with an overall increase in prevalence from 52.4% in 2006 to 62.1% in 2013. Children experienced the largest increase in polypharmacy of three or more psychotropic drug classes (4.4-10.1%). Anxiolytics, hypnotics, and sedatives comprised the most common additional CNS drug class among persons who were prescribed antidepressants. These findings show that the dispensation of antidepressants among the young is prevalent and growing in Sweden. The substantial degree of CNS polypharmacy in young patients receiving antidepressants requires careful monitoring and further research into potential benefits and harms.

Perinatal risk factors in Tourette's and chronic tic disorders: a total population sibling comparison study.

Adverse perinatal events may increase the risk of Tourette's and chronic tic disorders (TD/CTD), but previous studies have been unable to control for unmeasured environmental and genetic confounding. We aimed to prospectively investigate potential perinatal risk factors for TD/CTD, taking unmeasured factors shared between full siblings into account. A population-based birth cohort, consisting of all singletons born in Sweden in 1973-2003, was followed until December 2013. A total of 3 026 861 individuals were identified, 5597 of which had a registered TD/CTD diagnosis. We then studied differentially exposed full siblings from 947 942 families; of these, 3563 families included siblings that were discordant for TD/CTD. Perinatal data were collected from the Medical Birth Register and TD/CTD diagnoses were collected from the National Patient Register, using a previously validated algorithm. In the fully adjusted models, impaired fetal growth, preterm birth, breech presentation and cesarean section were associated with a higher risk of TD/CTD, largely independent from shared family confounders and measured covariates. Maternal smoking during pregnancy was associated with risk of TD/CTD in a dose-response manner but the association was no longer statistically significant in the sibling comparison models or after the exclusion of comorbid attention-deficit/hyperactivity disorder. A dose-response relationship between the number of adverse perinatal events and increased risk for TD/CTD was also observed, with hazard ratios ranging from 1.41 (95% confidence interval (CI): 1.33-1.50) for one event to 2.42 (95% CI: 1.65-3.53) for five or more events. These results pave the way for future gene by environment interaction and epigenetic studies in TD/CTD.

A total-population multigenerational family clustering study of autoimmune diseases in obsessive-compulsive disorder and Tourette's/chronic tic disorders.

The association between obsessive-compulsive disorder (OCD) and Tourette's/chronic tic disorders (TD/CTD) with autoimmune diseases (ADs) is uncertain. In this nationwide study, we sought to clarify the patterns of comorbidity and familial clustering of a broad range of ADs in individuals with OCD, individuals with TD/CTD and their biological relatives. From a birth cohort of 7 465 455 individuals born in Sweden between 1940 and 2007, we identified 30 082 OCD and 7279 TD/CTD cases in the National Patient Register and followed them up to 31 December 2013. The risk of 40 ADs was evaluated in individuals with OCD, individuals with TD/CTD and their first- (siblings, mothers, fathers), second- (half siblings) and third-degree (cousins) relatives, compared with population controls. Individuals with OCD and TD/CTD had increased comorbidity with any AD (43% and 36%, respectively) and many individual ADs. The risk of any AD and several individual ADs was consistently higher among first-degree relatives than among second- and third-degree relatives of OCD and TD/CTD probands. The risk of ADs was very similar in mothers, fathers and siblings of OCD probands, whereas it tended to be higher in mothers and fathers of TD/CTD probands (compared with siblings). The results suggest a familial link between ADs in general (that is, not limited to Streptococcus-related conditions) and both OCD and TD/CTD. Additional mother-specific factors, such as the placental transmission of antibodies, cannot be fully ruled out, particularly in TD/CTD.

Suicide in obsessive-compulsive disorder: a population-based study of 36 788 Swedish patients.

The risk of death by suicide in individuals with obsessive-compulsive disorder (OCD) is largely unknown. Previous studies have been small and methodologically flawed. We analyzed data from the Swedish national registers to estimate the risk of suicide in OCD and identify the risk and protective factors associated with suicidal behavior in this group. We used a matched case-cohort design to estimate the risk of deaths by suicide and attempted suicide in individuals diagnosed with OCD, compared with matched general population controls (1:10). Cox regression models were used to study predictors of suicidal behavior. We identified 36 788 OCD patients in the Swedish National Patient Register between 1969 and 2013. Of these, 545 had died by suicide and 4297 had attempted suicide. In unadjusted models, individuals with OCD had an increased risk of both dying by suicide (odds ratio (OR)=9.83 (95% confidence interval (CI), 8.72-11.08)) and attempting suicide (OR=5.45 (95% CI, 5.24-5.67)), compared with matched controls. After adjusting for psychiatric comorbidities, the risk was reduced but remained substantial for both death by suicide and attempted suicide. Within the OCD cohort, a previous suicide attempt was the strongest predictor of death by suicide. Having a comorbid personality or substance use disorder also increased the risk of suicide. Being a woman, higher parental education and having a comorbid anxiety disorder were protective factors. We conclude that patients with OCD are at a substantial risk of suicide. Importantly, this risk remains substantial after adjusting for psychiatric comorbidities. Suicide risk should be carefully monitored in patients with OCD.

Motivation and value influences in the relative balance of goal-directed and habitual behaviours in obsessive-compulsive disorder.

Our decisions are based on parallel and competing systems of goal-directed and habitual learning, systems which can be impaired in pathological behaviours. Here we focus on the influence of motivation and compare reward and loss outcomes in subjects with obsessive-compulsive disorder (OCD) on model-based goal-directed and model-free habitual behaviours using the two-step task. We further investigate the relationship with acquisition learning using a one-step probabilistic learning task. Forty-eight OCD subjects and 96 healthy volunteers were tested on a reward and 30 OCD subjects and 53 healthy volunteers on the loss version of the two-step task. Thirty-six OCD subjects and 72 healthy volunteers were also tested on a one-step reversal task. OCD subjects compared with healthy volunteers were less goal oriented (model-based) and more habitual (model-free) to reward outcomes with a shift towards greater model-based and lower habitual choices to loss outcomes. OCD subjects also had enhanced acquisition learning to loss outcomes on the one-step task, which correlated with goal-directed learning in the two-step task. OCD subjects had greater stay behaviours or perseveration in the one-step task irrespective of outcome. Compulsion severity was correlated with habitual learning in the reward condition. Obsession severity was correlated with greater switching after loss outcomes. In healthy volunteers, we further show that greater reward magnitudes are associated with a shift towards greater goal-directed learning further emphasizing the role of outcome salience. Our results highlight an important influence of motivation on learning processes in OCD and suggest that distinct clinical strategies based on valence may be warranted.

Population-based, multi-generational family clustering study of social anxiety disorder and avoidant personality disorder.

BACKGROUND: We aimed to provide unbiased estimates of familial risk and heritability of social anxiety disorder (SAD) and avoidant personality disorder (AVPD). METHOD: We identified 18 399 individuals diagnosed with SAD and 2673 with AVPD in the Swedish National Patient Register between 1997 and 2009. Risks (odds ratios; OR) for SAD in all biological and non-biological relatives of probands, compared to relatives of unaffected individuals were calculated. We also estimated the risks for AVPD in relatives of probands with SAD. RESULTS: The risk for SAD among relatives of SAD probands increased proportionally to the degree of genetic relatedness. The risks for first-degree relatives [OR 4.74, 95% confidence interval (CI) 4.28-5.25] were significantly higher than for second-degree and third-degree relatives. Second-degree relatives (OR 2.30, 95% CI 2.01-2.63) had significantly higher risk than third-degree relatives (OR 1.72, 95% CI 1.52-1.94). Relatives at similar genetic distances had similar risks for SAD, despite different degrees of shared environment. Heritability was estimated to be approximately 56%. There were no significant sex differences in the familial patterns. The risk of AVPD in relatives of SAD probands was significantly elevated, even after excluding individuals with both diagnoses (first-degree OR 3.54, second-degree OR 2.20, third-degree OR 1.62). Non-biological relatives (spouses/partners) also had elevated risks for both SAD (OR 4.01) and AVPD (OR 3.85). CONCLUSIONS: SAD clusters in families primarily due to genetic factors. SAD and AVPD are aetiologically related and may represent different expressions of the same vulnerability. The strong marital concordance observed in SAD/AVPD may indicate assortative mating but the exact mechanisms and implications require further investigation.

Are stressful life events causally related to the severity of obsessive-compulsive symptoms? A monozygotic twin difference study.

Traumatic or stressful life events have long been hypothesized to play a role in causing or precipitating obsessive-compulsive symptoms but the impact of these environmental factors has rarely been investigated using genetically informative designs. We tested whether a wide range of retrospectively-reported stressful life events (SLEs) influence the lifetime presence and severity of obsessive-compulsive symptoms (OCS) in a large Swedish population-based cohort of 22,084 twins. Multiple regression models examined whether differences in SLEs within twin pairs were significantly associated with differences in OCS. In the entire sample (i.e., both monozygotic [MZ] and dizygotic twin pairs), two SLEs factors, "abuse and family disruption" and "sexual abuse", were significantly associated with the severity of OCS even after controlling for depressive symptoms. Other SLEs factors were either not associated with OCS ("loss", "non-sexual assault") or were no longer associated with OCS after controlling for depression ("illness/injury"). Within MZ pair analyses, which effectively control for genetic and shared environmental effects, showed that only the "abuse and family disruption" factor remained independently related to within-pair differences in OCS severity, even after controlling for depressive symptoms. Despite being statistically significant, the magnitude of the associations was small; "abuse and family disruption" explained approximately 3% of the variance in OCS severity. We conclude that OCS are selectively associated with certain types of stressful life events. In particular, a history of interpersonal abuse, neglect and family disruption may make a modest but significant contribution to the severity of OCS. Further replication in longitudinal cohorts is essential before causality can be firmly established.

Disorders of compulsivity: a common bias towards learning habits.

Why do we repeat choices that we know are bad for us? Decision making is characterized by the parallel engagement of two distinct systems, goal-directed and habitual, thought to arise from two computational learning mechanisms, model-based and model-free. The habitual system is a candidate source of pathological fixedness. Using a decision task that measures the contribution to learning of either mechanism, we show a bias towards model-free (habit) acquisition in disorders involving both natural (binge eating) and artificial (methamphetamine) rewards, and obsessive-compulsive disorder. This favoring of model-free learning may underlie the repetitive behaviors that ultimately dominate in these disorders. Further, we show that the habit formation bias is associated with lower gray matter volumes in caudate and medial orbitofrontal cortex. Our findings suggest that the dysfunction in a common neurocomputational mechanism may underlie diverse disorders involving compulsion.

Long-term efficacy of Internet-based cognitive behavior therapy for obsessive-compulsive disorder with or without booster: a randomized controlled trial.

BACKGROUND: As relapse after completed cognitive behavior therapy (CBT) for obsessive-compulsive disorder (OCD) is common, many treatment protocols include booster programs to improve the long-term effects. However, the effects of booster programs are not well studied. In this study, we investigated the long-term efficacy of Internet-based CBT (ICBT) with therapist support for OCD with or without an Internet-based booster program. METHOD: A total of 101 participants were included in the long-term follow-up analysis of ICBT. Of these, 93 were randomized to a booster program or no booster program. Outcome assessments were collected at 4, 7, 12 and 24 months after receiving ICBT. RESULTS: The entire sample had sustained long-term effects from pre-treatment to all follow-up assessments, with large within-group effect sizes (Cohen's d = 1.58-2.09). The booster group had a significant mean reduction in OCD symptoms compared to the control condition from booster baseline (4 months) to 7 months, but not at 12 or 24 months. Participants in the booster group improved significantly in terms of general functioning at 7, 12 and 24 months, and had fewer relapses. Kaplan-Meier analysis also indicated a significantly slower relapse rate in the booster group. CONCLUSIONS: The results suggest that ICBT has sustained long-term effects and that adding an Internet-based booster program can further improve long-term outcome and prevent relapse for some OCD patients.

Effectiveness of internet-based cognitive behaviour therapy for panic disorder in routine psychiatric care.

OBJECTIVE: Guided Internet-based cognitive behaviour therapy (ICBT) for panic disorder has been shown to be efficacious in several randomized controlled trials. However, the effectiveness of the treatment when delivered within routine psychiatric care has not been studied. The aim of this study was to investigate the effectiveness of ICBT for panic disorder within the context of routine psychiatric care. METHOD: We conducted a cohort study investigating all patients (n = 570) who had received guided ICBT for panic disorder between 2007 and 2012 in a routine care setting at an out-patient psychiatric clinic providing Internet-based treatment. The primary outcome measure was the Panic Disorder Severity Scale-Self-report (PDSS-SR). RESULTS: Participants made large improvements from screening and pretreatment assessments to posttreatment (Cohen's d range on the PDSS-SR = 1.07-1.55). Improvements were sustained at 6-month follow-up. CONCLUSION: This study suggests that ICBT for panic disorder is as effective when delivered in a routine care context as in the previously published randomized controlled trials.

Cost-effectiveness and long-term effectiveness of internet-based cognitive behaviour therapy for severe health anxiety.

BACKGROUND: Severe health anxiety is a common condition associated with functional disability, making it a costly disorder from a societal perspective. Internet-based cognitive behaviour therapy (ICBT) is a promising treatment but no previous study has assessed the cost-effectiveness or long-term outcome of ICBT for severe health anxiety. The aim of this study was to investigate the cost-effectiveness and 1-year treatment effects of ICBT for severe health anxiety. METHOD: Cost-effectiveness and 1-year follow-up data were obtained from a randomized controlled trial (RCT) comparing ICBT (n = 40) to an attention control condition (CC, n = 41). The primary outcome measure was the Health Anxiety Inventory (HAI). A societal perspective was taken and incremental cost-effectiveness ratios (ICERs) were calculated using bootstrap sampling. RESULTS: The main ICER was -£1244, indicating the societal economic gain for each additional case of remission when administering ICBT. Baseline to 1-year follow-up effect sizes on the primary outcome measure were large (d = 1.71-1.95). CONCLUSIONS: ICBT is a cost-effective treatment for severe health anxiety that can produce substantial and enduring effects.

Changes in dopamine D2-receptor binding are associated to symptom reduction after psychotherapy in social anxiety disorder.

The dopamine system has been suggested to play a role in social anxiety disorder (SAD), partly based on molecular imaging studies showing reduced levels of striatal dopaminergic markers in patients compared with control subjects. However, the dopamine system has not been examined in frontal and limbic brain regions proposed to be central in the pathophysiology of SAD. In the present study, we hypothesized that extrastriatal dopamine D2-receptor (D2-R) levels measured using positron emission tomography (PET) would predict symptom reduction after cognitive behavior therapy (CBT). Nine SAD patients were examined using high-resolution PET and the high-affinity D2-R antagonist radioligand [(11)C]FLB 457, before and after 15 weeks of CBT. Symptom levels were assessed using the anxiety subscale of Liebowitz Social Anxiety Scale (LSAS(anx)). At posttreatment, there was a statistically significant reduction of social anxiety symptoms (P<0.005). Using a repeated measures analysis of covariance, significant effects for time and time × LSAS(anx) change on D2-R-binding potential (BP(ND)) were shown (P<0.05). In a subsequent region-by-region analysis, negative correlations between change in D2-R BP(ND) and LSAS(anx) change were found for medial prefrontal cortex and hippocampus (P<0.05). This is the first study to report a direct relationship between symptom change after psychological treatment and a marker of brain neurotransmission. Using an intra-individual comparison design, the study supports a role for the dopamine system in cortical and limbic brain regions in the pathophysiology of SAD.

Internet-based cognitive behaviour therapy for obsessive-compulsive disorder: a randomized controlled trial.

BACKGROUND: Cognitive behaviour therapy (CBT) is an effective treatment for obsessive-compulsive disorder (OCD) but access to CBT is limited. Internet-based CBT (ICBT) with therapist support is potentially a more accessible treatment. There are no randomized controlled trials testing ICBT for OCD. The aim of this study was to investigate the efficacy of ICBT for OCD in a randomized controlled trial. METHOD: Participants (n=101) diagnosed with OCD were randomized to either 10 weeks of ICBT or to an attention control condition, consisting of online supportive therapy. The primary outcome measure was the Yale-Brown Obsessive Compulsive Scale (YBOCS) administered by blinded assessors. RESULTS: Both treatments lead to significant improvements in OCD symptoms, but ICBT resulted in larger improvements than the control condition on the YBOCS, with a significant between-group effect size (Cohen's d) of 1.12 (95% CI 0.69-1.53) at post-treatment. The proportion of participants showing clinically significant improvement was 60% (95% CI 46-72) in the ICBT group compared to 6% (95% CI 1-17) in the control condition. The results were sustained at follow-up. CONCLUSIONS: ICBT is an efficacious treatment for OCD that could substantially increase access to CBT for OCD patients. Replication studies are warranted.

Clinical and genetic outcome determinants of Internet- and group-based cognitive behavior therapy for social anxiety disorder.

OBJECTIVE: No study has investigated clinical or genetic predictors and moderators of Internet-based cognitive behavior therapy (ICBT) compared with cognitive behavioral group therapy for (CBGT) for SAD. Identification of predictors and moderators is essential to the clinician in deciding which treatment to recommend for whom. We aimed to identify clinical and genetic (5-HTTLPR, COMTval158met, and BDNFval66met) predictors and moderators of ICBT and CBGT. METHOD: We performed three types of analyses on data from a sample comprising participants (N = 126) who had undergone ICBT or CBGT in a randomized controlled trial. Outcomes were i) end state symptom severity, ii) SAD diagnosis, and iii) clinically significant improvement. RESULTS: The most stable predictors of better treatment response were working full time, having children, less depressive symptoms, higher expectancy of treatment effectiveness, and adhering to treatment. None of the tested gene polymorphisms were associated with treatment outcome. Comorbid general anxiety and depression were moderators meaning that lower levels were associated with a better treatment response in ICBT but not in CBGT. CONCLUSION: We conclude that demographic factors, symptom burden, adherence, and expectations may play an important role as predictors of treatment outcome. The investigated gene polymorphisms do not appear to make a difference.

The offerings from the Hyperboreans.

The ancient Greeks believed that the fruits of agriculture could be harvested only if one first appeased the spirit of the primitive avatars from which the edible crop had been evolved over the centuries through hybridization and cultivation. On occasion, this appeasement was secured through the sacrifice of a human victim, a person who for various reasons could be considered to represent a similar primitivism. By the classical age, this extreme form of sacrificial appeasement appears to have been reserved for times of unusual crisis, such as pestilence or natural disaster, for at such times, the resurgent forces of primitivism seemed to threaten the entire civilization with regression back to its wilder origins. Other forms of appeasement were ordinarily substituted for the actual offering of a human victim. Amongst these was the enactment of puberty rites, for the natural growth and maturation of an individual could be thought to symbolize this same evolutionary process. Each infant is born as a wild creature who must develop into a socialized adult through the metaphoric death of its former self as it assumes the responsibilities of civilized life in crossing the threshold to sexual maturity. A similar symbolic victim was customarily represented by the offering of first fruits. A portion of the cultivated crop was prematurely cut and consecrated to redeem and release the ripening harvest from the dangerous contamination with the spirits of its pre-agricultural precedents. On the island of Delos, a special version of this consecration was performed. Each year, the various Greek cities would send a sheaf of unripened grain to the sanctuary of the god Apollo and his twin sister Artemis. Amongst these annual offerings, there was one that was supposed to have originated from the Hyperboreans, a mythical people who were thought to live in the original homeland of the two gods. This special Hyperborean offering differed from the others, for it was said to contain a secret item hidden within the sheaf. The mythical traditions about these Hyperboreans recalled the Hellenic peoples' Indo-European origins, back in the time before the tribal migrations that brought them eventually into the Mediterranean lands, and the secret offering pertained to Apollo's more ancient religion in that pre-Greek Hyperborean context.(ABSTRACT TRUNCATED AT 400 WORDS)