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For patients with major depressive disorder (MDD) experiencing side-effects or non-response to their first antidepressant, little is known regarding the effect of switching between a tricyclic antidepressant (TCA) and a selective serotonin reuptake inhibitor (SSRI).
To compare the switch between the TCA nortriptyline and the SSRI escitalopram.
Among 811 adults with MDD treated with nortriptyline or escitalopram for up to 12 weeks, 108 individuals switched from nortriptyline to escitalopram or vice versa because of side-effects or non-response (trial registration: EudraCT No.2004-001723-38 (https://eudract.ema.europa.eu/) and ISRCTN No.03693000 (http://www.controlled-trials.com)). Patients were followed for up to 26 weeks after switching and response was measured with the Montgomery–Åsberg Depression Rating scale (MADRS). We performed adjusted mixed-effects linear regression models with full information maximum likelihood estimation reporting β-coefficients with 95% CIs.
Switching antidepressants resulted in a significant decrease in MADRS scores. This was present for switchers from escitalopram to nortriptyline (n = 36, β = −0.38, 95% CI −0.51 to −0.25, P<0.001) and from nortriptyline to escitalopram (n = 72, β = −0.34, 95% CI −0.41 to −0.26, P<0.001). Both switching options resulted in significant improvement among individuals who switched because of non-response or side-effects. The results were supported by analyses on other rating scales and symptom dimensions.
These results suggest that switching from a TCA to an SSRI or vice versa after non-response or side-effects to the first antidepressant may be a viable approach to achieve response among patients with MDD.
Declarations of interest
K.J.A. holds an Alberta Centennial Addiction and Mental Health Research Chair, funded by the Government of Alberta. K.J.A. has been a member of various advisory boards, received consultancy fees and honoraria, and has received research grants from various companies including Johnson and Johnson Pharmaceuticals Research and Development and Bristol-Myers Squibb Pharmaceuticals Limited. D.S. has served on advisory boards for, and received unrestricted grants from, Lundbeck and AstraZeneca. A.F. and P.M. have received honoraria for participating in expert panels for Lundbeck and GlaxoSmithKline.
Depression and obesity are highly prevalent, and major impacts on public health frequently co-occur. Recently, we reported that having depression moderates the effect of the FTO gene, suggesting its implication in the association between depression and obesity.
To confirm these findings by investigating the FTO polymorphism rs9939609 in new cohorts, and subsequently in a meta-analysis.
The sample consists of 6902 individuals with depression and 6799 controls from three replication cohorts and two original discovery cohorts. Linear regression models were performed to test for association between rs9939609 and body mass index (BMI), and for the interaction between rs9939609 and depression status for an effect on BMI. Fixed and random effects meta-analyses were performed using METASOFT.
In the replication cohorts, we observed a significant interaction between FTO, BMI and depression with fixed effects meta-analysis (β=0.12, P = 2.7 × 10−4) and with the Han/Eskin random effects method (P = 1.4 × 10−7) but not with traditional random effects (β = 0.1, P = 0.35). When combined with the discovery cohorts, random effects meta-analysis also supports the interaction (β = 0.12, P = 0.027) being highly significant based on the Han/Eskin model (P = 6.9 × 10−8). On average, carriers of the risk allele who have depression have a 2.2% higher BMI for each risk allele, over and above the main effect of FTO.
This meta-analysis provides additional support for a significant interaction between FTO, depression and BMI, indicating that depression increases the effect of FTO on BMI. The findings provide a useful starting point in understanding the biological mechanism involved in the association between obesity and depression.
Recent studies point to overlap between neuropsychiatric disorders in symptomatology and genetic aetiology.
To systematically investigate genomics overlap between childhood and adult attention-deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD) and major depressive disorder (MDD).
Analysis of whole-genome blood gene expression and genetic risk scores of 318 individuals. Participants included individuals affected with adult ADHD (n = 93), childhood ADHD (n = 17), MDD (n = 63), ASD (n = 51), childhood dual diagnosis of ADHD–ASD (n = 16) and healthy controls (n = 78).
Weighted gene co-expression analysis results reveal disorder-specific signatures for childhood ADHD and MDD, and also highlight two immune-related gene co-expression modules correlating inversely with MDD and adult ADHD disease status. We find no significant relationship between polygenic risk scores and gene expression signatures.
Our results reveal disorder overlap and specificity at the genetic and gene expression level. They suggest new pathways contributing to distinct pathophysiology in psychiatric disorders and shed light on potential shared genomic risk factors.
In recent years, the Kraepelinian dichotomy has been challenged in light of evidence on shared genetic and environmental factors for schizophrenia and bipolar disorder, but empirical efforts to identify a transdiagnostic phenotype of psychosis remain remarkably limited.
To investigate whether schizophrenia spectrum and bipolar disorder lie on a transdiagnostic spectrum with overlapping non-affective and affective psychotic symptoms.
Multidimensional item-response modelling was conducted on symptom ratings of the OPerational CRITeria (OPCRIT) system in 1168 patients with schizophrenia spectrum and bipolar disorder.
A bifactor model with one general, transdiagnostic psychosis dimension underlying affective and non-affective psychotic symptoms and five specific dimensions of positive, negative, disorganised, manic and depressive symptoms provided the best model fit and diagnostic utility for categorical classification.
Our findings provide support for including dimensional approaches into classification systems and a directly measurable clinical phenotype for cross-disorder investigations into shared genetic and environmental factors of psychosis.
Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism contributes to the development of depression (major depressive disorder, MDD), but it is unclear whether neural effects observed in healthy individuals are sustained in MDD.
To investigate BDNF Val66Met effects on key regions in MDD neurocircuitry: amygdala, anterior cingulate, middle frontal and orbitofrontal regions.
Magnetic resonance imaging scans were acquired in 79 persons with MDD (mean age 49 years) and 74 healthy volunteers (mean age 50 years). Effects on surface area and cortical thickness were examined with multiple comparison correction.
People who were Met allele carriers showed reduced caudal middle frontal thickness in both study groups. Significant interaction effects were found in the anterior cingulate and rostral middle frontal regions, in which participants in the MDD group who were Met carriers showed the greatest reduction in surface area.
Modulatory effects of the BDNF Val66Met polymorphism on distinct subregions in the prefrontal cortex in MDD support the neurotrophin model of depression.
Individuals with a mental health disorder appear to be at increased risk of medical illness.
To examine rates of medical illnesses in patients with bipolar disorder (n = 1720) and to examine the clinical course of the bipolar illness according to lifetime medical illness burden.
Participants recruited within the UK were asked about the lifetime occurrence of 20 medical illnesses, interviewed using the Schedules for Clinical Assessment in Neuropsychiatry (SCAN) and diagnosed according to DSM-IV criteria.
We found significantly increased rates of several medical illnesses in our bipolar sample. A high medical illness burden was associated with a history of anxiety disorder, rapid cycling mood episodes, suicide attempts and mood episodes with a typically acute onset.
Bipolar disorder is associated with high rates of medical illness. This comorbidity needs to be taken into account by services in order to improve outcomes for patients with bipolar disorder and also in research investigating the aetiology of affective disorder where shared biological pathways may play a role.
Most studies of post-traumatic stress disorder (PTSD) in low- and
middle-income countries (LMICs) have focused on ‘high-risk’ populations
defined by exposure to trauma.
To estimate the prevalence of post-traumatic stress disorder (PTSD) in a
LMIC, the conditional probability of PTSD given a traumatic event and the
strength of associations between traumatic events and other psychiatric
Our sample contained a mix of 3995 twins and 2019 non-twins. We asked
participants about nine different traumatic exposures, including the
category ‘other’, but excluding sexual trauma.
Traumatic events were reported by 36.3% of participants and lifetime PTSD
was present in 2.0%. Prevalence of non-PTSD lifetime diagnosis was 19.1%.
Of people who had experienced three or more traumatic events, 13.3% had
lifetime PTSD and 40.4% had a non-PTSD psychiatric diagnosis.
Despite high rates of exposure to trauma, this population had lower rates
of PTSD than high-income populations, although the prevalence might have
been slightly affected by the exclusion of sexual trauma. There are high
rates of non-PTSD diagnoses associated with trauma exposure that could be
considered in interventions for trauma-exposed populations. Our findings
suggest that there is no unique relationship between traumatic
experiences and the specific symptomatology of PTSD.
Obesity has been shown to be associated with depression and it has been suggested that higher body mass index (BMI) increases the risk of depression and other common mental disorders. However, the causal relationship remains unclear and Mendelian randomisation, a form of instrumental variable analysis, has recently been employed to attempt to resolve this issue.
To investigate whether higher BMI increases the risk of major depression.
Two instrumental variable analyses were conducted to test the causal relationship between obesity and major depression in RADIANT, a large case–control study of major depression. We used a single nucleotide polymorphism (SNP) in FTO and a genetic risk score (GRS) based on 32 SNPs with well-established associations with BMI.
Linear regression analysis, as expected, showed that individuals carrying more risk alleles of FTO or having higher score of GRS had a higher BMI. Probit regression suggested that higher BMI is associated with increased risk of major depression. However, our two instrumental variable analyses did not support a causal relationship between higher BMI and major depression (FTO genotype: coefficient −0.03, 95% CI −0.18 to 0.13, P = 0.73; GRS: coefficient −0.02, 95% CI −0.11 to 0.07, P = 0.62).
Our instrumental variable analyses did not support a causal relationship between higher BMI and major depression. The positive associations of higher BMI with major depression in probit regression analyses might be explained by reverse causality and/or residual confounding.
The Sri Lankan Twin Registry (SLTR), established in 1997, is a unique resource for twin and genetic research in a low- and middle-income country (LMIC). It comprises of a volunteer cohort of 14,120 twins (7,060 pairs) and 119 sets of triplets, and a population-based cohort of 19,040 (9,520 pairs) twins and 89 sets of triplets. Several studies have been conducted using this registry, including the Colombo Twin and Singleton Study (CoTaSS 1; 4,387 twins, 2,311 singletons), which have explored the prevalence and heritability of a range of psychiatric disorders as well as gene-environmental interplay. Currently, a follow-up study (CoTaSS 2) of the same cohort is underway, looking at the prevalence and interrelationship of key cardiovascular and metabolic risk markers (e.g., metabolic syndrome). A significant feature of CoTaSS 2 is the establishment of a biobank. Current SLTR work is extending beyond mental health and the interface between mental and physical health to new horizons, extending collaborations with the wider global twin research community. Ethics and governance have been given special emphasis in the initiative. Capacity building and public engagement are two crucial components. Establishment of a state-of-the-art genetic laboratory was a major accomplishment. SLTR is a classic showcase of successful North–South partnership in building a progressive research infrastructure in a LMIC.
Little is known about the impact of different types of stressful events (for example divorce v. bereavement) on unipolar depression compared with bipolar disorder. Inconsistencies exist concerning the association between independent events (beyond an individual's control, such as bereavement) and bipolar disorder.
To examine the role of specific, independent and dependent events in mood disorders.
Life-event information was collected from 512 people with bipolar disorder, 1448 people with unipolar depression and over 600 controls.
Various events were associated with unipolar depression and bipolar disorder, but some event specificity was detected. For example, financial crisis was more strongly related to bipolar disorder rather than unipolar depression. Independent events were only related to unipolar depression and not bipolar disorder.
The events that were linked to bipolar disorder and unipolar depression were similar. Independent events were not associated with bipolar episodes, suggesting that life stress may be a consequence of, rather than a trigger for, bipolar episodes.
Copy number variants (CNVs) are submicroscopic deletions and duplications of genomic material that were previously thought to be rare phenomena. They have now been robustly associated with a variety of disorders such as autism, schizophrenia, and attention-deficit/hyperactivity disorder through an emerging research base in affective disorders. A complex picture is emerging of a polygenic, heterogeneous model of disease, with CNVs conferring broad susceptibility to a variety of neurodevelopmental disorders, rather than specific disorders per se. Although the insights gleaned thus far only represent a small piece of a much larger puzzle, progress has been rapid and new technologies promise even more insights into these hitherto opaque brain disorders. We will discuss CNVs, the current state of evidence for their role in the pathogenesis of classical psychiatric disorders, and the application of such knowledge in clinical settings.
White matter abnormalities have been implicated in the aetiology of major depressive disorder; however, the relationship between the severity of symptoms and white matter integrity is currently unclear.
To investigate white matter integrity in people with major depression and healthy controls, and to assess its relationship with depressive symptom severity.
Diffusion tensor imaging data were acquired from 66 patients with recurrent major depression and a control group of 66 healthy individuals matched for age, gender and IQ score, and analysed with tract-based spatial statistics. The relationship between white matter integrity and severity of depression as measured by the Beck Depression Inventory was examined.
Depressive illness was associated with widespread regions of decreased white matter integrity, including regions in the corpus callosum, superior longitudinal fasciculus and anterior corona radiata, compared with the control group. Increasing symptom severity was negatively correlated with white matter integrity, predominantly in the corpus callosum.
Widespread alterations in white matter integrity are evident in major depressive disorder. These abnormalities are heightened with increasing severity of depressive symptoms.
The increasingly large sample size requirements of modern adult mental
health research suggests the need for a data collection and diagnostic
application that can be used across a broad range of clinical and
To develop a data collection and diagnostic application that can be used
across a broad range of clinical and research settings.
We expanded and redeveloped the OPCRIT system into a broadly applicable
diagnostic and data-collection package and carried out an interrater
reliability study of this new tool.
OPCRIT+ performed well in an interrater reliability study with relatively
inexperienced clinicians, giving a combined, weighted kappa of 0.70 for
OPCRIT+ showed good overall interrater reliability scores for diagnoses.
It is now incorporated in the electronic patient record of the Maudsley
and associated hospitals. OPCRIT+ can be downloaded free of charge at
The question of whether a functional variant in the promoter of the
serotonin transporter gene (5-HTTLPR) influences response to adversity
and/or antidepressants has generated great interest and controversy. A
review of the literature suggests that the issue is complicated by
differences in methodology and sample ethnicity. When these confounders are
accounted for, there probably is a real, if small, effect of 5-HTTLPR on
response to both serotonin reuptake inhibitors and environmental
Background: Somatic symptoms often co-occur with psychological symptoms but this overlap is poorly understood. Some aspects of this overlap differ in the South Asian context, but it is not clear whether this is a reporting effect or an underlying difference in experienced illness. Methods: Home interviews were administered to 4,024 twins randomly selected from a population-based twin register in the Colombo district of Sri Lanka (the CoTASS study). These included assessments of psychological, somatic and fatigue symptoms. The data were analyzed using factor analytic and quantitative genetic approaches. Results: Confirmatory factor analysis showed that the symptoms from the three scales represented three separate dimensions, rather than all tapping into a single dimension. However, familial correlations among the data were most consistent with a common pathway model. This implies that a portion of the underlying vulnerability is common across psychological, fatigue and somatic symptoms. There were sex differences in the etiology of this model, with shared environmental and genetic influences playing different roles in men and women. Conclusions: There is a complex etiological relationship between psychological, fatigue and somatic symptoms. This is similar in Sri Lanka to Western countries, but there may be a greater influence from the family environment, suggesting that care needs to be taken when generalizing research findings between countries. People who complain of certain fatigue or somatic symptoms may well also have psychological symptoms, or may have genetic or environmental vulnerabilities to such problems.
The risk of weight gain is an important determinant of the acceptability and tolerability of antidepressant medication. To compare changes in body weight during treatment with different antidepressants, body weight and height were measured at baseline and after 6, 8, 12 and 26 wk treatment with escitalopram or nortriptyline in 630 adults with moderate-to-severe unipolar depression participating in GENDEP, a part-randomized open-label study. Weight increased significantly more during treatment with nortriptyline compared to escitalopram. The weight gain commenced during the first 6 wk of nortriptyline treatment, reached on average 1.2 kg at 12 wk (0.44-point BMI increase), and continued throughout the 6-month follow-up period. Participants who were underweight at baseline gained most weight. Participants who were obese at baseline did not gain more weight during treatment. Weight gain occurred irrespective of whether weight loss was a symptom of current depressive episode and was identified as an undesired effect of the antidepressant by most participants who gained weight. There was little weight change during treatment with escitalopram, with an average increase of 0.14 kg (0.05-point BMI increase) over 12 wk of treatment. In conclusion, treatment with the tricyclic antidepressant nortriptyline was associated with moderate weight gain, which cannot be explained as a reversal of symptomatic weight loss and is usually perceived as an undesired adverse effect. While treatment with nortriptyline may be recommended in underweight subjects with typical neurovegetative symptoms, escitalopram is a suitable alternative for subjects at risk of weight gain.
Fatigue is a common symptom in Western high-income countries but is often medically unexplained and little is known about its presentation in other populations.
To explore the epidemiology and aetiology of fatigue in Sri Lanka, and of its overlap with depression.
A total of 4024 randomly selected twins from a population-based register in Sri Lanka (Colombo district) completed home interviews including the Chalder Fatigue Questionnaire.
The prevalence of fatigue was similar to that in other countries, although prolonged fatigue may be less common. There was substantial comorbidity with a screen for lifetime depression. Non-shared environmental factors made the largest contributions, although genetic/family factors also contributed. The aetiology appeared consistent across the spectrum of severity.
The aetiology of fatigue is broadly similar in Sri Lanka and Western high-income countries. Abnormal experiences of fatigue appear to be the extreme form of more common fatigue, rather than representing independent entities with different genetic or environmental risk factors.