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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.
The medical burden in mood disorders is high; various factors are thought to drive this pattern. Little research has examined the role of childhood maltreatment and its effects on medical morbidity in adulthood among people with unipolar depression and bipolar disorder.
This is the first study to explore the association between childhood maltreatment and medical morbidity in bipolar disorder and in unipolar depression, and examine whether the impact of abuse and neglect are distinct or combined.
The participants consisted of 354 psychiatrically healthy controls, 248 participants with recurrent unipolar depression and 72 with bipolar disorder. Participants completed the Childhood Trauma Questionnaire and received a validated medical history interview.
Any type of childhood maltreatment, child abuse and child neglect were significantly associated with the medical burden in bipolar disorder, but not unipolar depression or for controls. These associations worked in a dose–response fashion where participants with bipolar disorder with a history of two or more types of childhood maltreatment had the highest odds of having a medical illness relative to those without such history or those who reported one form. No such significant dose–response patterns were detected for participants with unipolar depression or controls.
These findings suggest that childhood maltreatment may play a stronger role in the development of medical illnesses in individuals with bipolar disorder relative to those with unipolar depression. Individuals who had been maltreated with a mood disorder, especially bipolar disorder may benefit most from prevention and intervention efforts surrounding physical health.
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.
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.
Gram-negative bacilli frequently cause epidemics in high-risk newborn intensive care units. Recently, an epidemic caused by a multiply-resistant K. pneumoniae, serotype 21, occurred in the Vanderbilt University intensive care nursery. The background of this outbreak included an increasing endemic nosocomial sepsis rate, operation of the facility in excess of rated capacity, and increasingly inadequate nurse-to-patient staffing ratios. The epidemic lasted 11 weeks; 26 (12%) of the 232 infants at risk in the unit became colonized. Five infants developed systemic illness and one died. Cohorting, reinforcement of strict handwashing and isolation procedures, and closure of the unit to outborn admissions resulted in rapid termination of the outbreak. Followup studies performed on infants colonized with the epidemic bacterium demonstrated persistent fecal shedding up to 13 months following discharge from the hospital. This epidemic had a detrimental influence on high-risk newborn and obstetric health care delivery in an area encompassing portions of three states. Under a system of progressively more sophisticated referral units, nosocomial infections occurring at a tertiary center can have an impact on other hospitals within the network.
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.
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.
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.
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
Only some women with recurrent major depressive disorder experience
postnatal episodes. Personality and/or cognitive styles might increase
the likelihood of experiencing postnatal depression.
To establish whether personality and cognitive style predicts
vulnerability to postnatal episodes over and above their known
relationship to depression in general.
We compared personality and cognitive style in women with recurrent major
depressive disorder who had experienced one or more postnatal episodes
(postnatal depression (PND) group, n=143) with healthy
female controls (control group, n=173). We also examined
parous women with recurrent major depressive disorder who experienced no
perinatal episodes (non-postnatal depression (NPND) group,
The PND group had higher levels of neuroticism and dysfunctional beliefs,
and lower self-esteem than the control group. However, there were no
significant differences between the PND and NPND groups.
Established personality and cognitive vulnerabilities for depression were
reported by women with a history of postnatal depression, but there was
no evidence that any of these traits or styles confer a specific risk for
the postnatal onset of episodes.
Adverse drug reactions are important determinants of non-adherence to
antidepressant treatment but their assessment is complicated by overlap
with depressive symptoms and lack of reliable self-report measures.
To evaluate a simple self-report measure and describe adverse reactions
to antidepressants in a large sample.
The newly developed self-report Antidepressant Side-Effect Checklist and
the psychiatrist-rated UKU Side Effect Rating Scale were repeatedly
administered to 811 adult participants with depression in a
part-randomised multicentre open-label study comparing escitalopram and
There was good agreement between self-report and psychiatrists' ratings.
Most complaints listed as adverse reactions in people with depression
were more common when they were medication-free rather than during their
treatment with antidepressants. Dry mouth (74%), constipation (33%) and
weight gain (15%) were associated with nortriptyline treatment. Diarrhoea
(9%), insomnia (36%) and yawning (16%) were more common during treatment
with escitalopram. Problems with urination and drowsiness predicted
discontinuation of nortriptyline. Diarrhoea and decreased appetite
predicted discontinuation of escitalopram.
Adverse reactions to antidepressants can be reliably assessed by
self-report. Attention to specific adverse reactions may improve
adherence to antidepressant treatment.
There have been conflicting reports on whether the length polymorphism in
the promoter of the serotonin transporter gene (5-HTTLPR) moderates the
antidepressant effects of selective serotonin reuptake inhibitors
(SSRIs). We hypothesised that the pharmacogenetic effect of 5-HTTLPR is
modulated by gender, age and other variants in the serotonin transporter
To test the hypothesis that the 5-HTTLPR differently influences response
to escitalopram (an SSRI) compared with nortriptyline (a noradrenaline
The 5-HTTLPR and 13 additional markers across the serotonin transporter
gene were genotyped in 795 adults with moderate-to-severe depression
treated with escitalopram or nortriptyline in the Genome Based
Therapeutic Drugs for Depression (GENDEP) project.
The 5-HTTLPR moderated the response to escitalopram, with long-allele
carriers improving more than short-allele homozygotes. A significant
three-way interaction between 5-HTTLPR, drug and gender indicated that
the effect was concentrated in males treated with escitalopram. The
single-nucleotide polymorphism rs2020933 also influenced outcome.
The effect of 5-HTTLPR on antidepressant response is SSRI specific
conditional on gender and modulated by another polymorphism at the 5' end
of the serotonin transporter gene.
An association between depression and headache is well established, but the specificity to migraine is unclear.
To investigate the specificity of the association of depression and migraine.
People with recurrent depression (n=1259) were compared with psychiatrically healthy controls (n=851) to investigate headache defined according to International Headache Society criteria in each group.
All headache types were more prevalent in the case group than in the controls. However, the strongest association was between depression and migraine with aura (OR=5.6). Among participants with recurrent headaches, migraine with aura (but not other forms of headache) was highly significantly associated with depression.
The data suggest that not only is there a general relationship between headache and depression but also that among people with recurrent headache there is a specific association between depression and migraine with aura. The association is likely to be explained by overlapping aetiological risk factors.
Tricyclic antidepressants and serotonin reuptake inhibitors are
considered to be equally effective, but differences may have been
obscured by internally inconsistent measurement scales and inefficient
To test the hypothesis that escitalopram and nortriptyline differ in
their effects on observed mood, cognitive and neurovegetative symptoms of
In a multicentre part-randomised open-label design (the Genome Based
Therapeutic Drugs for Depression (GENDEP) study) 811 adults with moderate
to severe unipolar depression were allocated to flexible dosage
escitalopram or nortriptyline for 12 weeks. The weekly Montgomery–Åsberg
Depression Rating Scale, Hamilton Rating Scale for Depression, and Beck
Depression Inventory were scored both conventionally and in a more novel
way according to dimensions of observed mood, cognitive symptoms and
Mixed-effect linear regression showed no difference between escitalopram
and nortriptyline on the three original scales, but symptom dimensions
revealed drug-specific advantages. Observed mood and cognitive symptoms
improved more with escitalopram than with nortriptyline. Neurovegetative
symptoms improved more with nortriptyline than with escitalopram.
The three symptom dimensions provided sensitive descriptors of
differential antidepressant response and enabled identification of