The effect of smartphone-based monitoring and treatment including clinical feedback versus smartphone-based monitoring without clinical feedback in bipolar disorder: the SmartBipolar trial-a study protocol for a randomized controlled parallel-group trial.

INTRODUCTION: A substantial proportion of patients with bipolar disorder experience daily subsyndromal mood swings, and the term "mood instability" reflecting the variability in mood seems associated with poor prognostic factors, including impaired functioning, and increased risk of hospitalization and relapse. During the last decade, we have developed and tested a smartphone-based system for monitoring bipolar disorder. The present SmartBipolar randomized controlled trial (RCT) aims to investigate whether (1) daily smartphone-based outpatient monitoring and treatment including clinical feedback versus (2) daily smartphone-based monitoring without clinical feedback or (3) daily smartphone-based mood monitoring only improves mood instability and other clinically relevant patient-related outcomes in patients with bipolar disorder. METHODS AND ANALYSIS: The SmartBipolar trial is a pragmatic randomized controlled parallel-group trial. Patients with bipolar disorder are invited to participate as part of their specialized outpatient treatment for patients with bipolar disorder in Mental Health Services in the Capital Region of Denmark. The included patients will be randomized to (1) daily smartphone-based monitoring and treatment including a clinical feedback loop (intervention group) or (2) daily smartphone-based monitoring without a clinical feedback loop (control group) or (3) daily smartphone-based mood monitoring only (control group). All patients receive specialized outpatient treatment for bipolar disorder in the Mental Health Services in the Capital Region of Denmark. The trial started in March 2021 and has currently included 150 patients. The outcomes are (1) mood instability (primary), (2) quality of life, self-rated depressive symptoms, self-rated manic symptoms, perceived stress, satisfaction with care, cumulated number and duration of psychiatric hospitalizations, and medication (secondary), and (3) smartphone-based measures per month of stress, anxiety, irritability, activity, and sleep as well as the percentage of days with presence of mixed mood, days with adherence to medication and adherence to smartphone-based self-monitoring. A total of 201 patients with bipolar disorder will be included in the SmartBipolar trial. ETHICS AND DISSEMINATION: The SmartBipolar trial is funded by the Capital Region of Denmark and the Independent Research Fund Denmark. Ethical approval has been obtained from the Regional Ethical Committee in The Capital Region of Denmark (H-19067248) as well as data permission (journal number: P-2019-809). The results will be published in peer-reviewed academic journals, presented at scientific meetings, and disseminated to patients' organizations and media outlets. TRIAL REGISTRATION: Trial registration number: NCT04230421. Date March 1, 2021. Version 1.

Personality disorders in patients with newly diagnosed bipolar disorder, their unaffected first-degree relatives and healthy control individuals.

OBJECTIVE: Bipolar disorder (BD) is often a progressive mood disorder with a high prevalence of comorbid personality disorder (PD) ranging from 25 to 73 %. Previous studies have included patients with various illness duration of BD. Longer illness duration may be associated with increased prevalence of comorbid PD. This study investigated the prevalence of comorbid personality disorders in patients with newly diagnosed BD and their unaffected first-degree relatives (UR) compared with healthy control individuals (HC). METHODS: We included 204 patients with newly diagnosed BD, 109 of their UR and 188 HC. To assess comorbid PD according to DSM-IV, the SCID-II-interview was performed in full or partial remission. Subthreshold PD was defined as scores above cut-off in the SCID-II self-report questionnaires. Functioning was assessed using the Functioning Assessment Short Test. RESULTS: In total 52 (25.5 %) of the patients with newly diagnosed BD fulfilled criteria for a comorbid PD. Regarding UR, 7 (6.4 %) fulfilled the criteria for a PD. Subthreshold PD were more prevalent in BD (82.8 %) and UR (53.0 %) than in HC (35.1 %), p-values < 0.003). Patients with comorbid PD presented with impaired functioning compared with patients without PD. LIMITATIONS: Clinical diagnostic distinction between PD and BD is challenged by overlapping symptoms. CONCLUSION: A quarter of patients with newly diagnosed BD fulfill criteria for a comorbid PD, already at the time of the diagnosis with BD. A comorbid PD is associated with larger functional impairments. This emphasizes the need for early assessment of comorbid PD at time of BD diagnosis.

At the Core of Depression: A Diagnostic Interview of the Core Features of Depression.

INTRODUCTION: Valid and reliable methods for diagnosing depression are essential. The present study aimed to test the performance of a new diagnostic interview for depression focusing on the core symptoms of depression. METHOD: We developed a diagnostic interview for depression: the CORE Diagnostic Interview, CORE-DI, which assesses each of the core features of depression on the four dimensions: quality, reactivity, globality, and fluctuations over time. The diagnostic performance of this interview was tested in a clinical study including 83 individuals presenting with various depressive symptoms, who were interviewed independently (1) by means of the CORE-DI and the Mini-International Neuropsychiatric Interview (M.I.N.I.), and (2) by highly skilled specialists in depression representing gold standard diagnoses. RESULTS: We compared the outcome of the CORE-DI, the M.I.N.I., and the diagnosis made by clinicians, respectively, versus the gold standard diagnosis, using diagnostic efficiency statistics. The CORE-DI diagnosed depression with a high specificity (0.91, 95% CI: 0.85-0.97, for International Classification of Diseases [ICD]-10 criteria and 0.88, 95% CI: 0.81-0.95, for Diagnostic and Statistical Manual of Mental Disorders [DSM-5] criteria) compared to both M.I.N.I (specificity 0.44, 95% CI: 0.33-0.55) and clinical diagnoses (specificity 0.76, 95% CI: 0.67-0.85). The sensitivity of the CORE-DI was 0.61 (95% CI: 0.55-0.72) for ICD-10 criteria and 0.67 (95% CI: 0.57-0.77) for DSM-5 criteria. DISCUSSION/CONCLUSION: The CORE-DI increased the specificity of the depression diagnosis substantially compared to clinical diagnoses and the diagnoses obtained by M.I.N.I. The results point to the usefulness of an elaborated and systematic assessment of the core symptoms in the examination of patients with depressive symptoms and thereby indicate a way for further development of specific diagnostic tools for depression in both clinical and research settings. However, it should be noted that the sensitivity of the CORE-DI was modest, and the psychometric properties of the CORE-DI might be different in other settings with higher or lower prevalence or severity of depressive symptoms.

Diagnostic Stability of Comorbid Personality Disorders Among Patients Fully or Partially Remitted From First-Episode Depression: A 5-Year Follow-Up Study.

The diagnostic stability of comorbid personality disorders among patients with depression remains unclear. A total of 262 patients suffering from first-episode depression were assessed using the Structured Clinical Interview for DSM-IV Axis II Personality Disorders (SCID-II) and reassessed after 5 years. A total of 87 patients (33%) were diagnosed with a personality disorder at baseline, and 63 of them (72%) maintained a personality disorder diagnosis at follow-up (kappa coefficient 0.71). At cluster level, 63% maintained a diagnosis within cluster B and 48% maintained a cluster C disorder across the follow-up period (kappa coefficients of 0.54 and 0.64, respectively). Hence, comorbid personality disorders cannot be taken just as artifacts of the depressive mood that will remit spontaneously or with further treatment of the primary depression. Furthermore, the stability of personality disorders diagnoses was not predicted by clinical characteristics of the depression, nor of the course of the affective disorder during follow-up.

The validity of dysthymia to predict clinical depressive symptoms as measured by the Hamilton Depression Scale at the 5-year follow-up of patients with first episode depression.

BACKGROUND: In long-term follow-up studies on depression, the Eysenck Neuroticism Scale (ENS) at the score level of dysthymia has been found to be valid at predicting poor outcome. AIMS: The ENS dysthymia level was compared with the Beck Depression Inventory (BDI) level to predict the prevalence of depressive symptoms at the 5-year follow-up of patients initially diagnosed with first episode depression using the Hamilton Depression Scale (HAM-D) to express depressive symptoms. METHODS: A total of 301 in- or outpatients aged 18-70 years with a recent single depressive episode were assessed by ENS, BDI, and HAM-D from 2005-2007. At 5-year follow-up from 2011-2013, the participants were re-assessed by HAM-D. The HAM-D was used to measure depressive symptoms at the 5-year follow-up. The Mokken analysis was used to indicate scalability of the BDI and ENS. RESULTS: A total of 185 participants were available for the psychometric analysis of the ESN and BDI, and the scalability was found acceptable. In total, 99 patients were available for the predictive analysis. Both the ENS and the BDI were significantly associated with depressive symptoms (HAM-D17 ≥ 8) at the 5-year follow-up (p < 0.05). CONCLUSION: Dysthymia as measured by the two self-rating scales ENS and BDI can be considered part of a 'double depression' in patients with first episode depression, implying an existence of depressive symptoms at the 5-year follow-up. CLINICAL IMPLICATIONS: Evaluation of dysthymia or neuroticism is important to perform, even in patients with first episode depression, in order to identify 'double depression'.

[Depression]. / Depression.

The prevalence of depression is not clearly established, but estimated to 3-4% in a Danish questionnaire study. Lifetime's prevalences of 12-17% are reported in other community samples. In the current diagnostic system depression is defined categorically and operationally. It has been argued, that these diagnostic criteria represent an oversimplification, which has blurred the concept of depression. We suggest a greater emphasis on the depressed mood as the core symptom of depression, which may increase the specificity of the diagnosis. Furthermore, basic principles for the treatment of depression are presented.

Are variations in whole blood BDNF level associated with the BDNF Val66Met polymorphism in patients with first episode depression?

Brain derived neurotrophic factor (BDNF) seems to play an important role in the pathophysiology of affective disorders. The current study investigated whether blood level BDNF is correlated with the severity of depressive symptoms and recent (six months prior to onset of depression) experience of stressful life events (SLE) in a cohort of patients with a first depressive episode. 262 patients with first episode depression (females 174, males 88, age range 18-70, mean age 41) participated and control sample of 84 participants was included (females 52, males 32, age range 22-70, mean age 42). Symptomatology was rated using Hamilton Rating Scale for Depression (HAMD-17) and Becks Depression Inventory (BDI 21). No differences in whole blood BDNF was seen in relation to the BDNF Val66Met polymorphism and no significant correlations between whole blood BDNF and HAMD-17 or BDI 21 scores were found. No significant associations between the experiences of SLE before onset of depression and BDNF level were observed. Finally, peripheral BDNF differentiated between patients and healthy control persons. In the current sample of first episode depressed patients, the Val66Met polymorphism was not associated with whole blood BDNF and whole blood BNDF level was not associated with the experience of recent SLE.

[Genetics and stressful life events interact in depression]. / Genetik og stressende livsbegivenheder interagerer ved depression.

The aim of the present review was to present clinical aspects of recent research in genes, the experience of stressful life events and depression. 60-70% experience a moderate to severe stressful life event half a year prior to the first onset of depression, whereas later depressive episodes to a lesser extent are preceded by stressful life events. Clinical features do not differ between depressions with or without prior stressful life events. Certain genetic variations in the serotonin receptor system seem to increase the risk of developing depression in relation to experiencing stressful life events.

The effect of prolonged duration of untreated depression on antidepressant treatment outcome.

BACKGROUND: The duration of untreated illness has been considered a likely predictor of the course of psychotic disorders. However, there is only sparse data concerning the influence of treatment delay on the outcome of mood disorders. The present study aimed to assess the effect of prolonged untreated depression on the outcome of antidepressant treatment. METHOD: Patients aged 18-70 years with recent onset of the first lifetime depressive episode were systematically recruited by the Danish Psychiatric Central Research Register during a 2-year period. A total number of 399 individuals out of 1006 potential participants in the Register were interviewed, and 270 fulfilled the inclusion criteria. The validity of the diagnosis, duration of untreated illness, remission on first-line antidepressant treatment and a number of covariates, including psychiatric co-morbidity, personality disorders and traits, stressful life events prior to onset, and family history of psychiatric illness, were assessed by structured interviews. RESULTS: The remission rate was significantly decreased among patients with six months or more of untreated depression as compared to patients who were treated with antidepressant medication earlier after onset (21.1% versus 33.7%, OR=0.5, 95% CI 0.3 to 0.9, p=0.03). The negative influence of a prolonged DUI on the outcome did not seem confounded by any of a wide range of demographic and clinical variables. LIMITATIONS: The outcome was evaluated retrospectively. The findings cannot be generalized to patients outside hospital settings. CONCLUSION: Initiation of antidepressant treatment more than six months after onset of first episode depression reduces the chance of obtaining remission. The results emphasize the importance of early recognition and treatment of patients suffering from depression.

Promoter variants in IL18 are associated with onset of depression in patients previously exposed to stressful-life events.

BACKGROUND: Depression is accompanied by an inflammatory reaction and activation of cell mediated immunity (CMI) and stressors may induce the cytokine network in humans. The proinflammatory cytokine interleukin-18 (IL-18) is less investigated in depression but highly relevant since it is produced by activated macrophages and expressed in the brain. METHODS: The distribution of six polymorphisms in IL10, IL18 and NF was compared between patients with a single episode of depression either preceded by a stressful life event (n=182), or occurring without a prior stressful life event (n=106) and a group of healthy control individuals (n=335). RESULTS: The major C allele of the IL18 rs187238 and the major G allele of rs1946518 had a significantly higher prevalence among the patients with a stressful life event prior to onset of disease than both patients without a stressful life event and compared with the healthy controls individuals. None of the examined IL10 or NF alleles were differently distributed among these groups. LIMITATIONS: Data are nominally significant and not resistant to correction for multiple testing. CONCLUSION: The major C allele of the IL18 rs187238 and the major G allele rs1946518 have previously been associated with higher expression of IL-18 mRNA. Our data suggest that this genetic trend towards higher IL-18 production may increase the susceptibility to depression in response to stressful life events.

Differences between early and late onset adult depression.

BACKGROUND: It is unclear, whether age-of-onset identifies subgroups of depression. AIM: To assess the clinical presentation of depression with onset in the early adult age (18-30 years) as compared to depression with later onset (31-70 years). METHOD: A total number of 301 patients with first episode depression were systematically recruited. Characteristics including psychiatric co-morbidity, personality disorders and traits, stressful life events prior to onset, family history, and treatment outcome were assessed by structured interviews and compared by chi-square tests for categorical data, t-tests for continuous parametric data and Mann-Whitney U-test for continuous nonparametric data. Logistic and multiple regression analyses were used to adjust the analyses for potentially confounding variables. RESULTS: Patients with early onset of depression were characterised by a higher prevalence of co-morbid personality disorders, higher levels of neuroticism, and a lower prevalence of stressful life events preceding onset compared to patients with later age-of-onset. There were no differences in severity of the depressive episode, treatment outcome or family loading of psychiatric illness. CONCLUSION: Early adult onset of depression is associated with co-morbid personality deviances, whereas late onset is associated with environmental risk factors.

Clinical utility of Standardised Assessment of Personality - Abbreviated Scale (SAPAS) among patients with first episode depression.

BACKGROUND: Personality disorder frequently co-occurs with depression and seems to be associated with a poorer outcome of treatment and increased risk for recurrences. However, the diagnosing of personality disorder can be lengthy and requires some training. Therefore, a brief screening interview for comorbid personality disorder among patients suffering from depression would be of clinical use. METHOD: The present study aimed to assess the utility of the Standardised Assessment of Personality - Abbreviated Scale (SAPAS) as a screen for personality disorder in a population of patients recently diagnosed with first episode depression. A total number of 394 patients with an ICD-10 diagnosis of a single depressive episode were sampled consecutively via the Danish Psychiatric Central Research Register during a 2years inclusion period and assessed by the screening interview and, subsequently, by the Structured Clinical Interview for DSM-IV Personality Disorders. RESULTS: We found, that a cut-off of 3 on the screen correctly identified the presence of comorbid personality disorder in 73.1% of the patients. The sensitivity and specificity were 0.80 and 0.70, respectively. LIMITATIONS: The findings cannot be generalized to patients outside hospital settings. CONCLUSION: The study provides evidence for the clinical utility of SAPAS as a screening interview for comorbid personality disorder in a population of patients with a primary diagnosis of depression.

The influence of comorbid personality disorder and neuroticism on treatment outcome in first episode depression.

BACKGROUND: It has never been investigated whether comorbid personality disorder or neuroticism predicts a poor treatment outcome in first episode depression. METHODS: Medically treated patients discharged with a diagnosis of a single depressive episode from a psychiatric in- or outpatient hospital setting were consecutively sampled from the Danish Psychiatric Central Research Register. The patients participated in an extensive interview including the Schedules for Clinical Assessment in Neuropsychiatry, the Structured Clinical Interview for DSM-IV Axis II Personality Disorders and a detailed assessment of medical treatment history using standardised procedures (Treatment Response to Antidepressants Questionnaire, TRAQ). Remission was defined as a score of < or =7 on the Hamilton Depression Rating Scale, 17 items, and a score of > or =4 on the TRAQ following (1) a first adequate trial of antidepressant treatment, and (2) 2 trials of antidepressant treatment. Further personality traits were assessed by means of the Eysenck Personality Questionnaire. RESULTS: Among a total of 301 patients with a single depressive episode, 31.9% fulfilled diagnostic criteria for at least 1 personality disorder of any kind. Comorbid personality disorder was associated with a 2.2-times (95% CI: 1.1-4.2) increased risk of non-remission following the first antidepressant trial, whereas no effect was found following the second antidepressant trial (OR: 1.6; 95% CI: 0.8-3.4). A high level of neuroticism was associated with non-remission in first as well as second trials. CONCLUSION: Comorbid personality disorder and high levels of neuroticism in first episode depression predict an increased risk of non-remission from depression.

Does bereavement-related first episode depression differ from other kinds of first depressions?

BACKGROUND: It has never been investigated whether first depression differs in patients who have experienced bereavement compared to patients who have not. METHOD: Patients discharged with a diagnosis of a single depressive episode from a psychiatric in- or outpatient hospital setting were consecutively sampled from the Danish Psychiatric Central Research Register. Patients participated in an extensive interview including the Schedules for Clinical Assessment in Neuropsychiatry (SCAN) and the Interview of Recent Life Events (IRLE). RESULTS: Among 301 patients with a first depression, 26 patients (4.7%) had experienced death of a first degree relative (parent, sibling, child) or a near friend, 163 patients (54.2%) had experienced other moderate to severe stressful life events and 112 patients had not experienced stressful life events in a 6 months period prior to the onset of depression. Patients who had experienced bereavement did not differ from patients with other stressful life events or from patients without stressful life events in socio-demographic variables or in the phenomenology of the depression, psychiatric comorbidity, family history or response to antidepressant treatment. CONCLUSION: Bereavement-related first episode depression does not differ from other kinds of first depression.

No interactions between genetic polymorphisms and stressful life events on outcome of antidepressant treatment.

Genetic polymorphisms seem to influence the response on antidepressant treatment and moderate the impact of stress on depression. The present study aimed to assess, whether allelic variants and stressful life events interact on the clinical outcome of depression. In a sample of 290 systematically recruited patients diagnosed with a single depressive episode according to ICD-10, we assessed the outcome of antidepressant treatment and the presence of stressful life events in a 6-month period preceding onset of depression by means of structured interviews. Further, we genotyped nine polymorphisms in the genes encoding the serotonin transporter, brain derived neurotrophic factor, catechol-O-methyltransferase, angiotensin converting enzyme, tryptophan hydroxylase, and the serotonin receptors 1A, 2A, and 2C. We found no evidence that the effects of the genetic polymorphisms on treatment outcome were dependent on stressful life events experienced by the individual prior to onset of depression.

Interaction between genetic polymorphisms and stressful life events in first episode depression.

BACKGROUND: A polymorphism in the serotonin transporter (5-HTT) gene seems to moderate the influence of stressful life events on depression. However, the results from previous studies of gene-environment interactions in depression are inconsistent and might be confounded by the history of depression among participants. METHOD: We applied a case-only design, including 290 ethnically homogeneous patients suffering exclusively from first episode depression. Psychiatric mo-morbidity, personality traits and disorders and stressful life events in a six months period preceding onset of depression were evaluated by means of interviews and questionnaires. Additionally, we genotyped nine polymorphisms in the genes encoding the serotonin transporter, brain derived neurotrophic factor, catechol-O-methyltransferase, angiotensin converting enzyme, tryptophane hydroxylase, and the serotonin receptors 1A, 2A, and 2C. RESULTS: The low activity variants of the 5-HTT-linked polymorphic region in the serotonin transporter gene and the Met-allele of a single nucleotide polymorphism (Val66Met) in the gene encoding brain derived neurotrophic factor were independently associated with the presence of stressful life events prior to onset of depression, also when corrected for the effect of age, gender, marital status, personality disorder, neuroticism, and severity of depressive symptoms at the time of interview. CONCLUSION: Polymorphisms in the genes encoding the serotonin transporter and the brain derived neurotrophic factor interact with recent stressful life events on depression among patients with no history of previous depressive episodes.

Comparison of the antidepressant effects of venlafaxine and dosulepin in a naturalistic setting.

The relative efficacy of the various classes of antidepressants has not been established. Observational studies in naturalistic settings are important in evaluating treatment outcomes with antidepressants, since controlled clinical trials include only a minority of patients present in clinical practice. This study sought to evaluate in a naturalistic setting the treatment outcomes of dosulepin and venlafaxine for patients with depressive episodes. At the university hospital in Copenhagen, Denmark, between 1998 and early 2001, the first-line treatment for psychiatric inpatients with depression was dosulepin; after that time, venlafaxine was the first-line medication. We compared the treatment outcomes among inpatients during the respective periods. There was no significant difference in the primary outcome parameters between the two groups. A tendency in favour of dosulepin confirmed by a post-hoc analysis suggested that the failure to achieve significant difference was related to a type 2 error. However, missing data and possible confounders related to the different treatment periods weaken the results. This naturalistic study showed a non-significant trend for poorer treatment outcomes (probably because of an underpowered design) after replacing dosulepin with venlafaxine as first-line drug for depression in a naturalistic inpatient setting.

Do stressful life events predict medical treatment outcome in first episode of depression?

BACKGROUND: It is unclear whether medical treatment outcome in first episode depression differ for patients with and without stressful life events prior to onset of depression. METHODS: Patients discharged with a diagnosis of a single depressive episode from a psychiatric in- or outpatient hospital setting were consecutively sampled from the Danish Psychiatric Central Research Register. Patients participated in an extensive interview including the schedules for clinical assessment in neuropsychiatry (SCAN), the Structured Clinical Interview for DSM-IV axis II personality disorders (SCID-II) and the interview of recent life events (IRLE). Medical treatment history was assessed in detail using standardised procedures (TRAQ). Remission was defined as a score or= 4 on TRAQ following (1) first trial of antidepressant treatment (2) two adequate trials of antidepressant treatment. RESULTS: A total of 399 patients participated in the interview and among these 301 patients obtained a SCAN diagnosis of a single depressive episode. A total of 62.8% of the 301 patients experienced at least one moderate to severe stressful life event in a 6 months period prior to symptom onset. The presence of a stressful life event or the number of stressful life events did not predict remission from first or second antidepressant drug trial-nor when adjusted for differences in age, gender or prevalence of co-morbid personality disorders. CONCLUSIONS: Medical treatment outcome in first episode depression does not depend on the prevalence of moderate to severe stressful life events prior to symptom onset.

Validity of the diagnosis of a single depressive episode in a case register.

OBJECTIVE: To validate the ICD-10 diagnosis of a single depressive episode as used in daily clinical psychiatric practice and as recorded in the Danish Psychiatric Central Research Register. METHODS: Patients discharged with a diagnosis of a single depressive episode were consecutively sampled from the register and diagnosed according to an interview using the Schedules for Clinical Assessment in Neuropsychiatry (SCAN). RESULTS: A total of 75.4% of 399 patients with a register diagnosis of a single depressive episode also got this diagnosis according to the SCAN interview (82.8% for severe type of a single depression, 76.0% for moderate type of a single depression and 65.2% for mild type of a single depression). CONCLUSION: The ICD-10 diagnosis of a single depressive episode can be used in daily clinical practice with sufficient precision. The validity of the diagnosis is highest for severe and moderate type of depression and decreases for mild depression.