Prior psychiatric morbidity and differential psychopharmacological treatment patterns: Exploring the heterogeneity of bipolar disorder in a nationwide study of 9594 patients.

OBJECTIVES: Individuals with bipolar disorders (BD) have heterogenic pre-onset illness courses and responses to treatment. The pattern of illness preceding the diagnosis of BD may be a marker of future treatment response. Here, we examined associations between psychiatric morbidity preceding the diagnosis of BD and pharmacological treatment patterns in the 2 years following diagnosis. METHODS: In this register-based study, we included all patients with a diagnosis of BD attending Danish Psychiatric Services between January 1, 2012 and December 31, 2016. We examined the association between a diagnosis of substance use disorder, psychosis (other than schizophrenia or schizoaffective disorder), unipolar depression, anxiety/OCD, PTSD, personality disorder, or ADHD preceding BD and pharmacological treatment patterns following the diagnosis of BD (lithium, valproate, lamotrigine, antidepressants, olanzapine, risperidone, and quetiapine) via multivariable Cox proportional hazards regression adjusted for age, sex, and year of BD diagnosis. RESULTS: We included 9594 patients with a median age of 39 years, 58% of whom were female. Antidepressants, quetiapine, and lamotrigine were the most commonly used medications in BD and were all linked to prior depressive illness and female sex. Lithium was used among patients with less diagnostic heterogeneity preceding BD, while valproate was more likely to be used for patients with prior substance use disorder or ADHD. CONCLUSION: The pharmacological treatment of BD is linked to psychiatric morbidity preceding its diagnosis. Assuming that these associations reflect well-informed clinical decisions, this knowledge may inform future clinical trials by taking participants' prior morbidity into account in treatment allocation.

The efficacy of ball blankets on insomnia in depression in outpatient clinics: A randomised crossover multicentre trial.

Many patients with depression report insomnia symptoms that profoundly affect their health and well-being. Non-pharmacological treatments of insomnia may be preferable for some patients. In this randomised crossover trial, we investigated the efficacy of the Protac Ball Blanket® on insomnia among patients with depression. Included patients (n = 45) were diagnosed with unipolar depression, and with subjective insomnia and poor sleep quality (Pittsburgh Sleep Quality Index Score > 5). Each patient slept 2 weeks with a Protac Ball Blanket® and 2 weeks with a control duvet. Randomisation defined the order of the 2-week sleep periods. Patients served as their own control in this design. The primary outcome was changes in total night-time sleep. Secondary outcomes were sleep-onset latency, number of awakenings, wake after sleep onset, daily use of pro necessitate sedatives and hypnotics, subjective sleep quality (Pittsburgh Sleep Quality Index), insomnia severity (Insomnia Severity Index), symptoms of depression (Hamilton Depression Rating Scale, Major Depression Inventory), symptoms of anxiety (Beck Anxiety Index), and patient-reported outcomes concerning interpersonal sensitivity, neurasthenia, anxiety and depression (Self-Reported Symptom State Scale). Paired two-sided t-tests were used to compare the means of the differences of the outcomes. Protac Ball Blanket® increased total night-time sleep by 12.9 min (95% confidence interval: 1.21-24.63, p = 0.031). Among the secondary outcomes, Protac Ball Blanket® decreased Hamilton Depression Rating Scale by 2.78 (95% confidence interval: -5.44; -0.11, p = 0.042) and Insomnia Severity Index by 2.98 (95% confidence interval: -5.45; -0.50, p = 0.020). No changes were observed in sleep-onset latency, number of awakenings, wake after sleep onset, Pittsburgh Sleep Quality Index, Major Depression Inventory, Beck Anxiety Index, Self-Reported Symptom State Scale, and medication use. The results suggest that some patients may benefit from Protac Ball Blanket® as an add-on non-pharmacological treatment to improve sleep in depression.

Genetic liability to bipolar disorder and body mass index: A bidirectional two-sample Mendelian randomization study.

OBJECTIVES: Bipolar disorder is associated with increased body mass index (BMI), but it remains undetermined if this association is causal and, if so, in which direction it goes. Here, we sought to answer these questions using bidirectional two-sample Mendelian randomization, a method from genetic epidemiology that uses data from genome-wide association studies (GWAS) to examine whether a risk factor is causal for an outcome METHODS: We used summary statistics from GWAS of bipolar disorder and BMI conducted using data collected by the Psychiatric Genomics Consortium and the UK Biobank, respectively. The genetic instrument for bipolar disorder contained 53 SNPs and explained 0.5% of phenotypic variance, while the genetic instrument for BMI contained 517 SNPs and explained 7.1% of phenotypic variance RESULTS: Our findings suggest that genetic liability to bipolar disorder reduces BMI (slope from Egger regression = -0.195, p = 0.004). It follows that a twofold increase in the genetic liability to bipolar disorder leads to a 0.6 (kg/m2 ) reduction in BMI, predominantly driven by reduced fat mass. Conversely, we found no evidence that BMI causes changes in the risk of developing bipolar disorder CONCLUSION: The results of this study suggest that the increased BMI observed among individuals with bipolar disorder is not a direct consequence of genetic liability to bipolar disorder, but may more likely represent the sum of downstream correlates of manifest bipolar disorder, such as side effects of pharmacological treatment, poor diet, and sedentary lifestyle. As these factors are all modifiable, they can be targeted as part of clinical management.

Symptom severity and well-being of patients with mental illness during the COVID-19 pandemic: a two-wave survey.

PURPOSE OF THE ARTICLE: To examine changes in symptom severity and well-being during the coronavirus disease 2019 (COVID-19) pandemic among individuals with pre-existing mental illness. MATERIALS AND METHODS: In February 2021, we conducted a follow-up questionnaire-based survey among adults with mental illness, who responded to a similar survey on mental health in June 2020. The participants completed the 18-item Brief Symptom Inventory (BSI-18), the five-item World Health Organization Well-Being Index (WHO-5), and 14 questions evaluating worsening or improvement in mental health using the pre-pandemic period as reference. The survey data were merged with sociodemographic and clinical data from the medical records of all invitees to the first survey, enabling analysis of attrition and weighting of the results. RESULTS: A total of 613 of 992 (62%) invitees participated in the follow-up wave of the survey. The weighted mean WHO-5 and BSI-18 scores were 38 and 27, respectively, and did not differ statistically significantly from the first wave. Multivariate logistic regression showed that having a vocational education (skilled worker/craftsman) was positively associated with reporting deterioration in psychological well-being (OR: 2.95, 95%CI: 1.14-7.81), while being unemployed was negatively associated with reporting deterioration in psychological well-being (OR: 0.20, 95%CI: 0.07-0.56) from the first to the second survey wave. The most common reason for self-reported deterioration in mental health was loneliness (70%). CONCLUSIONS: Approximately one year into the COVID-19 pandemic, the level of symptoms remained high, whereas the level of psychological well-being remained low among patients with mental illness.

Treatment History Characteristics Associated With Use of Isocarboxazid: A Nationwide Register-Based Study.

PURPOSE/BACKGROUND: The monoamine oxidase inhibitor isocarboxazid (Marplan) is occasionally used in the treatment of depression, but there is only little knowledge on the nature of the use of isocarboxazid in clinical practice. We aimed to identify treatment history characteristics associated with this use. METHODS/PROCEDURES: Via the nationwide Danish registers, we identified all adult incident users of isocarboxazid in the period from 2001 to 2018, as well as up to 5 matched controls using another antidepressant (matched on date of redeemed prescription, age, sex, and region of residence). The 5-year treatment history of the isocarboxazid users and the controls was assessed via the Danish registers. The association between treatment history characteristics and isocarboxazid use was examined by multivariate conditional logistic regression. FINDINGS/RESULTS: We identified 1455 isocarboxazid users and 7045 controls using another antidepressant. The following characteristics were associated with statistically significant increased likelihood of receiving isocarboxazid treatment: Prior treatment with a selective serotonin reuptake inhibitor (odds ratio [OR], 1.80 with 95% confidence interval [CI], 1.46-2.23), a serotonin-norepinephrine reuptake inhibitor (OR, 4.90; 95% CI, 4.08-5.89), a noradrenergic and specific serotonergic antidepressant (OR, 1.56; 95% CI, 1.30-1.88), a tricyclic antidepressant (OR, 5.05; 95% CI, 4.19-6.08), other antidepressants (OR, 4.74; 95% CI, 3.74-6.01), lithium (OR, 6.70; 95% CI, 5.08-8.83), an antipsychotic (OR, 1.43; 95% CI, 1.19-1.73), and each diagnosis of depression received in relation to psychiatric hospital treatment (OR, 1.31; 95% CI, 1.23-1.39). Forty percent of those initiating isocarboxazid had received treatment with drugs from 5 or more different psychopharmacological classes in the 5 preceding years. IMPLICATIONS/CONCLUSIONS: These findings suggest that isocarboxazid is typically used for treatment-resistant depression, consistent with guideline recommendations.

Mental health of patients with mental illness during the COVID-19 pandemic lockdown: a questionnaire-based survey weighted for attrition.

BACKGROUND: Individuals with pre-existing mental illness may be particularly vulnerable to the negative impact that the coronavirus disease 2019 (COVID-19) pandemic seems to have on mental health. Accordingly, the objective of the present study was to assess whether patients with mental illness experienced deterioration in mental health during the COVID-19 lockdown of Denmark in the Spring of 2020. METHODS: We conducted a cross-sectional, questionnaire-based survey coupled with sociodemographic and clinical data from the medical records of all invitees. The latter enabled analysis of attrition and weighting of results. The online questionnaire included the 18-item Brief Symptom Inventory (BSI-18), the five-item World Health Organization Well-Being Index (WHO-5), and 14 questions evaluating worsening or improvement in symptoms during lockdown using the pre-pandemic period as reference. RESULTS: A total of 992 randomly drawn patients with mental illness from the psychiatric services of the Central Denmark Region responded to the questionnaire (response rate = 21.6%). The weighted mean WHO-5 and BSI-18 scores were 38 and 28, respectively. A total of 52% of the respondents reported that their mental health had deteriorated during the lockdown, while 33% reported no change, and 16% reported improvement. The most commonly reported reasons for deterioration were loneliness, disruption of routines, concerns regarding the coronavirus, less contact with family/friends, boredom, and reduced access to psychiatric care. CONCLUSION: More than half of the patients reported worsening of their mental health during the pandemic lockdown. There should be an increased emphasis on ensuring both social and clinical support for individuals with mental illness during pandemics.

Bipolar disorder and cannabis use: A bidirectional two-sample Mendelian randomization study.

Cannabis use is associated with a number of psychiatric disorders; however, the causal nature of these associations has been difficult to establish. Mendelian randomization (MR) offers a way to infer causality between exposures with known genetic predictors (genome-wide significant single nucleotide polymorphisms [SNPs]) and outcomes of interest. MR has previously been applied to investigate the relationship between lifetime cannabis use (having ever used cannabis) and schizophrenia, depression, and attention deficit hyperactivity disorder (ADHD), but not bipolar disorder, representing a gap in the literature. We conducted a two-sample bidirectional MR study on the relationship between bipolar disorder and lifetime cannabis use. Genetic instruments (SNPs) were obtained from the summary statistics of recent large genome-wide association studies (GWAS). We conducted a two-sample bidirectional MR study on the relationship between bipolar disorder and lifetime cannabis use using inverse variance weighted regression, weighted median regression, and Egger regression. Genetic liability to bipolar disorder was significantly associated with an increased risk of lifetime cannabis use; however, genetic liability to lifetime cannabis use showed no association with the risk of bipolar disorder. The sensitivity analyses showed no evidence for pleiotropic effects. The present findings support a causal effect of liability to bipolar disorder on the risk of using cannabis at least once. No evidence was found for a causal effect of liability to cannabis use on the risk of bipolar disorder. These findings add important new knowledge to the understanding of the complex relationship between cannabis use and psychiatric disorders.

COVID-19 vaccine willingness amongst patients with mental illness compared with the general population.

Patients with mental illness are at an increased risk of COVID-19 infection, morbidity, and mortality, and prioritisation of this group for COVID-19 vaccination programmes has therefore been suggested. Vaccine uptake may, however, be compromised by vaccine hesitancy amongst patients with mental illness, posing a critical public health issue. We conducted two surveys to provide weighted estimates of vaccine willingness amongst patients with mental illness and the general population of Denmark. Vaccine willingness was high in both groups, but slightly lower amongst patients with mental illness (84.8%), compared with the general population (89.5%) (p < .001). Based on these findings, vaccine hesitancy does not appear to be a major barrier for vaccine uptake amongst patients with mental illness in Denmark, but may be so in other countries with lower general vaccine willingness. Replication of the present study in other countries is strongly warranted.

Low-frequency rTMS inhibits the anti-depressive effect of ECT. A pilot study.

OBJECTIVE: Low-frequency repetitive transcranial magnetic stimulation (rTMS) of the prefrontal cortex has been shown to have a statistically and clinically significant anti-depressant effect. The present pilot study was carried out to investigate if right prefrontal low-frequency rTMS as an add-on to electroconvulsive therapy (ECT) accelerates the anti-depressant effect and reduces cognitive side effects. METHODS: In this randomised, controlled, double-blind study, thirty-five patients with major depression were allocated to ECT+placebo or ECT+low-frequency right prefrontal rTMS. The severity of depression was evaluated during the course using the Hamilton scale for depression (the 17-item as well as the 6-item scale) and the major depression inventory (MDI). Furthermore, neuropsychological assessment of cognitive function was carried out. RESULTS: The study revealed no significant difference between the two groups for any of the outcomes, but with a visible trend to lower scores for MDI after treatment in the placebo group. The negative impact of ECT on neurocognitive functions was short-lived, and scores on logical memory were significantly improved compared to baseline 4 weeks after last treatment. The ECT-rTMS group revealed generally less impairment of cognitive functions than the ECT-placebo group. CONCLUSION: The addition of low-frequency rTMS as an add-on to ECT treatment did not result in an accelerated response. On the contrary, the results suggest that low-frequency rTMS could inhibit the anti-depressant effect of ECT.

A general framework for moment-based analysis of genetic data.

In population genetics, the Dirichlet (also called the Balding-Nichols) model has for 20 years been considered the key model to approximate the distribution of allele fractions within populations in a multi-allelic setting. It has often been noted that the Dirichlet assumption is approximate because positive correlations among alleles cannot be accommodated under the Dirichlet model. However, the validity of the Dirichlet distribution has never been systematically investigated in a general framework. This paper attempts to address this problem by providing a general overview of how allele fraction data under the most common multi-allelic mutational structures should be modeled. The Dirichlet and alternative models are investigated by simulating allele fractions from a diffusion approximation of the multi-allelic Wright-Fisher process with mutation, and applying a moment-based analysis method. The study shows that the optimal modeling strategy for the distribution of allele fractions depends on the specific mutation process. The Dirichlet model is only an exceptionally good approximation for the pure drift, Jukes-Cantor and parent-independent mutation processes with small mutation rates. Alternative models are required and proposed for the other mutation processes, such as a Beta-Dirichlet model for the infinite alleles mutation process, and a Hierarchical Beta model for the Kimura, Hasegawa-Kishino-Yano and Tamura-Nei processes. Finally, a novel Hierarchical Beta approximation is developed, a Pyramidal Hierarchical Beta model, for the generalized time-reversible and single-step mutation processes.

The efficacy of a transdiagnostic sleep intervention for outpatients with sleep problems and depression, bipolar disorder, or attention deficit disorder: study protocol for a randomized controlled trial.

BACKGROUND: Patients with mental disorders have a higher prevalence of sleep problems than the general population. Sleep problems may include insomnia, circadian rhythm disorders, or hypersomnia. A transdiagnostic approach combining cognitive behavioral therapy for insomnia (CBT-I) with chronotherapy addressing a broad range of sleep problems has shown promising results in a limited number of studies. The aim of the study is to investigate the efficacy of a transdiagnostic sleep intervention for patients with sleep problems comorbid to bipolar disorder, unipolar depression, or attention deficit disorders. The primary hypothesis is that the intervention improves sleep quality compared with a control group. The secondary hypotheses are that the intervention increases subjective and objective sleep efficiency, reduces sleep onset latency, wake after sleep onset, number of awakenings, and severity of insomnia; and that it improves well-being, personal recovery, work ability, and consumption of sleep medication compared with a control group. METHODS: The study is a randomized controlled trial enrolling 88 outpatients with bipolar disorder, major depression, or attention deficit disorder with symptoms of various sleep problems (insomnia, circadian rhythm disorders, or hypersomnia). Patients are allocated to either an intervention group receiving six sessions of transdiagnostic sleep treatment or to a control group receiving a single session of sleep hygiene education. Assessments are made at baseline, at week two, and after 6 weeks in both groups. Actigraphy is performed continuously throughout the 6-week study period for all patients. The primary outcome is changes in the subjective appraisal of sleep quality (Pittsburgh Sleep Quality Index). The secondary outcomes are changes in sleep efficiency, sleep onset latency, wake after sleep onset, number of nocturnal awakenings (based on actigraph and sleep diary data), changes in insomnia severity (Insomnia Severity Index), well-being (WHO-5 Well-Being Index), personal recovery (INSPIRE-O), work ability (Work Ability Index), and consumption of sleep medication (sleep-diaries). DISCUSSION: The study was initiated in 2022 and the inclusion period will continue until mid-2024. The results may have implications for the development and implementation of additional treatment options for patients with mental disorders and comorbid sleep problems. TRIAL REGISTRATION: ClinicalTrials.gov. NCT05406414. Registered on June 6, 2022.

Clinical validation of the Aarhus Side effect Assessment Questionnaire(ASAQ).

BACKGROUND: Psychotropic medications are essential in the treatment of mental illness. Unfortunately, these medications are associated with side effects that may reduce adherence to treatment and quality of life. Therefore, systematic screening for side effects is fundamental to optimize treatment with psychotropic medications. Self-report of side effects is a practical alternative to time-consuming clinical assessments. We developed the Aarhus Side effect Assessment Questionnaire (ASAQ) in an attempt to strike the balance between extensive coverage of side effects and reasonable application time. AIM: The aim of the study was to validate the ASAQ using the clinician-rated Udvalg for Kliniske Undersøgelser (UKU) Side Effect Scale as gold standard reference. METHODS: A total of 122 inpatients and outpatients-mainly with psychotic (39%) and affective disorders (43%)-receiving treatment with psychotropic medication completed the ASAQ and the World Health Organization-Five Well-Being Index (WHO-5) and were subsequently rated on the UKU by trained raters. RESULTS: Using the UKU as the gold standard reference, the ASAQ demonstrated sensitivity values >75% for 77% of its 30 items (ranging from 37% for cutaneous disturbances to 98% for increased sweating) and specificity values >75% for 47% of its 30 items (ranging from 28% for reduced sleep to 98% for micturition disturbances). While 17% of the participants considered discontinuing their medication, 24% had recently refrained from taking their medication as prescribed. A negative correlation was found between the ASAQ and the WHO-5 and total scores (Pearson's correlation coefficient = -0.44). CONCLUSIONS: The self-reported ASAQ seems to be a sensitive tool for detecting side effects of psychotropic medications.

Clinical validation of the self-reported Glasgow Antipsychotic Side-effect Scale using the clinician-rated UKU side-effect scale as gold standard reference.

BACKGROUND: Antipsychotics are key for the treatment of psychotic and several non-psychotic disorders. Unfortunately, antipsychotic medications are associated with side effects, which may reduce quality of life and treatment adherence. Therefore, regular screening of antipsychotic side effects is essential. The Glasgow Antipsychotic Side-effect Scale is a patient self-report scale developed for this purpose. However, the Glasgow Antipsychotic Side-effect Scale has only been validated against another self-report side effect measure, which is suboptimal. OBJECTIVE: We aimed to validate the Glasgow Antipsychotic Side-effect Scale using the clinician-rated Udvalg for Kliniske Undersøgelser side-effect rating scale as the gold standard reference. RESULTS: 81 antipsychotic-treated outpatients with schizophrenia-spectrum disorders (age = 42±13 years; males = 43%, schizophrenia = 77%, illness duration: median = 11 years) completed the Glasgow Antipsychotic Side-effect Scale and were subsequently scored on the Udvalg for Kliniske Undersøgelser by trained raters. Sensitivity, specificity, positive predictive value and negative predictive value were calculated for paired Glasgow Antipsychotic Side-effect Scale and Udvalg for Kliniske Undersøgelser items. Sensitivity of Glasgow Antipsychotic Side-effect Scale items ranged from 33-96%, with 19 (86%) having >75% sensitivity. Lowest sensitivity emerged for "nocturnal enuresis" (33%), "galactorrhea" (50%) and "hyperkinesia" 14-99%, with 14 items (64%) having >75% specificity, being lowest for "asthenia" (14%), "polyuria/polydipsia" (35%), "sedation" (41%), "akathisia" (53%), "dystonia" (65%), "hyperkinesia" (68%), "hypokinesia" (70%) and "accommodation" (70%). Positive predictive value ranged from 7-85%, with six items (27%) having a positive predictive value >75%. Negative predictive value ranged from 40-98%, with 21 items (95%) having a negative predictive value >75%. The mean time to complete the Glasgow Antipsychotic Side-effect Scale was 4±2 minutes. CONCLUSION: The Glasgow Antipsychotic Side-effect Scale demonstrated satisfactory validity as a self-rated tool for antipsychotic side effects and may aid measurement-based care and decision-making.

Electroconvulsive therapy (ECT) for moderate-severity major depression among the elderly: Data from the pride study.

BACKGROUND: Electroconvulsive therapy (ECT) is usually reserved for treatment of severe major depressive disorder (MDD), but may be equally effective in the treatment of moderate-severity MDD. This possibility, however, has only been studied to a very limited extent. We therefore investigated the efficacy of ECT after stratifying patients into severe MDD and moderate-severity MDD. METHODS: We used data from the Prolonging Remission in Depressed Elderly (PRIDE) study, in which 240 patients (≥60 years) with MDD were treated with right unilateral ultrabrief pulse ECT, combined with venlafaxine. We used the six-item core depression subscale (HAM-D6) of the Hamilton Depression Rating Scale to define depression severity. Participants with baseline total scores ≥12 on the HAM-D6 were considered to have severe MDD, while those with HAM-D6 total scores <12 were considered to have moderate-severity MDD. RESULTS: Among the participants with severe MDD and moderate-severity MDD, the mean change in the HAM-D6 total score from baseline to endpoint was -8.2 (95% confidence interval (95%CI) = -7.5; -9.0, paired t-test: p < 0.001) and -5.9 (95%CI = -5.1; -6.6, paired t-test: p < 0.001), respectively. A total of 63% of those with severe MDD and 75% of those with moderate-severity MDD achieved remission (HAM-D6 total score ≤4) (Pearson's 2-sample chi-squared test of difference between groups: p = 0.27). LIMITATIONS: The PRIDE study was not designed to address this research question. CONCLUSIONS: ECT combined with venlafaxine appears to be an effective treatment for moderate-severity MDD. It may be appropriate to expand the indications for ECT to include patients with moderate-severity MDD.

Investigating the association between body fat and depression via Mendelian randomization.

Obesity and depression are major public health concerns that are both associated with substantial morbidity and mortality. There is a considerable body of literature linking obesity to the development of depression. Recent studies using Mendelian randomization indicate that this relationship is causal. Most studies of the obesity-depression association have used body mass index as a measure of obesity. Body mass index is defined as weight (measured in kilograms) divided by the square of height (meters) and therefore does not distinguish between the contributions of fat and nonfat to body weight. To better understand the obesity-depression association, we conduct a Mendelian randomization study of the relationship between fat mass, nonfat mass, height, and depression, using genome-wide association study results from the UK Biobank (n = 332,000) and the Psychiatric Genomics Consortium (n = 480,000). Our findings suggest that both fat mass and height (short stature) are causal risk factors for depression, while nonfat mass is not. These results represent important new knowledge on the role of anthropometric measures in the etiology of depression. They also suggest that reducing fat mass will decrease the risk of depression, which lends further support to public health measures aimed at reducing the obesity epidemic.