An umbrella review of candidate predictors of response, remission, recovery, and relapse across mental disorders.

We aimed to identify diagnosis-specific/transdiagnostic/transoutcome multivariable candidate predictors (MCPs) of key outcomes in mental disorders. We conducted an umbrella review (protocol  link ), searching MEDLINE/Embase (19/07/2022), including systematic reviews of studies reporting on MCPs of response, remission, recovery, or relapse, in DSM/ICD-defined mental disorders. From published predictors, we filtered MCPs, validating MCP criteria. AMSTAR2/PROBAST measured quality/risk of bias of systematic reviews/individual studies. We included 117 systematic reviews, 403 studies, 299,888 individuals with mental disorders, testing 796 prediction models. Only 4.3%/1.2% of the systematic reviews/individual studies were at low risk of bias. The most frequently targeted outcome was remission (36.9%), the least frequent was recovery (2.5%). Studies mainly focused on depressive (39.4%), substance-use (17.9%), and schizophrenia-spectrum (11.9%) disorders. We identified numerous MCPs within disorders for response, remission and relapse, but none for recovery. Transdiagnostic MCPs of remission included lower disease-specific symptoms (disorders = 5), female sex/higher education (disorders = 3), and quality of life/functioning (disorders = 2). Transdiagnostic MCPs of relapse included higher disease-specific symptoms (disorders = 5), higher depressive symptoms (disorders = 3), and younger age/higher anxiety symptoms/global illness severity/ number of previous episodes/negative life events (disorders = 2). Finally, positive trans-outcome MCPs for depression included less negative life events/depressive symptoms (response, remission, less relapse), female sex (response, remission) and better functioning (response, less relapse); for schizophrenia, less positive symptoms/higher depressive symptoms (remission, less relapse); for substance use disorder, marital status/higher education (remission, less relapse). Male sex, younger age, more clinical symptoms and comorbid mental/physical symptoms/disorders were poor prognostic factors, while positive factors included social contacts and employment, absent negative life events, higher education, early access/intervention, lower disease-specific and comorbid mental and physical symptoms/conditions, across mental disorders. Current data limitations include high risk of bias of studies and extraction of single predictors from multivariable models. Identified MCPs can inform future development, validation or refinement of prediction models of key outcomes in mental disorders.

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.

Association between lithium treatment and renal, thyroid and parathyroid function: A cohort study of 6659 patients with bipolar disorder.

OBJECTIVES: Although potential adverse effects of lithium treatment on renal and endocrine systems have been extensively investigated, most prior studies are limited by selected populations and short follow-up. METHODS: Within the Psychiatric Services of the Central Denmark Region, we identified all patients with bipolar disorder and ≥1 serum-lithium (se-Li) measurements between January 1, 2013, and July 20, 2022, and reference patients with bipolar disorder matched on age, sex, and baseline creatinine. Outcomes were diagnoses of renal, thyroid and parathyroid disease, and blood tests measuring creatinine, estimated glomerular filtration rate (eGFR), thyroid-stimulating hormone (TSH), parathyroid hormone (PTH) and calcium. Analyses included unadjusted multilevel regression to describe changes in biochemical markers, and adjusted Cox regression to compare rates of disease/biochemical outcomes between lithium users and reference patients. RESULTS: Among 1646 lithium users (median age 36 years, 63% women) and 5013 reference patients, lithium users had decreasing TSH and eGFR, stable PTH, and increasing calcium levels over time. Lithium use was associated with increased rates of renal, thyroid and parathyroid disease, and levels of biochemical markers outside normal ranges (hazard rate ratios: 1.07-11.22), but the absolute number of severe outcomes was low (e.g., chronic kidney disease: N = 10, 0.6%). Notably, the rate of blood testing was substantially higher among lithium users than among reference patients (e.g., mean number of creatinine tests during the second year of follow-up: lithium users = 2.5, reference patients = 1.4). CONCLUSIONS: Severely adverse renal and endocrine outcomes are rare during lithium treatment. Observational studies of long-term lithium treatment are prone to detection bias.

Risk of Mania After Methylphenidate in Patients With Bipolar Disorder.

BACKGROUND: Bipolar disorder and attention-deficit/hyperactivity disorder are common comorbidities. Attention-deficit/hyperactivity disorder is commonly treated with stimulants (eg, methylphenidate), which, however, have been suggested to cause treatment-emergent mania in patients with bipolar disorder. Here, we assessed the risk of mania, depressive episodes, and psychiatric admissions after initiation of methylphenidate treatment in patients with bipolar disorder. METHODS: Using Danish health registries, we identified all individuals registered with a diagnosis of bipolar disorder from January 1, 2000, to January 1, 2018, who were treated with methylphenidate. We applied a 1-year mirror-image model to compare the occurrence of mania, depression, and psychiatric admissions in the period leading up to and after methylphenidate treatment initiation. We furthermore assessed the trend in these outcomes from 4 years before to 1 year after initiation of methylphenidate treatment. RESULTS: A total of 1043 patients with bipolar disorder initiated treatment with methylphenidate. The number of manic episodes decreased by 48% after methylphenidate treatment initiation (P = 0.01), both among patients using mood stabilizers (-50%) and among patients not using mood stabilizers (-45%). The number of manic episodes, however, peaked approximately 6 months before methylphenidate. The results were similar for the secondary outcomes. CONCLUSIONS: Initiation of methylphenidate treatment was not associated with an increased risk of mania in patients with bipolar disorder. A decrease in mania, depressive episodes, and psychiatric admissions was observed after methylphenidate. However, these decreases seemed to be driven by regression to the mean after clinical deterioration preceding methylphenidate treatment, rather than by the methylphenidate treatment itself.

Escaping the Long Shadow Cast by Agranulocytosis: Reflections on Clozapine Pharmacovigilance Focused on the United Kingdom.

PURPOSE/BACKGROUND: A recent article in this journal presented a US perspective regarding the modernization of clozapine prescription and proposed an escape from the long shadow cast by agranulocytosis. METHODS: Here, an international group of collaborators discusses a point of view complementary to the US view by focusing on worldwide outcomes of clozapine usage that may be uneven in terms of frequency of clozapine adverse drug reactions. FINDINGS/RESULTS: Studies from the Scandinavian national registries (Finland and Denmark) did not find increased mortality in clozapine patients or any clear evidence of the alleged toxicity of clozapine. Data on clozapine-associated fatal outcomes were obtained from 2 recently published pharmacovigilance studies and from the UK pharmacovigilance database. A pharmacovigilance study focused on physician reports to assess worldwide lethality of drugs from 2010 to 2019 found 968 clozapine-associated fatal outcomes in the United Kingdom. Moreover, the United Kingdom accounted for 55% (968 of 1761) of worldwide and 90% (968 of 1073) of European fatal clozapine-associated outcomes. In a pharmacovigilance study from the UK database (from 2008 to 2017), clozapine was associated with 383 fatal outcomes/year including all reports from physicians and nonphysicians. From 2018 to 2021, UK clozapine-associated fatal outcomes increased to 440/year. IMPLICATIONS/CONCLUSIONS: The interpretation of fatal outcomes in each country using pharmacovigilance databases is limited and only allows gross comparisons; even with those limitations, the UK data seem concerning. Pneumonia and myocarditis may be more important than agranulocytosis in explaining the uneven distribution of fatal outcomes in clozapine patients across countries.

Revisiting the association between treatment with antidepressants and mania: A nationwide within-individual study of 3554 patients with bipolar disorder.

INTRODUCTION: Antidepressants are commonly used "off-label" for bipolar depression, despite concerns over the risk of potential treatment-emergent mania (or "manic switch"). Treatment-emergent mania is difficult to study with adequate power in clinical trials as it requires a large group of participants and long follow-up. Therefore, naturalistic register-based studies have been applied to assess this phenomenon. Here, we aimed to replicate previous findings and address key methodological limitations that were not previously taken into account. METHODS: We utilized data from nationwide Danish health registries to identify patients with bipolar disorder treated with an antidepressant, either with or without concomitant treatment with a mood stabilizer (drug treatment proxied via redeemed prescriptions). We plotted the incidence of manic and depressive episodes relative to the initiation of antidepressant treatment and compared the incidence of mania in the period prior to and following initiation of antidepressant treatment (within-individual design). RESULTS: In 3554 patients with bipolar disorder initiating treatment with an antidepressant, the number of manic episodes peaked approximately 3 months prior to initiation of antidepressant treatment, and the number of depressive episodes peaked around the initiation of antidepressant prescription. This temporal pattern suggests that antidepressants were used to treat post-manic depression. CONCLUSION: Within-individual designs do not control sufficiently for confounding by indication, when the treatment indication is time-varying. Thus, results from prior within-individual studies of antidepressant treatment in the context of bipolar disorder may be invalid due to time-varying confounding by indication.

Pharmacological treatment of bipolar disorder and risk of diabetes mellitus: A nationwide study of 30,451 patients.

OBJECTIVE: While treatment with antipsychotics and antiepileptics have been associated with an increased risk of diabetes mellitus (DM), lithium may have the opposite effect via inhibition of glycogen synthase kinase-3. The aim of this study was to investigate whether treatment of bipolar disorder with lithium, antipsychotics, or antiepileptics is associated with the risk of DM in a real-world clinical setting. METHODS: Using nationwide registers, we identified all patients diagnosed with bipolar disorder in Danish Psychiatric Services from January 1, 1996, to January 1, 2019 (N = 30,451). The risk of developing DM was operationalized via hospital diagnoses and redeemed prescriptions for glucose-lowering drugs. For lithium, antipsychotics, valproate, and lamotrigine, we calculated hazard rate ratios (HRR) for developing DM via adjusted Cox proportional hazards models. Potential cumulative dose-response-like associations were examined using the log-rank test. RESULTS: During follow-up (245,181 person-years), 2107 (6.9%) patients developed DM. Compared with non-users of the respective drugs, we found no clinically or statistically significant difference in the risk of developing DM among patients receiving lithium (n = 11,690; incidence rate of DM/1000 person-years (IR) = 8.87, 95% CI: 8.02-9.90; HRR = 0.94, 95% CI: 0.84-1.06) or lamotrigine (n = 11,785; IR = 7.58, 95% CI: 6.69-8.59; HRR = 0.89, 95% CI: 0.77-1.02), respectively. Conversely, for patients receiving valproate (n = 5171; IR = 12.68, 95% CI: 10.87-14.80; HRR = 1.34, 95% CI: 1.14-1.58) and antipsychotics (n = 22,719; IR = 12.00, 95% CI: 11.14-12.94; HRR = 1.65, 95% CI: 1.45-1.88), respectively, there was increased risk of developing DM. For antipsychotics, we observed a clear cumulative dose-response-like association with the risk of DM. CONCLUSIONS: Treatment with valproate and antipsychotics-but not with lithium and lamotrigine-was associated with increased risk of DM in a real-world cohort of patients with bipolar disorder.

Risk factors for suicide among patients having received treatment with electroconvulsive therapy: A nationwide study of 11,780 patients.

OBJECTIVES: Despite the putative anti-suicidal effect of electroconvulsive therapy (ECT), patients receiving ECT remain at high risk of dying from suicide due to the severity of their underlying mental illness. We aimed to quantify this risk and to identify risk factors for suicide among patients receiving ECT. METHODS: Using nationwide Danish registers, we identified all patients that initiated ECT between 2006 and 2016. These patients were matched on sex and age to 10 reference individuals from the general Danish population. Firstly, we compared 2-year suicide risk between patients initiating ECT and the matched reference individuals. Secondly, we investigated if any patient characteristics were associated with suicide following ECT via Cox proportional hazards regression. RESULTS: A total of 11,780 patients receiving ECT and 117,800 reference individuals were included in the analyses. Among the patients receiving ECT, 161 (1.4%) died from suicide within two years. Compared to the reference individuals, patients having received ECT had a substantially elevated suicide rate (Hazard rate ratio (HRR) = 44.48, 95%CI = 31.12-63.59). Among those having received ECT, the following characteristics were associated with suicide: Male sex (adjusted HRR (AHRR) = 2.32, 95%CI = 1.63-3.30), medium-term higher education (AHRR = 2.64, 95%CI = 1.57-4.44); long-term higher education (AHRR = 3.16, 95%CI = 1.68-5.94), history of substance use disorder (AHRR = 1.51, 95%CI = 1.01-2.26) and history of intentional self-harm/suicide attempt (AHRR = 4.18, 95%CI = 2.76-6.32). CONCLUSIONS: Those who are male, have obtained medium-/long-term higher education, or have a history of substance use disorder or intentional self-harm/suicide attempt, are at particularly elevated risk of suicide following ECT. These findings may guide clinical initiatives to reduce suicides.

Treatment of postpartum psychotic- or mood disorder requiring admission: A nationwide study from Denmark.

BACKGROUND: Postpartum psychotic- or mood disorders are psychiatric emergencies associated with risk of suicide and infanticide. Except from case reports, there are only few descriptions of its treatment. Therefore, we aimed to describe the treatment of women admitted with postpartum psychotic- or mood disorder in Denmark with emphasis on the use of electroconvulsive therapy (ECT). METHODS: We conducted a register-based cohort study of all women with incident postpartum psychotic- or mood disorder (no prior diagnoses of psychotic- or mood disorder or treatment with ECT) requiring admission in the period from 2011 to 2018. For these patients, we described the treatment and the 6-month readmission risk. RESULTS: We identified 91 women with postpartum psychotic- or mood disorder with a median admission length of 27 days (interquartile range: 10-45). Of those, 19% received ECT with a median time from admission to first ECT of 10 days (interquartile range: 5-16). The median number of ECT sessions was eight (interquartile range: 7-12). In the 6 months following discharge, 90% of the women received some form of psychopharmacological treatment (62% antipsychotics, 56% antidepressants, 36% anxiolytics/sedatives, 19% lithium, and 9% mood stabilizing antiepileptics), and 31% were readmitted. CONCLUSION: Psychiatric admission for incident postpartum psychotic- or mood disorder is rare in Denmark. Among those admitted, ECT and psychopharmacological treatment is commonly used. The 6-month readmission risk is high, warranting close follow-up. The fact that there is no international consensus on the optimal treatment of postpartum psychotic- or mood disorder is problematic and calls for action.

The use of electroconvulsive therapy (ECT) en bloc in Denmark: a nationwide register-based study.

OBJECTIVE: Electroconvulsive therapy (ECT) en bloc is defined as ECT administered on 2-3 consecutive days. In Denmark, ECT en bloc is recommended for severe conditions such as catatonia, treatment-resistant mania/psychosis, or imminent risk of suicide. To our knowledge, there are no recent reports on the use of ECT en bloc in clinical practice. Here, we provide such a report. METHODS: We characterized the use of ECT en bloc in the period from 2006-2019 based on data from Danish national registers. Furthermore, we compared mortality rates between patients receiving ECT en bloc and patients receiving standard regimen ECT (not en bloc). RESULTS: We identified 2173 patients who received a total of 2734 ECT en bloc treatment courses in Denmark in the period from 2006 to 2019 (6% of the total number of ECT treatment courses). The use of ECT en bloc was stable over the study period (range: 138-196 patients per year). The most common treatment indications were unipolar depression (41%), psychotic disorder (23%), and bipolar disorder (20%). The vast majority (90%) received ECT en bloc voluntarily. The 1-year mortality rate ratio for ECT en bloc compared to standard regimen ECT was 1.42 (95%CI: 1.03-1.95). CONCLUSION: The use of ECT en bloc in Denmark is stable both in terms of the number of patients treated and treatment indications. In keeping with ECT en bloc being used for severe conditions, those receiving this treatment have a higher mortality rate compared to those receiving standard ECT, warranting careful monitoring during follow-up.

A Within-Subject Before-After Study of the Impact of Antidepressants on Hemoglobin A1c and Low-Density Lipoprotein Levels in Type 2 Diabetes.

PURPOSE/BACKGROUND: Data on the effect of treatment with antidepressant drugs on metabolic control in diabetes are sparse. In this controlled within-subject before-after study, the impact of initiation and discontinuation of antidepressant treatment on hemoglobin A1c (HbA1c) and low-density lipoprotein (LDL) levels in type 2 diabetes was estimated. METHODS/PROCEDURES: All individuals with newly developed type 2 diabetes (first HbA1c ≥ 6.5%) between 2000 and 2016 in Northern and Central Denmark were identified using register-based health care data. Among these, we identified individuals initiating and discontinuing antidepressant treatment. Using a within-subject before-after design, we examined HbA1c and LDL in the 16 months leading up to and the 16 months after antidepressant treatment initiation or discontinuation, respectively. For comparison, we ran similar time trend analyses in a reference population of age- and sex-matched type 2 diabetes individuals not receiving antidepressant treatment. FINDINGS/RESULTS: Mean HbA1c decreased after initiation of antidepressant treatment (-0.16%; 95% confidence interval [CI], -0.18 to -0.13%). In the reference population, no material change in HbA1c over time (-0.03%; 95% CI, -0.04 to -0.01%) was seen. Mean LDL decreased not only in antidepressant initiators (-0.17 mmol/L; 95% CI, -0.19 to -0.15 mmol/L) but also in the reference population (-0.15 mmol/L; 95% CI, -0.16 to -0.13 mmol/L). Among antidepressant discontinuers, there was also a decrease in HbA1c (-0.32%; 95% CI, -0.37 to -0.28%), with no change in the reference population (-0.02%; 95% CI, -0.04 to 0.00%). Decreases in LDL were found both in antidepressant discontinuers (-0.09 mmol/L; 95% CI, -0.14 to -0.04 mmol/L) and in the reference population (-0.16 mmol/L0; 95% CI, -0.18 to -0.13 mmol/L). IMPLICATIONS/CONCLUSIONS: Antidepressant treatment in type 2 diabetes may have a beneficial effect on glycemic control, as the decrease in HbA1c after discontinuation of antidepressants likely reflects remission of depression. Conversely, antidepressant treatment does not seem to affect LDL levels.

Electroconvulsive therapy following incident bipolar disorder: When, how, and for whom?

OBJECTIVE: The use of electroconvulsive therapy (ECT) in the treatment of bipolar disorder (BD) remains poorly described. Based on data from Danish registries with complete nationwide coverage, this study of patients with incident BD aimed to describe when, how, and for whom ECT is used in the context of BD. METHODS: We identified patients receiving their first diagnosis of BD in the period from 2008 to 2018, who subsequently received ECT. Descriptive statistics were used to clarify when, how, and for whom ECT is used. RESULTS: We identified 1338 patients with incident BD who subsequently received ECT. The median age at the first ECT session was 50.6 years (interquartile range [IQR]: 26.4), and 62% of those treated with ECT were female. The median time from the diagnosis of BD to the first ECT treatment was 0.6 years (IQR: 2.6), and 58% of the patients receiving ECT had the first treatment within the first year after being diagnosed with BD. The most common indication for the first ECT treatment was depression (mainly non-psychotic depression), followed by mania (mainly psychotic mania). The first ECT session was typically provided to inpatients (97%), upon patient consent (98%) and with bilateral electrode placement (60%). CONCLUSIONS: A substantial proportion of the patients with incident BD who receive ECT require this treatment within the first year after the diagnosis. The most common indication for ECT is depression followed by (psychotic) mania. Inpatient voluntary ECT using bilateral electrode placement is the most common form of administration.

An International Adult Guideline for Making Clozapine Titration Safer by Using Six Ancestry-Based Personalized Dosing Titrations, CRP, and Clozapine Levels.

This international guideline proposes improving clozapine package inserts worldwide by using ancestry-based dosing and titration. Adverse drug reaction (ADR) databases suggest that clozapine is the third most toxic drug in the United States (US), and it produces four times higher worldwide pneumonia mortality than that by agranulocytosis or myocarditis. For trough steady-state clozapine serum concentrations, the therapeutic reference range is narrow, from 350 to 600 ng/mL with the potential for toxicity and ADRs as concentrations increase. Clozapine is mainly metabolized by CYP1A2 (female non-smokers, the lowest dose; male smokers, the highest dose). Poor metabolizer status through phenotypic conversion is associated with co-prescription of inhibitors (including oral contraceptives and valproate), obesity, or inflammation with C-reactive protein (CRP) elevations. The Asian population (Pakistan to Japan) or the Americas' original inhabitants have lower CYP1A2 activity and require lower clozapine doses to reach concentrations of 350 ng/mL. In the US, daily doses of 300-600 mg/day are recommended. Slow personalized titration may prevent early ADRs (including syncope, myocarditis, and pneumonia). This guideline defines six personalized titration schedules for inpatients: 1) ancestry from Asia or the original people from the Americas with lower metabolism (obesity or valproate) needing minimum therapeutic dosages of 75-150 mg/day, 2) ancestry from Asia or the original people from the Americas with average metabolism needing 175-300 mg/day, 3) European/Western Asian ancestry with lower metabolism (obesity or valproate) needing 100-200 mg/day, 4) European/Western Asian ancestry with average metabolism needing 250-400 mg/day, 5) in the US with ancestries other than from Asia or the original people from the Americas with lower clozapine metabolism (obesity or valproate) needing 150-300 mg/day, and 6) in the US with ancestries other than from Asia or the original people from the Americas with average clozapine metabolism needing 300-600 mg/day. Baseline and weekly CRP monitoring for at least four weeks is required to identify any inflammation, including inflammation secondary to clozapine rapid titration.

Self-Harm and Suicide Attempts Preceding and Following Electroconvulsive Therapy: A Population-Based Study.

OBJECTIVE: The beneficial effect of electroconvulsive therapy (ECT) on suicidality has been documented in clinical trials, whereas naturalistic studies on the topic are scarce and restricted to individuals with mood disorders. Here, based on population-based data from Danish registers, we aimed to investigate the course of self-harm and suicide attempts preceding and following ECT across 4 major mental disorders. This was done to examine whether data from the real-world clinical setting are compatible with the positive results from clinical trials. METHODS: We identified all patients diagnosed with unipolar depression (n = 8843), bipolar disorder (n = 2713), psychotic disorder (n = 2692), or personality disorder (n = 2085) who received ECT for the first time in the period from 2008 to 2019, as well as age-, sex-, diagnosis-, illness duration-, and admission-matched comparison groups not receiving ECT. A mirror-image model was used to examine whether the number of incidents of self-harm/suicide attempts changed following ECT (paired t test). RESULTS: There were substantial and statistically significant reductions in the number of incidents of self-harm/suicide attempts when comparing the month leading up to and the month following initiation of ECT for all diagnostic groups (unipolar depression: reduction, 83% [P < 0.001]; bipolar disorder: reduction, 72% [P < 0.001]; psychotic disorder: reduction, 82% [P < 0.001]; personality disorder: reduction, 83% [P < 0.001]). The analog results for the comparison groups not receiving ECT suggested that these reductions in self-harm/suicide attempts were partly mediated by a protective effect of admission. CONCLUSIONS: Data from the real-world clinical setting are compatible with results from clinical trials with regard to the protective effect of ECT on suicidality.

Monitoring of COVID-19 pandemic-related psychopathology using machine learning.

The COVID-19 pandemic is believed to have a major negative impact on global mental health due to the viral disease itself as well as the associated lockdowns, social distancing, isolation, fear, and increased uncertainty. Individuals with preexisting mental illness are likely to be particularly vulnerable to these conditions and may develop outright 'COVID-19-related psychopathology'. Here, we trained a machine learning model on structured and natural text data from electronic health records to identify COVID-19 pandemic-related psychopathology among patients receiving care in the Psychiatric Services of the Central Denmark Region. Subsequently, applying this model, we found that pandemic-related psychopathology covaries with the pandemic pressure over time. These findings may aid psychiatric services in their planning during the ongoing and future pandemics. Furthermore, the results are a testament to the potential of applying machine learning to data from electronic health records.

The impact of hospital-diagnosed depression or use of antidepressants on treatment initiation, adherence and HbA1c/LDL target achievement in newly diagnosed type 2 diabetes.

AIMS/HYPOTHESIS: We aimed to assess whether current antidepressant therapy or a history of hospital-diagnosed depression affects diabetes treatment initiation, adherence, and HbA1c and LDL-cholesterol target achievement. METHODS: In this register-based study, we included all individuals from Central and Northern Denmark with newly diagnosed type 2 diabetes, defined as a first-ever HbA1c measurement of ≥48 mmol/mol (6.5%), between 2000 and 2016. Individuals either diagnosed with depression at a psychiatric hospital in the 2 years prior to their diabetes diagnosis or currently receiving treatment with an antidepressant were compared with individuals with type 2 diabetes, but without depression treatment or previous history of depression. Outcome measures included initiation of glucose-lowering drugs and lipid-modifying agents, adherence to these medications (medication possession ratio >80%), and HbA1c (<53 mmol/mol [7%]) and LDL-cholesterol (<2.6 mmol/l) target achievement. The assessment of association between depression or antidepressant treatment and these outcomes was conducted using regression analyses with adjustment for potential confounders. RESULTS: We included a total of 87,650 individuals with first-ever HbA1c-diagnosed type 2 diabetes, of whom 0.9% (n = 784) had hospital-diagnosed depression and 11.4% (n = 9963) currently received antidepressant treatment. Compared with those without depression treatment, treatment with an antidepressant was associated with increased likelihood of glucose-lowering drug initiation (HR 1.39 [95% CI 1.34, 1.44]) and adherence (OR 1.27 [95% CI 1.18, 1.36]), lipid-modifying agent initiation (HR 1.17 [95% CI 1.11, 1.23]) and adherence (OR 1.25 [95% CI 1.09, 1.43]), and achievement of LDL (OR 1.08 [95% CI 1.03, 1.14]) but not HbA1c target (OR 0.99 [95% CI 0.93, 1.06]). The findings were similar for individuals who had hospital-diagnosed depression. CONCLUSIONS/INTERPRETATION: In individuals with newly diagnosed type 2 diabetes, antidepressant treatment and depression were associated with improved diabetes treatment quality. Graphical abstract.

Editorial Perspective: COVID-19 pandemic-related psychopathology in children and adolescents with mental illness.

The coronavirus disease (COVID-19) pandemic is likely to have negative health consequences way beyond those caused by the virus per se - including significant psychological distress. Children and adolescents who already live with a mental illness may be particularly vulnerable to the distress associated with the pandemic - due to, for example, fear of the virus as well as the significant societal changes launched to minimize spread of the virus (social distancing and quarantine). In this editorial perspective, we (a) provide data on COVID-19 pandemic-related psychopathology in children and adolescents from a large psychiatric treatment setting in Denmark, (b) give advice on how the likely harmful effects of the COVID-19 pandemic on the mental health of children and adolescents may be minimized, and (c) propose six lines of research into pandemic-related psychopathology with emphasis on children and adolescents. Finally, we underline the necessity of politicians, health authorities, and funding bodies supporting these research initiatives here and now.

Survival Rate Following Involuntary Electroconvulsive Therapy: A Population-Based Study.

OBJECTIVE: Involuntary electroconvulsive therapy (ECT) can be a lifesaving intervention for patients suffering from potentially lethal conditions who are unable to give informed consent. However, its use is not widespread, probably partly because of the scarce data on hard outcomes following involuntary ECT. In Denmark, involuntary ECT is only used when patients are at imminent/potential risk of dying if not receiving ECT. Here, we aimed to estimate the 1-year survival rate after the administration of involuntary ECT as a proxy for the effectiveness of this treatment. METHODS: We conducted a register-based cohort study involving (i) all patients receiving involuntary ECT in Denmark between 2008 and 2019, (ii) age- and sex-matched patients receiving voluntary ECT, and (iii) age- and sex-matched individuals from the general population. One-year survival rates were compared via mortality rate ratios. RESULTS: We identified 618 patients receiving involuntary ECT, 547 patients receiving voluntary ECT, and 3080 population-based controls. The survival rate in the year after involuntary ECT was 90%. For patients receiving involuntary ECT, the 1-year mortality rate ratios were 3.1 (95% confidence interval, 1.9-5.2) and 5.8 (95% confidence interval, 4.0-8.2) compared with those receiving voluntarily ECT and to the population-based controls, respectively. Risk factors for early death among patients receiving involuntary ECT were male sex, being 70 years or older and having organic mental disorder as the treatment indication. CONCLUSIONS: Treatment with involuntary ECT is associated with a high survival rate, suggesting that the intervention is effective. However, patients receiving involuntary ECT constitute a high-risk population that should be monitored closely after this treatment.

Incident psychopharmacological treatment and psychiatric hospital contact in individuals with newly developed type 2 diabetes - a register-based cohort study.

To investigate the association between newly developed type 2 diabetes (T2D) and incident psychopharmacological treatment and psychiatric hospital contact. Via Danish registers, we identified all 56 640 individuals from the Central and Northern Denmark Regions with newly developed T2D (defined by the first HbA1c measurement ≥6.5%) in 2000-2016 as well as 315 694 age- and sex-matched controls (without T2D). Those having received psychopharmacological treatment or having had a psychiatric hospital contact in the 5 years prior to the onset of T2D were not included. For this cohort, we first assessed the 2-year incidence of psychopharmacological treatment and psychiatric hospital contact. Secondly, via Cox regression, we compared the incidence of psychopharmacological treatment/psychiatric hospital contact among individuals with T2D to propensity score-matched controls - taking a wide range of potential confounders into account. Finally, via Cox proportional hazards regression, we assessed which baseline (T2D onset) characteristics were associated with subsequent psychopharmacological treatment and psychiatric hospital contact. A total of 8.3% of the individuals with T2D initiated psychopharmacological treatment compared to 4.6% of the age- and sex-matched controls. Individuals with T2D were at increased risk of initiating psychopharmacological treatment compared to the propensity score-matched controls (HR = 1.51, 95% CI = 1.43-1.59), whereas their risk of psychiatric hospital contact was not increased to the same extent (HR = 1.14, 95% CI = 0.98-1.32). Older age, somatic comorbidity, and being divorced/widowed were associated with both psychopharmacological treatment and psychiatric hospital contact following T2D. Individuals with T2D are at elevated risk of requiring psychopharmacological treatment.

The use of stimulants in depression: Results from a self-controlled register study.

OBJECTIVE: To investigate the effectiveness of stimulants in patients with depression, by using naturalistic outcome measures, such as psychiatric admissions, psychiatric bed-days and incidents of intentional self-harm or suicide attempts. METHODS: Via linkage of the Danish nationwide health registers, we identified all patients with a diagnosis of depression initiating stimulants, including methylphenidate, modafinil, amphetamine, dexamphetamine or lisdexamphetamine, from 1995 to 2012. We used a mirror-image model to test whether redemption of a stimulant prescription was associated with a reduction in psychiatric admissions, inpatient days and incidents of intentional self-harm or suicide attempts. Specifically, the number of these outcomes in the 2 years leading up to redemption of a stimulant prescription was compared to the two subsequent years. Similar outcomes were used in a reverse mirror-image model to investigate the effect of stimulant termination. RESULTS: A total of 3354, 935 and 105 patients diagnosed with depression redeemed prescriptions for methylphenidate, modafinil or amphetamine/dexamphetamine/lisdexamphetamine, respectively. Initiation of methylphenidate was not associated with a significant change in psychiatric admissions (mean: -0.02 admissions, p = 0.11) or inpatient days (mean: 0.13 days, p = 0.74). Similar findings were made for modafinil and the amphetamines. In addition, no clinically relevant change in psychiatric admissions or inpatient days was found after termination of a stimulant. After initiation of methylphenidate, the incidents of self-harm or suicide attempts were reduced by 54%, from 68 to 31 events (p = 0.004). No significant change in incidents of self-harm or suicide attempts were found for modafinil or the amphetamines. CONCLUSION: This nationwide study, using naturalistic outcomes, does not support the use of stimulants in patients with depression. However, the use of methylphenidate was associated with a 54% reduction in incidents of self-harm or suicide attempts, indicating that methylphenidate may potentially be useful in patients with depression with suicidal- or self-harming behaviour. However, further studies are needed, before any firm conclusions can be made.