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.

Clinical and sociodemographic characteristics associated with relapse following electroconvulsive therapy for bipolar disorder.

OBJECTIVES: Electroconvulsive therapy (ECT) is an effective treatment for bipolar disorder, but relapse following a successful ECT series is common. We aimed to identify clinical and sociodemographic characteristics associated with the risk of relapse following ECT in bipolar disorder. METHODS: Using data from nationwide Danish registers, we identified all patients receiving their first ECT series with an indication diagnosis of bipolar disorder between 2006 and 2018. We then followed these patients for relapse, defined as either psychiatric admission or a new ECT series, for 6 months following ECT. Associations between clinical and sociodemographic characteristics and relapse were examined via multivariable Cox proportional-hazards regression, yielding adjusted hazard rate ratios (aHRR). RESULTS: Of the 1473 patients receiving ECT for bipolar disorder (62% females, mean age = 53 years), 34% met the relapse criterion. The following characteristics were associated with an elevated risk of relapse; age <40 (aHRR = 1.54, 95% CI = 1.05-2.26); being a pensioner (aHRR = 1.73, 95% CI = 1.29-2.32), indication diagnosis for ECT being psychotic mania (aHRR = 1.63, 95% CI = 1.16-2.28), psychotic bipolar depression (aHRR = 1.37, 95% CI = 1.06-1.80), mixed episode (aHRR = 1.51, 95% CI = 1.13-2.02), or other bipolar episodes (aHRR = 1.68, 95% CI = 1.28-2.21); and treatment with antipsychotics prior to the course of ECT (aHRR = 1.32, 95% CI = 1.04-1.67). CONCLUSION: Patients with bipolar disorder face a particularly high risk of relapse following ECT if they present with the following characteristics when initiating ECT: age <40, being a pensioner, having received treatment with an antipsychotic before initiating ECT, or having psychotic bipolar depression, psychotic mania, mixed episodes, or other bipolar episodes as the indication for ECT. These findings may guide relapse monitoring following ECT in bipolar disorder.

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.

A target trial emulation comparing the antidepressant effectiveness of selective serotonin reuptake inhibitors (SSRIs) highlighting the importance of patent-related confounding by indication.

BACKGROUND: The comparative effectiveness of selective serotonin reuptake inhibitors (SSRIs) has been subjected to relatively little research. However, a recent study based on target trial emulation suggested that sertraline may be more effective than escitalopram. AIMS: To investigate whether sertraline, citalopram, and escitalopram differ in their effectiveness-assessed via the risk of psychiatric hospital admission and suicide following treatment initiation. The choice to focus on sertraline, citalopram, and escitalopram was made to limit confounding by indication, as the Danish depression treatment guideline from 2007 specifically listed these three SSRIs as first choice. METHOD: We conducted a target trial emulation based on data from Danish registers. We identified all individuals that initiated treatment for depression with sertraline, citalopram, or escitalopram in the period from January 1, 2007, to March 1, 2019. These individuals were followed until psychiatric hospital admission or suicide (separate analyses), death, 1 year after treatment initiation or end of data. Cox proportional hazards regression adjusted for relevant baseline covariates was performed to emulate randomized treatment allocation, comparing the rate of psychiatric hospital admission and suicide for individuals treated with sertraline (used as reference), citalopram or escitalopram, respectively. For escitalopram, we conducted a sensitivity analysis excluding data from the period during which the drug was sold under patent, as the price of the drug during that time likely entailed a different prescription pattern, increasing the risk of ("patent-related") confounding by indication. RESULTS: We identified 56,865, 118,145, and 31,083 individuals initiating treatment with sertraline, citalopram, and escitalopram, respectively. Using sertraline as reference, the adjusted hazard rate ratio (aHRR) for psychiatric admission was 0.98 (95% CI = 0.91-1.05) for citalopram and 1.21 (95% CI = 1.10-1.32) for escitalopram. Notably, in the sensitivity analysis only including patients initiating treatment after the escitalopram patent had expired, the increased risk of psychiatric hospital admission associated with escitalopram treatment was no longer present (aHRR = 0.98, 95% CI = 0.82-1.18). The results of the analyses of suicide were inconclusive, due to few outcome events. CONCLUSIONS: Sertraline, citalopram, and escitalopram do not seem to have differential effectiveness in the treatment of depression. Taking potential patent-related, time varying, confounding by indication (via severity) into account is critical for pharmacoepidemiological studies, including those employing target trial emulation.

The risk of diabetes and HbA1c deterioration during antipsychotic drug treatment: A Danish two-cohort study among patients with first-episode schizophrenia.

BACKGROUND: Antipsychotics increase the risk of developing diabetes, but clinical trials are not generalizable with short follow-up, while observational studies often lack important information, particularly hemoglobin A1c (HbA1c). METHODS: We followed two Danish cohorts with schizophrenia. First, using Danish nationwide registers, we identified all individuals diagnosed with first-episode schizophrenia (FES) between 1999 and 2019 (n = 31,856). Exposure was a redeemed prescription for an antipsychotic, and the outcome was diabetes, defined via hospital-based diagnosis and redeemed prescriptions for glucose-lowering drugs. Adjusted Cox regression calculated hazard rate ratios (HRR). Second, using data from the Central Denmark Region, we identified all individuals diagnosed with FES from October 2016 to September 2022 (n = 2671). Using a within-subject design, we analyzed the change in HbA1c during the 2 years after initiation of specific antipsychotics compared to the 2 years before. RESULTS: In the nationwide cohort, 2543 (8.0%) individuals developed diabetes (incidence rate = 9.39 [95% CI = 9.03-9.76] per 1000 person-years). Antipsychotics, compared to periods without, were associated with an increased risk of developing diabetes (HRR = 2.04, 95% CI = 1.75-2.38). We found a dose-response association, particularly for second-generation antipsychotics, and different risk rates for specific antipsychotics. In the Central Denmark Region cohort, a total of 9.2% developed diabetes but mean HbA1c levels remained stable at 37 mmol/mol during the 2 years after initiation of antipsychotic medication. CONCLUSION: This comprehensive real-world two-cohort study emphasizes that diabetes affects almost 10% of patients with FES. Antipsychotics increase this risk, while HbA1c deterioration requires longer treatment. These findings are important for clinicians and young patients with FES.

Depression Treatment Trajectories and Associated Social Determinants: A Three-Year Follow-Up Study in 66,540 Older Adults Undergoing First-Time Depression Treatment in Denmark.

OBJECTIVE: This study aimed to describe depression treatment patterns, identify unique trajectory groups using a group-based trajectory approach, and explore associated social determinants in older adults undergoing first-time depression treatment during a 3-year follow-up. METHODS: This Danish register-based cohort study included all adults aged ≥ 65 who initiated depression treatment by redeeming first-time antidepressant prescriptions (no prescriptions in the last 10 years) between 2006 and 2015. The outcome of interest during the 2-year follow-up was depression treatment, assessed as antidepressant prescriptions redemptions and psychiatric hospital contacts for depression. Latent class growth analyses were applied to model treatment trajectories during 3 years. Multinomial logistic regression analyses were used to analyze adjusted associations between social determinates and trajectory group membership. RESULTS: Among the 66,540 older adults (55.2% females, mean age: 77.3 years), we identified three distinct groups with unique patterns of depression treatment trajectories: 'brief-treatment' where individuals stopped depression treatment within 6 months (33.7%); 'gradual-withdrawal' (26.5%) where treatment was gradually stopped over 2 years; and 'persistent-treatment' where individuals continued depression treatment for the entire 3 years (39.8%). Females, single-person households, and residents of less-urbanized regions were associated with higher odds of membership in the 'persistent-treatment' group, while older age, widowhood or separation, and non-Danish ethnicities were associated with lower odds. CONCLUSIONS: Three distinct patterns of depression treatment trajectories were identified in older adults, indicating differential clinical courses of depression-potentially influenced by social determinants, including sex, marital status, urban residence, and ethnicity. Early patient stratification and targeted interventions are crucial in depression care for older adults.

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.