BACKGROUND: This exploratory study investigated cerebrospinal fluid (CSF) synaptic protein biomarkers in bipolar disorder (BD), aiming to highlight the neurobiological basis of the disorder. With shared cognitive impairment features between BD and Alzheimer's disease, and considering increased dementia risk in BD patients, the study explores potential connections. METHODS: Fifty-nine well-characterized patients with BD and thirty-seven healthy control individuals were examined and followed for one year. Synaptic proteins encompassing neuronal pentraxins (NPTX)1, NPTX2, and NPTX-receptor, 14-3-3 protein family epsilon, and zeta/delta, activating protein-2 complex subunit beta, synucleins beta-synuclein and gamma-synuclein, complexin-2, phosphatidylethanolamine-binding protein 1, rab GDP dissociation inhibitor alpha, and syntaxins 1B and 7 were measured in CSF using a microflow liquid chromatography-mass spectrometric multiple reaction monitoring set-up. Biomarker levels were compared between BD and HC and in BD before, during, and after mood episodes. RESULTS: The synaptic proteins revealed no statistically significant differences between BD and HC, neither at baseline, one-year follow-up, or in terms of changes from baseline to follow-up. Moreover, the CSF synaptic protein levels in patients with BD were unaltered compared to baseline when they stabilized in euthymia following an affective episode and at one-year follow-up. LIMITATION: It is uncertain what the CSF biomarker concentrations reflect since we yet do not know the mechanisms of release of these proteins, and we are uncertain of what increased or decreased levels reflect. CONCLUSION: This first-ever investigation of a panel of CSF protein biomarkers of synaptic dysfunction in patients with BD and HC individuals found no statistically significant differences cross-sectionally or longitudinally.
OBJECTIVES: This study aimed to investigate the neural underpinnings of emotional cognition subgroups in recently diagnosed patients with bipolar disorder (BD) and change over time over a 15-month follow-up period. METHODS: Patients and healthy controls (HC) underwent emotional and nonemotional cognitive assessments and functional magnetic resonance imaging (fMRI) at the baseline (BD n = 87; HC n = 65) and at 15-month follow-up (BD n = 44; HC n = 38). Neural activity during emotion reactivity and regulation in response to aversive pictures was assessed during fMRI. Patients were clustered into subgroups based on their emotional cognition and, with HC, were compared longitudinally on cognition and neural activity during emotion reactivity and regulation. RESULTS: Patients were optimally clustered into two subgroups: Subgroup 1 (n = 40, 46%) was characterized by heightened emotional reactivity in negative social scenarios, which persisted over time, but were otherwise cognitively intact. This subgroup exhibited stable left amygdala hyper-activity over time during emotion reactivity compared to subgroup 2. Subgroup 2 (n = 47, 54%) was characterized by global emotional cognitive impairments, including stable difficulties with emotion regulation over time. During emotion regulation across both time points, this group exhibited hypo-activity in the left dorsolateral prefrontal cortex. Additionally, patients in subgroup 2 had poorer nonemotional cognition, had more psychiatric hospital admissions and history of psychotic episodes than those in subgroup 1. CONCLUSIONS: Broad impairments in emotional cognition in approximately half of BD patients and associated nonemotional cognitive deficits may originate from insufficient recruitment of prefrontal resources, contributing to poorer clinical outcomes.
Current evidence for pharmacological treatment of mania during hospitalisation is insufficient as there are no larger well-designed randomised trials of comparative medical treatments of mania during inpatient stays. Moreover, there is considerable variation in pharmacological medication in clinical practice during hospitalisation for mania. Based on a hospital data overview, a systematic search of the literature and a three-day consensus meeting, this narrative review proposed an algorithm for optimised pharmacological treatment of mania during hospitalisation and its subsequent scientific evaluation.
Algorithms , Hospitalization , Mania , Humans , Mania/drug therapy , Antipsychotic Agents/therapeutic use , Antimanic Agents/therapeutic use , Bipolar Disorder/drug therapy , Bipolar Disorder/therapy
Bipolar disorder is associated with increased rates of many physical disorders, but the effects of medication are unclear. We systematically investigated the associations between sustained use of first line maintenance agents, lithium versus lamotrigine and valproate, and the risk of physical disorders using a nation-wide population-based target trial emulation covering the entire 5.9 million inhabitants in Denmark. We identified two cohorts. Cohort 1: patients with a diagnosis of bipolar disorder prior to first purchase (N = 12.607). Cohort 2: all 156.678 adult patients who had their first ever purchase (since 1995) of either lithium, lamotrigine or valproate between 1997 and 2021 regardless of diagnosis. Main analyses investigated the effect of sustained exposure defined as exposure for all consecutive 6-months periods during a 10-year follow-up. Outcomes included a diagnosis of incident stroke, arteriosclerosis, angina pectoris, myocardial infarction, diabetes mellitus, myxedema, osteoporosis, dementia, Parkinson's disease, chronic kidney disease and cancer (including subtypes). In both Cohorts 1 and 2, there were no systematic statistically significant differences in associations between sustained use of lithium versus lamotrigine and valproate, respectively, and any physical disorder, including subtypes of disorders, except myxedema, for which exposure to lithium increased the absolute risk of myxedema with 7-10 % compared with lamotrigine or valproate. In conclusion, these analyses emulating a target trial of "real world" observational register-based data show that lithium does not increase the risk of developing any kind of physical disorders, except myxedema, which may be a result of detection bias.
Bipolar disorder (BD) is often accompanied by persistent cognitive impairment. However, screening for cognitive impairment in the clinic is challenged by a lack of consensus on screening procedures. This study assesses cognitive impairment prevalence and screening feasibility in alignment with the International Society for Bipolar Disorder Targeting Cognition Task Force recommendations. Between January 2022 and May 2023, 136 newly diagnosed BD outpatients were assessed with the Screen for Cognitive Impairment in Psychiatry after 15-20 months of specialised care at the Copenhagen Affective Disorder Clinic. Cognitive impairment patterns and associations with cognitive complaints, perceived stress, and functioning were examined. Most screened patients (73 %) achieved full or partial remission, with 51 % being cognitively normal, 38 % showing global impairments, and 11 % displaying selective impairments. Among remitted patients, 56 % were cognitively normal, while 31 % and 13 % exhibited global or selective impairments, respectively. Both objectively impaired patient groups reported more subjective cognitive difficulties than those who were cognitively normal. The globally impaired group also demonstrated poorer functioning, more depressive symptoms and lower quality of life than cognitively normal patients. Across all patients, lower cognitive performance correlated with more cognitive complaints, lower functioning, lower quality of life, and more depressive symptoms. Cognitive screenings were relatively easily implementable, involving only a 1.5 h session including mood ratings, feedback and cognitive strategy discussion. The study highlights the clinical relevance and feasibility of cognitive screenings in BD patients, emphasizing the need for tailored interventions given frequent cognitive impairment in clinically stable individuals.
BACKGROUND: There is a significant contribution of genetic factors to the etiology of bipolar disorder (BD). Unaffected first-degree relatives of patients (UR) with BD are at increased risk of developing mental disorders and may manifest cognitive impairments and alterations in brain functional and connective dynamics, akin to their affected relatives. METHODS: In this prospective longitudinal study, resting-state functional connectivity was used to explore stable and progressive markers of vulnerability i.e. abnormalities shared between UR and BD compared to healthy controls (HC) and resilience i.e. features unique to UR compared to HC and BD in full or partial remission (UR n = 72, mean age = 28.0 ± 7.2 years; HC n = 64, mean age = 30.0 ± 9.7 years; BD patients n = 91, mean age = 30.6 ± 7.7 years). Out of these, 34 UR, 48 BD, and 38 HC were investigated again following a mean time of 1.3 ± 0.4 years. RESULTS: At baseline, the UR showed lower connectivity values within the default mode network (DMN), frontoparietal network, and the salience network (SN) compared to HC. This connectivity pattern in UR remained stable over the follow-up period and was not present in BD, suggesting a resilience trait. The UR further demonstrated less negative connectivity between the DMN and SN compared to HC, abnormality that remained stable over time and was also present in BD, suggesting a vulnerability marker. CONCLUSION: Our findings indicate the coexistence of both vulnerability-related abnormalities in resting-state connectivity, as well as adaptive changes possibly promoting resilience to psychopathology in individual at familial risk.
Background: Lipids influence brain function and mental health. Understanding the role of apolipoproteins in affective disorders could provide valuable insights and potentially pave the way for novel therapeutic approaches. Methods: We examined the apolipoprotein E genotype and ApoE-levels, lipid profiles, and the correlation with cognition in 204 monozygotic (MZ) twins with unipolar or bipolar disorder in remission or partial remission (affected, AT), their unaffected co-twins (high-risk, HR), and twins with no personal or family history of affective disorder (low-risk, LR). Results: The APOE genotype was not associated with affective disorders. No significant group differences in ApoE levels were found between the three risk groups. Post hoc analysis group-wise comparisons showed higher ApoE levels in the AT than HR twins and in the concordant AT twin pairs relative to the discordant twin pairs. Within the discordant twin pairs, higher ApoE levels were observed in the affected twins (AT = 39.4 mg/L vs. HR = 36.8 mg/L, p = 0.037). Limitations: The present study could benefit from a larger sample size. We did not assess dietary habits. Conclusions: The results did not support our main hypothesis. However, exploratory post hoc analysis suggests a role for plasma ApoE and triglycerides in affective disorders. Future research is needed.
BACKGROUND: Persistent cognitive impairment is frequent across bipolar disorder (BD) and major depressive disorder (MDD), highlighting an urgent need for pro-cognitive treatments. AIM: This study investigated effects of erythropoietin (EPO) on cognitive impairment and dorsal prefrontal cortex (dPFC) activity in affective disorders. METHODS: In this randomized, double-blinded, placebo-controlled trial, cognitively impaired patients with remitted BD or MDD received 1 weekly recombinant human EPO (40,000 IU/mL) or saline infusion for a 12-week period. Assessments were conducted at baseline, after 2 weeks of treatment (week 3), immediately after treatment (week 13) and at 6-months follow-up. Participants underwent functional MRI during performance on a n-back working memory (WM) task at baseline and week 3, and for a subgroup 6 weeks post-treatment (week 18). The primary outcome was a cognitive composite score at week 13, whereas secondary outcomes comprised sustained attention and functioning. WM-related dPFC activity was a tertiary outcome. RESULTS: Data were analysed for 101 of the 103 included patients (EPO, n = 58; saline, n = 43). There were no effects of EPO over saline on any cognitive or functional outcomes or on WM-related dPFC activity. CONCLUSIONS: The absence of treatment-related changes in cognition and neural activity was unexpected and contrasts with multiple previous preclinical and clinical studies. It is possible that the lack of effects resulted from a recent change in the manufacturing process for EPO. Nevertheless, the findings support the validity of dPFC target engagement as a biomarker model for pro-cognitive effects, according to which treatments that do not improve cognition should not modulate dPFC activity. TRIAL REGISTRATIONS: EudraCT no.: 2016-004023-24; ClinicalTrials.gov identifier: NCT03315897.
Cognitive Dysfunction , Depressive Disorder, Major , Erythropoietin , Humans , Depressive Disorder, Major/drug therapy , Depressive Disorder, Major/psychology , Mood Disorders/drug therapy , Erythropoietin/pharmacology , Erythropoietin/therapeutic use , Cognitive Dysfunction/drug therapy , Cognition , Prefrontal Cortex , Treatment Outcome , Double-Blind Method
BACKGROUND: The emerging use of biomarkers in research and tailored care introduces a need for information about the association between biomarkers and basic demographics and lifestyle factors revealing expectable concentrations in healthy individuals while considering general demographic differences. METHODS: A selection of 47 biomarkers, including markers of inflammation and vascular stress, were measured in plasma samples from 9876 Danish Blood Donor Study participants. Using regression models, we examined the association between biomarkers and sex, age, Body Mass Index (BMI), and smoking. RESULTS: Here we show that concentrations of inflammation and vascular stress biomarkers generally increase with higher age, BMI, and smoking. Sex-specific effects are observed for multiple biomarkers. CONCLUSION: This study provides comprehensive information on concentrations of 47 plasma biomarkers in healthy individuals. The study emphasizes that knowledge about biomarker concentrations in healthy individuals is critical for improved understanding of disease pathology and for tailored care and decision support tools.
Blood-based biomarkers are circulating molecules that can help to indicate health or disease. Biomarker levels may vary depending on demographic and lifestyle factors such as age, sex, smoking status, and body mass index. Here, we examine the effects of these demographic and lifestyle factors on levels of biomarkers related to activation of the immune system and cardiovascular stress. Measurements of 47 different proteins were performed on blood samples from nearly 10,000 healthy Danish blood donors. Measurement data were linked with questionnaire data to assess effects of lifestyle. We found that immune activation and vascular stress generally increased with age, BMI, and smoking. As these measurements are from healthy blood donors they can serve as a reference for expectable effects and inflammation levels in healthy individuals. Knowledge about the healthy state is important for understanding disease progression and optimizing care.
The aims were to investigate 1) differences in smartphone-based data on phone usage between bipolar disorder (BD) and unipolar disorder (UD) and 2) by using machine learning models, the sensitivity, specificity, and AUC of the combined smartphone data in classifying BD and UD. Daily smartphone-based self-assessments of mood and same-time passively collected smartphone data on smartphone usage was available for six months. A total of 64 patients with BD and 74 patients with UD were included. Patients with BD during euthymic states compared with UD in euthymic states had a lower number of incoming phone calls/ day (B: -0.70, 95%CI: -1.37; -0.70, p=0.040). Patients with BD during depressive states had a lower number of incoming and outgoing phone calls/ day as compared with patients with UD in depressive states. In classification by using machine learning models, 1) overall (regardless of the affective state), patients with BD were classified with an AUC of 0.84, which reduced to 0.48 when using a leave-one-patient-out crossvalidation (LOOCV) approach; similarly 2) during a depressive state, patients with BD were classified with an AUC of 0.86, which reduced to 0.42 with LOOCV; 3) during a euthymic state, patients with BD were classified with an AUC of 0.87, which reduced to 0.46 with LOOCV. While digital phenotyping shows promise in differentiating between patients with BD and UD, it highlights the challenge of generalizing to unseen individuals. It should serve as an complement to comprehensive clinical evaluation by clinicians.
Bipolar Disorder , Humans , Bipolar Disorder/diagnosis , Bipolar Disorder/psychology , Emotions , Machine Learning , Affect
BACKGROUND: Long-term studies comparing nonresponse to antidepressants for major depressive disorder (MDD) are lacking. AIMS: To present systematic population-based nation-wide register data on comparative 2-year non-response within six antidepressant drug classes and 17 different antidepressants in patients with MDD. METHOD: The study included all 106,920 patients in Denmark with a first main index diagnosis of MDD at a psychiatric hospital inpatient or outpatient contact and who subsequently had a purchase of an antidepressant in the period from 1995 to 2018. Non-response to first antidepressant within a 2-year study period was defined as switch to or add-on of another antidepressant, antipsychotic medication, lithium, or hospitalization. Analyses emulated a targeted trial in populations standardized according to age, sex, socioeconomic status, and comorbidity with psychiatric and physical disorders. RESULTS: Compared with sertraline, there was no difference for citalopram (RR: 1.00 [95% CI: 0.98-1.02]) but fluoxetine (1.13 [95% CI: 1.10-1.17]), paroxetine (1.06 [95% CI: 1.01-1.10]) and escitalopram (1.22 [95% CI: 1.18-1.25]) were associated with higher risk ratio of non-responses. Within selective noradrenaline reuptake inhibitors, sertraline outperformed reboxetine; within serotonin-norepinephrine reuptake inhibitors, venlafaxine outperformed duloxetine; within noradrenergic and specific serotonergic antidepressants, mirtazapine outperformed mianserin and within the class of other antidepressants, sertraline outperformed agomelatine and vortioxetine. Within tricyclic antidepressants, compared to amitriptyline, nortriptyline, dosulepin, and clomipramine had higher non-response, whereas there was no difference for imipramine. CONCLUSIONS: These analyses emulating a randomized trial of "real world" observational register-based data show that 2-year long-term non-responses to some antidepressants within six different drug classes are increased over others.
Depressive Disorder, Major , Humans , Antidepressive Agents/therapeutic use , Depressive Disorder, Major/drug therapy , Depressive Disorder, Major/epidemiology , Fluoxetine/therapeutic use , Selective Serotonin Reuptake Inhibitors , Sertraline/therapeutic use
Excessive oxidative stress-generated nucleoside damage seems to play a key role in bipolar disorder (BD) and may present a trait phenomenon associated with familial risk and is one of the putative mechanisms explaining accelerated atherosclerosis and premature cardiovascular diseases (CVD) in younger patients with BD. However, oxidative stress-generated nucleoside damage has not been studied in young BD patients and their unaffected relatives (UR). Therefore, we compared oxidative stress-generated damage to DNA and RNA in young patients newly diagnosed with BD, UR, and healthy control individuals (HC). Systemic oxidative stress-generated DNA and RNA damage levels were compared by analyzing urinary levels of 8-oxo-7,8-dihydro-2'-deoxyguanosine and 8-oxo-7,8-dihydroguanosine in participants aged 15-25 years, including 133 patients newly diagnosed with BD, 57 UR, and 83 HC. Compared with HC, damage to DNA was 21.8% higher in BD patients (B = 1.218, 95% CI = 1.111-1.335, p = <0.001) and 22.5% higher in UR (B = 1.225, 95% CI = 1.090-1.377, p = <0.002), while damage to RNA was 14.8% higher in BD patients (B = 1.148, 95% CI = 1.082-1.219, p = <0.001) and 14.0% higher in UR (B = 1.140, 95% CI = 1.055-1.230, p = < 0.001) in models adjusted for sex and age after correction for multiple comparison. Levels did not differ between patients with BD and UR. Our findings support higher oxidative stress-generated nucleoside damage being a trait phenomenon in BD associated with familial risk and highlight the importance of early diagnosis and treatment to prevent illness progression and development of premature CVD.
Bipolar Disorder , Cardiovascular Diseases , Humans , Bipolar Disorder/diagnosis , Bipolar Disorder/genetics , Nucleosides , RNA , DNA , Genetic Predisposition to Disease
AIM: This naturalistic clinical study aims to investigate differences between newly diagnosed patients with bipolar type I (BDI) and bipolar type II (BDII) disorders in socio-demographic and clinical characteristics, affective symptoms, cognition, functioning and comorbidity with personality disorders. METHODS: The BD diagnosis and type were confirmed using the Schedules for Clinical Assessment in Neuropsychiatry. Affective symptoms were assessed with the Young Mania Rating Scale, the Hamilton Depression Rating Scale, the Major Depressive Index, and the Altman Self-Rating Mania Scale. Functional impairment was assessed with the Functional Assessment Short Test. Cognitive impairment was evaluated by the Screen for Cognitive Impairment in Psychiatry and the Cognitive Complaints in Bipolar Disorder Rating Assessment. Finally, comorbid personality disorders were assessed with the Standardized Assessment of Personality-Abbreviated Scale and structured interview Structured Clinical Interview for DSM-disorders. RESULTS: 383 newly diagnosed patients were included (BDI: n = 125; BDII: n = 258). Against expectations, we found no more depressive symptoms in BDII compared with BDI nor any differences in cognitive, childhood trauma or overall functional impairment. The only difference was lower occupational impairment in the BDII group. LIMITATIONS: The self-reported measures of cognitive difficulties and childhood trauma involved potential bias (recall or other). Despite BD being newly diagnosed a diagnostic delay was observed. CONCLUSION: Patients newly diagnosed with BDII and BDI had similar burdens of depressive symptoms and cognitive and overall functional impairment, however patients with BDI had lower occupational functioning. No statistically significant difference was found in prevalence of comorbid personality disorders between patients with BDI and BDII.
Bipolar Disorder , Depressive Disorder, Major , Humans , Bipolar Disorder/diagnosis , Bipolar Disorder/epidemiology , Bipolar Disorder/psychology , Delayed Diagnosis , Depressive Disorder, Major/diagnosis , Depressive Disorder, Major/epidemiology , Mania/epidemiology , Comorbidity
BACKGROUND: Bipolar disorders (BD) figures on top of the World Health Organization classification of disabling disorders. It is unclear if there are socioeconomic, functioning, and cognition differences in young patients newly diagnosed with BD and whether these are different for young and adult patients newly diagnosed with BD. Understanding these differences is important for tailored treatment and support. METHODS: Participant groups included 401 patients newly diagnosed with BD, 145 of their unaffected first-degree relatives (UR) and 209 healthy control individuals (HC). First, we compared socio-economic status, functioning and cognition between young patients newly diagnosed with BD (150), UR (61) and HC (92) (15-25 years) and adult patients newly diagnosed with BD (251), UR (84) and HC (117) (>25 years), respectively. Second, within patients, we compared functioning and cognition between young and adult patients newly diagnosed with BD. RESULTS: In both participant groups, patients newly diagnosed with BD, and to a lesser degree UR, had lower socio-economic status and impaired functioning and cognition compared with HC. Further, young patients newly diagnosed with BD were less functionally impaired, than adults newly diagnosed with BD, whereas cognition did not differ between groups. LIMITATIONS: Applied tools for assessments of functioning and cognition are not validated below age 18. CONCLUSIONS: Overall, lower socio-economic status and impaired functioning and cognition were found both in young and adult patients newly diagnosed with BD and their UR compared with young and adult HC, respectively. Young patients were less functionally impaired than adults, but cognition was similarly impaired.
Bipolar Disorder , Adult , Humans , Adolescent , Bipolar Disorder/diagnosis , Bipolar Disorder/epidemiology , Cross-Sectional Studies , Economic Status , Case-Control Studies , Cognition
BACKGROUND: Abnormalities in cerebrospinal fluid (CSF)-amyloid-beta (Aß)42, CSF-Aß40, CSF-Aß38, CSF-soluble amyloid precursor proteins α and ß, CSF-total-tau, CSF-phosphorylated-tau, CSF-neurofilament light protein (NF-L), CSF-neurogranin, plasma-Aß42, plasma-Aß40, plasma-total-tau, plasma-NF-L and, serum-S100B during affective episodes may reflect brain changes that could impact cognitive function in patients with bipolar disorder (BD). The study aimed to investigate the association between these biomarkers indicative of Alzheimer's disease and those reflecting neurodegeneration alongside their impact on cognitive function in patients with BD and healthy control individuals (HC). The primary hypothesis was that GL and VL would increase with increasing levels of CSF-Aß42 based on data from T0 and T3 in BD and HC jointly. METHODS: In a prospective, longitudinal case-control study euthymic patients with BD (N = 85) and HC (N = 44) were evaluated with clinical assessment and neuropsychological testing at baseline (T0) and during euthymia after a year (T3). Patients' affective states were recorded weekly as euthymic, subthreshold level, major depression, or (hypo)mania. If an episode occurred during follow-up, the patient was also assessed in post-episode euthymia. Cognitive performance was measured as a global cognitive score (GL) for four cognitive domains including verbal learning and memory (VL). RESULTS: Estimated in a linear mixed model GL increased with 0.001 for each increase of 1 pg/ml of CSF-Aß42 (97.5%, CI 0.00043-0.0018, adjusted-p = 0.0005) while VL increased by 0.00089 (97.5%, CI 0.00015-0.0018, adjusted-p = 0.045) in BD and HC jointly. The association was weak, however stronger in patients with BD compared to HC. Associations between other biomarkers including CSF-neurogranin, and cognitive domains were overall weak, and none remained significant after adjustment for multiple testing. LIMITATIONS: Modest sample size. A complete data set regarding both CSF-AB-42 and cognitive test scores was obtained from merely 61 patients with BD and 38 HC individuals. CONCLUSION: CSF-Aß42 may be associated with cognitive dysfunction in patients with BD and HC individuals. The association appeared to be stronger in BD but with overlapping confidence intervals. Hence it remains uncertain whether the association is a general phenomenon or driven by BD.
BACKGROUND: During over half a century, science has shown that lithium is the most efficacious treatment for bipolar disorder but despite this, its prescription has consistently declined internationally during recent decades to approximately 35% ever use or less of patients with bipolar disorder. CONTENT: This narrative review provides an overview of the decreasing use of lithium in bipolar disorder internationally, shortly summarises the evidence for lithium's acute and prophylactic effects in bipolar disorder, discuss the challenges in relation to lithium including side effects, long-term risks and myths around lithium and provides two detailed examples on how specialised care models may result in successful increase of the use of lithium to 70% of patients with bipolar disorder largescale and improve care regionally and nationally. CONCLUSIONS: Decades of scientific investigations and education and teaching of clinicians and the public has not increased the use of lithium on a population-based large scale. It is argued that lithium should be the drug of choice for maintenance therapy as the single first-line treatment and that organizational changes are needed with specialised care for bipolar disorder to systematically and long-term change the use of lithium on a large-scale population-level.
BACKGROUND: Evidence-based use of antidepressant medications is of major clinical importance. We aimed to uncover precription patterns in a large cohort of patients with unipolar depression. MATERIAL AND METHODS: Using Danish nationwide registers, we identified individuals with a first-time hospital diagnosis of unipolar depression between January 1st, 2001, and December 31st, 2016. Redemeed prescriptions of antidepressants from five years before to five years after diagnosis were retreived. Lithium and relevant antipsychotics were included. Data were analyzed with descriptive statistics including sunburst plots. Cox regressions were used to rank the risk of treatment failure according to antidepressant category and depression severity, as measured by hazard ratios of drug shift. RESULTS: The full study population consisted of 113,175 individuals. Selective Serotonin Reuptake Inhibitors was the predominantly prescribed first-line group, both before (55.4%) and after (47.7%) diagnosis and across depression severities. Changes of treatment strategy were frequent; 60.8%, 33.7%, and 17.1% reached a second, third, and fourth treatment trial after the hospital diagnosis, respectively. More than half of patients continued their pre-diagnosis antidepressant after diagnosis. The risk of change of treatment strategy was generally lower in mild-moderate depression and higher in severe depression, with tricyclic antidepressants carrying the highest risk in the former and the lowest risks in the latter. Overall, prescribing were often not in accordance with guidelines. CONCLUSION: These findings uncover a potential for improving the clinical care for patients with unipolar depression through optimization of the use of marketed antidepressants.
Depressive Disorder , Humans , Depressive Disorder/drug therapy , Depressive Disorder/epidemiology , Antidepressive Agents/therapeutic use , Selective Serotonin Reuptake Inhibitors , Prescriptions , Denmark/epidemiology , Depression/drug therapy
BACKGROUND: Electroconvulsive therapy (ECT) is an efficient and rapid-acting treatment indicated for severe depressive disorders. While ECT is commonly accompanied by transient memory decline, the brain mechanisms underlying these side effects remain unclear. AIMS: In this exploratory functional magnetic resonance (fMRI) study, we aimed to compare effects of ECT versus pharmacological treatment on neural response during episodic memory encoding in patients with affective disorders. METHODS: This study included 32 ECT-treated patients (major depressive disorder (MDD), n = 23; bipolar depression, n = 9) and 40 partially remitted patients in pharmacological treatment (MDD, n = 24; bipolar disorder, n = 16). Participants underwent neuropsychological assessment, a strategic picture encoding fMRI scan paradigm, and mood rating. The ECT group was assessed before ECT (pre-ECT) and 3 days after their eighth ECT session (post-ECT). RESULTS: Groups were comparable on age, gender, and educational years (ps ⩾ 0.05). Within-group analyses revealed a selective reduction in verbal learning and episodic memory pre- to post-ECT (p = 0.012) but no decline in global cognitive performance (p = 0.3). Functional magnetic resonance imaging analyses adjusted for mood symptoms revealed greater activity in ECT-treated patients than pharmacologically treated No-ECT patients across left precentral gyrus (PCG), right dorsomedial prefrontal cortex (dmPFC), and left middle frontal gyrus (MFG). In ECT-treated patients, greater decline in verbal learning and memory performance from pre- to post-ECT correlated with higher PCG response (r = -0.46, p = 0.008), but not with dmPFC or MFG activity (ps ⩾ 0.1), post-ECT. CONCLUSIONS: Episodic memory decline was related to greater neural activity in the left PCG, but unrelated to increased dmPFC and MFG activity, immediately after ECT.
Depressive Disorder, Major , Electroconvulsive Therapy , Memory, Episodic , Humans , Electroconvulsive Therapy/adverse effects , Electroconvulsive Therapy/methods , Depressive Disorder, Major/diagnostic imaging , Depressive Disorder, Major/therapy , Brain/diagnostic imaging , Magnetic Resonance Imaging , Treatment Outcome
First-degree relatives of patients with bipolar disorder are at heightened risk of mood episodes, which may be attributed to the existence of endophenotypes i.e., heritable (neuro)biological changes present in patients and their unaffected relatives (UR). In this longitudinal MRI study, we aim to investigate the trajectories of aberrant reward-related functional changes identified in UR vs healthy controls (HC). Sixty-eight UR and 65 HC of similar age and gender distribution underwent MRI at baseline while performing a card guessing task. Of these, 29 UR and 36 HC were investigated with the same protocol following a 16-month period in average. We first identified brain regions showing group differences in the neural response to expected value (EV) and reward prediction error (PE) at baseline and analyzed how the reward-related response in these regions changed over time in UR vs HC. Relative to HC at baseline, UR showed lower EV signal in the right ventrolateral prefrontal cortex (vlPFC) and paracingulate gyrus and lower PE signal in the left vlPFC and dorsomedial PFC. The trajectories of these abnormalities in UR showed a normalization of the prefrontal EV signals, whereas the PE signals which correlated with depressive symptoms remained stable over time. While the UR showed both blunted EV and PE signals, none of these abnormalities increased over time, which is consistent with the observed stable mood symptoms.
Bipolar Disorder , Humans , Bipolar Disorder/diagnostic imaging , Magnetic Resonance Imaging , Brain/diagnostic imaging , Cerebral Cortex , Reward
INTRODUCTION: Chronotherapeutic interventions for bipolar depression and mania are promising interventions associated with rapid response and benign side effect profiles. Filtering of biologically active short wavelength (blue) light by orange tinted eyewear has been shown to induce antimanic and sleep promoting effects in inpatient mania. We here describe a study protocol assessing acute and long-term stabilizing effects of blue blocking (BB) glasses in outpatient treatment of bipolar disorder. PATIENTS AND METHODS: A total of 150 outpatients with bipolar disorder and current symptoms of (hypo)-mania will be randomized 1:1 to wear glasses with either high (99%) (intervention group) or low (15%) (control group) filtration of short wavelength light (<500 nm). Following a baseline assessment including ratings of manic and depressive symptoms, sleep questionnaires, pupillometric evaluation and 48-h actigraphy, participants will wear the glasses from 6 PM to 8 AM for 7 consecutive days. The primary outcome is the between group difference in change in Young Mania Rating Scale scores after 7 days of intervention (day 9). Following the initial treatment period, the long-term stabilizing effects on mood and sleep will be explored in a 3-month treatment paradigm, where the period of BB treatment is tailored to the current symptomatology using a 14-h antimanic schedule during (hypo-) manic episodes (BB glasses or dark bedroom from 6 PM to 8 AM) and a 2-h maintenance schedule (BB glasses on two hours prior to bedtime/dark bedroom) during euthymic and depressive states.The assessments will be repeated at follow-up visits after 1 and 3 months. Throughout the 3-month study period, participants will perform continuous daily self-monitoring of mood, sleep and activity in a smartphone-based app. Secondary outcomes include between-group differences in actigraphic sleep parameters on day 9 and in day-to-day instability in mood, sleep and activity, general functioning and objective sleep markers (actigraphy) at weeks 5 and 15. TRIAL REGISTRATION: The trial will be registered at www.clinicaltrials.gov prior to initiation and has not yet received a trial reference. ADMINISTRATIVE INFORMATION: The current paper is based on protocol version 1.0_31.07.23. Trial sponsor: Lars Vedel Kessing.
Bipolar Disorder , Humans , Bipolar Disorder/therapy , Antimanic Agents , Mania , Sleep , Ambulatory Care , Randomized Controlled Trials as Topic
