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BackgroundGiven the likelihood of progressive illness in bipolar disorder (BD), it is important to understand the benefits and risks of interventions administered early in illness course. We conducted a systematic review of the effectiveness of interventions in the early course of BD I or II.MethodsWe completed a systematic search on MEDLINE, PsycINFO, EMBASE, the Cochrane Central Register of Controlled Trials, CINAHL and Google Scholar from 1/1/1979 till 14/9/2022. We included controlled trials examining intervention effects on symptomatic, course, functional and tolerability outcomes of patients in the 'early course' of BD I or II. We classified patients to be in early course if they (a) were seeking help for the first time for a manic episode, (b) had a lifetime history of up to 3 manic episodes, or (c) had up to 6 lifetime mood episodes. Evidence quality was assessed using the GRADE approach.ResultsFrom 4135 unique publications we included 25 reports representing 2212 participants in 16 randomized studies, and 17,714 participants from nine non-randomized studies. Available evidence suggested that in early illness course, lithium use was associated with lower recurrence risk compared with other mood stabilizers. Mood stabilizers were also associated with better global functioning, compared with the use of antipsychotics in the medium term. While summative findings regarding psychological therapies were limited by heterogeneity, family-focused and cognitive-behavioral interventions were associated with reduced recurrence risk or improved symptomatic outcomes. There was some evidence that the same pharmacological interventions were more efficacious in preventing recurrences when utilized in earlier rather than later illness course.Conclusions and recommendationsWhile there are promising initial findings, there is a need for more adequately powered trials to examine the efficacy and tolerability of interventions in youth and adults in early illness course. Specifically, there is a compelling need to compare the relative benefits of lithium with other pharmacological agents in preventing recurrences. In addition to symptomatic outcomes, there should be a greater focus on functional impact and tolerability. Effective pharmacological and psychological interventions should be offered to those in early course of BD, balancing potential risks using shared decision-making approaches.

We here describe a multimodality neuroimaging containing data from healthy volunteers and patients, acquired within the Lundbeck Foundation Center for Integrated Molecular Brain Imaging (Cimbi) in Copenhagen, Denmark. The data is of particular relevance for neurobiological research questions related to the serotonergic transmitter system with its normative data on the serotonergic subtype receptors 5-HT1A, 5-HT1B, 5-HT2A, and 5-HT4 and the 5-HT transporter (5-HTT), but can easily serve other purposes.The Cimbi database and Cimbi biobank were formally established in 2008 with the purpose to store the wealth of Cimbi-acquired data in a highly structured and standardized manner in accordance with the regulations issued by the Danish Data Protection Agency as well as to provide a quality-controlled resource for future hypothesis-generating and hypothesis-driven studies.The Cimbi database currently comprises a total of 1100 PET and 1000 structural and functional MRI scans and it holds a multitude of additional data, such as genetic and biochemical data, and scores from 17 self-reported questionnaires and from 11 neuropsychological paper/computer tests. The database associated Cimbi biobank currently contains blood and in some instances saliva samples from about 500 healthy volunteers and 300 patients with e.g., major depression, dementia, substance abuse, obesity, and impulsive aggression. Data continue to be added to the Cimbi database and biobank.

Objective To examine whether late and very-late first-contact schizophrenia carry a risk for later development of dementia. Methods By linkage of the psychiatric and the somatic nation-wide registers of all out- and in-patients with hospital contact in Denmark, we identified all patients with first ever contact during the period from January 1994 to December 2001 with one of the index main diagnoses: late (age >=40) and very-late first-contact (age >=60) schizophrenia. First contact osteoarthritis patients as well as data on the general population were used as controls. The first diagnosis of dementia for each individual at discharge or at out-patient contact was established. The probability of getting a dementia diagnosis is estimated using Poisson regression models with dementia as the outcome of interest. Results Twelve thousand six hundred and sixteen and 7,712 individuals were included in the late and very-late sample, respectively. Follow-up time was between 3.00 and 4.58 years. The rate ratio (RR) of developing dementia in late and very-late first-contact schizophrenia compared to osteoarthritis patients were 3.47 (95%CI: 2.19-5.50) and 3.15 (95%CI: 1.93-5.14), respectively. Compared to the general population the RR were 2.36 (95%CI: 1.54-3.62) and 2.21 (95%CI: 1.39-3.50), respectively. Conclusion schizophrenic patients with late- and very-late first-contact with the psychiatric hospital system are at two to three times higher risk of subsequently getting a diagnosis of dementia compared to patients with osteoarthritis and compared to the general population. Copyright © 2008 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Objective: To examine whether very late first-contact delusional disorder carries a risk for later development of dementia.Methods: By linkage of the psychiatric and the somatic nationwide registers of all out- and in-patients with hospital contact in Denmark, we included all 60þ patients with first ever from 1 January 1994 to 31 December 2001 with the index main diagnosis: delusional disorder. First contact osteoarthritis patients as well as the general population were used as controls. A total of 1437 patients with persistent delusional disorder and 7302 patients with osteoarthritis were included. Median follow-up time until first diagnosis of dementia at discharge was 1.87 and 4.40 years, respectively. The probability of getting a dementia diagnosis was estimated using Poissonregression models with dementia as the outcome of interest.Results: Patients with very late first-contact delusional disorder had an 8.14 (95% CI, 6.51; 10.19) times increased rate of subsequently developing dementia compared with very late first contact osteoarthritis patients. Compared with the general population the rate ratio was 5.49 (95% CI, 4.81; 6.26).Conclusion: Very late first-contact delusional disorder increases the risk of subsequently getting a diagnosis of dementia 5-8 times compared with osteoarthritis patients and the general population. [ABSTRACT FROM AUTHOR]

Background: Depression and anxiety is prevalent among patients with dementia but the extent to which these conditions are treated with antidepressants has not previously been investigated.Methods: Nationwide register-based data in Denmark were used to identify all patients diagnosed with dementia or osteoarthritis at hospital admission or at first outpatient contact during the period 1995-2000. Rates of subsequent purchase of antidepressants from pharmacies were then calculated. Further, the rate of antidepressant use for patients with dementia was compared with the rate in a gender-, age-, and calendar-matched sample of the general population.Results: In total, 24,137 patients with a main diagnosis of dementia and 100,378 patients with a main first diagnosis of osteoarthritis were incorporated in the study. A total of 43.2% of patients with dementia received antidepressants during follow-up compared to 16.0% of patients with osteoarthritis. Among patients with a diagnosis of dementia, the rate of subsequently purchasing antidepressants was 4.17 times higher (95% CI = 4.05-4.29) than that of patients with a first diagnosis of osteoarthritis, and 8.85 times higher (95% CI = 8.68-9.03) than that of a gender-, age- and calendar-matched sample of the general population. The rate was increased in all subgroups of patients regardless of gender, age, socio-economic group and time since diagnosis.Conclusions: The findings challenge the widely held contention that depression and anxiety in patients with dementia is underdiagnosed and undertreated in clinical practice. [ABSTRACT FROM AUTHOR]

Background: It is currently not known whether elderly men and women present with different subtypes of depression and mania/bipolar disorder. The aim of this study was to compare the prevalence of subtypes of a single depressive episode and mania/bipolar disorder according to the ICD-10 for elderly men and women in a nationwide sample of all out- and inpatients in psychiatric settings.Methods: All patients older than 65 years who received a diagnosis of a single depressive episode and mania/bipolar disorder in the period from 1994 to 2002 at the end of their first outpatient treatment or at their first discharge from psychiatric hospitalization in Denmark were identified in a nationwide register.Results: A total of 9837 patients aged more than 65 years received a diagnosis of a single depressive episode (69.9% were women) and 443 a diagnosis of mania/bipolar disorder (61.6% were women) at the end of their first contact with psychiatric health care. Slightly more women than men received a diagnosis of mild (70.8%) or moderate depression (67.4%) compared to severe depression (65.9%). Men more often presented with a single depressive episode with comorbid substance abuse or comorbid somatic illness. No gender differences were found in the prevalence of depression with or without melancholic or psychotic symptoms. Men more often presented with mania/bipolar disorder with comorbid substance abuse.Conclusions: The distributions of the subtypes of a single depressive episode or mania/bipolar disorder are remarkably similar for male and female patients aged over 65 years with first contact with the psychiatric health-care system. [ABSTRACT FROM AUTHOR]

Background. Patients may present with cognitive impairment in the euthymic phase of affective disorder, but it is unclear whether the impairment is prevalent before onset of the illness. The aim of the present study was to examine the hypothesis that genetic liability to affective disorder is associated with cognitive impairment.Method. In a cross-sectional high-risk case-control study, healthy monozygotic (MZ) and dizygotic (DZ) twins with (High-Risk twins) and without (the control group/Low-Risk twins) a co-twin history of affective disorder were identified through nationwide registers. Cognitive performance of 203 High-Risk and Low-Risk twins was compared.Results. Healthy twins discordant for unipolar disorder showed lower performance on almost all measures of cognitive function: selective and sustained attention, executive function, language processing and working and declarative memory, and also after adjustment for demographic variables, subclinical symptoms and minor psychopathology. Healthy twins discordant for bipolar disorder showed lower performance on tests measuring episodic and working memory, also after adjustment for the above-mentioned covariables. The discrete cognitive impairment found seemed to be related to genetic liability, as the MZ High-Risk twins showed significant impairment on selective and sustained attention, executive function, language processing and working and declarative memory, whereas the DZ High-Risk twins presented with significantly lower scores only on language processing and episodic memory.Conclusions. The hypothesis that discrete cognitive impairment is present before the onset of the affective disorder and is genetically transmitted was supported. Thus, cognitive function may be a candidate endophenotype for affective disorders. [ABSTRACT FROM AUTHOR]

The association between treatment with Selective serotonin reuptake inhibitors (SSRIs) and suicide in children and adolescents on the individual and ecological level were examined in a nationwide Danish pharmacoepidemiological register-linkage study including all persons aged 10-17 years treated with antidepressants during the period 1995-1999 (n=2,569) and a randomly selected control population (n=50,000). A tripartite approach was used. In Part 1, changes in youth suicide and use of antidepressants were examined. In Part 2, we made an assessment of youth suicide characteristics. In Part 3, we analysed the relative risk (RR) of suicide according to antidepressant treatment corrected for psychiatric hospital contact to minimize the problem of confounding by indication. The use of SSRIs among children and adolescents increased substantially during the study period, but the suicide rate remained stable (Part 1). Among 42 suicides nationally aged 10-17 years at death, none was treated with SSRIs within 2 weeks prior to suicide (Part 2). There was an increased rate of suicide associated with SSRIs (RR=4.47), however, not quite significant (95% CI: 0.95-20.96), when adjusted for severity of illness (Part 3). Conclusively, we were not able to identify an association between treatment with SSRIs and completed suicide among children and adolescents. [ABSTRACT FROM AUTHOR]

BACKGROUND: There is increasing evidence that attitudes and beliefs are important in predicting adherence to treatment and medication in depressive and bipolar disorders. However, these attitudes have received little study in patients whose disorders were sufficiently severe to require hospitalization. METHOD: The Antidepressant Compliance Questionnaire (ADCQ) was mailed to a large population of patients with depressive or bipolar disorder, representative of patients treated in hospital settings in Denmark. RESULTS: Of the 1005 recipients, 49.9% responded to the letter. A large proportion of the patients (40-80%) had erroneous views as to the effect of antidepressants. Older patients (over 40 years of age) consistently had a more negative view of the doctor-patient relationship, more erroneous ideas concerning the effect of antidepressants and a more negative view of antidepressants in general. Moreover, their partners agreed on these negative views. Women had a more negative view of the doctor-patient relationship than men, and patients with a depressive disorder had a more negative view of antidepressants than patients with bipolar disorder. The number of psychiatric hospitalizations or the type of treating physician (general practitioner, psychiatrist in private practice, community psychiatrist, hospital psychiatrist, other doctor) did not affect attitudes and beliefs. CONCLUSION: Lack of knowledge about affective disorder and its treatment and a critical attitude, especially among older patients, may add to an adverse prognosis of depressive and bipolar disorders. [ABSTRACT FROM AUTHOR]

What follow up diagnoses are made in people with psychotic disorders?METHODSDesign: Prospective longitudinal study.Setting: The Netherlands; enrolment from April 1997 to October 2001.Population: 168 people living in The Hague, Netherlands who consulted a doctor for the first time about a suspected psychotic disorder and received an extensive diagnostic protocol. Exclusions: psychotic disorders induced by substance abuse. Prognostic factors: Diagnoses were compared at the start of the study and after 2.5 years.Outcomes: Diagnoses of schizophrenia, major depressive and bipolar disorder with psychotic features, and non-organic or organic psychotic disorders.Follow up period: 2.5 years.MAIN RESULTSMost people (120/168, 71%) were given the same diagnosis after 2.5 years as at the cohort's inception. The highest repeat diagnosis rate was for schizophrenic disorders (92/101, 91%), compared with 14/21 (67%) for psychotic mood disorders and 14/46 (30%) for other non-organic psychotic disorders. The proportion of people diagnosed with schizophrenic disorders rose from 101/168 (60.1%) at study's start to 125/168 (74.4%) at 2.5 years. The proportion of people with organic psychotic disorder diagnosis rose from 0/168 (0%) at study start to 5/168 (3.0%) at 2.5 years but it is not clear if this diagnostic category was available at first diagnosis. The proportion of people diagnosed with psychotic mood disorder and other non-organic psychotic disorders was lower at 2.5 years compared with study start (proportion of people with psychotic mood disorder diagnosis: 21/168 (12.5%) at study start v 17/168 (10.1%) at 2.5 years; proportion of people with other non-organic psychotic disorder diagnosis: 46/168 (27.4%) at study start v 21/168 (12.5%) at 2.5 years).CONCLUSIONSThe stability of a diagnosis of schizophrenia or of psychotic mood disorder is high over 2.5 years. The apparent prevalence of schizophrenia rises over time in people with psychotic disorders. NOTESThe authors infer from these data that their initial diagnostic protocol leads to stable diagnoses for each of the four categories of psychotic disorder. However, this interpretation assumes there is no underlying change in prevalence and that the two diagnostic assessments were both correct. It is not clear if these assumptions hold, so the conclusions should be treated with caution. The relative contributions to diagnoses of the diagnostic protocols and clinical judgement are also unclear. [ABSTRACT FROM AUTHOR]

Background: Patients with psychiatric disorders have increased all-cause mortality compared with the general population. Previous research has shown that there is a fourfold increased risk of sudden cardiac death (SCD) among the young., Objective: To investigate the incidence of SCD in patients with psychiatric disorders aged 18-90 years in the Danish population by systematically reviewing all deaths in 1 year., Methods: We examined all deaths in Denmark among residents aged 18-90 years in 2010 by reviewing death certificates and autopsy reports. All deaths were categorised as non-SCD or SCD based on the available information. Psychiatric disorder was defined according to International Classification of Diseases, 10th revision criteria or by redemption of a prescription for psychotropic medication within 1 year., Results: Of 4.3 million residents in 2010, we observed 45 703 deaths, of which 6002 were due to SCD. Overall, the incidence rate ratio of SCD was 1.79-6.45 times higher among patients with psychiatric disorders than in the general population and was age dependent (p<0.001 across all age groups). When adjusting for age, sex and comorbidities, psychiatric disorders were independently associated with SCD, with a HR of 2.31 (2.19 to 2.43, p<0.001), and HR was highest among patients with schizophrenic disorders, with a HR of 4.51 (3.95 to 5.16, p <0.001). Furthermore, 18-year-old patients with a psychiatric disorder had an expected 10-year excess loss of life. Patients aged 18-40 with a psychiatric disorder had 13% of excess life years lost caused by SCD., Conclusion: In this study, the rate of SCD in patients with psychiatric disorders is higher across all age groups than in the general population. Having a psychiatric disorder is independently associated with SCD. Patients with schizophrenic disease had the highest rates of SCD. Life expectancy for an 18-year old with a psychiatric disorder is estimated to be 10 years shorter in comparison with those without this disorder., Competing Interests: Competing interests: LVKe has within the preceding three years been a consultant for Teva and Lundbeck. LVKø has received speaker’s honorarium from AstraZeneca, Boehringer, Novartis and Novo Nordisk. JT-H is a consultant for Johnson and Johnson, Microport, Boston, Cytokinetics and Leo Pharma, and has received funding from John and Birthe Family foundation. The remaining authors declare no conflicts of interests., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Accumulating data support the association between increased inflammation and bipolar disorder (BD), and preliminary data suggest that augmentation with low-dose aspirin (LDA) may protect against the onset and deterioration of BD via anti-inflammatory pathways. The A-bipolar randomised controlled trial (RCT) aims to investigate whether adding LDA to standard treatment improves day-to-day mood instability (MI) in BD., Methods and Analysis: A two-arm, triple-blind, parallel-group, superiority RCT including 250 patients with newly diagnosed BD treated at the Copenhagen Affective Disorder Clinic, Denmark. Participants are randomised 1:1 to either 150 mg of acetylsalicylic acid daily (LDA) or a placebo for six months in addition to their regular treatment. Mood instability, calculated from daily smartphone-based mood evaluations, is the primary outcome measure due to its internal validity as a real-life measure for patients and external validity as it reflects patients' illness severity and functioning. Analyses will be conducted as intention-to-treat analyses using a linear mixed model including time (categorical) and the time-treatment interaction as fixed effects and with an unstructured covariance pattern to account for repeated measurements on each study participant. The trial is Good Clinical Practice monitored., Ethics and Dissemination: The Danish Research Ethics Committee (H-21014515) and the data agency, Capital Region of Copenhagen (P-2021-576) approved the trial. Results will be published in peer-reviewed journals., Trial Registration Number: NCT05035316., Competing Interests: Competing interests: CFB, MF-J, KWM, JLF and KC have no competing interests to declare. JZ has within the last 3 years received honoraria from Lundbeck Pharma A/S. LVK has within the preceding 3 years been a consultant for Lundbeck and Teva. MV has within the last 3 years served as consultant for Lundbeck and Janssen/Cilag., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: There is a compelling need for innovative intervention strategies for patients with affective disorders, given their increasing global prevalence and significant associated disability and impaired functioning. This study aimed to investigate whether a comprehensive multimodule individualized intervention (AWARE), targeting known mediators of functioning, improves functioning in affective disorders., Methods: AWARE was a randomized, controlled, rater-blind clinical trial conducted at two centers in the Capital Region of Denmark (Clinicaltrials.gov, NCT04701827). Participants were adults with bipolar disorder or major depressive disorder and impaired functioning. Participants were randomized to the six-month AWARE intervention or treatment as usual (TAU). The AWARE intervention is based on the International Classification of Functioning, Disability and Health (ICF) Brief Core Set for Bipolar and Unipolar Disorder.The primary outcome was observation-based functioning using the Assessment of Motor and Process Skills (AMPS). Secondary outcomes were functioning, QoL, stress, and cognition., Results: Between February 2021 and January 2023, 103 patients were enrolled; 50 allocated to AWARE treatment and 53 to TAU (96 included in the full analysis set). There was no statistically significant differential change over time between groups in the primary outcome (AMPS), however, both groups showed a statistically significant improvement at endpoint. The AWARE intervention had a statistically significant effect compared with TAU on secondary outcomes of patient-reported functioning, stress and cognition., Conclusion: Compared with TAU, the AWARE intervention was ineffective at improving overall functioning on the primary outcome, presumably due to the short duration of the intervention. Further development of effective treatments targeting functioning is needed.

Objectives: To assess whether bipolar disorders are associated with the risk of HIV infection and whether the risk of bipolar disorders is increased among people with HIV (PWH) and their siblings., Design: Nationwide, population-based, combined matched nested case-control and cohort study of PWH of Danish origin (1995-2021), a comparison cohort from the background population, matched on date of birth and sex, and sibling cohorts., Methods: Conditional logistic regression and Cox regression was used to calculate adjusted odds ratios (aORs) for HIV infection and hazard ratios (HRs) among PWH for bipolar disorder and receipt of lithium., Results: We included 5322 PWH and 53,220 comparison cohort members. In the case-control study, bipolar disorder was associated with an increased risk of HIV infection (aOR: 1.9, 95% confidence interval (CI): 1.2-3.0), especially when injection drug use was the route of infection (aOR: 7.6, 95% CI: 2.0-28.9). In the cohort study, we observed an increased risk of bipolar disorders among PWH, especially in the first 2 years of observation (HR: 4.2, 95% CI: 2.4-7.4), whereas the risk of receipt of lithium was lower and the CI crossed 1. The 20-year risk of bipolar disorders for PWH was approximately 1%. Siblings of PWH also had an increased risk of bipolar disorder, but not to the same degree as PWH and not of receipt of lithium., Conclusions: Bipolar disorders are associated with the risk of HIV infection, and PWH have increased risk of bipolar disorder and receipt of lithium beyond what familial factors could explain., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Long-acting injectable antipsychotics (LAIs) are not routinely offered to patients living with bipolar disorder type I (BP-I), despite widespread evidence that supports their benefits over oral antipsychotics, particularly in early disease., Methods: A round-table meeting of psychiatrists convened to discuss barriers and opportunities and provide consensus recommendations around the early use of LAIs for BP-I., Results: LAIs are rarely prescribed to treat BP-I unless a patient has severe symptoms, sub-optimal adherence to oral antipsychotics, or has experienced multiple relapses. Beyond country-specific accessibility issues (e.g., healthcare infrastructure and availability/approval status), primary barriers to the effective use of LAIs were identified as attitudinal and knowledge/experience-based. Direct discussions between healthcare providers and patients about treatment preferences may not occur due to a preconceived notion that patients prefer oral antipsychotics. Moreover, as LAIs have historically been limited to the treatment of schizophrenia and the most severe cases of BP-I, healthcare providers might be unaware of the benefits LAIs provide in the overall management of BP-I. Improved treatment adherence associated with LAIs compared to oral antipsychotics may support improved outcomes for patients (e.g., reduced relapse and hospitalization). Involvement of all stakeholders (healthcare providers, patients, and their supporters) participating in the patient journey is critical in early and shared decision-making processes. Clinical and database studies could potentially bridge knowledge gaps to facilitate acceptance of LAIs., Conclusion: This review discusses the benefits of LAIs in the management of BP-I and identifies barriers to use, while providing expert consensus recommendations for potential solutions to support informed treatment decision-making., (© 2024 The Author(s). Bipolar Disorders published by John Wiley & Sons Ltd.)

Background: Major depressive disorder (MDD) is one of the leading causes of burden of disease globally. We aimed to investigate whether global functioning is impaired in patients with MDD in full or partial remission compared to healthy control individuals (HC)., Methods: We conducted a systematic review and meta-analysis according to the PRISMA guideline. We searched the databases PubMed, EMBASE and PsycINFO from January 1st 1980 to February 1st 2023. We included studies of adults with a diagnosis/former diagnosis of MDD with assessment of global functioning performed during a state of full or partial remission. The methodological quality was assessed using the Joanna Briggs Institute (JBI) Critical Appraisal Checklist. Standardised mean differences (SMD) using random-effects models were calculated as the summary measure. We further performed meta-analyses of the mean raw score in patients with MDD for individual functioning scales., Results: Forty-two studies, comprising 17,999 patients with MDD and 35,550 HC, were included, 14 of which included both patients with MDD in full or partial remission and HC. Global functioning was lower in patients with MDD in full or partial remission compared with HC (SMD -2.00, 95 % CI: -0.9 to -3.03, 15 comparisons, I 2 : 99.8 %)., Limitations: Important information about the study participants and setting was not reported for most studies, or the reporting was unclear., Conclusion: Patients with MDD have lower levels of functioning compared with HC also when in full or partial remission. Assessment of functioning should be an essential component of managing patients with MDD, also during remission., Competing Interests: Declaration of competing interest RS has within the last three years been a speaker/consultant for Lundbeck. KM declares no conflicts of interest. MSC declares no conflicts of interest. LVK has within the last three years been a consultant for Lundbeck and Teva. MV has within the last three years been a speaker/consultant for Lundbeck and JanssenCilag., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Cognitive impairment is prevalent across neuropsychiatric disorders but there is a lack of treatment strategies with robust, enduring effects. Emerging evidence indicates that altitude-like hypoxia cognition training may induce long-lasting neuroplasticity and improve cognition. We will investigate whether repeated cognition training under normobaric hypoxia can improve cognitive functions in healthy individuals and patients with affective disorders and the neurobiological underpinnings of such effects., Methods: In sub-study 1, 120 healthy participants are randomized to one of four treatment arms in a double-blind manner, allowing for examination of separate and combined effects of three-week repeated moderate hypoxia and cognitive training, respectively. In sub-study 2, 60 remitted patients with major depressive disorder or bipolar disorder are randomized to hypoxia with cognition training or treatment as usual. Assessments of cognition, psychosocial functioning, and quality of life are performed at baseline, end-of-treatment, and at 1-month follow-up. Functional magnetic resonance imaging (fMRI) scans are conducted at baseline and 1-month follow-up, and [ 11 C]UCB-J positron emission tomography (PET) scans are performed at end-of-treatment to quantify the synaptic vesicle glycoprotein 2A (SV2A). The primary outcome is a cognitive composite score of attention, verbal memory, and executive functions. Statistical power of ≥ 80% is reached to detect a clinically relevant between-group difference with minimum n = 26 per treatment arm. Behavioral data are analyzed with an intention-to-treat approach using mixed models. fMRI data is analyzed with the FMRIB Software Library, while PET data is quantified using the simplified reference tissue model (SRTM) with centrum semiovale as reference region., Discussion: The results will provide novel insights into whether repeated hypoxia cognition training increases cognition and brain plasticity, which can aid future treatment development strategies., Trial Registration: ClinicalTrials.gov, NCT06121206 . Registered on 31 October 2023., (© 2024. The Author(s).)