Mikael Landén

University of Gothenburg | GU

Introduction: Bipolar disorder has been associated with significant structural brain changes, potentially driven by central nervous system (CNS) inflammation. This study aimed to investigate the relationship between inflammation biomarkers in cerebrospinal fluid (CSF) and longitudinal structural brain changes. Methods: We included 29 individuals wi...

This study represents the first large-scale investigation of rare (<1% population frequency) copy number variants (CNVs) in anorexia nervosa (AN). Large, rare CNVs are reported to be causally associated with anthropometric traits, neurodevelopmental disorders, and schizophrenia, yet their role in the genetic basis of AN is unclear. Using genome-wid...

Although specific risk factors for brain alterations in bipolar disorders (BD) are currently unknown, obesity impacts the brain and is highly prevalent in BD. Gray matter correlates of obesity in BD have been well documented, but we know much less about brain white matter abnormalities in people who have both obesity and BD. We obtained body mass i...

Current genetic research on obsessive-compulsive disorder (OCD) supports contributions to risk specifically from common single nucleotide variants (SNVs), along with rare coding SNVs and small insertion-deletions (indels). The contribution to OCD risk from rare copy number variants (CNVs), however, has not been formally assessed at a similar scale....

Background Electroconvulsive therapy (ECT) is an important treatment for several severe psychiatric conditions, yet its precise mechanism of action remains unknown. Increased inhibition in the brain after ECT seizures, mediated by γ-aminobutyric acid (GABA), has been linked to clinical effectiveness. Case series on epileptic patients report a posti...

Despite electroconvulsive therapy (ECT) being recognized as an effective treatment for major depressive episodes (MDE), its application is subject to controversy due to concerns over cognitive side effects. The pathophysiology of these side effects is not well understood. Here, we examined the effects of ECT on blood-based biomarkers of neuronal in...

Clinical studies on humans with a history of chronic abuse of alcohol or cocaine show cognitive impairments associated with hippocampal atrophy. Adult hippocampal neurogenesis is a process important for memory formation and has been shown to be impaired by alcohol and cocaine in rodent models. It has thus been suggested that a reduction in adult ne...

Brain network hubs are highly connected brain regions serving as important relay stations for information integration. Recent studies have linked mental disorders to impaired hub function. Provincial hubs mainly integrate information within their own brain network, while connector hubs share information between different brain networks. This study...

Understanding the genetic basis of neuro-related proteins is essential for dissecting the molecular basis of human behavioural traits and the disease aetiology of neuropsychiatric disorders. Here the SCALLOP Consortium conducted a genome-wide association meta-analysis of over 12,000 individuals for 184 neuro-related proteins in human plasma. The an...

Objective: Associations were examined between six psychiatric diagnoses in parents and a broad range of psychiatric and nonpsychiatric outcomes in their offspring. Methods: All individuals born in Sweden between 1970 and 2000 were linked to their biological parents (N=3,286,293) through Swedish national registers. A matched cohort design, with s...

Importance Electroconvulsive therapy (ECT), wherein a generalized epileptic seizure is induced, is a treatment for major depressive disorder (MDD). Currently, it is unclear whether there is an association between seizure length and treatment outcome. Objective To explore the association between seizure duration, potential confounding variables, an...

Background Lithium (Li) remains the treatment of choice for bipolar disorders (BP). Its mood-stabilizing effects help reduce the long-term burden of mania, depression and suicide risk in patients with BP. It also has been shown to have beneficial effects on disease-associated conditions, including sleep and cardiovascular disorders. However, the in...

Objective: Many but not all persons with bipolar disorder require hospital care because of severe mood episodes. Likewise, some but not all patients experience long-term occupational dysfunction that extends beyond acute mood episodes. It is not known whether these dissimilar outcomes of bipolar disorder are driven by different polygenic profiles....

Background and Hypothesis Schizophrenia (SCZ) and anorexia nervosa (AN) are 2 severe and highly heterogeneous disorders showing substantial familial co-aggregation. Genetic factors play a significant role in both disorders, but the shared genetic etiology between them is yet to be investigated. Study Design Using summary statistics from recent lar...

Multivariate techniques better fit the anatomy of complex neuropsychiatric disorders which are characterized not by alterations in a single region, but rather by variations across distributed brain networks. Here, we used principal component analysis (PCA) to identify patterns of covariance across brain regions and relate them to clinical and demog...

Objective To determine whether the rates of readmissions and suicide vary in psychotic unipolar depression based on whether patients receive maintenance electroconvulsive therapy (M‐ECT) following the initial series of ECT, and to examine if there is an age‐dependent association. Methods We used Swedish national registries to identify hospitalized...

Background The St. Göran Bipolar Project (SBP) was launched as a longitudinal outpatient study investigation. The overarching objective was to identify predictive factors associated with long-term outcomes of individuals with bipolar disorder, encompassing cognitive function, relapse rate, treatment responses, and functional outcome. Furthermore, t...

Background Electroconvulsive therapy (ECT) is an important treatment for several severe psychiatric conditions, yet its precise mechanism of action remains unknown. Increased inhibition in the brain after ECT seizures, mediated by γ-aminobutyric acid (GABA), has been linked to clinical effectiveness. Case series on epileptic patients report a posti...

Brain regions rarely act independently but form functional networks to address specific tasks. Recent studies suggest that psychiatric illnesses are associated with impaired functional integration across large-scale brain networks. ‘Hubs’ are brain regions that are highly connected to widespread areas of the brain, serving as important relay statio...

Objective The majority of patients hospitalized for treatment of a manic episode are readmitted within 2 years despite maintenance treatment. Electroconvulsive therapy (ECT) has been associated with lower rehospitalization rates in some psychiatric conditions, but its association with readmission after a manic episode has not been investigated. The...

The link between bipolar disorder (BP) and immune dysfunction remains controversial. While epidemiological studies have long suggested an association, recent research has found only limited evidence of such a relationship. To clarify this, we performed an exploratory study of the contributions of immune-relevant genetic factors to the response to l...

Background Offspring of parents with bipolar disorder have increased risks of their own psychopathology. However, a large‐scale survey of psychiatric, somatic, and adverse social outcomes up to adulthood, which could aid in prioritizing and tailoring prevention, is lacking. It also remains to clarify how risks are modified by other parental factors...

To date, four genome-wide association studies (GWAS) of obsessive-compulsive disorder (OCD) have been published, reporting a high single-nucleotide polymorphism (SNP)-heritability of 28\% but finding only one significant SNP. A substantial increase in sample size will likely lead to further identification of SNPs, genes, and biological pathways med...

Lithium is the gold standard treatment for bipolar disorder (BD). However, its mechanism of action is incompletely understood, and prediction of treatment outcomes is limited. In our previous multi-omics study of the Pharmacogenomics of Bipolar Disorder (PGBD) sample combining transcriptomic and genomic data, we found that focal adhesion, the extra...

Bipolar disorder (BD) features heterogenous clinical presentation and course of illness. It remains unclear how subphenotypes associate with genetic loadings of BD and related psychiatric disorders. We investigated associations between the subphenotypes and polygenic risk scores (PRS) for BD, schizophrenia, and major depressive disorder (MDD) in tw...

Bipolar disorder (BD) is a heritable mental illness with complex etiology. While the largest published genome-wide association study identified 64 BD risk loci, the causal SNPs and genes within these loci remain unknown. We applied a suite of statistical and functional fine-mapping methods to these loci, and prioritized 22 likely causal SNPs for BD...

Background Accurate diagnosis of bipolar disorder (BD) is difficult in clinical practice, with an average delay between symptom onset and diagnosis of about 7 years. A key reason is that the first manic episode is often preceded by a depressive one, making it difficult to distinguish BD from unipolar major depressive disorder (MDD). Aims Here, we...

Importance Psychiatric conditions in parents are associated with many psychiatric and nonpsychiatric outcomes in offspring. However, it remains unknown whether this intergenerational transmission is attributable to broader psychopathology comorbidity or to specific conditions. Objective To estimate associations between general and specific psychop...

Current genetic research on obsessive-compulsive disorder (OCD) supports contributions to risk specifically from common single nucleotide variants (SNVs), along with rare coding SNVs and small insertion-deletions (indels). The contribution to OCD risk from large, rare copy number variants (CNVs), however, has not been formally assessed at a similar...

Background: Lithium (Li) remains the treatment of choice for bipolar disorders (BP). Its mood-stabilizing effects help reduce the long-term burden of mania, depression and suicide risk in patients with BP. It also has been shown to have beneficial effects on disease-associated conditions, including sleep and cardiovascular disorders. However, the i...

Objective This study aimed to associate antidepressants with versus without antipsychotics with readmission and suicide in patients with psychotic unipolar depression. Methods Swedish national registers were used to identify inpatients with psychotic unipolar depression, treated 2007–2016. The participants collected antidepressants with or without...

Treatment response and resistance in major depressive disorder (MDD) are suggested to be heritable. Due to significant challenges in defining treatment-related phenotypes, our understanding of their genetic bases is limited. This study aimed to derive a stringent definition of treatment resistance and to investigate the genetic overlap between trea...

Importance Antidepressants are increasingly prescribed to pediatric patients with unipolar depression, but little is known about the risk of treatment-emergent mania. Previous research suggests pediatric patients may be particularly vulnerable to this adverse outcome. Objective To estimate whether pediatric patients treated with antidepressants ha...

While individuals with bipolar disorder are assumed to recover between mood episodes, some nevertheless experience lingering subsyndromal symptoms and suffer from cognitive and functional impairments. Here, we propose that these enduring impairments may be linked to aberrations in brain networks. To test this, we conducted a resting-state functiona...

Objective: The aims of this study were to investigate secular trends and distribution of body mass index (BMI) among individuals with bipolar disorders and the general population between 2008 and 2019. Methods: Data were from the Swedish National Quality Register for Bipolar Disorder, where 24,423 adults with bipolar disorders were identified, a...

Lithium is the gold standard treatment for bipolar disorder (BD). However, its mechanism of action is incompletely understood, and prediction of treatment outcomes is limited. In our previous multi-omics study of the Pharmacogenomics of Bipolar Disorder (PGBD) sample combining transcriptomic and genomic data, we found that focal adhesion, the extra...

Background Sunlight contains ultraviolet B (UVB) radiation that triggers the production of vitamin D by skin. Vitamin D has widespread effects on brain function in both developing and adult brains. However, many people live at latitudes (about > 40 N or S) that do not receive enough UVB in winter to produce vitamin D. This exploratory study investi...

The link between bipolar disorder (BP) and immune dysfunction remains controversial. While epidemiological studies have long suggested an association, recent research has found only limited evidence of such a relationship. To clarify this, we investigated the contributions of immune-relevant genetic factors to the response to lithium (Li) treatment...

Cross-sectional neuroimaging studies show that bipolar disorder is associated with structural brain abnormalities, predominantly observed in prefrontal and temporal cortex, cingulate gyrus, and subcortical regions. However, longitudinal studies are needed to elucidate whether these abnormalities presage disease onset or are consequences of disease...

Objectives We recently conducted the first longitudinal study comparing cardiometabolic risk indicators (CMRIs) between a cohort of individuals with bipolar disorders (BDs) and controls from the general population. Here, we sought to validate the findings in that study using an independent case-control sample. Methods We used data from the St. Gör...

Circulating proteins play key roles in inflammation and a broad range of diseases. To identify genetic influences on inflammation-related proteins, we conducted a genome-wide protein quantitative trait locus (pQTL) study of 91 plasma proteins measured using the Olink Target platform in 15,150 participants. We identified 180 pQTLs, of which 50 were...

Understanding the genetic basis of neuro-related proteins is essential for dissecting the molecular basis of human behavioral traits and the disease etiology of neuropsychiatric disorders. Here, the SCALLOP Consortium conducted a genome-wide association meta-analysis of over 12,500 individuals for 184 neuro-related proteins in human plasma. The ana...

Background: Obesity is highly prevalent and disabling, especially in individuals with severe mental illness including bipolar disorders (BD). The brain is a target organ for both obesity and BD. Yet, we do not understand how cortical brain alterations in BD and obesity interact. Methods: We obtained body mass index (BMI) and MRI-derived regional...

Understanding the genetic basis of neuro-related proteins is essential for dissecting the disease etiology of neuropsychiatric disorders and other complex traits and diseases. Here, the SCALLOP Consortium conducted a genome-wide association meta-analysis of over 12,500 individuals for 184 neuro-related proteins in human plasma. The analysis identif...

Treatment response and resistance in major depressive disorder (MDD) are suggested to be heritable. Due to significant challenges in defining treatment-related phenotypes, our understanding of their genetic bases is limited. This study aimed to derive a stringent definition of treatment resistance and to investigate genetic overlap between treatmen...

Background Bipolar disorder is a severe psychiatric syndrome defined by periodic mood shifts. Patients with bipolar disorder show cognitive impairments relative to healthy controls. The risk of developing schizophrenia, and partially also bipolar disorder, has previously been shown to increase with lower premorbid intelligence. It is not known if p...

Anorexia nervosa (AN) is one of the most lethal psychiatric disorders. To date, we lack adequate knowledge about the (neuro)biological mechanisms of this disorder to inform evidence-based pharmacological treatment. Gut dysbiosis is a trending topic in mental health, including AN. Communication between the gut microbiota and the brain is partly medi...

Purpose The Swedish National Quality Register for bipolar affective disorder, BipoläR, was established in 2004 to provide nationwide indicators for quality assessment and development in the clinical care of individuals with bipolar spectrum disorder. An ancillary aim was to provide data for bipolar disorder research. Participants Inclusion criteri...

BACKGROUND Electroconvulsive therapy (ECT) is the most effective treatment for severe depression, but the biological changes induced by ECT remain poorly understood. METHODS This study investigated alterations in blood serum proteins in 309 patients admitted to ECT for a major depressive episode. We analyzed 201 proteins in samples collected at th...

Individuals with bipolar disorder are at increased risk for cardiovascular diseases. Most studies have described increases in cardiometabolic risk indicators (CMRIs) using clinical cut-off values. Further, there are no longitudinal studies on CMRIs. We aimed to investigate continuous measures of CMRIs in individuals with bipolar disorder and contro...

Antidepressant medication is used extensively to treat bipolar depression despite uncertain efficacy. The cytochrome P450 (CYP) 2C19 enzyme metabolize several antidepressants, and polymorphisms in the corresponding gene CYP2C19 influence plasma concentration and hence treatment outcomes in major depressive disorder. Here, we investigate if CYP2C19...

Postsynaptic density is reduced in schizophrenia, and risk variants increasing complement component 4A ( C4A ) gene expression are linked to excessive synapse elimination. In two independent cohorts, we show that cerebrospinal fluid (CSF) C4A concentration is elevated in patients with first-episode psychosis (FEP) who develop schizophrenia (FEP-SCZ...

Objective: To assess the association and familial coaggregation between early-onset type 2 diabetes (diagnosed before age 45 years) and mood, anxiety, and stress-related disorders and estimate the contribution of genetic and environmental factors to their co-occurrence. Research design and methods: This population-based cohort study included ind...

Objective: Identifying biomarkers associated with response to electroconvulsive therapy (ECT) may aid clinical decisions. The authors examined whether greater polygenic liabilities for major depressive disorder, bipolar disorder, and schizophrenia are associated with improvement following ECT for a major depressive episode. Methods: Between 2013...

The pathophysiology of bipolar disorder remains to be elucidated and there are no diagnostic or prognostic biomarkers for the condition. In this explorative proteomic study, we analyzed 201 proteins in cerebrospinal fluid (CSF) from mood stable bipolar disorder patients and control subjects sampled from two independent cohorts, amounting to a total...

Among individuals with eating disorders (ED), those with co-occurring autism are often considered to have more severe presentations and poorer prognosis. However, previous findings have been contradictory and limited by small sample size and/or cross-sectional assessment of autistic traits. We examine the hypothesis that autism diagnosis and autism...

Mounting evidence indicates mitochondrial dysfunction in bipolar disorder pathophysiology. Here, we employed Proton Nuclear Magnetic Resonance Spectroscopy (¹H NMR) of cerebrospinal fluid (CSF) samples from well-characterized bipolar disorder patients (n = 67) and healthy controls (n = 55) in order to measure absolute concentrations of multiple met...

Importance: Knowledge of the effectiveness of electroconvulsive therapy (ECT) in the treatment of manic episodes is based on clinical experience, but empirical evidence is scarce. Moreover, prognostic factors associated with response to ECT in patients with mania are poorly understood. Objective: To investigate the response to ECT in patients wi...

Suicide is a major cause of death worldwide. Several biological systems have been implicated in suicidal behavior but studies of candidate biomarkers have failed to produce clinically relevant biomarkers for suicide prediction. The objective of the present study was to identify novel candidate biomarkers for suicidal behavior. We used a nested case...

Anorexia nervosa (AN) is one of the most lethal psychiatric disorders, and to date, we lack adequate knowledge about the (neuro)biological mechanisms of the disorder to inform evidence-based pharmacological treatment. Gut dysbiosis is a trending topic in mental health, including AN. Communication between the gut microbiota and the brain is partly m...