Severe depression tied to immune system imbalance, not just brain chemistry

Good news! What about lack of sunshine?

"... They found that this immune abnormality affects brain function, and the "Immune Neural Axis" imbalance is the core mechanism of depression, opening up the possibility for the discovery of new biomarkers and the development of new drugs for depression treatment. ...

performed a multi-omics analysis combining blood analysis, single-cell analysis, and patient-derived brain organoids (mini-brains). ..."

From the abstract:

"Major depressive disorder (MDD) with atypical features accompanied by psychotic symptoms represents a severe and under-researched subtype of depression and severe mental illness, characterized by significant personal and social impact.

This study aims to explore novel biomarkers through a precision medicine approach by combining clinical data, white blood cell (WBC) single-cell RNA sequencing (scRNA-seq), plasma proteomics, and brain organoid models to uncover immunological and neurological alterations in patients with this condition. Patients exhibited elevated stress, anxiety, depression, and increased WBC counts, although the difference in WBC count is not significant after adjusting for age.

Plasma proteomic profiling identified an upregulation of proteins implicated in synaptic formation, including Doublecortin-Like Kinase 3 (DCLK3) and Calcyon (CALY), as well as immune-related proteins such as Complement Component 5 (C5).

WBC scRNA-seq revealed significant neutrophil and monocyte transcriptomic alterations, suggesting increased inflammation and immune dysregulation. Patient-derived brain organoids display reduced growth and distinct gene expression patterns compared to controls, particularly under dexamethasone-induced stress conditions.

Combining WBC scRNA-seq, plasma proteomics, and brain organoid models offers a novel framework for understanding the pathophysiology of psychiatric disorders, which is one of the most complex disorders."

Depression tied to immune system imbalance, not just brain chemistry

Depression is Not Only a Disease of the Mind. KAIST Discovers the Immune-Brain Connection​ (original news release)

Exploration of Novel Biomarkers Through a Precision Medicine Approach Using Multi-Omics and Brain Organoids in Patients With Atypical Depression and Psychotic Symptoms (open access)

Figure 2

Differential WBC Single-cell Transcriptomic Profiles in the Patient Group Elevated Inflammatory Gene Expression in Neutrophils and Monocytes

Inflammation during pregnancy may prime offspring for anxiety

Good news! It has been suspected for decades that events during a woman's pregnancy may cause serious disorders etc. affecting her child possibly for the rest of the child's life. 

"Increased risk for anxiety may begin before birth, shaped by infection or stressful events during pregnancy, according to a new preclinical study ...

While scientists have long known that maternal difficulty during pregnancy may raise a child’s risk for psychiatric illness, the biological pathways between these prenatal experiences and later mental health have been unclear. ..."

From the highlights and abstract:

"Highlights

• Adverse gestational environment is a risk factor for psychiatric disorders

• Gestational adversity has variable neuronal transcriptomic effects

• The most affected hippocampal neurons are activated in a stressful environment

• Higher neuronal activity during transition from safe to threatening environment

Summary

An adverse gestational environment is a risk factor for the development of psychiatric disorders. Although studies have implicated modifications in neuronal DNA and chromatin, how these changes come about and lead to abnormal behaviors is not known.

We sought to identify persistent DNA/chromatin and transcriptomic signatures induced by a proinflammatory gestational environment in the ventral dentate gyrus (vDG), a hippocampal region linked to anxiety. 

A proinflammatory environment shifted DNA methylation of enhancers and promoters and altered synapse-related gene expression, resulting in transcriptional heterogeneity in the vDG.

In animals with prior adversity, exposure to a threatening environment recruited vDG neurons with the greatest transcriptional changes, notably in synapse-relevant genes that also tended to be differentially methylated.

Finally, vDG activity was increased during transition from a safe to a threatening environment in animals with prior adversity but not in controls, suggesting their enhanced perception of a potential threat.

Our data outline a proinflammatory gestational environment-induced neurobiological sequence that leads to anxiety."

Inflammation during pregnancy may prime offspring for anxiety | Cornell Chronicle

Adverse gestational environment configures a subpopulation of ventral dentate granule cells for recruitment to drive innate anxiety (open access)

Graphical abstract

Figure 2 An adverse gestational environment preferentially alters methylation at intermediately methylated CGs in vDGCs

Study identifies 55 independent genetic loci that link brain structure and various psychiatric disorders

Good news!

"... Their paper ... pinpoints several genetic loci (i.e., locations on a chromosome where a gene or genetic variant is found) that are linked both to the risk that an individual will develop a psychiatric condition and to specific patterns in the structure of the cortex. ..."

From the abstract:

"Both psychiatric vulnerability and cortical structure are shaped by the cumulative effect of common genetic variants across the genome. However, the shared genetic underpinnings between psychiatric disorders and brain structural phenotypes, such as thickness and surface area of the cerebral cortex, remain elusive.

Here we use pleiotropy-informed conjunctional false discovery rate analysis to investigate shared loci across genome-wide association scans of regional cortical thickness, surface area and eight psychiatric disorders in individuals of European ancestry.

Aggregating regional measures, we identified 55 independent genetic loci shared between psychiatric disorders and surface area, as well as 29 independent genetic loci shared with cortical thickness.

Risk alleles exhibited bidirectional effects on both cortical thickness and surface area, such that some risk alleles for each disorder were associated with increased regional brain size while other risk alleles were associated with decreased regional brain size.

Due to bidirectional effects, in many cases we observed extensive pleiotropy between an imaging phenotype and a psychiatric disorder even in the absence of a significant genetic correlation between them.

The impact of genetic risk for psychiatric disorders on regional brain structure did exhibit a consistent pattern across highly comorbid psychiatric disorders, with 80% of the independent genetic loci shared across multiple disorders displaying consistent directions of effect.

Cortical patterning of genetic overlap revealed a hierarchical genetic architecture, with the association cortex and sensorimotor cortex representing two extremes of shared genetic influence on psychiatric disorders and brain structural variation. Integrating multiscale functional annotations and transcriptomic profiles, we observed that shared genetic loci were enriched in active genomic regions, converged on neurobiological and metabolic pathways and showed differential expression in postmortem brain tissue from individuals with psychiatric disorders. Cumulatively, these findings provide a significant advance in our understanding of the overlapping polygenic architecture between psychopathology and cortical brain structure."

Study identifies genetic loci that link brain structure and various psychiatric disorders

The overlapping genetic architecture of psychiatric disorders and cortical brain structure (no public access)

The overlapping genetic architecture of psychiatric disorders and cortical brain structure (prepint, open access, but it is dated (10/5/2023), not sure whether it was updated to match the journal article)

Figure 1 Shared genetic loci between psychiatric disorders and cortical thickness and surface area measures

New drug evenamide shows promise for schizophrenia

Good news!

"A novel drug, evenamide, quieted overactive brain circuits in an animal model of schizophrenia, improving memory, social interaction, and dopamine balance, offering hope for tackling symptoms that current antipsychotics can’t touch. ...

Schizophrenia causes a mix of positive (delusions, hallucinations), negative (social withdrawal, loss of pleasure) and cognitive (memory, decision-making) symptoms. For some people with schizophrenia, though, existing antipsychotic medications only treat positive symptoms. Still others develop treatment resistance.

A new drug, evenamide, has performed promisingly well in pre-clinical trials using animal models, improving positive, negative, and cognitive symptoms of schizophrenia. ..."

From the abstract:

"Schizophrenia is characterized by positive, negative, and cognitive symptoms. However, current D2-based antipsychotic drugs only address primarily positive symptoms.

Limbic hippocampus hyperexcitability is a key pathological state of schizophrenia, representing an ideal therapeutic target.

Evenamide is a selective voltage-gated sodium channel blocker that reduces neuronal hyperexcitability.

We examined the effect of acute evenamide treatment on the hyperdopaminergic state, hippocampal hyperexcitability, social deficits, and recognition memory in the methylazoxymethanol acetate (MAM) neurodevelopmental model. Male and female Sprague-Dawley offspring from dams treated with saline or MAM on gestational day 17 were tested as adults (postnatal day >65). Electrophysiological recordings were made in the ventral tegmental area (VTA) and ventral hippocampus (vHipp) and social approach and novel object recognition were tested.

Evenamide (3 mg/kg i.p.) normalized the number of spontaneously active DA neurons in the VTA of female and male MAM rats and reduced pyramidal neuron hyperactivity in the vHipp. The hyperdopaminergic state in the VTA of female and male MAM rats was also rescued by local evenamide injection in the vHipp (1 µM).

Systemic evenamide also reversed the recognition memory impairment of female and male MAM rats.

For social deficits, only male MAM rats exhibit a reduced social sniffing time that was normalized by evenamide.

These findings suggest that evenamide’s efficacy in downregulating the hyperdopaminergic state, social deficits, and recognition memory impairment may result from its ability to attenuate vHipp hyperexcitability. Therefore, evenamide could offer a novel therapeutic strategy that is capable of addressing positive, cognitive, and negative symptoms of schizophrenia."

New drug evenamide shows promise for schizophrenia

Evenamide reverses schizophrenia-related dysfunction in a neurodevelopmental animal model (no public access)

Study finds an overlap between genes linked to subjective well-being and psychiatric disorders

Amazing stuff! About the fine line between sanity and madness! Which genes make you happy! 😊

Unfortunately, I was not able to find e.g. an original news release for this study, which is unusual. I suspect, research produced in South Korea is still not very well accessible.

"In psychology, the term subjective well-being (SWB) is used to describe the extent to which different people feel happy and satisfied with their lives. While some studies have found that there is a link between SWB and the diagnosis of some psychiatric disorders, such as depression and anxiety disorders, their possible genetic commonalities have not yet been clearly delineated.

Researchers ... recently carried out a study aimed at better understanding the genes that could contribute to people's feelings of happiness and life satisfaction, as well as their possible connection to psychiatric disorders.

Their findings ... pin-point some brain tissues and genes linked to SWB, suggesting that they might also play a part in the development of psychiatric disorders. ...

For instance, the team found that approximately 93% of the genetic variants linked to depression were also tied to how happy people feel in their everyday lives. ..."

From the abstract:

"Subjective well-being (SWB) is important for understanding human behaviour and health. Although the connection between SWB and psychiatric disorders has been studied, common genetic mechanisms remain unclear. This study aimed to explore the genetic relationship between SWB and psychiatric disorders. Bivariate causal mixture modelling (MiXeR), polygenic risk score (PRS) and Mendelian randomization (MR) analyses showed substantial polygenic overlap and associations between SWB and the psychiatric disorders.

Subsequent replication studies in East Asian populations confirmed the polygenic overlap between schizophrenia and SWB.

The conditional and conjunctional false discovery rate analyses identified additional or shared genetic loci associated with SWB or psychiatric disorders. Functional annotation revealed enrichment of specific brain tissues and genes associated with SWB.

The identified genetic loci showed cross-ancestry transferability between the European and Korean populations. Our findings provide valuable insights into the common genetic mechanisms underlying SWB and psychiatric disorders."

Study finds an overlap between genes linked to subjective well-being and psychiatric disorders

Polygenic overlap between subjective well-being and psychiatric disorders and cross-ancestry validation (no public access)

Scientists uncover 95 regions of the genome linked to PTSD

Good news, but that is a lot of regions!

"... Now, a new genetic study of more than 1.2 million people has pinpointed 95 loci, or locations in the genome, that are associated with risk of developing PTSD, including 80 that had not been previously identified. The study ... is the largest and most diverse of its kind, and also identified 43 genes that appear to have a role in causing PTSD. ..."

From the abstract:

"Post-traumatic stress disorder (PTSD) genetics are characterized by lower discoverability than most other psychiatric disorders. The contribution to biological understanding from previous genetic studies has thus been limited. We performed a multi-ancestry meta-analysis of genome-wide association studies across 1,222,882 individuals of European ancestry (137,136 cases) and 58,051 admixed individuals with African and Native American ancestry (13,624 cases). We identified 95 genome-wide significant loci (80 new). Convergent multi-omic approaches identified 43 potential causal genes, broadly classified as neurotransmitter and ion channel synaptic modulators (for example, GRIA1, GRM8 and CACNA1E), developmental, axon guidance and transcription factors (for example, FOXP2, EFNA5 and DCC), synaptic structure and function genes (for example, PCLO, NCAM1 and PDE4B) and endocrine or immune regulators (for example, ESR1, TRAF3 and TANK). Additional top genes influence stress, immune, fear and threat-related processes, previously hypothesized to underlie PTSD neurobiology. These findings strengthen our understanding of neurobiological systems relevant to PTSD pathophysiology, while also opening new areas for investigation."

Scientists uncover 95 regions of the genome linked to PTSD | Broad Institute Findings from the largest genetic study of PTSD to date could help explain why only some people develop the condition after experiencing trauma.

Genome-wide association analyses identify 95 risk loci and provide insights into the neurobiology of post-traumatic stress disorder (no public access)

A catatonic woman awakened after 20 years. Her story may change psychiatry

Amazing stuff! However, a very long article!

Another intriguing example that often physical factors are behind severe psychiatric disorders.

You may wonder why it took almost 20 years to discover that this catatonic patient had also lupus.

"... [patient] was diagnosed [in 2000?] with a severe form of schizophrenia, an often devastating mental illness that affects approximately 1 percent of the global population and can drastically impair how patients behave and perceive reality. ...

It would be nearly two decades before their paths crossed again. But in 2018, another chance encounter led to several medical discoveries reminiscent ...

[doctors] discovered that although [patient]’s illness was clinically indistinguishable from schizophrenia, she also had lupus, an underlying and treatable autoimmune condition that was attacking her brain.
After months of targeted treatments — and more than two decades trapped in her mind — [patient] woke up. ..."

How autoimmune disease can attack the brain, cause psychiatric symptoms - The Washington Post New research suggests that a subset of patients with psychiatric conditions such as schizophrenia may actually have autoimmune disease that attacks the brain

Credits: Human Progress Weekly Links

Survey of brain cell synaptic junctions shows striking similarities between schizophrenia and bipolar disorder

Good news! Are finally getting closer to better treatments!

"Although bipolar disorder and schizophrenia are diagnosed as distinct psychiatric conditions, both are considerably heritable with molecular roots that are poorly understood. Some people diagnosed with one disorder have symptoms and clinical features in common with the other, supporting the notion that the conditions lie on a spectrum. And human genetics studies have suggested that the junctions between brain cells, known as synapses, play a key role in both conditions. ...
Their analysis revealed changes in synapse proteins that were remarkably similar in the two conditions. In mice with a mutated gene that’s been linked to both conditions, the scientists found that related biochemical pathways were similarly altered. ...

Synaptic surprises

Isolating and purifying synapses from brain tissue samples is no easy task, but that is what the team had to do to analyze the structure’s proteins — its working parts — at a large scale. ...

In the current study, the researchers purified synapses from postmortem tissue from an area of the brain known as the dorsolateral prefrontal cortex, from 35 individuals who had been diagnosed with schizophrenia, 35 people with bipolar disorder, and 35 unaffected individuals. Collaborators in the Proteomics Platform analyzed the purified synapses by mass spectrometry, measuring the abundance of thousands of proteins and protein fragments in an unbiased way. ...

In samples from people with each disorder, the team observed changes in the levels of hundreds of proteins compared to control individuals. Strikingly, more than 200 of these proteins were either enriched or depleted similarly in both conditions. The scientists were surprised by how comparable the patterns of protein changes were between the disorders. ..."

From the highlights and abstract:

"Highlights

• Considerable and similar synapse proteome changes in SCZ and BP

• Core synaptic, mitochondrial, and ribosomal protein networks are reduced in SCZ/BP

• Increase in vesicle tethering-, trafficking- and autophagy-related protein networks

• Similar pathway changes in synapses from patients with SCZ/BP and Akap11-deficient mice

Summary

Synaptic dysfunction is implicated in the pathophysiology of schizophrenia (SCZ) and bipolar disorder (BP). We use quantitative mass spectrometry to carry out deep, unbiased proteomic profiling of synapses purified from the dorsolateral prefrontal cortex of 35 cases of SCZ, 35 cases of BP, and 35 controls. Compared with controls, SCZ and BP synapses show substantial and similar proteomic alterations. Network analyses reveal upregulation of proteins associated with autophagy and certain vesicle transport pathways and downregulation of proteins related to synaptic, mitochondrial, and ribosomal function in the synapses of individuals with SCZ or BP. Some of the same pathways are similarly dysregulated in the synaptic proteome of mutant mice deficient in Akap11, a recently discovered shared risk gene for SCZ and BP. Our work provides biological insights into molecular dysfunction at the synapse in SCZ and BP and serves as a resource for understanding the pathophysiology of these disorders."

Survey of brain cell junctions shows striking similarities between schizophrenia and bipolar disorder | Broad Institute An unbiased protein analysis comparing synapses from people with the disorders uncovers shared patterns.

Deep proteomics identifies shared molecular pathway alterations in synapses of patients with schizophrenia and bipolar disorder and mouse model (open access)

Graphical abstract

Scientists find key brain abnormality that may explain why some people are psychopaths

Are we finally coming closer to objective indicators or marker for psychopathic behavior? How much is inherited or developed during childhood?

Let's keep in mind that most individuals with psychiatric disorders are not dangerous.

"... By looking at the brain scans of the individuals who scored higher on the psychopathy test, the researchers noticed that an area of the forebrain, known as the striatum, was about 10% larger in psychopathic people compared to individuals with low or no psychopathic traits. ...
It’s also the first time that psychopathy was linked to enlarged striatum in both males and females. ..."

From the abstract:

"Prior studies have inconsistently reported increased volumes of the striatum in adults with psychopathy. A meta-analysis presented here indicates an overall effect size of d = 0.44. Nevertheless, variability in findings exist, and questions remain on confounding clinical conditions and generalizability to females. This study tests the hypothesis that striatal volumes are increased in adults with psychopathic traits, and that this relationship is mediated by stimulation-seeking and impulsivity. Striatal volume was assessed using magnetic resonance imaging in 108 adult community-dwelling males alongside psychopathy using the Psychopathy Checklist – Revised. ... Correlational analyses showed that increased striatal volumes were associated with more psychopathic traits (p = .001). Effects were observed for all striatal regions, controlling for age, substance dependence and abuse, antisocial personality disorder, attention deficit hyperactivity disorder, social adversity, and total brain volume. An analysis of 18 psychopathic individuals showed that striatal volumes were increased 9.4% compared with 18 matched controls (p = .01). Psychopathy in females was also significantly associated with increased striatal volume (p = .02). Stimulation-seeking and impulsivity partly mediated the striatal-psychopathy relationship, accounting for 49.4% of this association. Findings from these two samples replicate and build on initial studies indicating striatal enlargement in adults with psychopathy, yielding an updated effect size of d = 0.48. Results are consistent with the notion that striatal abnormalities in individuals with psychopathy partly reflect increased sensation-seeking and impulsivity, and support the hypothesis of abnormal reward processing in psychopathy."

Scientists find key brain abnormality that may explain why some people are psychopaths

Larger striatal volume is associated with increased adult psychopathy (no public access)

Largest study of its kind reveals that many psychiatric disorders arise from common genes

Good news!

"To identify these multi-purpose [pleiotropic] gene variants, the researchers used a technique called genome-wide association to analyze genetic data from 494,162 healthy control subjects and 232,964 people diagnosed with at least one of eight common psychiatric disorders. The analysis identified 109 gene variants that affect the risk for more than one psychiatric disorder.

Certain disorders shared many variants, allowing the researchers to divide the conditions into three groups of genetically-related conditions: disorders characterized by compulsive behaviors (anorexia nervosa, obsessive-compulsive disorder and, to a lesser extent, Tourette syndrome); mood and psychotic disorders (bipolar disorder, major depression and schizophrenia); and early-onset neurodevelopmental disorders (autism spectrum disorder, ADHD and Tourette syndrome). The researchers also found evidence that genes associated with multiple disorders show increased expression beginning in the second trimester of pregnancy and appear to play an important role in brain development"

Largest study of its kind reveals that many psychiatric disorders arise from common genes