Multiple biomarkers of depression involved in several brain circuits are altered in patients with unipolar depression.
The first comprehensive meta-analysis of all biomarkers quantified to date in cerebrospinal fluid (CSF) of individuals with unipolar depression showed that several could be “clinically meaningful” because they suggest neuroimmunological alterations, disturbances in the blood-brain barrier, hyperactivity in the hypothalamic-pituitary-adrenal (HPA) axis, and impaired neuroplasticity as factors in depression pathophysiology.
However, said study investigator Michael E. Benros, MD, PhD, professor and head of research at Mental Health Centre Copenhagen and University of Copenhagen, Denmark, this is on a group level. “So in order to be relevant in a clinical context, the results need to be validated by further high-quality studies identifying subgroups with different biological underpinnings,” he told Medscape Medical News.
Identification of potential subgroups of depression with different biomarkers might help explain the diverse symptomatology and variability in treatment response observed in patients with depression, he noted.
The study was published online April 20 in JAMA Psychiatry.
Multiple Pathways to Depression
The systematic review and meta-analysis included 97 studies investigating 165 CSF biomarkers.
Of the 42 biomarkers investigated in at least two studies, patients with unipolar depression had higher CSF levels of interleukin 6, a marker of chronic inflammation; total protein, which signals blood-brain barrier dysfunction and increased permeability; and cortisol, which is linked to psychological stress, compared with healthy controls.
Depression was also associated with:
lower CSF levels of homovanillic acid, the major terminal metabolite of dopamine
gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the CNS thought to play a vital role in the control of stress and depression
somatostatin, a neuropeptide often coexpressed with GABA
brain-derived neurotrophic factor (BDNF), a protein involved in neurogenesis, synaptic plasticity, and neurotransmission
amyloid-β 40, implicated in Alzheimer’s disease
transthyretin, involved in transport of thyroxine across the blood-brain barrier
Collectively, the findings point toward a “dysregulated dopaminergic system, a compromised inhibitory system, HPA axis hyperactivity, increased neuroinflammation and blood-brain barrier permeability, and impaired neuroplasticity as important factors in depression pathophysiology,” the investigators write.
“It is notable that we did not find significant difference in the metabolite levels of serotonin and noradrenalin, which are the most targeted neurotransmitters in modern antidepressant treatment,” said Benros.
However, this could be explained by substantial heterogeneity between studies and the fact that quantification of total CSF biomarker concentrations does not reflect local alteration within the brain, he explained.
Many of the studies had small cohorts and most quantified only a few biomarkers, making it hard to examine potential interactions between biomarkers or identify specific phenotypes of depression.
“Novel high-quality studies including larger cohorts with an integrative approach and extensive numbers of biomarkers are needed to validate these potential biomarkers of depression and set the stage for the development of more effective and precise treatments,” the researchers note.
Which Ones Hold Water?
Reached for comment, Dean MacKinnon, MD, associate professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine, Baltimore, Maryland, noted that this analysis “extracts the vast amount of knowledge” gained from different studies on biomarkers in the CSF for depression.
“They were able to identify 97 papers that have enough information in them that they could sort of lump them together and see which ones still hold water. It’s always useful to be able to look at patterns in the research and see if you can find some consistent trends,” he told Medscape Medical News.
MacKinnon, who was not part of the research team, also noted that “nonreplicability” is a problem in psychiatry and psychology research, “so being able to show that at least some studies were sufficiently well done, to get a good result, and that they could be replicated in at least one other good study is useful information.”
When it comes to depression, MacKinnon said, “We just don’t know enough to really pin down a physiologic pathway to explain it. The fact that some people seem to have high cortisol and some people seem to have high permeability of blood-brain barrier, and others have abnormalities in dopamine, is interesting and suggests that depression is likely not a unitary disease with a single cause.”
He cautioned, however, that the findings don’t have immediate clinical implications for individual patients with depression.
“Theoretically, down the road, if you extrapolate from what they found, and if it’s truly the case that this research maps to something that could suggest a different clinical approach, you might be able to determine whether one patient might respond better to an SSRI or an SNRI or something like that,” MacKinnon said.
The study was funded by unrestricted grants from the Lundbeck Foundation. Benros reported grants from Lundbeck Foundation during the conduct of the study. MacKinnon has disclosed no relevant financial relationships.
JAMA Psychiatry. Published online April 20, 2022. Abstract
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