Multiple biomarkers of depression involved in several brain circuits are altered in patients with unipolar depression.
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.
Dr. Michael E. Benros
However, said study investigator Michael E. Benros, MD, PhD, professor and head of research at Mental Health Centre Copenhagen and University of Copenhagen, 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 this news organization.
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 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 wrote.
“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 Dr. 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 noted.