【Review】Depression treatment moves towards precision medicine, and immune targeted therapy "comorbid depression"

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Author: Wang Shu

The relationship between immune disorders and major depressive disorder (MDD) crosses the "fault line" of the traditional diagnostic classification of depression
.
One side of the "fault line" is the diagnosis of depression
according to traditional methods.
If the patient has other causes that explain the phenotype of depression, they are not diagnosed as depressed
.
On the other side of the line is a large group of people exhibiting severe depressive symptoms in the setting of a primary immune disorder, such as rheumatoid arthritis, Crohn's disease, or systemic lupus erythematosus
.
These patients cannot be diagnosed with depression, only as "comorbid depression.
"

"Comorbid depression" does not conform to traditional diagnostics because a disturbance of the immune system can lead to depression (associated with clinical inflammation) and do not respond to conventional antidepressants
.
But immunomodulators can improve the efficacy
of antidepressants in these patients.
For example, patients with depression who are accompanied by elevated pro-inflammatory biomarkers do not respond to traditional antidepressants, but new immune-based therapies may solve this problem
.
Thus, defining a class of depressive groups with specific representations (inflammation-depressive comorbidities) can increase the rate of treatment response in that population: a major advance
in clinical psychiatry.

On January 17, 2022, Husseini K.
Manji, head of neuroscience research and development at Johnson & Johnson in the United States, published an article in the journal Nature Reviews Drug Discovery that outlines the development of drugs for the diagnosis and treatment of this new patient group in depression (comorbid depression) and reviews the current state
of neuroimmune drug development for the treatment of mood disorders.

1

The causal relationship between immune disorders and depression

A large number of studies have shown that immune disorders and depression are correlated: elevated levels of pro-inflammatory cytokines and proteins in the blood and cerebrospinal fluid (CSF) in patients with MDD, weakened adaptive immune responses, changes in relative abundance of specific immune cell types, bias towards autoimmunity, increased microglia activation, and other immune changes
.

Figure 1: Increased pro-inflammatory cytokines in major depression

Immune activation can increase the incidence of depressive symptoms in the short to medium term: about one-third of patients with hepatitis who receive treatment with the pro-inflammatory cytokine interferon-α (IFNα) develop major depressive symptoms
after 4-48 weeks.
In many patients who develop major depressive episodes after IFNα treatment, taking SSRI antidepressants may improve these depressive symptoms
.
In addition, injections of the typhoid vaccine increase IL-6 levels in the blood and cause transient symptoms
of depression or anxiety within 24-48 hours.

Genetic evidence of a causal relationship between immune-associated genes and depression: Pathway analysis of 44 single nucleotide polymorphisms (SNPs) in the genome-wide association study (GWAS) gene table in patients with depression showed enrichment
of 19 pathways, including cytokines and immune response pathways.
Many genetic variants significantly associated with MDD are located in noncoding regions of the genome and are enriched
at epigenetic activity regulatory sites in fetal and adult brain tissue and peripheral blood lymphoid cells.

Although emerging genetic research data supports the hypothesis that immune disorders lead to the onset of depression, no clear evidence
of causation has been found.

2

Immunity - Targets the criteria for precise treatment of depression

To successfully develop an immune-targeted compound for the treatment of major depressive disorder, several criteria must be met: (1) causality: The link between immune dysfunction and depression must be causal or contributing factors
to the onset of depressive symptoms.
(2) Targeting: The upstream or downstream molecules in the immune pathway must be targetable and can be intervened
by peripheral or central administration.
(3) Diagnosability: There must be a definite indicator that can screen out patients with specific inflammatory-depressive comorbidities to treat them specifically, and the final diagnostic method must be generalizable, affordable and usable
.
(4) Traditional conventional treatment cannot achieve results: When comparing and analyzing patients who meet or do not meet treatment criteria, the selected group of depressed patients must not achieve therapeutic effects
according to conventional treatment.

3

Diagnosis of depression

1) Biomarkers with diagnostic potential

Some immunolabels can be used to distinguish between depressed and non-depressed patients and to quantify the level
of immune disorders.
These markers include CRP (highly sensitive C-reactive protein), cytokine levels, quantitative PCR levels of genome-wide gene expression and specific mRNAs, in vitro LPS-stimulated cytokine or gene expression levels, and quantitative immune cell counts
.
For example, in patients with depression, the expression of congenital immunity-related genes is up-regulated, while the expression of genes related to adaptive immunity is down-regulated
.

Patients with current depression who are resistant to drugs or who are depressive without medication can distinguish between healthy controls and those who have been relieved during treatment through mRNA transcripts
.
These characteristics reflect inflammatory body activation and glucocorticoid resistance
.
In addition, the expression characteristics of six mRNAs (P2RX7, IL1B, IL6, TNF, CXCL12, and GR) can distinguish antidepressant-resistant patients from those who respond to antidepressants: elevated levels of IL1B, IL6, TNF, and FKBP5 mRNA in patients with drug-resistant depression, and decreased
levels of GR mRNA.

Figure 2: Multiple immunolabels associated with major depressive disorder

In addition to changes in protein and gene levels, patients with depression were found to have a higher number of white blood cells, a higher number of neutrophils, fewer T lymphocytes or B lymphocytes, an increase in the neutrophil/lymphocyte ratio, and an increase in the CD4+/CD8+ T cell ratio
.

2) Phenotypes with diagnostic potential

Although there are no clear criteria to optimize patients with depression who choose immuno-targeted therapy, some depression phenotypes are significant
in patients with elevated inflammatory markers.
Studies have found that inflammation may have a specific effect on
cognitive processes such as loss of pleasure and reward stimulation.
Informatic, clinical, and imaging studies have shown a link
between haelopathy, depression, and the function of dopaminergic circuits at the midbrain margin.

Figure 3: Neuroimaging biomarkers of inflammation

Inflammatory cytokines have been shown to have a direct effect on midbrain limbic dopamine transmission, which is associated
with a reduced willingness to work toward a reward and a reduced ability to learn for rewards.
This effect, at least to some extent, involves a reduction in dopamine precursors, as neuroimaging and in vivo microdialysis studies of human or non-human primates have shown that inflammatory cytokines such as IFNα reduce the release of dopamine in the ventral striatum and are associated
with depressive symptoms including euphoria and psychomotor slowdown.
In non-human primate models, this effect can be reversed
by the dopamine prodrug levodopa.

4

Antidepressant-immuno-targeted drugs

Few studies have tested the antidepressant effects
of immunomodulatory drugs in patients with depression or bipolar disorder.
Existing studies have focused on immunomodulatory drugs to improve the depressive symptoms complicated by patients with primary immune disorders or to affect immune processes
associated with synaptic function in preclinical models.

For example, some cytokines — including TNF, IL-6, and IL-1β — are considered "neuroactive" because they can modulate synaptic plasticity (such as neurogenesis or dendritic remodeling, and/or mediate neuron-glial interactions
).
Several clinical trials targeting mood disorders have evaluated the potential antidepressant effects
of small molecule drugs that target molecules that interact with cytokines.
The most commonly used drugs are nonsteroidal anti-inflammatory drugs (NSAIDs
).

Figure 4: Antidepressant effects of immunomodulatory drugs

Drugs evaluated to date include: monoclonal antibodies that neutralize cytokines or cytokine receptors, compounds that regulate cytokine-inducing molecules (e.
g.
, cyclooxygenase, prostaglandins, kynureine metabolites), and molecules
that affect cytokine-induced production, maturation, processing, release, and downstream signaling.

One small molecule drug that has been tested for potential antidepressant effects that penetrates the brain is Minocycline (tetracycline
).
Minocycline regulates immune function
by inhibiting the activation, migration and/or proliferation of T cells, neutrophils and microglia, inhibiting the release of pro-inflammatory cytokines and increasing the release of anti-inflammatory and anti-apoptotic molecules.
In addition, minocycline indirectly reduces the pro-inflammatory activation of the Kineurenine pathway by reducing the expression of cytokines produced in the pro-inflammatory response, thereby reducing the release
of the cynorenine metabolite.

Figure 5: Immuno-targeted therapy for major depression and its mechanism of action

summary

Immune mechanisms play an important role in the pathophysiology of depressive symptoms in a specific group of patients with major depression and provide clues to the development of new therapeutic methods and personalized medical methods in neuropsychiatry, with the ultimate goal of improving the therapeutic outcomes
of patients with depression.

Immune mechanisms are promising targets: chronic inflammation is not unique to MDD and has pathophysiological effects
in some other psychiatric disorders (such as schizophrenia) as well as neurodegenerative diseases.

【References】

1.
Drevets, W.
C.
, Wittenberg, G.
M.
, Bullmore, E.
T.
 et al.
 Immune targets for therapeutic development in depression: towards precision medicine.
 Nat Rev Drug Discov 21, 224–244 (2022).

https://doi.
org/10.
1038/s41573-021-00368-1

The images in the article are from references