Understanding the Neurobiological and Psychological Aspects

Major depression is a complex condition that intertwines neurobiological and psychological elements. Various viruses can infiltrate and disrupt the brain's neurobiological mechanisms, which may lead to this debilitating disorder.

As one of the predominant causes of disability and suicide globally, major depression—officially termed major depressive disorder (MDD)—is a profoundly challenging illness. It is characterized by symptoms severe enough to hinder daily functioning, distinguishing it from mere sadness or the casual use of the term "depression." Factors contributing to MDD include lifestyle choices, genetics, and environmental influences, which encompass viral infections capable of affecting brain health.

In this discussion, I will delve into four herpesviruses implicated in major depression based on existing literature. Notably, herpesviruses can enter a dormant state within certain body cells post-infection, allowing them to reactivate later, particularly in response to stress.

Due to the generally low quality of many studies—often limited by small sample sizes and numerous unaccounted confounding variables—I will focus on those studies that exhibit adequate quality and relevance.

Section 1.1: Varicella-Zoster Virus (VZV; Human Herpesvirus-3)

More than 90% of children contract VZV, which may manifest as chickenpox (varicella) or remain asymptomatic. Once infected, VZV remains dormant in peripheral sensory neurons and can reactivate years later to cause shingles (zoster). Emerging evidence suggests that VZV reactivation has broader health implications beyond shingles alone.

A 2014 longitudinal study conducted in Taiwan tracked one million individuals, excluding those with prior psychiatric conditions. The study identified 1,888 cases of herpes zoster, matched with 7,552 uninfected individuals. The results revealed that those with herpes zoster had a higher incidence of major depression (2.2% vs. 1.4%) and any depressive disorder (4.3% vs. 3.2%). These differences were statistically significant, indicating a 49% and 32% increased risk for major depression and any depressive disorder, respectively, after adjusting for confounding factors (e.g., age, sex, income).

The authors postulated that these findings might relate to impaired VZV immunity, as previous studies indicated lower VZV-specific T-cell immunity in individuals experiencing major depression. Poorly managed VZV or shingles can damage nerve cells and lead to chronic pain conditions such as postherpetic neuralgia. Additionally, VZV's ability to infect neurons can trigger inflammatory responses in the brain, contributing to neuroinflammation linked to major depression.

[What is Depression? - Helen M. Farrell - YouTube]

This video explores the nature of depression, its symptoms, and its impact on individuals’ lives.

Section 1.2: Epstein-Barr Virus (EBV; Human Herpesvirus-4)

EBV has infected over 90% of the global population, primarily during childhood through oral transmission. The initial infection may lead to common childhood illness symptoms or may be asymptomatic. EBV establishes a lifelong latent presence in B-cells, with potential for reactivation.

A 2021 study in Denmark monitored 1,440,590 individuals born between 1977 and 2005 until 2016, identifying 12,510 cases of infectious mononucleosis. Those with EBV infections faced a 40% increased risk of major depression later in life, with adjusted risks of 45% for females and 28% for males. This risk persisted even five years post-infection, confirming EBV's role as an independent risk factor for major depression.

Although prior research has suggested a correlation between EBV and major depression, these studies typically had small sample sizes. The 2021 study stands out as the first large-scale investigation providing robust evidence of EBV's association with major depression.

The exact mechanism by which EBV contributes to major depression remains unclear, but it is believed to involve immune dysfunction. EBV's ability to activate B-cells to produce auto-reactive antibodies that attack the neuronal myelin sheath may also play a role in the pathophysiology of major depression.

Section 1.3: Cytomegalovirus (CMV; Human Herpesvirus-5)

Approximately 80% of the population is infected with CMV, which remains latent in myeloid immune cells for life. In individuals with a healthy immune system, CMV often causes mild symptoms, but it can lead to severe complications in immunocompromised individuals.

Recent studies suggest that CMV may also independently increase the risk of major depression. A 2017 longitudinal study involving 771 elderly Latinos indicated that those seropositive for CMV had a 38% increased risk of major depression compared to seronegative individuals. Notably, the association was significant only in women, indicating a 70% increased risk.

Similar findings have emerged from previous research, highlighting a correlation between higher CMV antibody levels and mental health issues, including depression. A 2021 brain imaging study revealed that individuals with major depression and CMV showed reduced gray matter volume and neural connectivity in regions involved in emotional regulation.

[Using Your Nervous System to Enhance Your Immune System - YouTube]

This video discusses the interplay between the nervous and immune systems, offering insights on how to optimize immune function.

Section 1.4: Human Herpesvirus 6 (HHV-6)

HHV-6 is nearly ubiquitous, with most people exposed early in life, typically through maternal saliva. Most infections are asymptomatic, though some may present with mild fever and rash. Following infection, HHV-6 can remain latent in B-cells and T-cells, with potential for reactivation leading to encephalitis in vulnerable individuals.

A 2018 German study analyzed post-mortem brain samples from individuals with schizophrenia, bipolar depression, and major depression. The results indicated a higher prevalence of HHV-6-specific DNA in the brains of individuals with major depression (67%) compared to non-psychiatric controls (4%), suggesting a significant association.

Despite these findings, no longitudinal studies have directly linked HHV-6 reactivation to increased major depression risk. While the evidence indicates a higher prevalence of HHV-6 in those with major depression, the causal relationship remains to be established.

Viral Etiology and Major Depression

Beyond herpesviruses, various other viral infections, including Borna disease virus, human T-cell lymphotropic virus, and influenza, have also been associated with major depression. The microbial hypothesis of mental illness posits that a combination of viral infections and individual immune responses may significantly contribute to the development of major depression.

Understanding the interplay between viral infections and neurological health is crucial. While current technology cannot track viral reactivations in live subjects, ensuring a robust immune system may help mitigate the risks associated with viral exposure.

In conclusion, major depression is a multifaceted illness influenced by both biological and psychological factors. It is essential to approach the treatment of major depression holistically, without stigmatization, recognizing the role of infectious agents in mental health.

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