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FEATURE
Breaking the Barrier: Exploring the Blood–Brain Barrier’s Connection to Depression
ALYSSA CAI, Harvard College '27
THURJ Volume 14 | Issue 2
The Depression Epidemic
Fig. 1. Past-year depression trends in Americans from 2015–2020 (Goodwin et al., 2022)
Today, mental health difficulties are more prevalent than ever, with approximately 300 million people suffering from depression worldwide. Moreover, the World Health Organization predicts that depression will surpass ischemic heart disease—the most common cardiovascular disease that restricts blood flow—to become the most prevalent disease by 2030 (Moukaddam & Tucci, 2017).
Depression is a multifaceted disease, and it is evident that unipolar depression, the most common form of depression, is not the only psychiatric condition reaching epidemic proportions. Unipolar depression occurs when an individual solely experiences depressive episodes; by comparison, bipolar depression occurs when an individual experiences both manic (characterized by elated and energized behavior) and depressive (characterized by sad and hopeless behavior) episodes ("Bipolar Disorder," n.d.). An estimated 60 million people worldwide suffer from bipolar depression, and an additional 21 million people suffer from schizophrenia. The mental health epidemic has had significant consequences, as hospitals, outpatient care, and community outreach centers are unable to accommodate the high patient demand for psychiatric care. Medical centers have overstretched services, underfunded patient care, and overwhelmed staff members due to an influx of patients in need of mental health support. The impact on the healthcare sector is only a portion of the problem; the economic costs of mental health have drastically risen over the years, indicating that mental health issues are on the rise and are more costly than ever. Unipolar depression and related conditions in the United States cost around $83.1 billion in 2000 and $280 billion in 2020 (Moukaddam & Tucci, 2017; "Reducing the Economic Burden of Unmet Mental Health Needs," 2022). The toll of depression has also induced high rates of burnout amongst both patients and healthcare providers alike, resulting in losses of enthusiasm, overall cynicism, and low senses of accomplishment (Moukaddam & Tucci, 2017).
Beyond their direct impacts on individuals worldwide, depression and similar psychiatric disorders are associated with a slew of other physical ailments. Depression, especially in people of older ages, can result from other serious medical illnesses such as diabetes, cancer, heart disease, and Parkinson’s disease ("Depression," n.d.). Depression is also predictive of subsequent myocardial infarction (heart attack), exacerbates existing cardiovascular disease, and increases mortality following myocardial infarction ("Depression," n.d.).
Because of the physical, economic, and social impacts of depression, as well as the urgency that results from the rising depression diagnoses, there is a paramount need to understand more about depression and mental health. Between 2004 and 2019, nearly 36,500 depression-related research papers were included in the Web of Science Core Collection database, and a total of 157 countries and territories conducted research on depression (Wang et al., 2021). This breadth of research indicates that depression is receiving attention from many regions around the world, a recognition of the issue’s severity. However, depression is a complicated disease that requires a nuanced understanding of behavioral, social, physical, and biological phenomena, making it challenging to characterize from any one perspective. Many people attribute depression to a primarily social problem, with the cognitive theory of depression positing that people’s negative appraisal of their life events makes them more susceptible to the development and recurrence of depressive episodes (Joormann & Gotlib, 2010). By comparison, the hopelessness theory of depression suggests that combinations of negative cognitive styles and negative life events create a sense of hopelessness in patients and is thereby sufficient by itself to bring about the disease (Cheek et al., 2015). Recently, more research into the physiological components of depression revealed that the blood–brain barrier (BBB), an important structure in the brain, could play a prominent role in depressive disorders, dispelling theories that focus solely on the psycho-social components of depression.
What is the Blood–Brain Barrier?
The BBB is a semipermeable membrane that allows cerebral blood vessels to regulate the passage of molecules into the brain, which is critical for maintaining the brain’s healthy function. To create the strongest defense against outside forces, the BBB is composed of endothelial cells, pericytes, capillary basement membrane, and astrocyte end-feet. (Dotiwala et al., 2023). Endothelial cells form the innermost layer of blood vessels in the brain and play a central role in the BBB. Peripheral endothelial cells, which are found outside of the brain, are transcellularly permeable, resulting in “high rates of caveolin-mediated transcytosis, diaphragm-containing pores termed fenestrae, or large discontinuities or gaps in the endothelial layer” (Aird, 2007). By comparison, the endothelial cells lining blood vessels in the brain are particularly tightly packed together, preventing the free movement of molecules past the cells. These cerebral endothelial cells lack fenestrations and exhibit low rates of transcytosis—properties that greatly limit transcellular permeability—which is critical for their barrier function. Additionally, the endothelial cells found in the brain have tight junctions between them, which are protein complexes that connect adjacent cells and create a seal that further restricts the passage of substances (Sandoval & Witt, 2008). These junctions act as molecular gates, selectively permitting the entry of necessary nutrients like glucose and amino acids to the brain while simultaneously blocking the passage of potentially harmful substances such as pathogens and toxins. Astrocytes—star-shaped cells that surround blood vessels in the brain—contribute to BBB function by releasing signaling molecules that help regulate endothelial cells and maintain the integrity of tight junctions. (Kubotera et al., 2019). Together, these components result in the cohesive structure of the BBB, united to provide the brain with a strong defense against any potentially harmful molecules or pathogens. Because of the BBB’s important role in regulating the ions and molecules that enter the brain, the breakdown or disruption of function in the BBB results in a multitude of health issues: BBB breakdown contributes to the pathology of neurological conditions such as multiple sclerosis and has also been associated with neurodegenerative disorders such as Alzheimer’s (Profaci et al., 2020). For example, the dysfunction of just one transporter in the BBB, the MCT8 thyroid hormone transport, can result in psychomotor retardation syndromes (Vatine et al., 2017). Additionally, the degradation or dysfunction of the BBB can lead to nonspecific leakage of molecules to and from the brain, often leading to detrimental effects (Horowitz et al., 1992; Cornford et al., 1998).
Fig. 2. A diagram of the components and layers of the BBB (D'Agata et al., 2017)
Depression’s Link to the Blood–Brain Barrier
Fig. 3. Image of compromised BBB in cases of Depression (Medina-Rodriguez & Beurel, 2022)
As more investigation is conducted on the BBB and its connection to various neurological conditions, novel information about its relationship with depression has emerged. Recent research has shown that disruption of the BBB is associated with Major Depressive Disorder (MDD). Using dynamic nuclear imaging, investigators measured the functionality of endothelial cells in MDD patients using the relative uptake ratio (RUR) of blood flow in the brachial artery after hyperemic challenge (Medina-Rodriguez & Beurel, 2022). They found that MDD patients exhibit lower RUR than healthy controls, with a low RUR indicating poorer endothelial functioning. Interestingly, the serum—the non-clotting liquid component of the blood—of MDD patients has also been found to promote apoptosis of endothelial cells in vitro when compared to the serum of patients without depression. Together, these results indicate that reduced endothelial function in MDD patients may be partially due to factors in their blood reducing the function or inducing apoptosis of endothelial cells (Politi et al., 2007). To further elucidate the relationship between the BBB and depression, researchers have investigated mouse models of MDD. Mice subjected to chronic social defeat stress—intended to simulate the effects of MDD—were found to have reduced expression of Claudin-5, a highly enriched tight junction protein vital to the physical barrier properties of the BBB (Green et al., 2019). Stress-susceptible mice also exhibited abnormal blood vessel morphology in the nucleus accumbens—the part of the brain that controls motivation and action— and suffered cerebrovascular microbleeds, both of which are indicative of vascular pathology after stress (Menard et al., 2017; Lehmann et al., 2020). Finally, vascular endothelial growth factor (VEGF) was implicated in promoting paracellular (the passage of molecules between adjacent epithelial cells) and transcellular (the translocation of molecules through the cells) barrier function (Park-Windhol & D'Amore, 2016). Unsurprisingly, increased VEGF levels were associated with BBB disruption, and this disruption was linked to depressive-like behaviors, thus demonstrating another potential link between BBB and MDD (Matsuno et al., 2022).
Implications of Research and Future Applications
It may seem evident that, given the association between BBB disruption and depression, novel depression therapies should seek to restore BBB function. However, targeting BBB permeability for therapeutic interventions presents a significant paradox. On one side, there has been a longstanding pursuit of increasing BBB permeability as a key goal to combat brain-related diseases, thereby allowing drugs to penetrate the brain. Thus, it has been hypothesized that increasing BBB permeability could enhance conventional antidepressant effects for MDD patients. However, the restoration of BBB integrity through the reduction of harmful inflammation alone has also shown efficacy in producing antidepressant effects. For example, blocking inflammatory molecules such as tumor necrosis factors or IL-6 results in a restoration of BBB integrity and the reversal of depressive-like behaviors in mice (Cheng et al., 2017; Menard et al., 2017; Li et al., 2019). Understanding this phenomenon of BBB permeability complicates the therapeutic realm, providing two opposing paths forward in the treatment of diseases such as MDD. However, this understanding also provides broader insight into why current therapies lack the efficacy patients need, motivating future research seeking to understand and harness the BBB. By doing so, investigators can produce therapeutics and treatment methods that may improve the psychiatric conditions of people currently suffering from depression worldwide.
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