Influence of SARS-CoV-2 virus on bipolar disorder


Researchers have found that disorders in COVID-19 showing the greatest similarity to those in BD are cytokine disorders, tryptophan metabolism, sleep disorders and structural changes in the central nervous system (CNS).

These changes, especially intensified in severe infections, may be a trigger for the development of BD in particularly vulnerable people, e.g., with family history, or cause an acute episode in patients with a pre-existing BD.

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In our study, we collected the previously reported cases of (hypo)mania that occurred in patients after infection with the SARS-CoV-2 virus, both in those who had never been treated for psychiatric diseases and in those with a psychiatric history [Table 1].

These descriptions are in many cases inconsistent, differ in the manner of examination and diagnostics, and access to all data is impossible.

Therefore, it is difficult to talk about a reliable analysis of all the factors that could have caused a manic episode in the patients we collected. Nevertheless, we decided that the mere appearance of them shortly after infection with SARS-CoV-2 is a sufficient reason to analyze the similarities between the disorders caused by the infection and those that are present in patients with BD in order to assess whether SARS -CoV-2 may be a risk factor for developing this disorder. We consider this particularly important given the debilitating and progressive nature of BD and the still not fully understood effects of SARS-CoV-2.

We have divided the disorders of homeostasis that occur in patients with BD and its recognized risk factors into:

  • (a) cytokine and inflammatory disorders,
  • (b) use of corticosteroids, (c) HPA axis disorders,
  • (d) sleep disorders,
  • (e) BDNF deficiency,
  • (f) hyperactivity of the kynurenine pathway,
  • (g) structural changes in the CNS,
  • (h) neurotransmission disorders,
  • (i) oxidative stress.

These factors create a complex system in which most of them interact with each other, creating a self-reinforcing cycle that results, as we argue, in the development of affective disorders—including BD.

Our observation shows that SARS-CoV-2 infection affects most of the above-mentioned factors with varying severity. In our opinion, the most visible disorder that occurs in SARS-CoV-2 and that may affect the development of BD in patients is systemic inflammation and cytokine storm.

In the case of SARS-CoV-2, an increase in the concentration of inflammatory cytokines such as IL-1β, IL-2, IL-6, IL-7 and TNF-α comes to the fore, along with the rise in IL-4 and IL-10 concentrations in a later stage of infection [70,72,74,75].

Thus, Th1 activation occurs, followed by Th2 activation. A similar cytokine profile is found among BD patients. They also have an increase in the concentration of inflammatory cytokines, and some researchers also note the activation of Th2 and an increase in the concentration of anti-inflammatory IL-4, IL-5 and IL-10 in patients in the manic phase [63,65,67,81].

Although the exact meaning and mechanism of the influence of anti-inflammatory cytokines on the development of manic symptoms has not been studied, this similarity between SARS-CoV-2 and BD may be significant. As far as inflammatory cytokines are concerned, they cause a decrease in synaptic activity, hippocampal neurogenesis, degeneration of limbic structures and disturbances in neural signaling, in addition, they influence the activation of the kynurenine pathway and the HPA axis, ROS production, CNS structural changes and indirectly affect neurotransmission [51,52,57,58,59].

Another clearly visible disorder in COVID-19 is the activation of the kynurenine pathway through increased activation of IDO under cytokine storm conditions. In addition, the cytokine profile in COVID-19 patients contributes to a stronger activation of the microglial IDO variant, the end products of which are mainly 3-HK and QA [177,179,181].

These are metabolites that cause neurodegeneration, excitotoxicity and ROS generation. BD also increases the production of kynurenine and its metabolites, and in the case of mania it is precisely the high concentration of 3-HK and QA that occur in patients [172,173].

The properties of kynurenine metabolites may contribute to cell death and cell signaling disturbances in brain regions associated with BD in COVID-19 patients. Another disorder that has a strong similarity between SARS-CoV-2 and BD patients is oxidative stress. In both cases, there is an increase in the level of LPO and oxidative and nitrosative damage to proteins and RNA, as well as the depletion of antioxidant systems [269,272,273,287,289].

In patients with BD, this can occur over an extended period of time, while in patients with SARS-CoV-2 the process is quite rapid. The very use of the ACE2 receptor by the virus causes a reduction in systemic antioxidant resources and an increase in ROS production, which increases even after the onset of a cytokine storm [158,283].

This causes damage to the nerve structures, signal transduction pathways and morphometric changes in the brain of patients that can initiate symptoms of BD, especially when these changes occur rapidly as in the case of SARS-CoV-2. Brain disorders in patients with SARS-CoV-2 similar to those in patients with BD and which may influence the development of its symptoms are mainly WM abnormalities.

They may affect signaling pathways between the PFC, FC and LS and cause a subsequent hyperactivation of intact fibers which may result in the characteristic symptoms of BD [201,204,205]. The above-mentioned inflammatory cytokines, kynurenine metabolites and oxidative stress contribute to the development of WM anomalies and disorders of nerve signal transduction.

Another common point of BD and SARS-CoV-2 is sleep disturbance. Not only is insomnia one of the symptoms of mania, but it can also contribute to its development. Sleep disorders, on the other hand, are one of the more common complications of COVID-19 reported by patients.

Their influence on the development of BD symptoms may include the activation of the HPA axis and the induction of the secretion of neurotransmitters such as DA, GABA and GLU [3,135,136,137,138]. Disturbances in neurotransmission are widely described in BD.

In mania, they mainly concern catecholaminergic and glutamatergic hyperactivity as well as GABAergic, cholinergic and serotonergic hypoactivity [212,232,233,246,249].

Changes in neurotransmission in COVID-19 are not well understood and remain hypothetical. There are hypotheses regarding SARS-CoV-2 capabilities to lower dopaminergic, cholinergic, GABAergic and serotonergic transmission, which would result in a picture resembling that of depression, not mania [251,252].

However, when considering the risk of BD, it should be remembered that the depressive phase also belongs to the disease picture. Another factor with no definite answer is BDNF. In BD there is an overall decrease in its level, although there is a theory that the mania state itself is caused by temporary BDNF overactivity, which may be confirmed by the formation of manic symptoms after sleep deprivation followed by a sudden increase in BDNF [143,144,145,146,150].

In COVID-19 there is mainly a decrease in BDNF level, and this may be due to the affinity of SARS-CoV-2 for the ACE2 receptor, which is involved in the BDNF formation pathway [155,156,157,158]. However, in the case of patients who developed “long-COVID”, which also included cognitive disorders, there is a visible increase in its level [160].

We therefore believe that the rapid clinical improvement of patients and the subsequent rapid normalization of BDNF or the temporary overactivity of BDNF resulting from sleep disorders could mediate the development of mania. In the case of the HPA axis, it is also difficult to come to unambiguous conclusions.

The hypothalamic–pituitary–adrenal axis (HPA axis or HTPA axis) is a complex set of direct influences and feedback interactions among three components: the hypothalamus (a part of the brain located below the thalamus), the pituitary gland (a pea-shaped structure located below the hypothalamus), and the adrenal (also called “suprarenal”) glands (small, conical organs on top of the kidneys). These organs and their interactions constitute the HPA axis.

The HPA axis is a major neuroendocrine system[1] that controls reactions to stress and regulates many body processes, including digestion, the immune system, mood and emotions, sexuality, and energy storage and expenditure. It is the common mechanism for interactions among glands, hormones, and parts of the midbrain that mediate the general adaptation syndrome (GAS).[2]

While steroid hormones are produced mainly in vertebrates, the physiological role of the HPA axis and corticosteroids in stress response is so fundamental that analogous systems can be found in invertebrates and monocellular organisms as well.

The HPA axis, hypothalamic–pituitary–gonadal axis (HPG), hypothalamic–pituitary–thyroid axis (HPT), and the hypothalamic–neurohypophyseal system are the four major neuroendocrine systems through which the hypothalamus and pituitary direct neuroendocrine function.[1]

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In BD, especially in the manic phase, hyperactivation of the HPA axis is more visible, especially in people with a short course of the disease [105]. On the other hand, studies in COVID-19 are ambiguous and, in addition to descriptions of hypercortisolemia, there are also reports of hypocortisolemia and AI [110,111,114,115,116].

It cannot be ruled out that in patients who develop an increase in cortisol, it may be associated with an increased risk of mania, especially when there are large diurnal fluctuations in cortisol. The last factor, which is the only external one and is not a disorder caused by SARS-CoV-2, is the effect of treatment with corticosteroids.

Their mania-inducing effect is generally recognized, and the doses and cycle duration recommended for the treatment of COVID-19 coincide with those that pose a high risk of developing manic symptoms [85,86,91,92,98]. In the cases we collected, 38.8% of patients received steroids and we cannot exclude that steroids were the cause of mania in these patients, but in more than 60% they were not included in treatment, which may indicate a different mechanism of mania development [Table 1].

Figure 1. Convergence of disorders caused by SARS-CoV-2 and factors contributing to the development and course of BD/mania. Disorders inside the common part of both circles coincide with each other the most. Disorders outside the common part of the circles are different, inconclusive or inconsistent (explained in the main text). Abbreviations: ↑—increased concentration/activity; ↓—decreased concentration/activity; 3-HK—3-hydroxykynurenine; 5-HT—serotonin; BD—bipolar disorder; BDNF—brain-derived neurotrophic factor; GABA—γ-Aminobutyric acid; HPA—hypothalamic-pituitary-adrenal; IL-1β—interleukin-1β; IL-2—interleukin-2; IL-4—interleukin-4; IL-6—interleukin-6; IL-10—interleukin-10; LPO—lipid peroxidation; QA—quinolinic acid; ROS—reactive oxygen species; TAC—total antioxidant capacity; TNF-α—tumor necrosis factor α; WM—white matter.

As can be seen, many of the disorders caused by SARS-CoV-2 overlap with those found in BD patients [Figure 1]. However, their ability to induce mania or full-blown BD in previously healthy and unburdened individuals may not be as significant. Looking at the statistics, we can see that affective disorders concern from 4 to almost 14%, and newly diagnosed cases account for about 4% of patients [3].

So far, there are no data limited to cases of mania, but assuming that depressive episodes occur much more often, it can be concluded that mania is only a small fraction of the previously mentioned 14 and 4% of patients.

Comparing this with the lifetime risk of BD, assessed from 0.1% to 2.4%, we can see that COVID-19 related mania or BD cases do not go beyond this risk [11]. However, most cases of BD begin with depressive episodes, which are much more common than mania after COVID-19, and a definitive diagnosis of BD may not be made for many years after the first affective episode.

In addition, depressed patients are more susceptible to other risk factors for the development of BD, and SARS-CoV-2 may sensitize patients to those factors and thus contribute to the development of BD. We also believe that the disorders caused by SARS-CoV-2 are so similar to those seen in BD that, even if they are insufficient to trigger an episode in previously healthy individuals, they may be a serious risk factor for relapse in people currently in euthymia or accelerate the onset of the disease in people who are particularly vulnerable to it, e.g., genetically burdened or who have a family history of this disorder.

It is also worth noting that the cases of mania that have been associated with COVID-19 in the literature concern patients whose symptoms appeared up to 3 weeks after the diagnosis of the infection [Table 1].

Additionally, some disorders caused by COVID-19 may last up to several months, and although the appearance of affective symptoms will no longer be associated with SARS-CoV-2, prolonged disorders may contribute to their appearance [201,204].

Clinicians should also pay attention to patients with more severe COVID-19 because most of the changes we have described are proportional to the severity of the coronavirus disease, and more severe lesions increase the risk of developing BD.

In addition, corticosteroid therapy, a recognized risk factor for mania, should be limited to those really requiring it.

In patients with the highest risk of developing an affective episode, e.g., seriously ill patients with BD, currently in euthymia, a control of individual disorders caused by SARS-CoV-2 may be considered, e.g., taking care of patients’ sleep hygiene—melatonin supplementation may prove to be helpful and is sometimes used as a adjunctive treatment in BD [292,293], support of antioxidant systems—in some cases, supplementation with N-acetylcysteine proves to be useful, especially in relation to depressive symptoms BD [294,295].

In patients with severe cytokine storm, the use of tocilizumab may be helpful [296,297], although its effect on the symptoms of BD is inconclusive [298]. In the future, in order to better assess the influence of SARS-CoV-2 on the development of BD, there is a need for prospective studies evaluating the effect of the virus on the systems and factors contributing to the pathogenesis and course of BD, as well as longer observation of patients for the emergence of affective disorders, in particular episodes of mania or hypomania.

Additionally, future research may attempt to consider the association of SARS-CoV-2 with various forms of BD such as rapid cycling, childhood and adolescent BD or unipolar mania, which we did not include in our work due to the current lack of relevant literature.

Corticosteroids (CCSs) have been used to treat a variety of inflammatory conditions as an immunosuppressive medication for decades. However, many CCSs, including prednisone, methylprednisolone, dexamethasone, and adreno corticotropic, have been shown to have adverse psychiatric consequences [1].

Despite being an efficacious and resolute drug for anti-inflammatory reactions, it is also an immunosuppressive medicine; however, its frequent use globally has also led to an increase in mental health issues and concerns [2]. Corticosteroids inhibit the synthesis of inflammatory proteins while increasing the release of anti-inflammatory ones by various signaling pathways such as nuclear factor kappa B (NF—ƙB), mitogen-activated protein kinase (MAP kinase), etc., but while doing so, they cause other concerns such as immunosuppression, osteoporosis, glaucoma, hypertension, growth retardation, etc., [3].

It was further confirmed by Wolkowitz et al. (2009) that increased levels of CCSs, particularly glucocorticoids (GC), induce the occurrence of psychiatric symptoms. It has also been proposed that stress-induced hypothalamic–pituitary–adrenal axis activation accelerates psychosomatic symptoms by altering neurotransmitter levels in cortical regions [4].

Steroid-induced psychiatric symptoms are diverse and range from mild to severe forms involving behavioral, affective, and cognitive regions in the brain [5]. Although the current causative mechanism is not known, there is evidence of significantly reduced immunoreactivity to corticotropin, norepinephrine, and beta-endorphin affecting the hippocampus and amygdala regions of the cerebral cortex [6]. Moreover, to date, there is no registered drug available for the treatment of CCC-induced NPDs.

Psychiatric symptoms brought on by steroids replicate and induce metabolic, neurologic, and cardiovascular complications. In addition to this, steroids induce withdrawal symptoms, mood disorders, paraneoplastic syndrome, bipolar disorder, etc., in affected patients. While NPDs are on the rise globally, due to extrinsic and intrinsic factors, the prospect of an additional patient add-on load due to CCS usage significantly raises the alarm, and is a vexing concern.

Therefore, better and more targeted therapeutic approaches are needed in this direction [7,8,9,10]. In the last two decades, the introduction of genetic medicine, “Gene editing” or “Gene therapy”, has revolutionized the medical field with its fascinating concepts and personalized approaches.

The genetic medicine concept was initiated when oligonucleotide-based therapies provided therapeutic relief for many diverse pathologies (cancer, neuromuscular diseases, hemophilia 1, etc.) [11], followed by adeno-associated virus (AAV) gene transfer to CNS [12] and now the CRISPR/Cas9 approach. The advent of the CRISPR approach is reported to be a targeted therapeutic approach for neuropsychiatric forms such as seizures, autism, and cognitive decline.

The pathological pathways of NPDs are so complicated that they further upset the balance between excitation and inhibition [13] mechanisms and are likely to be of multifactorial descent, encompassing both genetic predisposition and environmental factors [14,15].

Also, many reports suggest a deeper genetic involvement in conditions such as depression, obsessive-compulsive disorders, etc., and in such conditions gene therapy seems to fit perfectly by disrupting the causative genes [16]. As mentioned earlier, the rate of such neuropsychiatric complications is relatively higher in subjects administered CCSs, a synthetic analog of the natural steroidal compounds synthesized by the adrenal cortex in humans [17].

It has been recounted that patients on CCSs for more than 10–14 weeks very frequently exhibit complications of mania (27.8%), psychosis (13.9%), delirium (10.1%), and depression (40.5%) [18]. In such cases, gene therapy can play a pivotal role in better prognosis [19].

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