The COVID-19 virus has been estimated to have infected over 2 billion people worldwide (Ceban et al., 2022). While the severe acute respiratory syndrome coronavirus 2 is known to cause respiratory disease, it has been attributed to various neuropsychiatric conditions including depressive and anxiety disorders, posttraumatic stress disorder, and even psychosis (Iqbal et al., 2020). Furthermore, symptoms can persist from several weeks to months after the acute infection. Brain fog, a constellation of indistinct neurocognitive symptoms encompassing inattention, mental fatigue, word-finding difficulty, and memory impairment, is common among patients with post-COVID-19 syndrome (also called long COVID-19, long haulers or chronic COVID-19 syndrome) (Theoharides et al., 2021). In one prospective cohort study, it was found that up to 81% of COVID-19 survivors have impairment in at least one cognitive domain after 3 months of being discharged from the hospital (Mazza et al., 2021). In a meta-analysis looking at both hospitalized and nonhospitalized patients, 22 and 32% developed cognitive impairment and chronic fatigue, respectively (Ceban et al., 2022). The mechanisms behind this phenomenon remain unclear but it may be related to functional brain changes in areas like the cingulate cortex, an increase of proinflammatory cytokines like tumor necrosis factor alpha and interleukin-6, and neuroinflammation caused by pathogenic or stress stimuli that activate microglia (Chowdhury et al., 2020; Theoharides et al., 2021; Hugon et al., 2022).
The treatment for post-COVID-19 syndrome generally necessitates a multidisciplinary approach involving symptom monitoring, physical rehabilitation, and social support (Aiyegbusi et al., 2021). Some propose the use of naturally occurring flavonoids like luteolin that may attenuate neuroinflammation by the inhibition of microglia and mast cells, which is one of the causes thought to be behind post-COVID-19 syndrome (Theoharides et al., 2021). Though at this time there is no empirical evidence of its efficacy or reports of it success in COVID-19–induced brain fog. To date, there are no specific pharmacological treatments for COVID-19–induced brain fog. In this report, two patients with COVID-19–related brain fog were treated with bupropion.
Patient is a 26-year-old white male in a committed relationship and employed as a mathematician with no significant psychiatric or medical history. There were no other relevant genetic, substance, or family history. He contracted COVID-19 with symptoms of mild fever, malaise, and parageusia. He had no severe symptoms during his acute COVID-19 infection including hypoxia, chest pain/pressure, or severe shortness of breath that required hospitalization. After recovering from the acute infection, he had difficulty focusing short-term memory impairment inattention and mental exhaustion for the next 4 months for which he sought psychiatric evaluation. He was notably distressed as his job demanded peak mental performance. Although he reported low mood and energy, he did not meet criteria for a psychiatric disorder. It was determined that he had COVID-19–related brain fog with mild associated depressive symptoms. After baseline vital signs were unremarkable, it was agreed to initiate bupropion 150-mg extended release (XL) once daily to target his cognitive symptoms. Over the next 4 months, the dose was titrated to 450-mg XL once daily; his mood rapidly improved but his attention mental energy and focus improved more gradually as the dose was increased over time. He reported no adverse effects.
Patient is a 25-year-old African American single female employed as a nurse with no psychiatric or medical history. She had no other known positive genetic family or psychosocial history. She presented for a psychiatric evaluation with complaints of diminished concentration inability to focus easily distractable poor short-term memory and constant mental fatigue after contracting COVID-19 3 months prior. Her initial COVID-19 symptoms were mild malaise and cough. She had no severe symptoms of an acute COVID-19 infection including hypoxia dyspnea or chest pressure. She had associated symptoms of depression including low-mood hypersomnia and poor motivation however did not meet criteria for another psychiatric condition. After stable vital signs including blood pressure were established, she was started on bupropion 150-mg XL once daily. After 1 month on that dose, her cognitive symptoms that included inattention and memory impairment completely resolved and she felt back to her baseline functioning. The dose was not increased. She reported no adverse effects.
These are the first known cases to describe patients with a positive response to bupropion for COVID-19–related brain fog. In both cases, routine labs (i.e. complete blood cell count chemistries and thyroid function test) were unremarkable. Imaging studies were not done. Both patients were high functioning and without significant medical or psychiatric history. Their symptoms of mental exhaustion difficulty focusing easily distractable inattention and poor short-term memory began after the acute COVID-19 infection making the post-COVID-19 syndrome the most likely culprit.
Bupropion an atypical antidepressant FDA approved for depression and smoking cessation was chosen due to its several unique mechanisms to target the specific symptoms of brain fog. Bupropion and its active metabolite (2S3S)-hydroxybupropion inhibit the reuptake of dopamine and norepinephrine; in addition are noncompetitive antagonists to the nicotinic acetylcholine receptors (Carroll et al., 2014). While this makes it useful as an antidepressant and antismoking agent, it also makes it effective in other disorders like attention-deficit hyperactivity disorder a disorder that has many overlapping symptoms with brain fog (Huecker et al., 2022). A functional MRI study shows hypometabolism in the cingulate cortex in brain fog, which can possibly be mitigated by bupropion’s propensity to increase neural activity in the dorsal anterior cingulate and ventral medial prefrontal cortex (Dean et al., 2016; Hugon et al., 2022). Another potential cognitive domain bupropion may help treat is memory impairment; as it was shown in a rat model to block the loss of hippocampal cell proliferation (Onoue et al., 2014). Bupropion has been shown to reduce the level of proinflammatory cytokines that has been tied with most of the post-COVID neuropsychiatric complications (Wilkes, 2006; Mazza et al., 2021; Theoharides et al., 2021; Ceban et al., 2022).
Limitations of this paper include the intrinsic nature of case reports – lack of control and low sample size. Another limitation was the lack of neurocognitive and psychiatric scales used. The diagnosis was made from a thorough clinical history and obtaining collateral information (i.e. family members prior physicians medical records). Symptoms were monitored and assessed during each clinical encounter.
While these cases demonstrate the promise of a commonly used agent in COVID-19–related brain fog, more rigorous study is required to test the treatment in this growing and debilitating complication of post-COVID-19 syndrome.
Conflicts of interest
There are no conflicts of interest.
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