Review BMJ - Cognitive and mental health outcomes in long covid, 2025, Aretouli et al

[Kalliope]

Abstract​

Roughly one in five adults who meet criteria for long covid present with objective or subjective cognitive dysfunction or elevated symptoms of depression or anxiety lasting ≥12 weeks from an acute covid illness.

These neuropsychiatric sequelae have considerable functional consequences at the level of the individual, society, and the broader economy. Neuropsychiatric long covid symptoms are thought to be causally diverse, and a range of risk factors as well as biological, psychological, and environmental mechanisms have been hypothesized to contribute to symptom development and persistence.

When present, objective cognitive deficits tend to be modest for most individuals, with some evidence suggesting increased risk of dysfunction and decline specifically for older adults with a history of severe acute illness. Longitudinal data suggest a delayed emergence of psychiatric symptoms may occur in the weeks and months after an acute covid illness.

Emerging research points to the early recovery period as a potential window of opportunity for intervention to alter patient trajectories, though evidence based treatment remains lacking.

Cognitive and mental health outcomes in long covid

Roughly one in five adults who meet criteria for long covid present with objective or subjective cognitive dysfunction or elevated symptoms of depression or anxiety lasting ≥12 weeks from an acute covid illness. These neuropsychiatric sequelae have considerable functional consequences at the...

www.bmj.com

 

[Kalliope]

One of the rapid responses is from an Alexis J Gilbert - Consultant in Health Protection, medically retired due to Severe Long Covid and M.E.

quote:

As a public health consultant forced into medical retirement by Long Covid and M.E., I commend Aretouli et al. for their comprehensive review of neuropsychiatric outcomes. However, its focus solely on the neuropsychiatric impacts of long covid illustrates a fundamental problem with the way long covid, Myalgic Encephalomyelitis, and other Infection-Associated Chronic Conditions (IACCs) are managed by health systems; patients with complex multi-system illnesses do not have a specialty that provides the holistic care they need and multi-disciplinary care does not exist.

Full response

 

[Maat]

Snap!

Consent to treatment is not a static thing. It is an ongoing process and can be withdrawn at any time, as long as you have mental capacity to consent.

Given my age and my health, I had a long conversation with my solicitors this morning concerning an enduring power of attorney for health and social care which we discussed earlier in the year. So she knows I have capacity as of today's date. The trouble I have is who in the heck would want that role for me! Plus its expensive.

So I started re-checking the other available options I'd looked at before, and came across this:

NSW Australia where it is confined in it's application to criminals - forensic psychiatry.

Details Page

Mental Health and Cognitive Impairment Forensic Provisions Act 2020​

Summary​

This Information Bulletin is to inform staff about changes made by new legislation.
File link: Mental Health and Cognitive Impairment Forensic Provisions Act 2020
File size: 395 KB
Document type: Information Bulletin
Document number: IB2021_013
Publication date: 24 March 2021
Author branch: Mental Health
Branch contact: (02) 9461 7074
Review date: 24 March 2026
Policy manual: Not applicable
File number: H21/65832
Status: Active

Functional group​

• Clinical/Patient Services - Mental Health

Applies to​

• Local Health Districts
• Chief Executive Governed Statutory Health Corporations
• Specialty Network Governed Statutory Health Corporations

Distributed to​

• Public Health System

Audience​

• Mental Health Staff
• Area Mental Health Directors

Being aware the the new Mental Health Bill 2025 legislation is still going through Parliament. It was published on 7 November 2024. I checked the Bill does not include the phrase cognitive impairment. Unfortunately, I'm going to have to read the whole thing. together with a refresh of the Mental Health Act 1983 to be doubly sure, for my own purposes.

 

[Eleanor]

Emerging research points to the early recovery period as a potential window of opportunity for intervention to alter patient trajectories, though evidence based treatment remains lacking.

As Groucho Marx put it: "If we had some ham, we could have ham and eggs, if we had some eggs."

 

[Sean]

and the broader economy.​

Guess who the target audience is for this paper.

Emerging research points to the early recovery period as a potential window of opportunity for intervention to alter patient trajectories, though evidence based treatment remains lacking.​

As we have been suggesting for [checks notes] decades.

 

[Utsikt]

Emerging research points to the early recovery period as a potential window of opportunity for intervention to alter patient trajectories, though evidence based treatment remains lacking.
As we have been suggesting for [checks notes] decades.

Except that our proposals is to leave the patients alone and let them get enough rest. They are probably proposing CBT and/or physical rehab of some sort.

 

[Sean]

Indeed.

The one thing they could do to help us is the one thing they are completely incapable of even considering, let alone doing, which is to get off our backs.

 

[rvallee]

So, this is a literature review of a flawed literature mostly built out of flawed data, leading, unsurprisingly, to a flawed review, which misses most of the important points, and brings entirely unrelated ones to the forefront. As is tradition with a flawed process analyzing flawed data.

If they would just drop everything related to mental health or psychology, especially the awful biopsychosocial nonsense, it would already be massively improved. As it is, it's just mostly flawed and misleading.

And it shows how hopeless this all is. The flawed data leading to flawed literature leading to flawed reviews are never corrected. If this were software, it would be a bug-ridden mess where bugs never get corrected, they just write new code using the old code to bring entirely new bugs and not much more. All the bugs are still there, they just duplicate functionality, making the whole thing unusable, because usability is not even part of the evaluation process, and they can't even do it competently anyway.

About five years after the onset of the covid-19 pandemic, a reliable diagnostic marker for long covid is lacking, as is a consensus definition or generally agreed upon set of diagnostic criteria

So clearly this is all that matters. For better or worse, medicine is built entirely around those markers and an understanding of the problems with biology. The rest is so under-performing it's completely wasted since the only meaningful progress will be made with an understanding of the biology, all of which will render the rest obsolete, so might as well not do the things that are useless and will be made obsolete since all it does is slow down the process of finding the problem, and thus the solution.

Medicine had the choice between doing something useful, or holding on to their ideology. And they have so far held on to the ideology. To great harm and misery, and it's not about to change. Just a fully impotent profession without its tools, literally less useful than software developers without a computer.

 

[Evergreen]

Except that our proposals is to leave the patients alone and let them get enough rest. They are probably proposing CBT and/or physical rehab of some sort.

And the O' Dowd et al. 2020 early intervention study didn't go well. 8/28 in the intervention group did not complete 6-month questionnaires. Acceptability was low:

Most participants (twelve) found parts of the intervention acceptable, but fifteen reported one or more problems with acceptability.

and the intervention was not effective:

 

[Dolphin]

Research must consider Post Exertional Malaise as a neurological event underpinning fluctuating cognitive dysfunction in Long Covid

www.bmj.com

20 August 2025
Selina R Shaw
General Practitioner
Nil
Amersham Health Centre, NHS
Amersham Health Centre, Chiltern Avenue, Amersham , HP6 5AY
Nil

Dear Editor,

As a clinician, I read with interest the article “Cognitive and mental health outcomes in Long Covid” and commend the authors for addressing this important topic. However, the article underscores limitations in the field: current research often examines neurocognitive dysfunction in isolation, without considering the systemic metabolo-neuroimmune disorders that drive its pathophysiology.

In clinical practice, patients with Long Covid (LC) frequently present with overlapping syndromes, including post-exertional malaise (PEM—the hallmark of ME/CFS) (1), dysautonomia, and mast cell activation symptoms (2). Cognitive dysfunction in LC fluctuates with exacerbation these conditions and cannot be understood in isolation from them.

PEM warrants recognition as a neurological pathology resulting from metabolic and immune dysregulation (3). Approximately 48 hr after a triggering event—physical, cognitive, or emotional—patients experience what is colloquially termed a “crash.” This involves a surge in neurological symptoms that may render them unable to function: profound fatigue, cognitive slowing, hypersomnia, photophobia, phonophobia, tinnitus, nausea, headaches, migraines, executive dysfunction, word-finding difficulties, working memory impairment, pain, and worsening dysautonomia with orthostatic intolerance, mood disorders. Although these symptoms may be present at baseline, they rapidly escalate in the disabling cacophony of the “crash”. Many patients report diurnal variation, with symptoms peaking midday and easing somewhat towards night, repeating daily until resolution, suggesting a neuroimmune process with a circadian rhythm. Patients often experience disablement until the episode resolves over days or weeks.

After an episode of PEM, patients may return to their prior cognitive baseline (which is often already impaired) or decline to a new, lower baseline, suggesting cumulative neurological injury. Conversely, strict avoidance of PEM—though often impossible when basic activities exceed the trigger threshold—may allow partial neurological recovery. Elevated neurofilament light chain and GFAP in LC, proteins consistent with traumatic brain injury, support the hypothesis of repeated neuroinflammatory damage (4).

Recent work demonstrates that exercise exceeding the aerobic threshold causes skeletal muscle damage and necrosis in LC patients with PEM (3). Since the aerobic threshold is pathologically lowered in this group, even minimal daily movements may induce metabolic tissue damage. Necrosis is a powerful immune stimulus, yet the link between peripheral tissue injury and delayed onset neurological deterioration remains unexplored. Similarly, the unexplained 48 hr lag between exertion and symptom onset invites parallels with type IV hypersensitivity, in which delayed immune responses arise during T-cell recruitment.

Immune-mediated brainstem inflammation has also been observed in post-Covid patients (5). The brainstem houses structures implicated in the symptoms exacerbated during PEM—autonomic control centres, circadian regulators, arousal and alertness networks, cognitive processing hubs, pain modulators, and the locus coeruleus and nucleus of the solitary tract. These nuclei may mediate profound fatigue and malaise in response to systemic inflammation. Thus, a surge in peripheral inflammation from exertion-induced necrosis could be detected by an inflamed brainstem, precipitating an exaggerated sickness response that disables the patient until inflammation partially resolves. Research is urgently needed to test this hypothesis and identify therapeutic targets.

Currently, no intervention can terminate PEM once initiated. No amount of compensatory rest prevents its emergence after a trigger. However, clinicians report that long-term low-dose naltrexone (LDN) can reduce the frequency and severity of PEM in some patients. Its mechanisms—mast cell stabilization, microglial modulation, natural killer cell functional restoration—may yield further insights into PEM pathophysiology (6).

I urge the research community to prioritise cross-disciplinary investigation into cognitive dysfunction and its fluctuating nature in the context of PEM in Long Covid. Such work could transform understanding and inform targeted therapies for the millions worldwide who remain debilitated by this condition.

References
1. An Y, Guo Z, Fan J, Luo T, Xu H, Li H, et al; Prevalence and measurement of post-exertional malaise in post-acute COVID-19 syndrome: A systematic review and meta-analysis. Gen Hosp Psychiatry. 2024 Nov–Dec;91:130-42. doi:10.1016/j.genhosppsych.2024.10.011. Epub 2024 Oct 20.

2. Theoharides TC, Twahir A, Kempuraj D. Mast cells in the autonomic nervous system and potential role in disorders with dysautonomia and neuroinflammation. Ann Allergy Asthma Immunol. 2024 Apr;132(4):440-54. doi:10.1016/j.anai.2023.10.032. Epub 2023 Nov 10.

3. Appelman B, Charlton BT, Goulding RP, Kerkhoff TJ, Breedveld EA, Noort W, et al. Muscle abnormalities worsen after post-exertional malaise in long COVID. Nat Commun. 2024 Jan 4;15(1):17. doi:10.1038/s41467-023-44432-3.

4. Plantone D, Stufano A, Righi D, Locci S, Iavicoli I, Lovreglio P, et al. Serum biomarkers of neuro-axonal and astroglial injury in long COVID. Sci Rep. 2024 Mar 18;14(1):6429. doi:10.1038/s41598-024-57093-z.

5. Rua C, Raman B, Rodgers CT, Newcombe VFJ, Manktelow A, Chatfield DA, et al. Quantitative susceptibility mapping at 7 T in COVID-19: brainstem effects and outcome associations. Brain. 2024 Dec;147(12):4121-30. doi:10.1093/brain/awae215.

6. Sasso EM, Eaton-Fitch N, Smith P, Muraki K, Marshall-Gradisnik S. Low-dose naltrexone restored TRPM3 ion channel function in natural killer cells from long COVID patients. Front Mol Biosci. 2025 May 19;12:1582967. doi:10.3389/fmolb.2025.1582967.
Competing interests: No competing interests