Depression as a moderator and mediator of functional status in patients with Long COVID: […] from the PERCEIVE cohort in Australia, 2025, Seboka+

[SNT Gatchaman]

Depression as a moderator and mediator of functional status in patients with Long COVID: a cross-sectional and longitudinal observational study from the PERCEIVE cohort in Australia

Spoiler: Authors

Binyam Tariku Seboka; Joel Smith; Kristyn Whitmore; Brodie Baranow; Erin Howden; Jayashri Kulkarni; Quan L Huynh; Thomas H Marwick

BACKGROUND
In patients with post-acute sequelae of COVID-19 (PASC), depression has been associated with symptom severity, the duration since infection and ongoing functional impairment. However, the interconnections between these factors remain inadequately understood.

OBJECTIVES
This study aimed to explore the roles of depressive symptoms in moderating and mediating the relationships between post-COVID-19 conditions and functional capacity.

METHODS
The PERCEIVE study recruited 1794 participants from Victoria and Tasmania through online advertisements based on possible PASC for a cross-sectional study. Of these, 461 participated in the longitudinal study. Post-COVID-19 duration and symptoms were recorded, and depressive symptoms and functional capacity were self-reported using the 9-item Patient Health Questionnaire and the Duke Activity Status Index (DASI), respectively. The association of depression with functional capacity was explored using ordinary least squares (OLS) regression, with companion OLS models, Sobel-Goodman tests and 1000 bootstrap iterations to assess mediation. Longitudinal data were analysed to assess changes in functional capacity and depressive symptoms over time, with mediation analysis using mixed models to explore depression as a mediator.

RESULTS
Participants had a mean DASI score of 35 (SD 21). Fatigue (18%), shortness of breath (11%) and chest pain (6%) were common symptoms, with severe depression linked to fatigue (93%) and shortness of breath (66%). The severity of post-COVID-19 symptoms was associated with severe depression (β=6.31, 95% CI 5.42 to 7.21) and reduced functional capacity (β=−6.40, 95% CI −9.20 to –3.61), with depression mediating 36% of the association between post-COVID-19 symptom severity and functional capacity. PASC was associated with higher depression scores (β=2.06, 95% CI 1.15 to 2.97) and lower functional capacity (β=−3.99, 95% CI −6.21 to –1.77), with depression mediating 51% of the association between PASC and reduced functional capacity. The longitudinal analysis suggested that depression is associated with the relationship between PASC and changes in functional capacity over time (unstandardised estimate=−5.16, p<0.001).

CONCLUSION
Depression plays a key role in exacerbating post-COVID-19 functional impairment. This observation underscores the need for targeted physical and mental health interventions to enhance long-term recovery for those with severe conditions.

Web | DOI | PDF | BMJ Open | Open Access

 

[SNT Gatchaman]

From limitations —

The study used observational data and is, therefore, unable to determine causality or to disentangle the potential bidirectional relationships between PASC, depressive symptoms and functional capacity. Additionally, the absence of pre-COVID-19 baseline mental health data, which prevents definitive attribution of depressive symptoms solely to PASC.

Another limitation is potential recruitment bias, as participation relied partly on self-selection through online advertisements and mailing lists, likely including only individuals who were motivated to participate. Further, the mediation model was based on the parsimonious model, which eliminates multiple and bidirectional links to facilitate data interpretation.

It is also important to interpret our findings with caution, as there is potential symptom overlap between depression and PASC. Our sensitivity analysis, which excluded the fatigue item from the PHQ-9, yielded consistent results; however, the possibility of residual confounding remains.

 

[BrightCandle]

The PHQ-9 has the issue of conflating symptoms with depression which the disease has like sleep disturbance, little energy, appetite changes, cognitive issues and reduced speaking speed. 5 of the 9 items do this and hence distort the questionnaire substantially for PASC and other diseases with these symptoms driven not by mental state but physical symptoms.

The DASI is quite limited for assessing functional capacity because its completely binary, you can either do the thing or you can't and has no concept of payback. It leaves it to the patient to determine if PEM or fatiguability is relevant to whether the task like walking up the stairs can be done. It has no concept of combined exertion or general variance of condition and so beyond just lacking awareness of PEM it also can't deal with other conditions well with variance in symptoms like MS. In general its a pretty poor functional assessment questionnaire.

Neither of these questionaries is appropriate for this condition, they conflate physical symptoms with mental ones and don't handle energy limiting conditions with fluctuations and payback at all. Thus the results this combination will produce will be very variable and fail to capture the severity range of the disease, so any correlation they might have between function and depression is being pushed thorugh two very biased and distorted views.

Not news to us, these questionaries are used extensively in poor quality research that ignores the presentation of the disease.

 

[Joan Crawford]

The PHQ-9 has the issue of conflating symptoms with depression which the disease has like sleep disturbance, little energy, appetite changes, cognitive issues and reduced speaking speed. 5 of the 9 items do this and hence distort the questionnaire substantially for PASC and other diseases with these symptoms driven not by mental state but physical symptoms.

The DASI is quite limited for assessing functional capacity because its completely binary, you can either do the thing or you can't and has no concept of payback. It leaves it to the patient to determine if PEM or fatiguability is relevant to whether the task like walking up the stairs can be done. It has no concept of combined exertion or general variance of condition and so beyond just lacking awareness of PEM it also can't deal with other conditions well with variance in symptoms like MS. In general its a pretty poor functional assessment questionnaire.

Neither of these questionaries is appropriate for this condition, they conflate physical symptoms with mental ones and don't handle energy limiting conditions with fluctuations and payback at all. Thus the results this combination will produce will be very variable and fail to capture the severity range of the disease, so any correlation they might have between function and depression is being pushed thorugh two very biased and distorted views.

Not news to us, these questionaries are used extensively in poor quality research that ignores the presentation of the disease.

"Not news to us, these questionaries are used extensively in poor quality research that ignores the presentation of the disease."

Spot on. Cheap, unhelpful, low quality work. Tells nobody anything useful. Likely misleading and can even be used to justify inaction and patient blaming for the predicament they find themselves in.

 

[Trish]

It's time funders stopped funding, medical journals stopped publishing and academics stopped wasting their time on this sort of junk.

I wonder whether it was someone's PhD project. We see so many like this.

So another generation of young keen scientists and clinicians are taught that it's OK to use inappropriate questionnaires, online recruitment and stats packages and get it published as 'research'.

Garbage in garbage out.

Why do they do it?

 

[Yann04]

Depression as a moderator and mediator of functional status in patients with Long COVID: a cross-sectional and longitudinal observational study from the PERCEIVE cohort in Australia

Functional Status as a moderator and mediator of Scores on the PHQ-9 in Long COVID : False Positives and the Inadequacy of PHQ-9 for the Chronically Ill.

Change a few words in how the results are interpreted and you’ve got yourself a valuable contribution to the field.

 

[Utsikt]

This is the «depression questionnaire» PHQ-9, if anyone are wondering why «depression» is correlated with having worse symptoms..

 

[rvallee]

This is the «depression questionnaire» PHQ-9, if anyone are wondering why «depression» is correlated with having worse symptoms..

The most absurd thing is that if they simply worked the association the other way around, they are actually describing reality. Obviously being ill leads to all of this, a child can not only understand it but could explain it just as easily. But the "bi-directional" relationship only ever works one way, even when it's the direction that not only makes the least sense, but doesn't even make sense as it's basically a bootstrapped model, i.e. it supports itself using itself.

Especially this questionnaire, it basically captures the experience of illness. But it's interpreted as the experience of a mood disorder, showing that medicine actually understands neither, and intentionally so. Honestly this is little different from repeatedly kicking someone as soon as they try to get up, then justify kicking them because they won't even put the effort to get up. It's just naked bullying.

And it's the first time I've noticed this ridiculous flaw in this garbage questionnaire but they literally allow for opposite problems to be the same: eat too much or eat too little, sleep too little or sleep too much. As if they are the same thing. This all just looks like a discipline entirely lacking in anything professional, we'd get much better results out of literally randomly selecting people and having them try to do better. I have no doubt that such a random system would work better than this, it might as well be intentional failure.

 

[BrightCandle]

This is the DASI functional capacity test.

 

[Hoopoe]

These days I think I've stopped believing in depression as valid clinical entity.

It's just a nonspecific indicator that something is wrong. By the time a professional is consulted everyone already knows this. That something could be almost anything.

The diagnosis just seems to function as a way to justify treatment and give it an air of credibility and pretend that something useful was done. Occasionally the treatment might help, but more out of coincidence than clinical validity of these absurdly unspecific alleged indicators of depression.

This is also the fault of patients who are too insecure to object and too willing to go along with this.

People become unhappy and desperate and lose hope for many good reasons. It's easy to blame a mysterious chemical imbalance in the brain or allegedly dysfunctional thought patterns. Figuring out what the problem is and how to solve it is hard. These depression questionnaires are not "taking unhappiness seriously" but the opposite.

 

[Utsikt]

These days I think I've stopped believing in depression as valid clinical entity.

Depression is quite real, but the questionnaires that are used to identify it suffers from the same flaw as most questionnaires - it assumes there is no alternative explanation for the symptoms.

It’s a bit like treating every case of coughing with chemo because you think they have lung cancer due to their coughing.

I’ve stopped trusting the judgement of any HCW that wants me to fill in questionnaires, except for FUNCAP.

 

[Trish]

These days I think I've stopped believing in depression as valid clinical entity.

I think we need to be careful about making such judgements without specialist knowledge either as a doctor or from personal experience of both depression due to circumstances and depression that seems to come from nowhere and is unrelated to circumstances.
Whatever depression is, questionnaires are a very inadequate way of diagnosing it.

 

[Hoopoe]

Unsurprisingly people who can't function in life are unhappy. They are normal human beings who have needs that cause suffering if not met. Will a diagnosis of depression help get these needs met or will it be an obstacle?

Is it dangerous to discuss unhappiness with no reference to circumstances?

Is it more productive to ask ourselves how the circumstances lead to unhappiness and how they can be changed, or more productive to assume some ill-defined internal factor that is allegedly causing this unhappiness?

 

[Yann04]

Depression is quite real, but the questionnaires that are used to identify it suffers from the same flaw as most questionnaires - it assumes there is no alternative explanation for the symptoms.

Do you think there is this “one thing” called depression. And things misdiagnosed as depression are muddling it up.

Or do you think Depression is an umbrella term that can refer to many things.

depression as valid clinical entity.

I also have some doubts about the clinical construct. In no way do I doubt the validity and experience of people diagnosed with depression. I just have a hard time seeing it as a useful construct as it seems to muddle a lot of different things together.

Maybe I’d feel similarly if “chronic fatigue” was a clinical category of that makes sense.

I guess this is similar to how a lot of people on this forum feel about POTS/MCAS/hEDS.

more productive to assume some ill-defined internal factor that is allegedly causing this unhappiness?

I think the experience of pwDepression might point to the fact there is a (group of?) illnesses that can produce those symptoms. Not simply it always being a reaction to external situations. Though I dont doubt a reaction to external situations does get diagnosed as depression often.

 

[Utsikt]

Do you think there is this “one thing” called depression. And things misdiagnosed as depression are muddling it up.

Or do you think Depression is an umbrella term that can refer to many things.

It’s something I think a lot about, and I haven’t really gotten my head around it yet so here are some scattered thoughts:

I think there exists some mental state that is characterised by a longer period of depressed mood, apathy, hopelessness, etc. that could reasonably be classified as depression.

I think some naturally resolve over time, especially if you get help to avoid or break negative spirals, and some are remarkably persistent.

I have no idea about the cause or how to fix it. We probably know very little about it.

I think the word depression has lost all meaning in regular language, and also in most context in medical settings.

I think depression can co-occur with severe illness, but not all instances of «depressive symptoms» are depression.

I think most attempts at capturing depression through standardised formats are futile.

I think the only way to have any reasonable accuracy when determining if someone are depressed is to have conversations with them over time. Done by someone who knows what the alternative explanations for the symptoms look like, and are able to make a neutral judgement.

(The last point is based on personal experience of everyone (carers and GP) thinking I’m depressed and my psychologist being adamant that I very clearly am not).

 

[Sean]

It's time funders stopped funding, medical journals stopped publishing and academics stopped wasting their time on this sort of junk.

Exactly. The blame does not lie entirely with the authors. The whole system is rotten. Which is why it is proving so difficult to get it to change. They are all up to their eyeballs in the swamp they have created, with honourable exceptions.

Why do they do it?

They get rewarded for it.

Especially this questionnaire, it basically captures the experience of illness. But it's interpreted as the experience of a mood disorder, showing that medicine actually understands neither, and intentionally so.

Spot on.

These days I think I've stopped believing in depression as valid clinical entity.

Whatever depression is, questionnaires are a very inadequate way of diagnosing it.

I think the depression and anxiety diagnoses have the same problem as the placebo effect. They encompass a whole range of unrelated phenomena that are being shoved under a simplistic and false unifying label, full of unjustified causal attributions.

Mental health is real, mood matters and can be an important symptom/indicator, but it's claims have gone way too far on way too little evidence, and become a fad bordering on a cult, especially psychosomatics. Unfortunately the people in charge of it have made it abundantly clear they are not interested in cleaning up their act quite the opposite, in fact.

So here we are.

 

[Trish]

Is it dangerous to discuss unhappiness with no reference to circumstances?

Is it more productive to ask ourselves how the circumstances lead to unhappiness and how they can be changed, or more productive to assume some ill-defined internal factor that is allegedly causing this unhappiness?

I think that depends entirely on the situation and we shouldn't generalise or judge whether someone's unhappiness has cause based on circumstances. For someone with a condition like ME/CFS there is good reason to be unhappy with feeling ill all the time and with the huge limitations it places on how we live our lives. And of course any medical and care system should focus on ensuring the person gets all the support an care they need and want.

That's different from severe clinical depression that is not caused by their life circumstances. I don't think that should be dismissed as unhappiness due to life circumstances. I think there are biological changes involved.

To give a simple example from my experience, I am grateful never to have experienced severe clinical depression. I have had some periods of misery, unhappiness, melancholy, sadness, anger, grief due to personal circumstances at some times in my life, as has pretty well everybody.

I have also had multiple short periods of a few days of depression at a time in the midst of a generally happy, healthy and fortunate time of life that seem to come out of the blue and descend like a black cloud. It was only after many years of such episodes lasting a few days at a time that I associated the black clouds with premenstrual hormonal changes and found a biochemical treatment that helped significantly.

That's why I say we shouldn't assume that all depression is unhappiness due to life circumstances. There are chemical causes too, as also in bipolar disorder and severe clinical depression.

 

[rvallee]

Depression is quite real, but the questionnaires that are used to identify it suffers from the same flaw as most questionnaires - it assumes there is no alternative explanation for the symptoms.

It's deeper than the questionnaires themselves and mostly revolves around health problems where only the subjective experience of symptoms can be used. It all seems to be a giant hodge-podge simply because medicine has no idea how to deal with subjective experience. This is something they could only do by working with those experiencing it, and this is also something they are not able to do because of the power asymmetry and a culture that views this 'relationship' more as a teacher-student type than a cooperative effort.

This is probably the most important next frontier in medicine, one that would make it grow like no other technology could. It's what's stopping it from moving forward and being effective. Although ironically I can only see AI fulfilling this, by simply bypassing all the awful attempts at formalizing the process of listening to people and engaging directly in a continuous effort of engagement.

Most likely 90% of the DSM is BS. It tries to describe real problems but has no real expertise or insight about it. Not much different than old superstitions.