[...] Can Generalized Anxiety Disorder Be Distinguished From [MDD], Healthy People by [...] lncRNAs in Peripheral Blood, 2025, Kong et al

[forestglip]

An Alternative Approach to Future Diagnosis: Can Generalized Anxiety Disorder Be Distinguished From Major Depressive Disorder, Healthy People by Differentially Expressed lncRNAs in Peripheral Blood

Lingming Kong, Liang Zhang

[Line breaks added]

Purpose
Symptomatic diagnosis combined with unclear pathological mechanism and diverse etiology may increase misdiagnosis risk for generalized anxiety disorder (GAD) in the clinical setting. This study aimed to confirm the diagnostic value of aberrantly expressed long non-coding RNAs (lncRNAs) for GAD.

Patients and Methods
Eighty sex- and age-matched patients with GAD and major depressive disorder (MDD) and healthy controls (HCs) were enrolled using a convenient sampling method. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to verify lncRNA expression levels in all participants, and a receiver operating characteristic (ROC) curve was used to test the accuracy of aberrantly expressed lncRNAs in differentiating health conditions.

Results
ΔCt values of ENST00000505825, NONHSAG017299, NONHSAT078768, NONHSAT029028, NONHSAT101077, NONHSAT031726, TCONS_l2_00010607 in GAD patients were less than in HCs (P<0.05 or 0.01).

The total severity score of HAMA-14 and somatic anxiety scores were negatively correlated with ΔCt values of ENST00000505825, NONHSAG017299, NONHSAT078768, NONHSAT029028, NONHSAT101077, NONHSAT031726, ENST00000505825, TCONS_l2_00010607, and NONHSAT131696, and psychic anxiety scores were negatively associated with the ΔCt value of ENST00000505825 (P<0.05 or 0.01).

The AUC of the combined ROC curve between patients with GAD and healthy people was 0.810, with sensitivity and specificity of 0.825 and 0.762, respectively (P<0.05 or 0.01). The AUC of the combined ROC curve between patients with GAD and MDD patients was 0.938, with sensitivity and specificity of 0.850 and 0.900, respectively (P<0.05 or 0.01).

Conclusion
ENST00000505825, NONHSAG017299, NONHSAT078768, NONHSAT029028, NONHSAT101077, NONHSAT031726, TCONS_l2_00010607, which may serve as biomarkers for the GAD diagnosis and differentiation between GAD and MDD, can improve the diagnostic accuracy and avoid misdiagnosis to a certain extent. It is also beneficial for personalized treatment of GAD.

Link | PDF (Neuropsychiatric Disease and Treatment) [Open Access]

 

[rvallee]

The validity and homogeneity of MDD is highly debatable in any context, but the diagnostic validity of GAD is basically on par with throwing bones down some stairs and reading horoscopes as confirmation.

Plus, the idea that even when fully valid they would be mutually exclusive enough to separate out clusters is basically adding some tea leaves and working out how many of them land face up or down as a second validation.

Then you have the design problem of a bootstrapped approach, where the result of a poorly validated cohort is used to validate the cohort validation. Might as well check whether they can swim or else they're witches.

 

[forestglip]

The validity and homogeneity of MDD is highly debatable in any context, but the diagnostic validity of GAD is basically on par with throwing bones down some stairs and reading horoscopes as confirmation.

Plus, the idea that even when fully valid they would be mutually exclusive enough to separate out clusters is basically adding some tea leaves and working out how many of them land face up or down as a second validation.

I don't understand your point. Is there a diagnostic criteria you'd like to see them use when doing a study? How would you suggest researchers change their approach when studying people with anxiety disorders?

Then you have the design problem of a bootstrapped approach, where the result of a poorly validated cohort is used to validate the cohort validation.

What does this mean? I see them reporting the difference they found between cohorts split by diagnostic criteria. I don't see them saying anything like "these differences in lncRNA validate that the criteria used for GAD is excellent for diagnosis". How could they have reported the results better?

 

[Utsikt]

My issue with GAD is that it requires ‘excessive anxiety and worry’. It’s very easy to pawn patients off as excessive worriers if you take a BPS approach to medicine, and the other symptoms are so commonplace among sick people that they really don’t tell you much.

This study proved that differential expression of lncRNAs in peripheral blood can be used as a potential biomarker for clinical diagnosis of GAD, which can improve diagnostic accuracy and avoid misdiagnosis to a certain extent.

This becomes an issue if we start using biomarkers to diagnose GAD, because then the biomarker can taken to ‘prove’ that your anxiety is excessive, and not just that you have anxiety in general or even a high, but justified, level of anxiety.

 

[forestglip]

My issue with GAD is that it requires ‘excessive anxiety and worry’. It’s very easy to pawn patients off as excessive worriers if you take a BPS approach to medicine, and the other symptoms are so commonplace among sick people that they really don’t tell you much.

This becomes an issue if we start using biomarkers to diagnose GAD, because then the biomarker can taken to ‘prove’ that your anxiety is excessive, and not just that you have anxiety in general or even a high, but justified, level of anxiety.

What's a better way to word it?

 

[rvallee]

I don't understand your point. Is there a diagnostic criteria you'd like to see them use when doing a study? How would you suggest researchers change their approach when studying people with anxiety disorders?

I don't know about various anxiety diagnoses, for sure GAD is just a dumpster on which lots of unrelated stuff, including us, is dumped into. I don't think it's actually a thing, not even as useful as chronic fatigue. I don't know how anxiety can be validated other than as self-reports, so that naturally makes it very heterogeneous.

What does this mean? I see them reporting the difference they found between cohorts split by diagnostic criteria. I don't see them saying anything like "these differences in lncRNA validate that the criteria used for GAD is excellent for diagnosis". How could they have reported the results better?

The diagnoses can't be made reliably. It's not possible to know what goes in, but trying to differentiate two concepts that can't be validated, then using this as validation is just not useful.

It's not really a reporting problem so much as a design problem. I don't think this can be made useful, but that's just my take on it.

 

[rvallee]

What's a better way to word it?

Sadly, anxiety is the word for it, but it's been completely distorted by psychosomatic ideology to be applied to all sorts of unrelated things.

It's the biggest problem with GAD. Anxiety is worrying about specific things. But there are people who aren't anxious about things, but physicians don't know what their problem is, so they call it general anxiety, which is specifically being anxious, in general. Makes no sense.

Or even worse, in our case, when the worry is perfectly legitimate, but they don't understand the reason, so they call it excessive because it fits their ideology, even though that worry isn't necessarily anxiety, it's just worrying about normal things, which is perfectly healthy behavior, where, in fact, not worrying is problematic.

It's similar to how fatigue is so often used to mean motivation. The problem isn't with the words themselves, but about how they've been distorted to apply onto unrelated things, entirely on purpose. This is entirely medicine's fault, and there is no remedy for it. They basically mixed things that can't be unmixed, so when they need to study them separately, well, oops, too late.

 

[Utsikt]

What's a better way to word it?

If you’re asking about the paper, they could have discussed the issue of how the GAD diagnosis implies that the anxiety is excessive, and how a biomarker can’t be taken to prove that the anxiety is in fact excessive.

 

[forestglip]

I don't know about various anxiety diagnoses, for sure GAD is just a dumpster on which lots of unrelated stuff, including us, is dumped into. I don't think it's actually a thing, not even as useful as chronic fatigue. I don't know how anxiety can be validated other than as self-reports, so that naturally makes it very heterogeneous.

Sadly, anxiety is the word for it, but it's been completely distorted by psychosomatic ideology to be applied to all sorts of unrelated things.

It's the biggest problem with GAD. Anxiety is worrying about specific things. But there are people who aren't anxious about things, but physicians don't know what their problem is, so they call it general anxiety, which is specifically being anxious, in general. Makes no sense.

Why is anxiety necessarily "worrying about specific things"? In my view, anxiety is like pain. Pain can be caused by trauma or it can be caused by seemingly nothing in the case of chronic pain conditions. Anxiety can be caused by a threat or by seemingly nothing in the case of anxiety disorders. Are they supposed to invent a new word before diagnosing anyone or studying them?

I'm not sure what you want anyone to do differently though, especially in regard to this thread's paper. From your first post, it appeared to be criticism of this study, but I don't see what specifically is the issue there. If you were a researcher that thought lncRNA might be decreased in the population of people who report having high anxiety for no apparent reason, what would you have done differently from these researchers? Sure, a couple sentences in the conclusion are a bit overly confident for a preliminary finding, but in terms of criteria or the "design problem of a bootstrapped approach"?

 

[forestglip]

If you’re asking about the paper, they could have discussed the issue of how the GAD diagnosis implies that the anxiety is excessive, and how a biomarker can’t be taken to prove that the anxiety is in fact excessive.

I meant instead of "excessive anxiety or worry" in the DSM criteria, which I thought you were criticising.

 

[Utsikt]

I meant instead of "excessive anxiety or worry" in the DSM criteria, which I thought you were criticising.

Ideally, I would remove the entire concept of GAD. It’s about as useful of a clinical entity as what General Coughing Disorder would have been if it was a thing.

 

[forestglip]

Ideally, I would remove the entire concept of GAD. It’s about as useful of a clinical entity as what General Coughing Disorder would have been if it was a thing.

So should there be no diagnosis for this condition of having anxiety all the time that isn't explained by any other diagnosis like PTSD or OCD? No effort to recruit a bunch of people who also have the same thing to a study to try to figure out what's wrong? How would you do that without a criteria?

If tons of people were suffering from persistent coughing and there was no other explanation that would fit better - no signs of an infection, nothing stuck in the throat - why would it be bad to call this condition generalized coughing disorder?

 

[V.R.T.]

As someone who Is diagnosed with generalized anxiety disorder, I can see both sides of this argument.

I was diagnosed by a gp age 19 because I reported insomnia, unexplained physical symptoms, what I now understand to be DPDR And depression. My entire life people have been telling me that I'm anxious when I am not. I was diagnosed with autism later in life. I do not feel this diagnosis of GAD fit what I was reporting at 19 but it has stuck in my record and affected my every interaction with doctors.

Generalised Anxiety Disorder can mean anything from this person is having debilitating panic attacks, to this person obsessively worries about everything, to this person feels ill and I think its psychosomatic, to this person seems twitchy and nervous and I dont understand them. In my case the doctor thought all 4 things. But all of them could have been explained by something else and I was diagnosed by a GP not a mental health professional. I belive this is common.

The concept of anxiety is not comparable to coughing because coughing is easy to define and obvious to diagnose. Anxiety is a nebulous concept and means many things in our culture.

However, if people suffering from unexplained symptoms lumped together as GAD like me have LCRNA markers in common that can help with diagnosis and eventually treatment, I would welcome that. Even without the addiction issues and ME i later developed, what was diagnosed as GAD would have significantly impacted my life. In many ways it is the thing that limited my pre ME life the most.

 

[Utsikt]

So should there be no diagnosis for this condition of having anxiety all the time that isn't explained by any other diagnosis like PTSD or OCD?

It could just be persistent anxiety (PA).

No effort to recruit a bunch of people who also have the same thing to a study to try to figure out what's wrong?

That’s not what I said. They could study pwPA.

How would you do that without a criteria?

There would have to be inclusion criteria like for any study. But it would be based anxiety and not everything else.

 

[forestglip]

It could just be persistent anxiety (PA).

That’s not what I said. They could study pwPA.

There would have to be inclusion criteria like for any study. But it would be based anxiety and not everything else.

Oh ok. I assume the creators were worried about striking a balance of false positives vs. false negatives when including other required symptoms, like Fukuda/ICC/CCC and their laundry lists of symptoms for ME/CFS.

For clinical use, maybe something like "persistent anxiety", like the simpler IOM for ME/CFS, could be used. But for research, I'd think decreasing heterogeneity would be useful.