Secondary causes of depression

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thelastpsych

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After reading a lot about neurometabolic disorders in depression, and cases of refractory patients that get better after an intervention like vitamin D or folate, I was wondering:

1) What are your go-to screening tests for depression? Is it worth it to quantify folate and B12 levels? What about testosterone on males or tests like DHEA suppresion?

2) I've read the CANMAT on supplements (Clinician guidelines for the treatment of psychiatric disorders with nutraceuticals and phytoceuticals: The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce - PubMed) that omega-3 supplementation is actually RECOMMENDED for depressed patients along with SSRIs (1-2g eicosapentaenoic acid a day) ...do you guys use it? What about MTHF, Vitamin D, probiotics? Am I missing something else?

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The psychiatric interview my go to tool for diagnosing depression. We use the PHQ 9 for quantitative monitoring because it is quick and pragmatic in a 30 minute followup. I test B12 in patients over 65 and correct if needed. I haven't found MTHF helpful most of the time so only look at that if a patient is indeed refractory after usual treatment and actual adherence to treatment. Many patients in my region have vitamin D deficiency and I have seen some mild improvement with correcting that so we supplement vitamin D if it is low on lab. Probiotics do not have convincing evidence but I don't waste time arguing with patients who want to take them. I haven't seen patients improve with omega-3 anecdotally unless their depression is mild to moderate and so have chalked that up to placebo effect, and the evidence on that is mixed at best and not impressive. If a patient wants to take Omega-3 I do not discourage it. Most patients I see that are refractory are refractory because they do not adhere to prescribed medication or engage seriously in therapy or continue to use alcohol, so I focus on these things. ECT is still king in effectiveness for patients with true refractory Major Depressive Disorder.

TLDR? Focus on the fundamentals, that is where you will find the most success. I do a lot of motivational interviewing and rapport building, which is more energy intensive than checking folate.
 
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I see a lot of un- or under- diagnosed iron deficiency, particularly in women, who get sent to me for "treatment resistent depression" that's actually fatigue.

OSA is also dramatically under recognized and under dignaosed. Psych meds ain't gonna help much when the brain is starved of oxygen most of the night.

Poorly controlled asthma and COPD, similarly, gosh I wonder why their "depressionanxiety" isn't getting better! Ditto heart failure.

B12 I have found useful but more in context of pts with neuropathy who feel physically better after it's treated and therefore mentally, not as primary depression treatment.

Nearly everyone in my neck of the woods is vitamin d deficient so it's basically a blanket recommendation for me, but I don't test for it generally.

Some patients have this mindset that their mental health needs to be fixed and then they'll be able to focus on their physical health. This is a false premise and it has to be dismantled via education to both pts and their pcps. I do a lot of education around restructuring priorities and taking a big picture view of what it means to feel well.
 
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I see a lot of un- or under- diagnosed iron deficiency, particularly in women, who get sent to me for "treatment resistent depression" that's actually fatigue.

OSA is also dramatically under recognized and under dignaosed. Psych meds ain't gonna help much when the brain is starved of oxygen most of the night.

Poorly controlled asthma and COPD, similarly, gosh I wonder why their "depressionanxiety" isn't getting better! Ditto heart failure.

B12 I have found useful but more in context of pts with neuropathy who feel physically better after it's treated and therefore mentally, not as primary depression treatment.

Nearly everyone in my neck of the woods is vitamin d deficient so it's basically a blanket recommendation for me, but I don't test for it generally.

Some patients have this mindset that their mental health needs to be fixed and then they'll be able to focus on their physical health. This is a false premise and it has to be dismantled via education to both pts and their pcps. I do a lot of education around restructuring priorities and taking a big picture view of what it means to feel well.
Beyond this, just general sleep hygiene/sufficient sleep is likely even more contributory nationally to depression than OSA (although I agree OSA is a top priority to r/o when sx suggest its presence).

Nourishing one's body with food adequately and regularly, preferably with close to a Mediterranean diet almost assuredly plays a role in the pathogenesis of depression.

Spending less time on social media and more time in nature as well as regular physical exercise are top flight recommendations.

All of these discussions are much higher yield than chasing minimally evidenced based vitamins/supplementation. Folate was supposed to be some mythical thing for the past 2 decades, there's a reason you don't get lunch invites for methylfolate much these days... And please God don't go chasing down testosterone levels in the average male. The number of guys who believe shooting some T is the answer to their problems is unbelievably high, we do not need physicians reinforcing that.
 
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Well done, to the above posts #2-#5.

Nailed it.

Standing applause. [Insert the Leo di caprio standing clapping gif here]
 
As for Testosterone, the data isn't supportive of it in a role for TRD or MDD. It does seem to have effect on PDD in low T populations.
 
Nourishing one's body with food adequately and regularly, preferably with close to a Mediterranean diet almost assuredly plays a role in the pathogenesis of depression.

👍 Carlat podcast has actually brought this up multiple times that Mediterranean diet has pretty good evidence for depressive symptom treatment. Way more high yield than continuing the typical crappy american diet and chasing dubious supplements.
 
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Beyond this, just general sleep hygiene/sufficient sleep is likely even more contributory nationally to depression than OSA (although I agree OSA is a top priority to r/o when sx suggest its presence).

Nourishing one's body with food adequately and regularly, preferably with close to a Mediterranean diet almost assuredly plays a role in the pathogenesis of depression.

Spending less time on social media and more time in nature as well as regular physical exercise are top flight recommendations.

All of these discussions are much higher yield than chasing minimally evidenced based vitamins/supplementation. Folate was supposed to be some mythical thing for the past 2 decades, there's a reason you don't get lunch invites for methylfolate much these days... And please God don't go chasing down testosterone levels in the average male. The number of guys who believe shooting some T is the answer to their problems is unbelievably high, we do not need physicians reinforcing that.

Re: testosterone... I have had exactly ONE guy I actually was worried his testosterone was an issue. Anxiety was vastly improved, but had low libido, reported hypogonadism, some generalized fatigue... I actually WANTED him to go talk to a urologist but he wasn't interested. I sensed some very deep seated dynamic issues around that resistance but graduated residency before I could suss it out lol.
 
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As for Testosterone, the data isn't supportive of it in a role for TRD or MDD. It does seem to have effect on PDD in low T populations.
I will say, I've had 2 cases (once in M4, once during PGY-2) where patients had severe, severe, TRD with only abnormalities being low-T (talking testosterone levels of ~50 for both). Think depression severity of staring at a ceiling all day and only eating one meal and using the bathroom, responding to questions 15 seconds after you ask it, etc. Everything was tried on these guys including 15+ sessions of ECT, stimulants, etc with minimal or no response. Started them on testosterone and was like they just woke up within a couple days of administration.

Not suggesting that we should be looking at testosterone on everyone or even most TRD cases, but those guys had near-miraculous recoveries and I do think it's worth investigating when everything else is coming back negative.
 
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I always agree that at the individual level, EBM is not always great.

Just at the systematic review / MA level, I would not generally attempt this for the TRD population. In a specific, low T population, it may be worth a shot given how low likelihood response will be after several treatment failures, and if ECT/TMS is already trialed. There was one paper I had seen back in 2020 that looked at this question generally across studies. There are so few studies that looked into it, that I had also looked at each study included individually, and scoured the methodologies. Overall, data that does exist does not support consistent effect in bonafide depression, though there seems to be effectiveness in Low T groups with persistent depressive disorder. Data quality is surprisingly good for such a small pool of studies.

I will say, I've had 2 cases (once in M4, once during PGY-2) where patients had severe, severe, TRD with only abnormalities being low-T (talking testosterone levels of ~50 for both). Think depression severity of staring at a ceiling all day and only eating one meal and using the bathroom, responding to questions 15 seconds after you ask it, etc. Everything was tried on these guys including 15+ sessions of ECT, stimulants, etc with minimal or no response. Started them on testosterone and was like they just woke up within a couple days of administration.

Not suggesting that we should be looking at testosterone on everyone or even most TRD cases, but those guys had near-miraculous recoveries and I do think it's worth investigating when everything else is coming back negative.
 
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I do many of the things already mentioned but also iron studies as iron deficiency without anemia can exacerbate and/or present with depression and anxiety. This is common in people with heavy menses
 
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I do many of the things already mentioned but also iron studies as iron deficiency without anemia can exacerbate and/or present with depression and anxiety. This is common in people with heavy menses

Low iron can also contribute to restless leg syndrome which then contributes to poor sleep quality. Iron studies and CBC are one of those low cost, possibly high yield, low treatment risk labs that I generally have a pretty low threshold to do, especially if fatigue is a persistent complaint.
 
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Low iron can also contribute to restless leg syndrome which then contributes to poor sleep quality. Iron studies and CBC are one of those low cost, possibly high yield, low treatment risk labs that I generally have a pretty low threshold to do, especially if fatigue is a persistent complaint.
Another clinical pearl is to check iron and B12/folate in anemia regardless of the MCV - so many times patients are deficient in multiple and their MCV only reflects the sum/net effects of their deficiencies.
 
I will say, I've had 2 cases (once in M4, once during PGY-2) where patients had severe, severe, TRD with only abnormalities being low-T (talking testosterone levels of ~50 for both). Think depression severity of staring at a ceiling all day and only eating one meal and using the bathroom, responding to questions 15 seconds after you ask it, etc. Everything was tried on these guys including 15+ sessions of ECT, stimulants, etc with minimal or no response. Started them on testosterone and was like they just woke up within a couple days of administration.

Not suggesting that we should be looking at testosterone on everyone or even most TRD cases, but those guys had near-miraculous recoveries and I do think it's worth investigating when everything else is coming back negative.
T levels around 50 without a history of exogenous T use historically or any other medical history pointing towards a urologic abnormality are exceptionally rare. It's a bit like saying that Vit D supplementation is helpful only for folks who levels are <5. I fully believe such a case could exist but this absolutely should be at the bottom of the a very extensive list after exactly what you described above.
 
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T levels around 50 without a history of exogenous T use historically or any other medical history pointing towards a urologic abnormality are exceptionally rare. It's a bit like saying that Vit D supplementation is helpful only for folks who levels are <5. I fully believe such a case could exist but this absolutely should be at the bottom of the a very extensive list after exactly what you described above.
Right, was just bringing up that if we're starting to look for things that are much less common or considering the million dollar work-up then ordering a testosterone level is worthwhile. If even T levels aren't that low it can still be worth a trial if they're well below normal range.


I always agree that at the individual level, EBM is not always great.

Just at the systematic review / MA level, I would not generally attempt this for the TRD population. In a specific, low T population, it may be worth a shot given how low likelihood response will be after several treatment failures, and if ECT/TMS is already trialed. There was one paper I had seen back in 2020 that looked at this question generally across studies. There are so few studies that looked into it, that I had also looked at each study included individually, and scoured the methodologies. Overall, data that does exist does not support consistent effect in bonafide depression, though there seems to be effectiveness in Low T groups with persistent depressive disorder. Data quality is surprisingly good for such a small pool of studies.
I haven't specifically looked into it, but how many TRD patients have you met that don't also have chronic depressive symptoms that would technically meet PDD criteria? Maybe I'm off base, but Idk that I can think of any TRD patients I've worked with who had acute TRD that wasn't due to either an easily identifiable, often severe and traumatic, social stressor or a separate medical issue.
 
Right, was just bringing up that if we're starting to look for things that are much less common or considering the million dollar work-up then ordering a testosterone level is worthwhile. If even T levels aren't that low it can still be worth a trial if they're well below normal range.



I haven't specifically looked into it, but how many TRD patients have you met that don't also have chronic depressive symptoms that would technically meet PDD criteria? Maybe I'm off base, but Idk that I can think of any TRD patients I've worked with who had acute TRD that wasn't due to either an easily identifiable, often severe and traumatic, social stressor or a separate medical issue.
Weird anecdote but my neighbor was the most delightful old lady who babysat for me a child and was beloved by so many. She also had episodic depressive episodes (I think with psychotic features) that were completely unmanageable with medication. She got ECT each episode and would return to her normal lovely self in-between episodes. Definitely TRD and definitely not PDD or another medical issue.
 
I haven't specifically looked into it, but how many TRD patients have you met that don't also have chronic depressive symptoms that would technically meet PDD criteria? Maybe I'm off base, but Idk that I can think of any TRD patients I've worked with who had acute TRD that wasn't due to either an easily identifiable, often severe and traumatic, social stressor or a separate medical issue.
Makes sense though. Are those folks actually PDD or are they just low T masquerading as PDD, and the symptoms meet our PDD criteria. I'm more in favor of the latter, given that chronic anergia/fatigue would be seen in a low T group, which may show up to a psychiatry office before a urologic clinic. Which to me, further evidences that mechanistically the MDD syndrome (and TRD syndrome) is overall not related to the low T syndrome, and that TRT is overall not helpful in MDD management.

However, as I suggested, when you get into a deep TRD episode, EBM breaks down anyway if you have exhausted med +augment, +ketamine/tms/ect. So at that point, why not try it if they are low T. As you suggested, there may be people out there where extraordinarily low T levels, whose symptoms are masquerading as TRD, and an SSRI just isn't going to get at the underlying issue - if it is, in fact, low T presenting as a depressive syndrome.
 
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Right, was just bringing up that if we're starting to look for things that are much less common or considering the million dollar work-up then ordering a testosterone level is worthwhile. If even T levels aren't that low it can still be worth a trial if they're well below normal range.



I haven't specifically looked into it, but how many TRD patients have you met that don't also have chronic depressive symptoms that would technically meet PDD criteria? Maybe I'm off base, but Idk that I can think of any TRD patients I've worked with who had acute TRD that wasn't due to either an easily identifiable, often severe and traumatic, social stressor or a separate medical issue.
What you describe is certainly a compelling case for treating the patient with testosterone. I'm curious, given the degree to which testosterone levels fluctuate during the day, did you test multiple times or just once before deciding to treat? And how did you determine appropriate dose? It sounds like this was inpatient, who took over prescribing at discharge?
 
Weird anecdote but my neighbor was the most delightful old lady who babysat for me a child and was beloved by so many. She also had episodic depressive episodes (I think with psychotic features) that were completely unmanageable with medication. She got ECT each episode and would return to her normal lovely self in-between episodes. Definitely TRD and definitely not PDD or another medical issue.
Yes, but Idk that I'd call that true TRD if ECT is consistently and significantly effective unless we're talking about needing 20+ sessions. Medication-resistant, sure. However, to me TRD means true treatment resistance, not the bs definition of "failed 3 meds" that may all be SSRIs that is the medico-legal definition.

What you describe is certainly a compelling case for treating the patient with testosterone. I'm curious, given the degree to which testosterone levels fluctuate during the day, did you test multiple times or just once before deciding to treat? And how did you determine appropriate dose? It sounds like this was inpatient, who took over prescribing at discharge?
I don't recall the levels in the M4 case. I remember the guy was on the unit for 3-4 months prior, everything was negative other than low-T, he'd had around 25 or 30 sessions of ECT with almost no improvement. Guy would literally spend the entire day laying in bed staring at the ceiling and only getting up to eat a small breakfast and use the bathroom. Was initially offered testosterone replacement but declined because he didn't want to take more pills or other forms, but I talked to him about IM and he was agreeable. Within a few days he was walking around the unit, eating 3 meals, grossly functioning. Still had high depression and some severe psychological distress but was functional. Idk who took over after d/c.

The PGY-2 case has actually been discussed on this forum previously, but patient was one of the most severe cases I've seen along with the first one here. Not only did he have severe depression, but also the only case of transient global amnesia I've been confident about (was amnestic for about 8 months). Initial T level was low, consulted endocrine/uro who retested and turned out levels were truly low. They recommended not treating until he'd been outpatient for at least 6-8 weeks as they said that T levels can come back falsely low during hospitalization, however they didn't specify if that was medical or psych hospitalizations. We decided to go ahead an treat against their advice (probably the only time I can recall directly going against a consultants' advice) because he'd been there for months, had already failed at least 6 or 7 meds including TCAs, antipsychotics, stimulants, and benzos for possible catatonia. He also had 10-15 ECT sessions with no change whatsoever. Idr the dose, but after it was started he began to improve within days and was close to his baseline within about a week. We referred him to both outpatient psych as well as endocrine for outpatient f/up. Interestingly, the guy was readmitted 1-2 months later for suspected hypomania, which self-resolved after admission.
 
What you describe is certainly a compelling case for treating the patient with testosterone. I'm curious, given the degree to which testosterone levels fluctuate during the day, did you test multiple times or just once before deciding to treat? And how did you determine appropriate dose? It sounds like this was inpatient, who took over prescribing at discharge?
If you're genuinely curious, here's a good link: Testosterone Therapy for Hypogonadism Guideline Resources

Otherwise, just send to either us in primary care or urology. Some endocrinologists will do this, some will not.
 
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DRUG CLASS/DRUG

LEVEL OF EVIDENCE

AVAILABLE LITERATURE

COMMENTS

REFERENCES

**Reflects authors’ global assessment of evidence; --- little or no convincing evidence; +/- limited evidence; + moderately strong evidence; ++ strong evidence; +++ very strong/unequivocal evidence

KEY​

ACEangiotensin-converting enzymeARBsangiotensin II blockersBPHbenign prostatic hyperplasiaDIDdrug-induced depressionFAAFederal Aviation AdministrationFDAUS Food and Drug AdministrationRCTrandomized, controlled trial
Beta blockers
+/-​
Case reports, RCTs, large scale meta-analysesEvidence is conflicting—propranolol may have the strongest association with symptoms after starting or increasing dose.13, 16, 30–41
Calcium channel blockers
+/-​
Case reports, case series, prescription symmetry analysis, cohort study examining suicide ratesResults are conflicting—newer agents have fewer reports.42–48
ACE inhibitors
+/-​
Prescription symmetry analysisSome reports have found antidepressant effects.46, 49–51
ARBs
+/-​
Case reportsPreliminary data suggest some ARBs may have antidepressant effects.52, 53
Antiobesity drugs: rimonabant, taranabant
++​
Case reports, meta-analysesNeither agent approved in US. Taranabant is no longer being developed due to psychiatric side effects.54–56
Alpha interferons
++​
Uncontrolled and controlled studiesNo comment57–61
Beta interferons
---​
4 RCTs and 1 naturalistic studyNo comment62–67
Finasteride
+​
Case series, prospective noncontrolled trialEvidence of DID only exists for men treated for alopecia; no evidence for BPH, but caution warranted, given high doses69, 70
Isotretinoin
+++​
Over 400 case reports, prescription symmetry analysis, case-crossover studyNo comment71–74
Progesterone inserts (Norplant®)
+​
Case reports, case series, large trialsLarge trials suggest that women with higher baseline depressive scores may be at risk as well as women with relationship dissatisfaction75–81
Leukotriene antagonists (montelukast)
+/-​
Collection of single case reports; 3 double-blind RCTsConflicting data—cases suggest association; recent analysis of 3 RCTs found no association82–84
Corticosteroids
+​
Case control study, cross-sectional analysisResults of trials are suggestive of DID, especially in patients aged >65, but not conclusive85–88
Varenicline
+​
Case reports, case seriesEnhanced FDA warnings—banned by the FAA; increased anxiety reported in 1 placebo RCT.




Rogers, D. and R. Pies (2008). "General medical with depression drugs associated." Psychiatry 5(12): 28-41.
 
Isotretinoin +++, no comment. So spot on lmao.
 
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Isotretinoin +++, no comment. So spot on lmao.

Except there's newer meta-analyses and studies that show that isotretinoin doesn't seem to be associated with a higher risk of depression. So I'd say not so spot on.

This "study" also just seems to be two guys giving their opinions on med classes.
 
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Except there's newer meta-analyses and studies that show that isotretinoin doesn't seem to be associated with a higher risk of depression. So I'd say not so spot on.

This "study" also just seems to be two guys giving their opinions on med classes.
I have seen multiple cases of severe SI that resolved with people coming off of it and that did not exist prior to going onto it. Clearly just my n=1 anecdote, but if my child gets problematic acne it would certainly be low on the list of what I would want them to use.
 
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I have seen multiple cases of severe SI that resolved with people coming off of it and that did not exist prior to going onto it. Clearly just my n=1 anecdote, but if my child gets problematic acne it would certainly be low on the list of what I would want them to use.
Its typically reserved for either treatment resistant cases or very severe, usually cystic, acne because of its side effect profile/birth defect risk.
 
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I have seen multiple cases of severe SI that resolved with people coming off of it and that did not exist prior to going onto it. Clearly just my n=1 anecdote, but if my child gets problematic acne it would certainly be low on the list of what I would want them to use.

I’ve also seen that a couple times and I’ve also had kids who did just fine on it. So yeah, anecdotes both ways for me too but not sure it’s fair at this point to give it a royal “3 plus signs”. I don’t see derm typically go to it anyway unless multiple trials have been unsuccessful previously. The major confounder of course in this particular area is that severe acne itself is highly likely to be significantly distressing.

Its typically reserved for either treatment resistant cases or very severe, usually cystic, acne because of its side effect profile/birth defect risk.

The birth defect risk is absolutely unequivocal and extremely high but that’s why the whole iPledge program exists and they make females have 2 forms of birth control. I wouldn’t put depressive sx and SI as the same level of risk for birth defects though.
 
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