Low dose imipramine for multiple functional somatic syndromes

[Daisymay]

Lancet Psychiatry. 2017 Apr 10. pii: S2215-0366(17)30126-8. doi: 10.1016/S2215-0366(17)30126-8. [Epub ahead of print]
Imipramine versus placebo for multiple functional somatic syndromes (STreSS-3): a double-blind, randomised study.
Agger JL1, Schröder A2, Gormsen LK3, Jensen JS2, Jensen TS4, Fink PK2.
Author information

Abstract
BACKGROUND:
Functional somatic syndromes, including chronic fatigue syndrome or irritable bowel syndrome, often co-exist. Treatment guidelines supported by high quality evidence exist for most functional somatic syndromes, but are lacking for multiple comorbid functional somatic syndromes. We aimed to assess the effect of the tricyclic antidepressant, imipramine, in patients with multiple functional somatic syndromes defined by the criteria for multiorgan bodily distress syndrome, a unifying diagnosis that encompasses most functional somatic syndromes and somatoform disorders.

METHODS:
In this single-centre, double-blind, randomised trial done in a Danish university hospital setting, participants were patients consecutively referred (age 20-50 years) fulfilling criteria for multiorgan bodily distress syndrome with no concurrent comorbid depression or anxiety disorder. Participants were randomly assigned (1:1) to receive either 10 weeks of low-dose imipramine or placebo (oral daily doses of 25-75 mg). The hospital pharmacy handled randomisation (computer-generated) and masking, providing sequentially numbered packs of study drug that were given serially to the participants. All others involved were masked to allocation. Primary outcome was patient-rated overall health improvement on a 5-point clinical global improvement scale. Improvement was defined as patients responding "better" or "much better" as opposed to "unchanged" and "worse" or "much worse" when rating their overall health status after 10 weeks of minimum 25 mg study drug. Analyses included patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01518634.

FINDINGS:
Between Jan 30, 2012, and Nov 24, 2014, 138 patients were randomly assigned; 70 to receive imipramine and 68 to receive placebo. The study was completed on May 1, 2015. 125 patients received at least one dose of study drug: 65 received imipramine and 60 received placebo. Treatment was terminated prematurely for eight (12%) patients receiving imipramine and seven (12%) patients receiving placebo. Data were missing for two (3%) patients receiving imipramine and three (5%) patients receiving placebo. Of the 120 patients (96%) who provided primary outcome data, 33 (53%) receiving imipramine reported their overall health status as "better" or "much better" compared with 14 patients (25%) receiving placebo. The improvement after imipramine was significantly greater than after placebo (odds ratio 3·3 [95% CI 1·6-6·8]; p=0·001). Number needed to treat was 3·6 (95% CI 2·3-8·9). Analysis of the worst-case scenario for patients with missing outcome did not change the interpretation of the results. 32 patients (49%) receiving imipramine and 10 patients (17%) receiving placebo had at least one adverse event of moderate intensity (p=0·0001); eight patients (12%) receiving imipramine and three patients (5%) receiving placebo had at least one adverse event of severe intensity (p=0·1496). One patient (1%) receiving placebo experienced a serious adverse event (a subdural haematoma sustained after an accident). Adverse events caused dropout in four patients (6%) receiving imipramine and three patients (5%) receiving placebo.

INTERPRETATION:
Imipramine treatment compared with placebo significantly improved overall health in patients with multiple functional somatic syndromes when both treatments were supported by regular contacts with clinicians. Adverse events were more common in the imipramine group, but only rarely led to discontinuation of treatment.

FUNDING:
The Danish Foundation, Trygfonden.

 

[Snowdrop]

For those of us who are clueless as to what Imipramine is:

https://www.drugbank.ca/drugs/DB00458

 

[hixxy]

CFS and IBS are associated with aberrant mast cells and its possible other functional somatic syndromes are as well . A likely reason for these improvements is the anti-histamine effect of imipramine rather than its anti-depressant effect.

 

[Effi]

Agger JL1, Schröder A2, Gormsen LK3, Jensen JS2, Jensen TS4, Fink PK2.

 

[Snowdrop]

CFS and IBS are associated with aberrant mast cells and its possible other functional somatic syndromes are as well . A likely reason for these improvements is the anti-histamine effect of imipramine rather than its anti-depressant effect.

If this is true then could someone leave a comment in the comments section? Or is that for subscribers?

ETA: I don't see where the drug is described as having an effect on histamine.

 

[hixxy]

@Snowdrop Says it on wikipedia and most TCAs do have an effect on histamine anyway.

 

[Snowdrop]

Ahh, OK. I see that an acknowledged action of the drug is also as a histamine antagonist.

 

[dreampop]

Also, didn't the Light's find that the brain is stuck with excessive delta waves in me/cfs? Wikipedia says it shortens delta wave time in sleep, so maybe its due to that. I would be happy to try it if it didn't cause orthostatic hypotension.

 

[GreyOwl]

CFS and IBS are associated with aberrant mast cells and its possible other functional somatic syndromes are as well . A likely reason for these improvements is the anti-histamine effect of imipramine rather than its anti-depressant effect.

It's also a calcium channel blocker, and I'm intrigued by this at the moment.

 

[Sidereal]

CFS and IBS are associated with aberrant mast cells and its possible other functional somatic syndromes are as well . A likely reason for these improvements is the anti-histamine effect of imipramine rather than its anti-depressant effect.

I agree. It's notable that low dose tricyclics can sometimes be helpful in conditions such as ME/CFS, IBS and MCAS where aberrant mast cells are involved but regular doses of tricyclics (not to mention SSRIs/SNRIs) tend to make things worse. This would suggest that the antidepressant (serotonergic) effects of these drugs are harmful while the antihistaminergic and/or anticholinergic "side effects" of tricyclics are producing the benefits, just as you would expect if mast cell degranulation were playing a role in the many weird & varied symptoms. I think trials such as this one should incorporate a H1 antagonist only arm to dissociate the antidepressant effect from the antihistamine effect of these antidepressants. Say, impiramine vs diphenhydramine vs placebo. If an antihistamine is as useful as the tricyclic, it would remove the tendentious interpretation of these data which is that these conditions are a variant of depression.

 

[GreyOwl]

I agree. It's notable that low dose tricyclics can sometimes be helpful in conditions such as ME/CFS, IBS and MCAS where aberrant mast cells are involved but regular doses of tricyclics (not to mention SSRIs/SNRIs) tend to make things worse. This would suggest that the antidepressant (serotonergic) effects of these drugs are harmful while the antihistaminergic and/or anticholinergic "side effects" of tricyclics are producing the benefits, just as you would expect if mast cell degranulation were playing a role in the many weird & varied symptoms. I think trials such as this one should incorporate a H1 antagonist only arm to dissociate the antidepressant effect from the antihistamine effect of these antidepressants. Say, impiramine vs diphenhydramine vs placebo. If an antihistamine is as useful as the tricyclic, it would remove the tendentious interpretation of these data which is that these conditions are a variant of depression.

Anti-cholinergics can be a problem though, so I wonder whether the arms of your theoretical study should include an antihistamine such as cetirizine which does not interfere with the cholinergic system.

 

[cigana]

I didn't notice any improvement when on imipramine, if anything I felt worse.

 

[CFS_for_19_years]

Full text here:

http://sci-hub.cc/10.1016/S2215-0366(17)30126-8

 

[Sidereal]

Anti-cholinergics can be a problem though, so I wonder whether the arms of your theoretical study should include an antihistamine such as cetirizine which does not interfere with the cholinergic system.

Yeah. It can also be of slight benefit to some. You're right, it would be good to have an antihistamine that doesn't do both.

 

[Prefect]

Anti-cholinergics can be a problem though, so I wonder whether the arms of your theoretical study should include an antihistamine such as cetirizine which does not interfere with the cholinergic system.

It says Cetirizine doesn't cross the blood brain barrier. If many of your symptoms are due to action of histamine on sensory receptors (such as those in the vestibular system) would it still work?

What about Claritin? It's supposed to be non-drowsy.

I'm very interested in this because since my SSRI pooped out I have major vestibular sensory overload that makes me anxious (and in turn the tension the anxiety creates may be causing it all to get worse or even give me vestibular migraines) and have been wondering if I should try an antihistamine.

I don't want to try the crazy antihistamine diets that get suggested around here, it pretty much eliminates everything and is likely unproved.

 

[Solstice]

It says Cetirizine doesn't cross the blood brain barrier. If many of your symptoms are due to action of histamine on sensory receptors (such as those in the vestibular system) would it still work?

What about Claritin? It's supposed to be non-drowsy.

I'm very interested in this because since my SSRI pooped out I have major vestibular sensory overload that makes me anxious (and in turn the tension the anxiety creates may be causing it all to get worse or even give me vestibular migraines) and have been wondering if I should try an antihistamine.

I don't want to try the crazy antihistamine diets that get suggested around here, it pretty much eliminates everything and is likely unproved.

I'm on a pretty strict diet which helps heeps. Brain fog, pain, gut all are better whilst on it. If I eat something I shouldn't be eating I notice it immediately whether I know upfront it's in my meal or not. I'm also on cetirizine and daosin which helps a little too. It's in no way a cure though, atleast not for me. It just makes the days more bearable.