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Dr. Bob is Robert Hsiung, MD,
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Posted by floatingbridge on August 14, 2010, at 2:37:58
In reply to Treatment Resistant Depression., posted by bleauberry on August 13, 2010, at 19:33:52
Unofficially, seems that opoid response could be noticed (and noted) in a patient. We know from previous babble threads that not all respond. Well, I guess that could mean the person does not 'process' opoids (oh please forgive the complete lack of scientific language). So I guess I just wrote myself out of that :)
So, exercise, (good) sex, meditation, love, laughter increase endorphines. Easier to accomplish when feeling good. Anything else?
LDN?
Posted by SLS on August 14, 2010, at 4:43:23
In reply to Re: Treatment Resistant Depression., posted by linkadge on August 13, 2010, at 19:42:23
> I think TRD is probably related to mitochondrial decay, glial reductions, prefronal atrophy, decreased limbic interconnectivity, enlarged amygdala volume, decreased cortical grey matter, white matter hyperintensities, vascular insufficiancy etc. etc.
You've been reading again!
No fair!
Good stuff.
- Scott
Posted by bleauberry on August 14, 2010, at 8:06:05
In reply to Re: Treatment Resistant Depression., posted by linkadge on August 13, 2010, at 19:42:23
I totally agree with you LInk. The things you mentioned though are so hard, if not impossible, to identify, diagnose, or validate. But doing all that with the endorphin system, well, even a caveman could do it. My point is I don't get it...why all the hoopla on selected neurotransmitters as if they were everything there is in depression...but no mention of the big player endorphins. And no mention of all the things you listed either. Instead, keep pounding the serotonin-n-friends drugs despite they fail one after another after another. Kind of like trying to sift for gold in about a 10 foot area of a stream but not daring to go further upstream or downstream. So what if you can't find any gold in that 10 feet, keep looking there. Ya know? I'm just saying the endorphin system is a big player but that unlike the other systems it is very easy to test.
> I think its more complicated than that. I think that TRD is more hardwired.
>
> "You can mess around all you want with serotonin, norepinephrine, dopamine etc. but if you don't have the right circutry in place, its not going to do anything" - a quote by Dr. Manjii.
>
> I think TRD is probably related to mitochondrial decay, glial reductions, prefronal atrophy, decreased limbic interconnectivity, enlarged amygdala volume, decreased cortical grey matter, white matter hyperintensities, vascular insufficiancy etc. etc.
>
> I personally think its a myth to believe that some magic chemical is going to come along and make it all better. It may take years of rehabilitative therapty for the brain to overcome such alterations.
>
> Linakadge
>
>
>
>
>
Posted by bleauberry on August 14, 2010, at 8:25:18
In reply to Re: Treatment Resistant Depression., posted by ed_uk2010 on August 13, 2010, at 22:35:06
Well, this is not really true. Yes, opioids do exert psychoactive effects. However, those effects differ. Some people become dysphoric. They don't need more endorphins help. Some people become euphoric...they also do not need endorphin help...they are just getting high from the excess. Other people however go from depressed to normal...pure normal...not high, not drugged, not euphoric, just plain normal...THAT is an easy diagnosis.
As far as the acceptance of something as a diagnostic tool, I personally could care less what academia accepts or not. They are so far removed from the real world they live in theory textbooks and statistics. More often than not, their conclusions of today are proven wrong 10 years from today. Many diagnostic tests of all kinds have errors, false negatives, false positives, and are prone to subjective interpretation or faulty interpretation. I don't trust em. They are not the gods many people see them as. They are not the authority and certainly not mine. If someone wants to wait for something to become "accepted" or "scientifically validated" (even there full of errors) they are going to probably remain ill for a very long time waiting. I guess overall what I am saying is that our depression and our health is in nobody's hands except our own. It is no one else's baby. A doctor can sure help and guide things, but it is not his baby. It's your life, my life, and we are responsible. For me to not take action in ruling in or ruling out something as simple as the endorphin hypothesis is irresponsible. IMO.
Vicodin is a diagnostic tool. It can rule in or rule out a suspect chemistry by observing the resulting behavior comparing pre-drug and during-drug. In the manner described above. Two doctors at my post op followup said they have seen papers recently of opioids treating depression, so they were not surprised at the idea. To them, it is already scientifically validated because it was in their medical journals, and to them is probably not quite accepted but at least in an open minded direction. No matter how much something is validated, there will always be a group of critics claiming the opposite. In the meantime, people stay sick.
If someone just doesn't want to mess with a full blown opioid, fine, they can still do some pretty good detective work with DPA, DLPA, LDN. Which years into TRD makes more sense than yet another antidepressant.
Ok, let's just take your position at face value and accept it. Ok, so someone has TRD, is given vicodin for surgery, experiences profound relief of depression and even some euphoria. Ok, opioids can do that. Doesn't mean anything. Except that...LDN or DLPA have a very high likelihood of coming close to the same result...a patient free of depression...because those substances work on the same chemistry as vicodin. That same patient staying instead with the ssris, antipsychotics, and mood stabilzers, is probably going to remain ill for a long time.
>
> In order for something to gain acceptance as a diagnostic tool, its usefulness has to have been scientifically validated. Vicodin is not a diagnostic tool for anything except response to Vicodin :) Opioids frequently produce mood changes, elevation or otherwise, regardless of whether the person who took the drug is suffering from depression or not.
>
>
Posted by bleauberry on August 14, 2010, at 8:31:19
In reply to Re: Treatment Resistant Depression. » bleauberry, posted by floatingbridge on August 14, 2010, at 2:37:58
> So, exercise, (good) sex, meditation, love, laughter increase endorphines. Easier to accomplish when feeling good. Anything else?
>
> LDN?The ones I am aware of are:
LDN
DLPA
DPA
AccupunctureTramadol is handed out like candy, and gets rave reviews in depression, so that is a possibility as long as someone doesn't mind the word addiction as being a part of living a productive life free of depression. But it has other mechanisms as SNRI, which complicates it. Me, positive response to vicodin, horrible rersponse to tramadol, modest response LDn or DLPA (even modest is a million miles better than all the cocktails were able to achieve).
Posted by ed_uk2010 on August 14, 2010, at 8:58:20
In reply to Re: Treatment Resistant Depression. » ed_uk2010, posted by bleauberry on August 14, 2010, at 8:25:18
>Some people become dysphoric. They don't need more endorphins help.
Some of the people who become dysphoric after a single dose become euphoric after repeated doses. In the same way that response to an SSRI does not prove that a person has serotonin deficiency, response to an opioid does not prove that a person has endorphin deficiency. It's unwise to presume that we understand so much.
>Other people however go from depressed to normal...pure normal...not high, not drugged, not euphoric, just plain normal...THAT is an easy diagnosis.
It's not a diagnosis, it's an assumption - an assumption that endorphin deficiency is the underlying problem. Again, it is unwise to presume that we understand the mechanisms behind such a response. Unfortunately, an excellent acute response to an opioid does not mean that the benefits will last. They might do, or they might not. I think that's the same with just about everything ie. the long term response it impossible to predict with any accuracy.
>Except that...LDN or DLPA have a very high likelihood of coming close to the same result...
I doubt that a response to Vicodin can predict response to LDN or DLPA. LDN, opioid agonists and DLPA have different mechanisms of action. A response to Vicodin might predict a response to say, oxycodone, because these drugs have the same mechanism of action.
>That same patient staying instead with the ssris, antipsychotics, and mood stabilzers, is probably going to remain ill for a long time.
I fully understand the need for new and novel treatments for psychiatric illness. I do not dispute that.
I think you have a tendency to present theory as if it were fact. This is what I disagree with.
Posted by sigismund on August 14, 2010, at 19:14:31
In reply to Re: Treatment Resistant Depression. » bleauberry, posted by ed_uk2010 on August 14, 2010, at 8:58:20
>It's not a diagnosis, it's an assumption - an assumption that endorphin deficiency is the underlying problem. Again, it is unwise to presume that we understand the mechanisms behind such a response. Unfortunately, an excellent acute response to an opioid does not mean that the benefits will last. They might do, or they might not. I think that's the same with just about everything ie. the long term response it impossible to predict with any accuracy.
Just like the neurotransmitter theory of depression?
I said to my shrink that the neurotransmitter hypothesis was dead and he perked up immediately and then we talked about psychopaths in high places.
Posted by emmanuel98 on August 14, 2010, at 19:52:55
In reply to Re: Treatment Resistant Depression. » ed_uk2010, posted by sigismund on August 14, 2010, at 19:14:31
I was in the hospital and doing a two-week washout from ensam so I could start parnate. I was severely depressed. I asked the p-doc there if I could try suboxone. Opiates kept my depression at bay for five years (self-precribed, using higher and higher dosages. I got off them by working with a suboxone doctor). Suboxone can't be used to OD (contains naltrexone) and it's hard to use higher and higher dosages also because of the naltrexone and because it's taken sublingually and because precriptions are carefully monitored. She said she would consult about it, but by that time, I was on parnate and felt fine within 48 hours.
Posted by bleauberry on August 15, 2010, at 12:06:34
In reply to Re: Treatment Resistant Depression. » bleauberry, posted by ed_uk2010 on August 14, 2010, at 8:58:20
I agree with everything you have said. In fact, everything stated could apply equally as well to a discussion of any other neurotransmitter or drug. But all that was off the path. It appears that the primary body of the message was completely missed. Took some sidepaths and completely lost the main road.
> >Some people become dysphoric. They don't need more endorphins help.
>
> Some of the people who become dysphoric after a single dose become euphoric after repeated doses. In the same way that response to an SSRI does not prove that a person has serotonin deficiency, response to an opioid does not prove that a person has endorphin deficiency. It's unwise to presume that we understand so much.
>
> >Other people however go from depressed to normal...pure normal...not high, not drugged, not euphoric, just plain normal...THAT is an easy diagnosis.
>
> It's not a diagnosis, it's an assumption - an assumption that endorphin deficiency is the underlying problem. Again, it is unwise to presume that we understand the mechanisms behind such a response. Unfortunately, an excellent acute response to an opioid does not mean that the benefits will last. They might do, or they might not. I think that's the same with just about everything ie. the long term response it impossible to predict with any accuracy.
>
> >Except that...LDN or DLPA have a very high likelihood of coming close to the same result...
>
> I doubt that a response to Vicodin can predict response to LDN or DLPA. LDN, opioid agonists and DLPA have different mechanisms of action. A response to Vicodin might predict a response to say, oxycodone, because these drugs have the same mechanism of action.
>
> >That same patient staying instead with the ssris, antipsychotics, and mood stabilzers, is probably going to remain ill for a long time.
>
> I fully understand the need for new and novel treatments for psychiatric illness. I do not dispute that.
>
> I think you have a tendency to present theory as if it were fact. This is what I disagree with.
>
Posted by ed_uk2010 on August 15, 2010, at 13:50:28
In reply to Re: Treatment Resistant Depression. » ed_uk2010, posted by bleauberry on August 15, 2010, at 12:06:34
>But all that was off the path. It appears that the primary body of the message was completely missed. Took some sidepaths and completely lost the main road.
I think the message is that we should be willing to try something different and novel when the usual treatments haven't helped? Trying the 6th SSRI after 5 haven't worked isn't likely to be effective!
Posted by linkadge on August 15, 2010, at 21:15:48
In reply to Re: Treatment Resistant Depression. » linkadge, posted by ed_uk2010 on August 13, 2010, at 22:35:57
>Sounds like dementia!
Exactly.
Linkadge
Posted by linkadge on August 15, 2010, at 21:23:25
In reply to Re: Treatment Resistant Depression. » bleauberry, posted by ed_uk2010 on August 15, 2010, at 13:50:28
Opiates like codiene and morphine act as fairly potent sigma-1r agonists. Sigma agonists have documented antidepressant, anxiolytic and cognitive enhancing effects.
Whose to say that the "AD" effect of opiates is not related to other targets of select opiates?
As eluded to, some studies suggest increased opioid like activity in depression. Socially defeated "depressed" animals show increased MU opioid neurotransmission.
Linkadge
Posted by Phillipa on August 15, 2010, at 21:34:33
In reply to Re: Opiates as sigma agonists, posted by linkadge on August 15, 2010, at 21:23:25
All I know is one percocet had me laughing and that is all I took the days was on them. Dumb docs. Phillipa
Posted by SLS on August 16, 2010, at 4:55:08
In reply to Re: Opiates as sigma agonists, posted by linkadge on August 15, 2010, at 21:23:25
> As eluded to, some studies suggest increased opioid like activity in depression. Socially defeated "depressed" animals show increased MU opioid neurotransmission.
Do you think that this might be an effect secondary to the stimulus rather than a cause of the depression? Perhaps the numbing effect of opioidergic neurotransmission is protective against psychic pain. Just thinking...
- Scott
Posted by violette on August 16, 2010, at 8:33:24
In reply to Re: Opiates as sigma agonists » linkadge, posted by SLS on August 16, 2010, at 4:55:08
"Perhaps the numbing effect of opioidergic neurotransmission is protective against psychic pain. Just thinking"
That's true, Scott. Unsure if this is in context with what Linkadge said (?), but it is true that the brain releases opoids when psychic pain is too overwhelming - dissociation is a primary example.
If at a young age you experienced overwhelming psychic pain leading to repeated dissociation (I have) the brain's 'hardwiring' does not develop as a normal child's.
Posted by floatingbridge on August 16, 2010, at 11:39:29
In reply to Re: Opiates as sigma agonists » linkadge, posted by SLS on August 16, 2010, at 4:55:08
Interesting discussion. Higher percentage of addicts w/ histories of abuse...?
Posted by sigismund on August 16, 2010, at 13:48:28
In reply to Re: Opiates as sigma agonists » linkadge, posted by SLS on August 16, 2010, at 4:55:08
> Perhaps the numbing effect of opioidergic neurotransmission is protective against psychic pain. Just thinking...
I wish it bloody well worked.
Posted by sigismund on August 16, 2010, at 13:53:21
In reply to Re: Opiates as sigma agonists » SLS, posted by violette on August 16, 2010, at 8:33:24
>That's true, Scott. Unsure if this is in context with what Linkadge said (?), but it is true that the brain releases opoids when psychic pain is too overwhelming - dissociation is a primary example.
>If at a young age you experienced overwhelming psychic pain leading to repeated dissociation (I have) the brain's 'hardwiring' does not develop as a normal child's.
Certainly people in extreme mental states can find ways of comforting themselves, rocking themselves to sleep and developing bony calluses on the foreheads like autistic or deprived kids do, losing themselves in sounds they make and other things, fascinating, isn't it?
There's that theory about autism and some milk protein which acts on opiate receptors?
Posted by ed_uk2010 on August 16, 2010, at 16:34:20
In reply to Re: Treatment Resistant Depression. » ed_uk2010, posted by sigismund on August 14, 2010, at 19:14:31
>I said to my shrink that the neurotransmitter hypothesis was dead and he perked up immediately...
Well yeah, depression is complex. Depression is not a single condition, it's a group of conditions which have similar symptoms. There are probably many different causes. Anyone who claims that 'depression is caused by low serotonin' clearly has no idea what they are talking about. Even if a subset of patients were found to have low serotonin (difficult to measure), this obviously won't apply to everyone. SSRIs are known to be effective for a proportion of cases of depression. This does not, however, prove that low serotonin was the cause of their illness. This sort of backwards logic is not very scientific. Opioids are effective for pain but that doesn't mean that the pain was caused by low endorphins!
Posted by sigismund on August 16, 2010, at 20:22:02
In reply to Re: Treatment Resistant Depression. » sigismund, posted by ed_uk2010 on August 16, 2010, at 16:34:20
> Opioids are effective for pain but that doesn't mean that the pain was caused by low endorphins!
If it's good enough for serotonin, it's good enough for opiates :)
I'd trade 95% (too low?) of psych drugs for opium.
These days I might even be able to use it twice a week, you know, if I hadn't etc etc etc
Posted by linkadge on August 16, 2010, at 21:46:24
In reply to Re: Treatment Resistant Depression. » ed_uk2010, posted by sigismund on August 16, 2010, at 20:22:02
SSRIs actually don't raise serotonin
"In this study, we demonstrate that chronic treatment with citalopram, a widely prescribed and highly selective SERT inhibitor [3], [26], causes a suppression of 5-HT synthesis in the mouse brain"
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0006797
Linkadge
Posted by europerep on August 17, 2010, at 14:16:04
In reply to Re: Treatment Resistant Depression. » bleauberry, posted by ed_uk2010 on August 14, 2010, at 8:58:20
> It's not a diagnosis, it's an assumption - an assumption that endorphin deficiency is the underlying problem. Again, it is unwise to presume that we understand the mechanisms behind such a response.
>
> I think you have a tendency to present theory as if it were fact.
>but ed, I am sure you know all about dr. bodkin's "experiments" with buprenorphine back in the 20th century (haha), and he's still practicing it.. delta agonists have clearly been shown to exhibit antidepressant effects in mice, some tricyclics (definitely amitriptyline and nortriptyline) increase endogenous activity at delta receptors which contributed to their usefulness in pain, but very probably also to their high efficacy in depression, and one could go on like that.. these are facts, and I guess there is not one statement on here with which I agree more than when bleauberry said it would be irresponsible to not add the endogenous opioid system into the equation.. some patients with TRD show totally paradox reactions to opioids, i.e. feeling normal as was said, but also having less problems going off of them.. I didn't talk about it much because I wanted to make one comprehensive post about it, right now I just do not have the energy for it: I did try buprenorphine for the past 4 months, dosage up to 9mg/d (maximum in TRD is around 12mg/d).. it DID work in the beginning, and that was NOT due to the general opioid euphoria.. this euphoria is mu-receptor-mediated, and buprenorphine plasme levels peak at 45min to 1 hour after intake (sublingual).. also, "recreational" users say the effect is strongest at about an hour.. my improvement started some 4-5 hours after taking it - and subsided some 4-5 hours later.. I was very confused, until I found out that the response I had was basically identical to the plasma level over time-curve of nurbuprenorphine, the active metabolite, which is a delta-agonist.. but it has a much much shorter halflife, and so the effect disappeared quickly.. unfortunately I was not able to reproduce it after the first one to two weeks.. now I wonder what conclusions to draw from that... also, I was not "high", I cleaned up my kitchen for the first time in quite some time, and I did not only finish what I set as a target, but I looked for something else to do because I was quicker than I expected.. now I say I do "this", and ten minutes into it I am just unable to go on.. this is so disappointing... unfortunately, I think that there is no specific delta-agonist that I could try out to verify my hypothesis... but I have no doubt that there is something about it, and I think it's more than just a hypothesis that has yet to prove it's value.. it's by far no solution for everyone as I just experienced, but it is a solution for some... it scares me that it isn't one for me, who knows what will work instead, or if anything will work at all...
Posted by sigismund on August 17, 2010, at 17:16:44
In reply to Re: Treatment Resistant Depression. » ed_uk2010, posted by europerep on August 17, 2010, at 14:16:04
That was all very interesting.
Certainly what you say here.........
>. it DID work in the beginning, and that was NOT due to the general opioid euphoria.. this euphoria is mu-receptor-mediated, and buprenorphine plasme levels peak at 45min to 1 hour after intake (sublingual).. also, "recreational" users say the effect is strongest at about an hour.. my improvement started some 4-5 hours after taking it - and subsided some 4-5 hours later.
is broadly consistent with what people on bupe maintenance report as compared with methadone maintenance...that it is less depressing.
As you would know, a proportion of such people are self-medicating for depression.
Posted by linkadge on August 17, 2010, at 20:11:55
In reply to Re: Treatment Resistant Depression. » europerep, posted by sigismund on August 17, 2010, at 17:16:44
The tcas also have kappa agonism and NMDA antagonism. This might produce an anti-tollerance effect.
Posted by europerep on August 18, 2010, at 14:22:44
In reply to Re: Treatment Resistant Depression., posted by linkadge on August 17, 2010, at 20:11:55
> The tcas also have kappa agonism and NMDA antagonism. This might produce an anti-tollerance effect.
>
kappa-agonism is bad though.. well, talk about reductionism, but, in general kappa-agonism produces dysphoria.. that's why the development of kappa agonists for non-mu-pain medication was not pursued.. kappa-antagonism may be good, well it very probably is, and guess what, buprenorphine is a kappa-antagonist..also, what I forgot to say yesterday, going down from 9mg to doses less than a mg in rather quick steps produced absolutely no withdrawal in me.. I wanted to get rid off it even quicker to start a new med, but I told myself to be patient, not take a risk of withdrawal and not disturb my endogenous opioids too much by quitting all at once..
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