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Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 43 to 67 of 67. Go back in thread:
Posted by hello123 on January 28, 2015, at 18:45:12
In reply to Re: feeling like im out of options » hello123, posted by europerep on January 28, 2015, at 16:50:02
"namely decades of successful use by experienced clinicians -- you dismiss anyway."
and the last clinician i talked to, with her decades of experience, insists Emsam at its lowest dose, has all the same interactions with foods as oral Selegiline. and when i mentioned to her a doc prescribed Ketamine for my Depression in the past, she said she had never heard of it being used for Depression.
and a couple of years ago when i mentioned to the same psychiatrist that i will be seeing on 2/10, that Wellbutrin actually caused a decrease in my libido, he said something along the lines of "but Wellbutrin doesnt cause a decrease in libido." i corrected him, saying Wellbutrin doesnt cause a decreased libido in most cases.
Posted by baseball55 on January 28, 2015, at 19:57:27
In reply to Re: feeling like im out of options, posted by hello123 on January 28, 2015, at 18:15:00
The active ingredient in buprenorphine that can relieve depression is buproprion - an opiate. Naloxone (which is the active ingredient in naltrexone) is mixed with buproprion in order to prevent overdose or abuse of the drug by opiate addicts. The naloxone itself has no anti-depressant properties.
Posted by hello123 on January 28, 2015, at 21:08:16
In reply to Re: feeling like im out of options » hello123, posted by baseball55 on January 28, 2015, at 19:57:27
> The active ingredient in buprenorphine that can relieve depression is buproprion - an opiate. Naloxone (which is the active ingredient in naltrexone) is mixed with buproprion in order to prevent overdose or abuse of the drug by opiate addicts. The naloxone itself has no anti-depressant properties.
im referring to this med currently in Clinical Trials:ALKS-5461 is a combination of buprenorphine, a moderate partial agonist of the μ-opioid receptor (MOR) and antagonist/very weak partial agonist of the κ-opioid receptor (KOR),[9][10][11] and samidorphan, a selective antagonist of the MOR.[12][13] The combination of these two drugs results in what is functionally a selective blockade of KORs with minimal or negligible effects on the MOR.[13][11]
Through activation of the KOR, dynorphins, opioid peptides that are the endogenous ligands of the KOR and that can, in many regards, be figuratively thought of as functional inverses of the morphine-like, euphoric and stress-inhibiting endorphins,[14] induce dysphoria and stress-like responses in both animals and humans,[15] as well as psychotomimetic effects in humans,[16][17] and are thought to be essential for the mediation of the dysphoric aspects of stress.[18] In addition, dynorphins are believed to be critically involved in producing the changes in neuroplasticity evoked by chronic stress that lead to the development of depressive and anxiety disorders, increased drug-seeking behavior, and dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis.[14][18][19] In support of this, in knockout mice lacking the genes encoding the KOR and/or prodynorphin (the endogenous precursor of the dynorphins), many of the usual effects of exposure to chronic stress are completely absent, such as increased immobility in the forced swimming test (a widely-employed assay of depressive-like behavior) and increased conditioned place preference for cocaine (a measure of the rewarding properties and addictive susceptibility to cocaine).[20] Accordingly, KOR antagonists show robust efficacy in animal models of depression, anxiety, anhedonia, drug addiction, and other stress-related behavioral and physiological abnormalities.[14][15][21][22] As such, there has been great interest in developing KOR antagonists for the treatment of these and other psychiatric conditions in humans.[14][21] Progress has been limited until recently however, due to difficulty in finding selective KOR antagonists with suitable drug profiles (e.g., good pharmacokinetic parameters, short-acting KOR inactivation, lack of toxicity, etc.) for clinical development and use in humans.[15][21]
It has been known for decades that buprenorphine binds to at high affinity and antagonizes the KOR.[23][24] In addition, there have been many reports over the years supporting the idea of it being effective in the management of depressive and anxious symptomatology, and two small clinical trials have shown it to produce remission even in depressive patients refractory to conventional antidepressants and electroconvulsive therapy.[14][25][26][27][28][29][30][31][32][33][34][35] However, buprenorphine has never previously been seriously pursued for mental health indications, presumably due to concerns about its liability for abuse and dependence (and the additional difficulty in gaining regulatory approval that would certainly come with that).[36] In conjunction with samidorphan, as in ALKS-5461, however, its potential for abuse and dependence appears to be effectively negated.[37] As a result, it seems that ALKS-5461 may allow for buprenorphine to be employed safely and unrestrictedly in the treatment of depression and other conditions that it has shown efficaciousness in but that it would otherwise be used to treat likely only very rarely.
this is info from its Wikipedia article
Posted by ed_uk2010 on January 29, 2015, at 9:49:25
In reply to ALKS-5461, posted by hello123 on January 28, 2015, at 21:08:16
Hello :)
Buprenorphine is an opioid with high binding affinity for mu opioid receptors, but it only partially stimulates them; this is responsible for its typical opioid-like pain relieving properties. Buprenorphine also acts on other opioid receptors (kappa and delta), but as an antagonist ie. it blocks them, with no stimulation. Partial agonist activity at mu receptors combined with antagonist activity at kappa receptors may elevate mood in some types of depression, but mu agonist drugs can cause dependence, and bupe is not an exception. Buprenorphine also has an active metabolite called norbuprenorphine, with somewhat different opioid properties.
Buprenorphine is used both for pain relief (for moderately severe pain), and as part of the treatment for opioid dependence. Like methadone, it relieves opioid withdrawal symptoms and reduces the risk of relapse into IV drug misuse. Bupe is generally safer than methadone - which is very dangerous in overdose. Withdrawal symptoms from bupe and methadone can be rather prolonged, especially if high doses have been taken. Bupe withdrawal symptoms are less intense, however.
Bupropion is the generic name for Wellbutrin, an antidepressant. Bupropion has a similar name to buprenorphine but is not related to it in any way.
Buprenorphine is not similar to naltrexone. The fact that bupe stimulates mu receptors whereas naltrexone potently blocks them makes the drugs very different clinically.
Naltrexone and naloxone are different drugs too. They have similar effects but are used differently in practice. Naloxone is a short acting opioid antagonist - it blocks all opioid receptors, but is most potent at blocking the mu receptors, followed by the kappa receptors. It's used a lot by injection to treat opioid overdose, and in combination with buprenorphine to discourage the IV misuse of Suboxone tablets. Naltrexone is a long acting opioid antagonist - it blocks opioid receptors but for a much longer duration than naloxone. Naltrexone is used by mouth for a variety of reasons. It is sometimes used to decrease relapse after opioid detox, and to reduce drinking after alcohol detox. If naltrexone is taken by someone who is physically dependent on opioids, it will rapidly induce severe withdrawal symptoms. As a result, it can only be started once withdrawal is complete - with the aim of preventing relapse by blocking drug effects if opioids are taken. Low dose naltrexone (usually 4.5mg/day), has been recommended by alternative practitioners for a huge range of illnesses.
ALKS-5461 is a combination product containing buprenorphine and samidorphan. It is being studied for TR-depression. The idea is that samidorphan blocks the activity of buprenorphine at the mu receptor, and therefore presumably prevents dependence. In this combination, buprenorphine is still able to block the kappa receptors, which is thought to improve depression. Presumably, this combination will have more antagonist activity at the kappa receptors than naltrexone, while having minimal effect at the mu receptors. Naltrexone is a very strong mu antagonist, which may cause some unpleasant effects except at very low doses....
Posted by ed_uk2010 on January 29, 2015, at 9:52:09
In reply to Re: feeling like im out of options, posted by hello123 on January 28, 2015, at 17:40:25
>youre way off the mark, europrep. i thought id take the time to explain how, but i doubt it would be any use.
I don't think europerep was intending to be critical. I think s/he was mainly suggesting that you look to more established treatment options when choosing what you want to try next.
So, look at the post in a positive light if you can!
Posted by europerep on January 29, 2015, at 16:39:00
In reply to Re: feeling like im out of options, posted by hello123 on January 28, 2015, at 18:15:00
Hmm, there is a bit of confusion in the thread now. Ed has already pointed out everything about the different mechanisms of action, so I'll just reply directly to what you said.
I don't think it is rational to try naltrexone as a substitute for buprenorphine, for various reasons. Primarily, it lacks the properties of buprenorphine and norbuprenorphine on mu- and delta-receptors, which I would personally suspect to play at least some role in the antidepressant effects of buprenorphine. And naltrexone is actually fairly extensive used for various illnesses (compared to buprenorphine in treatment-resistant depression), so if naltrexone had antidepressant properties, we would have some solid knowledge about it. Not necessarily from the Journal of Clinical Psychiatry, but certainly from patients. I just have difficulty understanding why you seem to have some faith in science and pharmacological treatments, but you stubbornly refuse to try tranylcypromine or phenelzine. Some people call them the gold standard for treatment-resistant depression.
As for what I said about clinicians, I of course meant clinicians who can back their statements up with science, as those who recommend MAOIs for treatment-resistant depression can.
I don't want this here to become some kind of proving-each-other-wrong thing, because that is not my intention. I would personally like it if you reflected a bit about where you're most likely to find a working treatment, and then go in that direction. But you're obviously free to decide, so I'll leave it at that.
Posted by europerep on January 29, 2015, at 16:40:02
In reply to Re: feeling like im out of options, posted by ed_uk2010 on January 29, 2015, at 9:52:09
> s/he was
Haha, I can clear this up, I'm a he :)...
Posted by ed_uk2010 on January 29, 2015, at 17:01:36
In reply to Re: feeling like im out of options » ed_uk2010, posted by europerep on January 29, 2015, at 16:40:02
> > s/he was
>
> Haha, I can clear this up, I'm a he :)...I thought you were a man.... but I realised I didn't know what I was basing my assumption on.
Posted by ed_uk2010 on January 29, 2015, at 17:11:14
In reply to Re: feeling like im out of options » hello123, posted by europerep on January 29, 2015, at 16:39:00
>you stubbornly refuse to try tranylcypromine or phenelzine.....
I don't get the impression that Hello is being stubborn :) I suspect that s/he (I have an impression of a man somehow) has possibly had two problems:
1. Unwillingness to prescribe certain medications on the part of the psychiatrist. Many psychiatrists are unfamiliar with MAOIs and may never prescribe them.
2. Anxiety about the effects that certain medications might have, partly based on past experience with other meds. This may have created a reluctance to try MAOIs. Understandably, some people also feel anxious about the dietary restrictions associated with MAOIs and the possible consequences of eating the wrong foods.
Naturally, the tendency to feel negative and/or anxious about the available treatment options is increased by the depression itself.
Am I right Hello?
I hope so! I seem to be writing on people's behalf!
Posted by hello123 on January 29, 2015, at 17:47:03
In reply to Re: feeling like im out of options » hello123, posted by europerep on January 29, 2015, at 16:39:00
> Hmm, there is a bit of confusion in the thread now. Ed has already pointed out everything about the different mechanisms of action, so I'll just reply directly to what you said.
>
> I don't think it is rational to try naltrexone as a substitute for buprenorphine, for various reasons. Primarily, it lacks the properties of buprenorphine and norbuprenorphine on mu- and delta-receptors, which I would personally suspect to play at least some role in the antidepressant effects of buprenorphine. And naltrexone is actually fairly extensive used for various illnesses (compared to buprenorphine in treatment-resistant depression), so if naltrexone had antidepressant properties, we would have some solid knowledge about it. Not necessarily from the Journal of Clinical Psychiatry, but certainly from patients. I just have difficulty understanding why you seem to have some faith in science and pharmacological treatments, but you stubbornly refuse to try tranylcypromine or phenelzine. Some people call them the gold standard for treatment-resistant depression.
>
> As for what I said about clinicians, I of course meant clinicians who can back their statements up with science, as those who recommend MAOIs for treatment-resistant depression can.
>
> I don't want this here to become some kind of proving-each-other-wrong thing, because that is not my intention. I would personally like it if you reflected a bit about where you're most likely to find a working treatment, and then go in that direction. But you're obviously free to decide, so I'll leave it at that.
>I was simply hoping to benefit from from Naltrexones Kappa antagonism, since it has been shown to benefit Depression. The medication in Clinical Trials that i posted on works to treat Depressin with its blockade of the Kappa receptors. The FDA thinks this med has so much potential to benefit people that it has fast-tracked its approval:
http://mentalhealthdaily.com/2014/08/05/new-antidepressant-alks-5461-trials-2016-expected-availability/some info of Kappa antagonism from this article: "So why block the kappa receptor? When the kappa-opioid receptor becomes activated, naturally occurring peptides called dynorphins are released. Some research suggests that dynorphin levels are elevated among people with depression. Therefore blocking the kappa receptor will result in dynorphin reductions and may yield an antidepressant-like response.
Although dynorphins are important in a persons stress response, at high levels they block the release of glutamate. Blocking glutamate in the brain can prevent neuroplasticity, lead to poorer learning abilities, and can induce learned helplessness. Since ALKS-5461 would be blocking dynorphin, it is thought that glutamate would get released to increase hippocampal plasticity and thereby reversing learned helplessness.
Additionally, blocking dynorphin can improve signaling of dopamine, which could lead to further reductions in depressive symptoms as a result of stress. Many researchers believe that kappa-opioid receptor antagonists may be a valid treatment option for both depression and anxiety in the future. In animal studies with kappa-opioid receptor antagonists, significant improvements in depression, anxiety, anhedonia, drug addiction, and stress-related behaviors has been shown."
and i dont know why youd say i seem stubborn about trying either of those MAOI's after i posted this in one of my posts above:
"thats good to hear the effects from MAOI's feel much different than Reuptake Inhibitors for you. Thanks and it makes me feel more hopeful about trying them."though i am nervous about trying something with strong MAO-A inhibition because of the food restrictions.
also, as i said, i have Depersonalization, and Naltrexone has been shown to benefit this. http://www.ncbi.nlm.nih.gov/pubmed/15876908
and if you Google "naltrexone Depersonalization", you will see much talk about it on Forums about it being used to treat Depersonalization.
Posted by hello123 on January 29, 2015, at 18:03:21
In reply to Re: feeling like im out of options, posted by hello123 on January 29, 2015, at 17:47:03
and im guessing at least part of the reason Buprenorphine was chose to be combined with the new med that blocks the addictive properties of it, while leaving its Kappa antagonism alone, is because as the article i posted on the med thats being fast-tracked says, the Kappa receptor is essential to the Stress Response of the body, so im guessing a med that completely blocks the Kappa receptor, like Naltrexone, was seen as too strong. but a decrease in endogenous in stimulation of the Kappa receptor has indeed been shown to help Depression. and i likely would have tried Buprnorphine if it were available.
but look, as i have said, i have Depersonalization. as a result, my world is much smaller than it used to be. so little things bother me. if i werent in this situation, i probably wouldnt bother correcting you on things. i likely wouldnt even be on this site.
Posted by ed_uk2010 on January 29, 2015, at 18:17:24
In reply to Re: feeling like im out of options, posted by hello123 on January 29, 2015, at 17:47:03
>I was simply hoping to benefit from from naltrexone's kappa antagonism, since it has been shown to benefit depression....
It's an interesting option.
My opinion of naltrexone as a potential treatment for depression is that its very potent mu opioid antagonism may be an issue. It is a kappa antagonist as well, albeit less potent. A selective kappa antagonist would be more interesting as an antidepressant.
Mu agonists, such as morphine and hydrocodone frequently produce short-lived (but often marked) mood elevation followed by tolerance and dependence. The potential for problems is high, including the risk of worsening depression in the long run. Chronic use of mu agonists also disrupts the endocrine system, causing sexual dysfunction. Dependence on opioids may result in a state where the ability to experience pleasure naturally is reduced. I wouldn't be surprised if the long-term use of methadone is associated with more depression than buprenorphine (Suboxone etc) maintenance. In fact, I believe I've read that it is.
Mu antagonists such as naltrexone can sometimes feel subjectively unpleasant. I would be concerned about the potential for any potent mu antagonist to block the effects of natural endorphins in the body. This could, theoretically at least, aggravate anhedonia.
Really, it would probably be best to avoid hitting the mu receptor when treating depression.
Posted by ed_uk2010 on January 29, 2015, at 18:20:41
In reply to Re: feeling like im out of options, posted by hello123 on January 29, 2015, at 18:03:21
>depersonalization...
Do you experience this all the time, or just sometimes? Is it associated with the presence of depression or anxiety? What does it feel like for you?
I've only ever experienced D/P during severe anxiety states. Other people experience is during depression, or independently of both depression and anxiety.
Posted by hello123 on January 29, 2015, at 18:40:50
In reply to Re: feeling like im out of options » hello123, posted by ed_uk2010 on January 29, 2015, at 18:20:41
i feel emotionally disconnected from everything around me. and i feel like this all the time, 24/7. and this causes my anxiety.
Posted by hello123 on January 29, 2015, at 18:44:49
In reply to Re: feeling like im out of options, posted by hello123 on January 29, 2015, at 18:40:50
the Depersonalization causes my anxiety as well as my depression.
Posted by hello123 on January 29, 2015, at 19:00:37
In reply to Re: feeling like im out of options, posted by hello123 on January 29, 2015, at 18:44:49
like i said i just feel disconnected from everything. some things have a very limited effect on my emotions, but thats very few things. and feeling like this leaves me feeling sOoOooOOo empty. i just cant form much of an emotional connection with anything.
with the Cyproheptadine that i said benefitted me in the past so much. my world went from feeling so incredibly small, i just felt like nothing else in the world outside of the emptieness inside me existed, my pupils wouldnt even react to light, to feeling like i could experience about 90% of what i normally felt of the world. it was amazing. but now id say im down to about 20%
Posted by ed_uk2010 on January 29, 2015, at 19:21:55
In reply to more on my Delersonalization experience, posted by hello123 on January 29, 2015, at 19:00:37
Well, you clearly don't want meds which are going to cause further emotional numbness. It seems that lack of feeling is a major part of your illness.
Nortriptyline could be a good choice in the sense that it's not normally 'numbing' like SSRIs can be. Comparing nortrip with Strattera.... both drugs have been studied for depression in large trials. Nortrip was effective, Strattera was not effective. Make of that what you will, but I wouldn't personally choose Strattera. Whatever you take, start with a small dose.
Posted by hello123 on January 30, 2015, at 14:51:57
In reply to Re: more on my Delersonalization experience, posted by ed_uk2010 on January 29, 2015, at 19:21:55
> Well, you clearly don't want meds which are going to cause further emotional numbness. It seems that lack of feeling is a major part of your illness.
>
> Nortriptyline could be a good choice in the sense that it's not normally 'numbing' like SSRIs can be. Comparing nortrip with Strattera.... both drugs have been studied for depression in large trials. Nortrip was effective, Strattera was not effective. Make of that what you will, but I wouldn't personally choose Strattera. Whatever you take, start with a small dose.
>Well, thanks Ed_UK for helping me get an idea for my treatment together. id like to try Nortryptiline, but i react very badly to Histamine receptor antagonism. Just taking Diphenhydramine makes me feel much worse for about 2 days. and many other psych meds i took with H1 antagonism did the same. I only tolerated Cyproheptadine with its H1 blocking because its benefits eventually made it to where antihistamines didnt bother me.
So, im considering Strattera, and if i get a benefit, but still have room for improvement, i might just switch to Nortriptyline and see if it is any better.
but i suppose we will see how it goes with my pdoc on 2/10. hopefully he will have a good idea, not just on meds, but on more extensive tests i could have done that might pinpoint a problem.like i was saying, i havent seen him in about 5 years, and i dont remember him at all being an unreasonable pdoc. and his prescribing style seemed more liberal than conservative, like the pdoc ive been seeing.
but yeah, thanks for your time, Ed.
Posted by ed_uk2010 on January 30, 2015, at 15:15:50
In reply to Re: more on my Delersonalization experience, posted by hello123 on January 30, 2015, at 14:51:57
>I only tolerated Cyproheptadine with its H1 blocking because its benefits eventually made it to where antihistamines didnt bother me.
Oh right. Cyproheptadine is a more potent antihistamine than nortriptyline. Desipramine has little antihistamine effect.
Posted by europerep on January 31, 2015, at 16:22:03
In reply to Re: feeling like im out of options, posted by hello123 on January 29, 2015, at 18:03:21
> and im guessing
I don't get why you always want to make a deathmatch out of every time you are criticized or someone points out flaws in your reasoning. Look, you use speculative and crude logic, or you even yourself call it "guessing", to arrive at irrational treatment choices. This is not a judgment or a condemnation, but just what I observe in your posts here. Naltrexone is not not used to treat depression in the way buprenorphine sometimes is because it's "too strong", but because it has a very different pharmacology. Yes of course, *maybe* it could work for you. But it's not reasonable to think that it will.
I have no stake in what treatments you pursue, and this whole thing is not in any way personal. I have had these types of exchanges with other members before, because I regularly see it here that people suffer and are desperate, but for some reason won't even try to obtain treatments that would really be promising for them. It puzzles me why that is. Members here, both me and others, have told you to look into tranylcypromine and phenelzine for a long time, but the fact that you never mention them in your independent reflections suggests to me that you actually don't even really dismiss them, they are completely outside of what you consider as possible treatments.
Now Ed tells you that there are two meds available to target nortriptyline, one has shown efficacy in treating depression and the other one hasn't, but you go for that latter one based on nothing more than a hunch. I don't get this, and I do not think that it serves you well.
But I realize that my participation in threads like these does not really have any constructive effect, and I also admittedly project the priorities that I set for myself in my own treatment onto others. Maybe you have set different priorities for yourself, and you of course have every right to do so. I sincerely wish you good luck with whatever you'll try next.
Posted by ed_uk2010 on January 31, 2015, at 17:21:54
In reply to Re: feeling like im out of options » hello123, posted by europerep on January 31, 2015, at 16:22:03
Strattera's metabolite is a kappa opioid partial agonist. This could be one reason why the development of Strattera as an antidepressant was dropped.
I suppose some doctors may be more willing to prescribe Strattera than TCAs. Partly because it's less dangerous in overdose... and partly because doctors in the US seem to like prescribing new/advertised drugs rather than old ones ;)
Tricyclic antidepressants are extremely dangerous in overdose. It has to be said this doesn't sit well with pdocs who are feeling risk averse!
Desipramine vs nortriptyline:
Antihistamine effect: Desipramine, very low. Nortriptyline, moderate.
Selectivity as an NRI versus SRI. Desipramine, high. Nortriptyline, quite high.
Cholinergic receptor blockage. Desipramine, low. Nortriptyline, moderate.
Serotonin 5-HT2 receptor blockage. Desipramine, very low. Nortriptyline, moderate.
Alpha-1 adrenolytic. Desipramine, low. Nortriptyline, moderate.
Weight gain risk. Desipramine, low. Nortriptyline, moderate. If you didn't gain weight on cyproheptadine, you probably won't gain weight on either.
As you can see, desipramine is a more selective NRI than nortriptyline. Whether this is a good thing or a bad thing depends on the individual.
Posted by Phillipa on January 31, 2015, at 20:19:06
In reply to Re: feeling like im out of options, posted by ed_uk2010 on January 31, 2015, at 17:21:54
Ed true know of not a soul that takes a TCI. Heart issues and others, and yes the OD one also. PJ
Posted by hello123 on February 1, 2015, at 0:24:20
In reply to Re: more on my Delersonalization experience, posted by ed_uk2010 on January 30, 2015, at 15:15:50
> Oh right. Cyproheptadine is a more potent antihistamine than nortriptyline. Desipramine has little antihistamine effect.
>Ed, do you have any of the number for Desipramines affinity for the Histamine receptor?
Posted by ed_uk2010 on February 1, 2015, at 7:28:27
In reply to Re: feeling like im out of options » ed_uk2010, posted by Phillipa on January 31, 2015, at 20:19:06
> Ed true know of not a soul that takes a TCI. Heart issues and others, and yes the OD one also. PJ
Tricyclics are very widely prescribed here but not for depression. Amitriptyline is the main TCA used, for chronic pain conditions. Cymbalta is little used for this purpose. I know a lot of people on TCAs, but none on Cymbalta... or Strattera for that matter.
Posted by ed_uk2010 on February 1, 2015, at 7:55:28
In reply to Re: more on my Delersonalization experience, posted by hello123 on February 1, 2015, at 0:24:20
> > Oh right. Cyproheptadine is a more potent antihistamine than nortriptyline. Desipramine has little antihistamine effect.
> >
>
> Ed, do you have any of the number for Desipramines affinity for the Histamine receptor?Yes, but remember, affinity values are of no meaning in isolation. The pharmacological effects of a drug depend on the concentration of the drug achieved at the receptor site in vivo, as well as the affinity, and a drug's comparative affinity for other sites is very important.
Different experiments come up with somewhat different results, but out of all sites, desipramine has the highest affinity for the human NE transporter, with a Ki of approximately 2. Remember that affinity values are of no meaning in isolation, but potentially useful for the comparison of a specific drug's binding to different sites. The affinity of desipramine for the human H1 histamine receptor is many times lower than its affinity for the NE transporter, with a Ki of around 60. Do not use Ki affinity values to casually compare the affinity of different drugs for the same site, because different drugs achieve very different concentrations at the receptor.
Anyway, the point is, because desipramine binds to human brain NE uptake sites with far higher affinity than H1 sites, it is possible to achieve reuptake inhibition with very little antihistamine effect. This is noticeable clinically; desipramine is unlikely to cause a subjective antihistamine-type sedation. Bear in mind, a lot of the subjective effects of antihistamine such as diphenhydramine are not due to H1 antagonism (these drugs are not selective)... many of the subjective effects are anticholinergic.
It's interesting that one of the drugs you have benefited from a great deal is a potent antihistamine, cyproheptadine. No doubt its benefits on mood were not due to histamine antagonism, however. Cyproheptadine has affinity for the 5-HT2a receptor with a Ki of around 1, which may be relevant. Its affinity for the H1 histamine receptor is extremely high, at around 0.06.
This is the end of the thread.
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