![[dr. bob]](/dr-bob-sm.gif)
Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 21 of 21. This is the beginning of the thread.
Posted by Robert Fairburn on October 3, 2003, at 17:41:52
Has anyone found that nearly all tricyclics dont work for them but one or two SSRI agents do. the fact that some classes of drugs seem to work for some people yet other classes of anti-depressant drugs make things worse has made be put some thoughts down.
I am wondering if there is a sub class of poeple that only find SSRI effective. I know that lots and lots of people respond well to tricyclic drugs. Im just wondering if there are large number of chemical imbalances. Hence the large number of different reactions to various meds
Here is a possible listing of chemical imbalances and why some drugs work and why some don't
Type 1 People who are low of norepinephrine either in receptor cell sensitivity of production of neropinephrine (These people should respond well to tricyclics that increase neropinephrine)
But respond poorly to SSRI drugsType 2 People who are low in seratonin or have low seratonin receptor sensitivity ie too few receptors or the receptors themselves are insensitive) These people should respond well
To ssri drugs best but get some effectiveness from some tricyclicsType 3 People who are low in both neropinephrine and seratonin. I would think that such a person is very depressed. These people might respond to Effexor or high doses of tricyclics I would suspect that they would find SSRI drugs less effective
Type 4 people high in Norepinephrine or have a large number of norepinephrine receptors, but have low levels of seratonin. These people are aggrevated by tricyclic drugs but not SSRI drugs. Might be the problem with some anxiety disorders such as GAD or panic attacks
Type 5 People who have high levels of seratonin or receptor cell sensitivity This condition might be a rare condition but might explain why buspar works on some people who have anxiety problems
For all you backyard biochemist out there please comment
Posted by loolot on October 3, 2003, at 18:10:55
In reply to My grand theory about SSRI vs Tricyclics, posted by Robert Fairburn on October 3, 2003, at 17:41:52
Nice list, makes sense but you forgot dopamine, which I believe is why many of us dont like any of these much!! I need norepinephrine and dopamine, so ssris dont do it for me
Posted by stjames on October 3, 2003, at 18:56:37
In reply to My grand theory about SSRI vs Tricyclics, posted by Robert Fairburn on October 3, 2003, at 17:41:52
Type 3 People who are low in both neropinephrine and seratonin. I would think that such a person is very depressed. These people might respond to Effexor or high doses of tricyclics I would suspect that they would find SSRI drugs less effective
This is me, however one is not "low" on NT's,
it is the regulation that is off. One cannot be
low on NT's, this would cause death or major thing like parkinsons.
Posted by zeugma on October 3, 2003, at 19:09:09
In reply to Re: My grand theory about SSRI vs Tricyclics, posted by loolot on October 3, 2003, at 18:10:55
it's been observed by many that SSRIs' and MAOI's work better for atypical depression, while tricyclics work well for 'endogeneous' or 'vital' depression (these are old terms that were more widely used when the tricyclics where the AD's of choice).
It's now thought by some that SSRI's, through boosting 5-HT, diminish dopaminergic transmission (this is thought to be responsible for SSRI 'poopout,' which parenthetically DOES seem to be more of a problem for this class of medication than for any other.)
On the other hand, it's now thought that tricyclics and other NRI's boost dopaminergic transmission indirectly, because the NE reuptake mechanism actually has a higher affinity for dopamine than for norepinephrine. This is thought to explain why Effexor and tricyclics are so much more effective for anhedonic, melancholic depressions (the ones that used to be called 'endogeneous'). This also may account for the fact that TCA's and other NRI's can be effective in the treatment of ADHD- thought to be primarily a dopaminergic disorder. Here's a link to an article which tries to point out the differential actions of these drugs on aspects of depression:
http://psychservices.psychiatryonline.org/cgi/content/full/52/11/1469
Posted by stjames on October 3, 2003, at 19:42:43
In reply to Re: My grand theory about SSRI vs Tricyclics, posted by zeugma on October 3, 2003, at 19:09:09
TCA's are dirty drugs, which often makes them more effective.
Posted by Eddie Sylvano on October 3, 2003, at 19:49:54
In reply to Re: My grand theory about SSRI vs Tricyclics, posted by zeugma on October 3, 2003, at 19:09:09
I think that the tradional monoamine model tends to make people think within the confines of that handful of modulators. There are plenty of other chemicals at play, though. Nicotinic compounds, opiatelike compounds, GABA, glutamate, plenty o' hormones, nitric oxide, etc. The current drugs also don't just affect one transmitter, but initiate a cascade of effects, aftereffects, and similar changes when drug plasma levels drop and feedback loops come into play. It's a crazy, messy system that I think can only be modeled through the gathering and computer evaluation of lots and lots of information on chemical states at various stages in time. A computer is the only way to find useful patterns in the reams of seemingly disconnected events going on in the brain (or any natural system).
Posted by DSCH on October 3, 2003, at 20:01:09
In reply to My grand theory about SSRI vs Tricyclics, posted by Robert Fairburn on October 3, 2003, at 17:41:52
The monoamine hypothesis... as I understand it...
Serotonin: level/regulation determines emotional sense of well-being, the degree to which the person is prey to compulsive behaviors, and sleep patterns.
Norepinepherine: level/regulation determines motivation, ability to focus, mental energy and overall willpower.
Dopamine: level/regulation determines physical coordination, energy and sense of well-being; interest in physical or thrilling activites; impulsiveness; pleasure/reward-seeking, and the degree one is prey to delusional thinking.
One notes that in Dr. Kramer's "Listening to Prozac", the "better than well" responders to Prozac were all relatively high achieving types suffering from emotional discontent. Most of them were rather sucessful at what they did (perhaps even a bit workaholic).
Amotivation and anhedonia are probably not going to be addressed well by a SSRI.
Posted by zeugma on October 3, 2003, at 20:28:07
In reply to maybe, posted by Eddie Sylvano on October 3, 2003, at 19:49:54
Nicotinic receptors are important- smoking a cigarette always makes me feel more sociable, less depressed- of course the long-term side effects are scary. Maybe certain AD's stimulate nicotinic receptors- bupropion and nortriptyline- these are two that help smokers come off their habit.
Also the TCA's have analgesic properties that the SSRI's don't, so maybe they affect the opiate system somehow.
I've heard also that nicotinic agonists are being tested for ADHD. That's promising, since stimulating nicotinic receptors releases NE and DA and also seems to have intrinsic antidepressant and attentional activity.
Posted by stjames on October 3, 2003, at 22:00:20
In reply to Re: My grand theory about SSRI vs Tricyclics, posted by DSCH on October 3, 2003, at 20:01:09
> The monoamine hypothesis... as I understand it...
However, if this were the answer AD's would work very quickly, as reuptake ihibition happens almost
at once on starting AD's. Neurogenisis increases
6-8 weeks after starting AD's & I suspect it is several factors that account of AD's working.Seeking to increase NT's does not work for a number of reasons. Taking more precusrors does not yield more NT's due to feedback loops. Even if you could, reuptake would follow suit and increase, deactivating them. Also, precursors are abundant
in all foods.
Posted by jay on October 3, 2003, at 22:09:28
In reply to maybe, posted by Eddie Sylvano on October 3, 2003, at 19:49:54
> I think that the tradional monoamine model tends to make people think within the confines of that handful of modulators. There are plenty of other chemicals at play, though. Nicotinic compounds, opiatelike compounds, GABA, glutamate, plenty o' hormones, nitric oxide, etc. The current drugs also don't just affect one transmitter, but initiate a cascade of effects, aftereffects, and similar changes when drug plasma levels drop and feedback loops come into play. It's a crazy, messy system that I think can >only be modeled through the gathering and >computer evaluation of lots and lots of >information on chemical states at various stages >in time. A computer is the only way to find >useful patterns in the reams of seemingly >disconnected events going on in the brain (or >any >natural system).
Yes. true, but the older meds do 'muck' around with a number of more systems than most newer ones. I still recall having times where I was on Elavil, felt a fair bit of side effects, but I didn't feel the 'numbness' and apathy the newer meds bring on, and the effects of older meds seemed to last as long as taking them. Some of those effects where nasty, but some where good. I have been taking a big amount of Prozac for months and in many ways I have looked back and craved some of the mild sedation, as well as some of the more 'jumpier' effects of the old meds. Some tricyclics (not all) also seem to be kind to the sexual function. Anti-cholinergic properties can sometimes be helpful in depression, acting in a pro-dopamine fashion.Now Prozac seems like a placebo pill to me. I honestly think that is why they have found combos of tricyclics with SSRI's sometimes work better than SSRI's.
IMHO...
Jay
Posted by jonh kimble on October 4, 2003, at 0:23:02
In reply to maybe, posted by Eddie Sylvano on October 3, 2003, at 19:49:54
respond better to tca's. Obviosly this is a massive generalization, but a recent study in a magazine I read stated this as a generaliztion. Interesting, but dont take it terrible seriously, as I said it was just one study in a magazine article.
Posted by DSCH on October 4, 2003, at 8:27:14
In reply to Re: My grand theory about SSRI vs Tricyclics, posted by stjames on October 3, 2003, at 22:00:20
> > The monoamine hypothesis... as I understand it...
>
> However, if this were the answer AD's would work very quickly, as reuptake ihibition happens almost
> at once on starting AD's. Neurogenisis increases
> 6-8 weeks after starting AD's & I suspect it is several factors that account of AD's working.
>
> Seeking to increase NT's does not work for a number of reasons. Taking more precusrors does not yield more NT's due to feedback loops. Even if you could, reuptake would follow suit and increase, deactivating them. Also, precursors are abundant
> in all foods.Then why does DLPA help me, eh? :-)
Note I said 'level/regulation'.
Posted by stjames on October 4, 2003, at 11:20:16
In reply to Re: My grand theory about SSRI vs Tricyclics » stjames, posted by DSCH on October 4, 2003, at 8:27:14
> Then why does DLPA help me, eh? :-)
>Could be placebo effect. It will help those who
are malnurished & we do not have RDA's for aminos
yet but the are everywhere in foods. If DLPA is phenyalamine there maybe some other effects to take into account.
Posted by DSCH on October 4, 2003, at 13:11:24
In reply to Re: My grand theory about SSRI vs Tricyclics, posted by stjames on October 4, 2003, at 11:20:16
>
> > Then why does DLPA help me, eh? :-)
> >
>
> Could be placebo effect. It will help those who
> are malnurished & we do not have RDA's for aminos
> yet but the are everywhere in foods. If DLPA is phenyalamine there maybe some other effects to take into account.DLPA is racemic phenylalanine. That and/or protein drinks containing L-phenylalanine and L-tyrosine help my ability to concentrate; when they are taken away, it suffers. And that is concurrent with meat with virtually every meal.
Posted by Eddie Sylvano on October 5, 2003, at 15:22:43
In reply to Re: My grand theory about SSRI vs Tricyclics » stjames, posted by DSCH on October 4, 2003, at 13:11:24
I've read at least a dozen times now about studies suggesting that antidepessants' main utility is their inducement of neuronal growth in the hippocampus. It takes several weeks for the growth to mature, and the researchers believe that this is why the antidepressant effects of ADs don't manifest until the 3th or 4th week. The most recent article I read was an experiment on mice. Now, I don't know hoe scientists can accurately gague dperession in mice, but they took some depressed mice, gave them SSRIs, and somehow killed off any new hiccocampal growth that follwed. The control group was given SSRIs and left alone, the reult being that the neuronaly pruned mice didn't show any improvement.
The articles also seem to be uniform in their assessment that untreated depression shrinks the hippocampus. The longer depression is allowed, the worse the damage, and the harder to reverse. After a successful treatment of depression with drugs, discontinuation of the drugs allows the shrinkage to begin anew, leading to a relapse months or years alter, depending on the extent of the prior treatment and previous brain condition. None of the articles ever mention what is causing the atrophy of neurons to begin with, though stress and the chemicals relased during stress (cortisol) are implicated. The hippocampus is associated with the formation of memory, motivation, and emotional response (mood). Here's the first link I found on google:
http://ivy_league0.tripod.com/rhyme_of_the_ancient_wanderer/id69.htmlIt seems that the hope for future drugs is to identify the mechanism by which current antidepressants cause neuronal regrowth (which is incidental to their immediate chemical effect), and create drugs which more specifically (and potentially more quickly) facilitate growth.
Posted by Questionmark on October 7, 2003, at 12:53:04
In reply to Seen this a lot, posted by Eddie Sylvano on October 5, 2003, at 15:22:43
Great thread, people. Some really good points.
First i wanted to mention something in response to zeugma. You said "Maybe certain AD's stimulate nicotinic receptors- bupropion and nortriptyline- these are two that help smokers come off their habit." i wonder if some do. i'm not sure about others, but i know that bupropion is a nicotinic ANtagonist, which is why it's helpful for smokers-- cuz it prevents the nice/buzzlike/pleasureable effects of smoking (nicotine). i'd love to find a nicotinic agonist though-- one that works a little longer than nicotine and has a little fewer side effects.
But i really wanted to comment on the theory that antidepressants are effective primarily through increasing nerve growth factor and neuronal regeneration/growth in the hippocampus. i think this theory is extremely presumptuous. i mean, it certainly doesn't seem like increased neuro-regeneration in the hippocampus would be a bad thing, and i imagine it would be quite a good thing. But to say that it's the primary means by which antidepressants exert their antidepressant effects is a big stretch, in my opinion. i believe that the enhanced neuronal growth in the hippo. is a RESULT, or beneficial EFFECT, of the positive action/s that antidepressants have on mood and such (the neurochemical mechanisms involved in mood and such). Certainly the presence of cortisol and other stress hormones and chemicals are often highly elevated in depression, and this is believed to be detrimental to the hippocampus in particular. But i believe that the reduction in cortisol (and other "bad" stuff) from antidepressants is a secondary effect-- again, a result of the beneficial effects the drug has on the biochemical mechanisms of mood. This reduction in cortisol and what have you is probably then the main cause of increased hippocampal regrowth. Sure then this effect probably has some beneficial qualities, but i believe they are subsequent to the other effects mentioned. i don't get scientists and researchers sometimes. Just because the increase in hippocampal cell growth does not occur until a few weeks or so
after starting an antidepressant, and this is relatively the same as when antidepressants start to exert their beneficial effects, does NOT mean that the latter is caused by the former. Wouldn't it be just as reasonable to assume that the former is a result of the latter?? i bet you if/once they ever do make drugs that directly increase NGF or neuronal regrowth in the hippocampus, it will have a very limited effect on depression. i very well could be wrong (and i hope i am, i think), and they could be right, but even so i think it is quite presumptuous for them to make this theory such a strong option at this point. For one thing, if they're wrong many of us will have gotten our hopes up for nothing. But i'll stop rambling now.
Oh wait, and yeah, i think that's a really good question that Eddie asked about how scientists can gauge depression in a rat. Two ways i'm aware of in which they do this is by 1) measuring/comparing activity in different rats (physical activity and movement, etc.), and 2) through the forced swim test. This is basically when they drop a rat in a bucket of water it can't get out of and they measure how long it can swim for. i've read about this test being used in so many studies it's ridiculous. Besides sounding incredibly cruel, how much can you seriously freaking associate depression with how long a rat can swim in a bucket? i'm just a dumb undergraduate, so maybe i'm missing something, but it always amazes me how much researches over-assume and presuppose. This further makes me question the validity of the antidepressants-work-by-increasing-neuron-regeneration-in-the-hippocampus theory. Okay, sorry, i'll seriously stop rambling now.
Posted by zeugma on October 7, 2003, at 20:28:50
In reply to Silly researchers., posted by Questionmark on October 7, 2003, at 12:53:04
Questionmark, two points:
First, I didn't know that bupropion is a nicotinic antagonist. Reboxetine is also a nicotinic antagonist. From what I can understand (so far), nicotinic receptors are a species of cholinergic receptors, so anticholinergic drugs would also block nicotinic receptors (like nortriptyline). I would like to know a lot more about the nicotinic receptors: another bit of fascinating info I've gathered is that smokers are much less likely to develop Alzheimer's and Parkinson's, which should make nicotinic receptors the focus of a LOT of current research.
Second, I COMPLETELY agree that this hippocampal growth thing is overblown and the result of shoddy thinking on the part of researchers. No doubt hippocampal growth is a good thing (as you say) but it seems like an effect and not a cause, and it also strikes me that in 50 years of product development the most effective antidepressants are still the ones discovered by accident (the TCA's and MAOI's). Considering that that it is still essentially unknown how these drugs work (and these are among the most extensively studied drugs in existence) it suggests that advances are going to be slow and most likely the result of fortunate accidents like the ones that brought these drugs into use.
Posted by Eddie Sylvano on October 8, 2003, at 9:17:53
In reply to Re: maybe, posted by zeugma on October 3, 2003, at 20:28:07
> Also the TCA's have analgesic properties that the SSRI's don't, so maybe they affect the opiate system somehow.
-------------That some ADs exhibit clear analgesic properties has always interested me. Along with the idea that glucocorticoids play a role in stress, and stress plays a role in depression, I'd wondered if plain old aspirin, which inhibits the production of prostaglandins (another stress related compaound) has any antidepressant qualities. Depression is correlated highly with heart disease, though the nature of the connection hasn't been elucidated. It seems possible, though, that stress hormones are at play in both. Indeed, PMDD (premenstrual dysphoric disorder) occurs in correlation with the release of prostaglandins (and many other hormones, admittedly). Researchers seem to equate the relief in mood brought about by analgesics in those cases as related to pain relief, but it could be one and the same.
The only study I could find on the impact was this:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8730644&dopt=AbstractThe idea that stress (or events predisposing one to high stress responses) underlies depression seems pretty plausible to me, which would make stress hormones a chief suspect.
Posted by Questionmark on October 8, 2003, at 19:04:09
In reply to Re: Silly researchers. » Questionmark, posted by zeugma on October 7, 2003, at 20:28:50
Zeugma, i'm pretty sure that usually, if not always, whenever a substance is referred to as being anticholinergic, it is actually just a muscarinic antagonist and not a nicotinic antagonist. They should just always use the term "antimuscarinic" instead of "anticholinergic," but i'm pretty sure that's the case. Nicotinic drugs are really interesting though, i agree.
Eddie, good points. And good question about aspirin and what not. But i wanted to point out that aspirin is believed to help heart disease by making it more difficult for blood to clot basically. Also, i think the correlation between stress and depression is cyclical-- stress aggravating and sometimes even causing depression, and depression causing more stress hormones, etc. to be released.
Posted by Eddie Sylvano on October 9, 2003, at 8:51:42
In reply to Re: Silly researchers., posted by Questionmark on October 8, 2003, at 19:04:09
>But i wanted to point out that aspirin is believed to help heart disease by making it more difficult for blood to clot basically
----------There must be a role for anti-inflammatory drugs in coronary heart disease as well. A lot of what I've read describes the initial process of plaque formation beginning with chronic immune regulated inflammation along the arterial wall that becomes a locus for LDL cholesterol infiltration, breakdown, and accumulation. The inflammation and high blood pressure work together to cause the problem, with platelet aggregation following and compounding the issue.
Curiously, there've been several studies indicating a link between statins and mood as well. It seems like the markers are just all over the board when it comes to depression.
Posted by Questionmark on October 15, 2003, at 22:21:55
In reply to Re: Silly researchers., posted by Eddie Sylvano on October 9, 2003, at 8:51:42
Wow. Weird. That's really interesting. (just wanted to say that, sorry).
> >But i wanted to point out that aspirin is believed to help heart disease by making it more difficult for blood to clot basically
> ----------
>
> There must be a role for anti-inflammatory drugs in coronary heart disease as well. A lot of what I've read describes the initial process of plaque formation beginning with chronic immune regulated inflammation along the arterial wall that becomes a locus for LDL cholesterol infiltration, breakdown, and accumulation. The inflammation and high blood pressure work together to cause the problem, with platelet aggregation following and compounding the issue.
> Curiously, there've been several studies indicating a link between statins and mood as well. It seems like the markers are just all over the board when it comes to depression.
This is the end of the thread.
Psycho-Babble Medication | Extras | FAQ
Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.org
Script revised: February 4, 2008
URL: http://www.dr-bob.org/cgi-bin/pb/mget.pl
Copyright 2006-17 Robert Hsiung.
Owned and operated by Dr. Bob LLC and not the University of Chicago.