![[dr. bob]](/dr-bob-sm.gif)
Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 28 to 52 of 125. Go back in thread:
Posted by detroitpistons on March 16, 2006, at 12:51:41
In reply to Re: Never thought I'd hear this....., posted by linkadge on March 16, 2006, at 11:28:39
Link,
> >Also seen in non-manic humans taking >amphetamines and cocaine, no?
>
> I don't know what you would classify it as, but if a drug induced lack of sleep, hypersexuality, hyperhedonia, hallucinations, euphoria, hyperlocomotion, then I would say that drug has induced a manic episode.Link, just to give you a bit of my own experience, I've done drugs like cocaine and ecstasy recreationally, and I would most definitely think that the high mirrors mania completely in myself (at least the euphoric part of mania).
As a side note, after taking these drugs, I would crash incredibly hard, much much harder than any of the other people who took them with me. Also, my high seemed to be much more intense and pleasurable than theirs. They seemed to experience little, if any effect on mood even immediately (morning, or more accurately, afternoon after) after the high wore off. It would take me days to recover after taking these drugs. In one case, a major depression started a couple weeks after having done cocaine all night. Of course, this could be purely coincidence.
> >They exhibit their depressive behaviors in the >absence of drugs.
>
> Most of the time we induce depression in animals by subjecting them to repeated mild, chronic stressors. Genetically speaking, I am only aware of the flinders rats, which still really only exhibit depression in response to cholinergic drugs.
>
>
> >This is the thing. To my knowledge, a rodent >model of mania in the absence of drugs does not >yet exist.
>
> I would argue that an animal model of depression, in the absence of chronic stressors, doesn't really exist.
>
>
> >Also seen in non-manic humans taking >amphetamines and cocaine, no?
>
> I don't know what you would classify it as, but if a drug induced lack of sleep, hypersexuality, hyperhedonia, hallucinations, euphoria, hyperlocomotion, then I would say that drug has induced a manic episode.
>
>
> >I admit that I really don't know enough about >this stuff. However, the question raised is >whether or not a manic reaction to therapeutic >dosages of antidepressants indicates bipolar >disorder. I guess the best way to assess this >question is via a longitudinal investigation of >people who have experienced this reaction, both >retrospectively and prospectively.
>
> I see it as a continuoum. Especially when we are talking about norepinephrine active drugs, we see
> a lot of behaviors such as irritability in people taking the drug for depression, even if they never get diagnosed with mania. Its like steroids, a lot of the problems associated with them are dose dependant, and also dependant on individual tolerances. A theraputic dose doesn't really mean anything in my oppinion. By friend can drink 10 cups of coffee and not get anxious, I drink 1 and have a panic attack. But, off coffee, I don't have those panic attacks.
>
>
>
> >He needed to create a hyperlocomotive state >using a combination of amphetamine + >chlordiazepoxide to produce a state that was >responsive to valproate.
>
> I think that it depends on the animal, and the situation. Stress increases PKC, and antidepressants increase PKC, so it could be additive. I personally noted that my "manic episode" was a combination of severe stress, and high doses of antidepressants. There are so many factors.
>
> >Can amphetamine alone switch someone from >depression into mania?
>
> I would say so. Perhaps high doses would be needed.
>
> >The irony is this: Dr. Manji evaluates the >validity of an animal model of mania by >determining whether or not it is attenuated by a >mood stabilizer. This is tantamount to >diagnosing bipolar disorder by evaluating >response vs non-response to a mood stabilizer.
>
> That is exactly my point. If mood stabalizers serve as antidotes to manic episodes (of any origin), then there is no way to determine what exactly caused the manic episode. I heard of a lady who treated her "bipolar disorder" with antidepressants alone. If she felt a manic epsiode coming on, she simply lowered the antidepressant dose.
>
> Here is another interesting article. It suggests how elevated PKC can cause impaired thinking, impaired memory, and impulsivity. At the bottom, it notes how it was able to create these conditions using norepinephrine active drugs, (if I recall it was an NRI used) It basically said how lithium or tegretol were able to block the effects of norepinephrine drugs in these domains.
>
> http://www.nimh.nih.gov/press/prenzyme.cfm
>
>
> Linkadge
>
>
Posted by linkadge on March 16, 2006, at 13:49:37
In reply to Re: Never thought I'd hear this..... » linkadge, posted by detroitpistons on March 16, 2006, at 12:51:41
Not saying that this couldn't be indicitive of something, but I don't know if it is conclusive.
Recretional drugs are meant to make you high. Perhaps your friends are just less sensitive than you are :)
There are tons of reasons why depression can happen in early years. Depression is not uncommon in this agegroup. There are hormonal reasons, as well as social, and acedemic reasons. My brother was teased till the point that he developed major depression. Early onset, but he's not bipolar.
Like I said before, its not for me to make any judgement. These diseases are very complex.
I personally didn't care much about diagnosis so long as I found meds that helped.
Linkadge
Posted by gardenergirl on March 16, 2006, at 14:33:35
In reply to Re: Never thought I'd hear this....., posted by linkadge on March 16, 2006, at 13:49:37
I haven't read this whole thread, but I just wanted to give props to y'all for having such a great and civil discussion. The mutual respect you have for each other comes through loud and clear.
Thanks!
gg
Posted by SLS on March 16, 2006, at 16:07:47
In reply to Re: Never thought I'd hear this....., posted by linkadge on March 16, 2006, at 11:28:39
Hi Linkadge.
Thanks again for the link.
I have yet to review the others you posted.
You make some very valid points. I would be more convinced if I were to see a rat made "manic" by administering a SSRI or TCA.
I'll have to ponder whether or not a cocaine high resembles a true mania. On the surface, the descriptions of the experiences are similar. I have never experienced a cocaine high to be able to compare them. I tried it once as an experiment. It did nothing for me.
You know, it might be interesting to discuss the persistence of a manic reaction beyond the elimination of the drug. How long does a cocaine high last for once the cocaine is discontinued. How long does a manic reaction to an AD last once it is discontinued?
- Scott
Posted by detroitpistons on March 16, 2006, at 16:09:51
In reply to Re: Never thought I'd hear this....., posted by linkadge on March 16, 2006, at 13:49:37
> Not saying that this couldn't be indicitive of something, but I don't know if it is conclusive.
>I'm not convinced of anything one way or the other at this point. I'm just trying to find out as much as I can and look at both sides of the equation.
> Recretional drugs are meant to make you high. Perhaps your friends are just less sensitive than you are :)
>Could be...I was just throwing that out there to see what you guys thought. I just get the feeling that this happens because there is a very tenuous and fragile balance in my brain.
> There are tons of reasons why depression can happen in early years. Depression is not uncommon in this agegroup. There are hormonal reasons, as well as social, and acedemic reasons. My brother was teased till the point that he developed major depression. Early onset, but he's not bipolar.
>That's also entirely reasonable and possible. Although I seem to get depressed for no apparent reason. A couple times there's been a trigger, a couple times not.
Right now I'm split between unipolar vs bipolar II. Actually, I'm leaning ever so slightly towards the BPII simply because there are so many "soft" signs. For example, antidepressants worked for me the first time, and then all subsequent trials more or less failed, the last one bringing on hypomania. According to a prominent doctor who specializes in BPII (Dr. Phelps -- www.psycheducation.org), this would be a very typical pattern for BPII patients. He is basing this from his experience with many BPII patients....
Again, all of this isn't enough to fully convince me. I sway back and forth between the two extremes. Only time will tell what the truth is.
> Like I said before, its not for me to make any judgement. These diseases are very complex.
>
> I personally didn't care much about diagnosis so long as I found meds that helped.
>I agree on the one hand, but on the other hand I'm impatient to either validate or rule out this diagnosis. I shouldn't be impatient because it's not going to change anything, but that's my stubborn nature I guess.
Thanks for your input, Link. It keeps my views more balanced.
Posted by detroitpistons on March 16, 2006, at 16:37:59
In reply to Re: Never thought I'd hear this....., posted by SLS on March 16, 2006, at 16:07:47
> I'll have to ponder whether or not a cocaine high resembles a true mania.
I've never been delusional or had psychotic symptoms while on coke. But it was very euphoric with rapid and excessive speech, happiness, optimism, flight of ideas, expansive mood, grandiosity (extremely high confidence), tons of energy, extreme desire to socialize, increased interest in sex, psychomotor agitation, feeling that your thoughts are very lucid and you are brilliant.
On the surface, the descriptions of the experiences are similar. I have never experienced a cocaine high to be able to compare them. I tried it once as an experiment. It did nothing for me.
>You should have taken more. Just kidding ;)
> You know, it might be interesting to discuss the persistence of a manic reaction beyond the elimination of the drug. How long does a cocaine high last for once the cocaine is discontinued. How long does a manic reaction to an AD last once it is discontinued?
>Depending on the strength, it can last anywhere from 30 minutes to more than an hour after it is snorted. I don't know this from experience, but crack lasts for even less time. Generally, these manic-like symptoms fade away with the high.
Ecstasy lasts several hours and the manic-like symptoms also leave with the high. For me, I get severely depressed (more than anybody else that I know of) when the high is finished. It's almost like an accelerated cycling from mania to depression, or a microcosm of the entire process.
Posted by linkadge on March 16, 2006, at 16:57:49
In reply to Re: Never thought I'd hear this..... » linkadge, posted by detroitpistons on March 16, 2006, at 16:09:51
>I'm not convinced of anything one way or the >other at this point. I'm just trying to find out >as much as I can and look at both sides of the >equation.
Thats the right thing to do.
>Could be...I was just throwing that out there to >see what you guys thought. I just get the >feeling that this happens because there is a >very tenuous and fragile balance in my brain.For me, personaly, what I didn't like about the bipolar diagnosis was that the mood stabalizers just left me flat. They were never able to target things like anhedonia, and they never got me feeling back to myself. I think that may be more diagnositc of bipolar, when a mood stabalizer helps the depression too. (but I don't know about that idea)
>That's also entirely reasonable and possible. >Although I seem to get depressed for no apparent >reason. A couple times there's been a trigger, a >couple times not.
I know what you're saying.
>Right now I'm split between unipolar vs bipolar >II. Actually, I'm leaning ever so slightly >towards the BPII simply because there are so >many "soft" signs. For example, antidepressants >worked for me the first time, and then all >subsequent trials more or less failed, the last >one bringing on hypomania. According to a >prominent doctor who specializes in BPII (Dr. >Phelps -- www.psycheducation.org), this would be >a very typical pattern for BPII patients. He is >basing this from his experience with many BPII >patients....
The mania may be more indictive. The fact that a drug poops out - I don't know. Antidepressant poop out is a lot more common that admitted to by doctors. They poop out left and right for unipolar people too. I am personally fairly antidepressant resistant, but there have been quite a few times where my depression actually improved when coming *off* an AD, such as the last time.
>Again, all of this isn't enough to fully >convince me. I sway back and forth between the >two extremes. Only time will tell what the truth >is.
Bingo.
>I agree on the one hand, but on the other hand >I'm impatient to either validate or rule out >this diagnosis. I shouldn't be impatient because >it's not going to change anything, but that's my >stubborn nature I guess.I know what you're saying. I think a lot of us fit into categories of our own. I started feeling better the day I said WTF, who says I have to fit into this category? I personally think that a lot of the recent changes in psychatric thinking are really just a front to try and accomodate the strange, unexpected, and bizzare outcomes that have resulted from their theories. Remember, the drugs came first, the theories to explain their actions second.
If you make med changes slowly (I can never do that myself) it will probably lead to a better outcome in my opinion.
>Thanks for your input, Link. It keeps my views >more balancedNo problem. I wouldn't want you to take just my view anyway.
Linkadge
Posted by linkadge on March 16, 2006, at 17:04:37
In reply to Re: Never thought I'd hear this..... » SLS, posted by detroitpistons on March 16, 2006, at 16:37:59
>How long does a manic reaction to an AD last >once it is discontinued?
Thats my point, a lot of patients aren't given the chance to find out. They are slapped with a bipolar disgnosis, and thats that.
If I recall, Larry had a bad reaction to Luvox, I assume it remitted once he discontinued. One of my reactions to a medication remitted with discontinuation. I would hate to think that my mother went through 25 years of lithium when a simply coming of the TCA would have sufficed.
Linkadge
Posted by SLS on March 17, 2006, at 7:38:46
In reply to Re: Never thought I'd hear this....., posted by linkadge on March 16, 2006, at 11:28:39
> That is exactly my point. If mood stabalizers serve as antidotes to manic episodes (of any origin), then there is no way to determine what exactly caused the manic episode.
My point is this: The cluster of behaviors that we see with the administration of amphetamine, and that you have listed, is not a sufficient criterion for true mania such that these investigators needed to find other models to use. They judged the validity of their models based upon the capacity of mood stabilizers to reverse them. The hyperlocomotive and hyperlibidinal effects produced by psychostimulants are thus not equivalent to mania, and the presence of these behaviors is not sufficient to presume a valid animal model. Otherwise, I imagine they would have used cocaine. So far, I don't believe that they have been able to reproduce mania in rodents using SSRIs. Hopefully, they will develop a strain of rodent that exhibits such a reaction so as to serve as a model for mania. Of course, this would only go to reinforce the notion that there must be a genetic bipolar diathesis present to display a manic reaction to antidepressants.
My mania lasted for weeks after the antidepressants were discontinued, despite lithium treatment. I think this is one factor that leads me to believe that a manic reaction to antidepressants is fundamentally different from the acute behavioral states produced by psychostimulants. Mania involves a self-perpetuating process, most likely effected by kindling and probably facilitated through second messenger events. My guess is that antidepressant-induced mania gains inertia the longer it is allowed to continue. The sooner it is recognized and the offending drugs discontinued, the more quickly the mania will dissipate.
I wish Depakote were around when I became manic the first time. I believe that it would have been best if I were allowed to continue taking the antidepressants and just have added Depakote. My current treatment resistance probably developed because Nardil was given and withdrawn multiple times within a short period of time and the precipitation of severe mania followed by severe depression on each occassion. Again, Depakote would have prevented this as my mania are very responsive to it. It is also responsive to Zyprexa, but not to the older APs. I should think that combining Nardil and Zyprexa would be a great combination for bipolar depression.
I'm not saying that it is impossible for an SSRI to produce a manic reaction in someone who is not bipolar. Prednisone seems to be sufficient to do that. However, I think the odds are that for someone who has an affective disorder, the precipitation of mania by the administration of an antidepressant is reflective of bipolar disorder.
- Scott
Posted by linkadge on March 17, 2006, at 9:55:15
In reply to Re: Never thought I'd hear this..... » linkadge, posted by SLS on March 17, 2006, at 7:38:46
>My point is this: The cluster of behaviors that >we see with the administration of amphetamine, >and that you have listed, is not a sufficient >criterion for true mania such that these >investigators needed to find other models to use.
Some of the models we have today may not be conclusive, but I don't think that is reason to ignore them.
>They judged the validity of their models based >upon the capacity of mood stabilizers to reverse >them. The hyperlocomotive and hyperlibidinal >effects produced by psychostimulants are thus >not equivalent to mania, and the presence of >these behaviors is not sufficient to presume a >valid animal model.
Psychosis and mania have been effectively treated with drugs that were active in these paradigms.
We can aruge that these behaviors aren't identical to human mania, but we could argue the same thing for rodent depression. That doesn't negate the fact that the model is oftentimes highly predictive of drug sucess in humans.
>Otherwise, I imagine they would have used >cocaine. So far, I don't believe that they have >been able to reproduce mania in rodents using >SSRIs.I don't know.
>Hopefully, they will develop a strain of
>rodent that exhibits such a reaction so as to >serve as a model for mania. Of course, this >would only go to reinforce the notion that there >must be a genetic bipolar diathesis present to >display a manic reaction to antidepressants.It is my contention that long term rat studies may show things that the short term ones don't. Rat studies are brief, but in yours and my mothers case, a manic reaction was not evident right away.
>My mania lasted for weeks after the >antidepressants were discontinued, despite >lithium treatment.
Hey I've got a good one for you. An interesting phenomina, is that sometimes severe manic episodes can happen upon *discontinuation* of an antidepressant. Now would these people be bipolar? I would argue no. They are undergoing a dopamine rebound. Regular people + dopamine overflow = strange behavior.
>I think this is one factor
>that leads me to believe that a manic reaction >to antidepressants is fundamentally different >from the acute behavioral states produced by >psychostimulants. Mania involves a self->perpetuating process, most likely effected by >kindling and probably facilitated through second >messenger events.Stimulants can cause seizures in no time at all. I guess that implies they can cause kindling in no time at all too?
>My guess is that
>antidepressant-induced mania gains inertia the >longer it is allowed to continue. The sooner it >is recognized and the offending drugs >discontinued, the more quickly the mania will >dissipate.This is probably true.
>Again, Depakote would have prevented this as my >mania are very responsive to it. It is also >responsive to Zyprexa, but not to the older APs. >I should think that combining Nardil and Zyprexa >would be a great combination for bipolar >depression.
Depakote can be helpfull. It has a stronger anti-kindling effect than lithium. Lithium can actually be proconvulsant.
>I'm not saying that it is impossible for an SSRI >to produce a manic reaction in someone who is >not bipolar. Prednisone seems to be sufficient >to do that. However, I think the odds are that >for someone who has an affective disorder, the >precipitation of mania by the administration of >an antidepressant is reflective of bipolar >disorder.
I think that the moment we understand how these drugs work, is the moment we can quantify (with any certainty) how and why they fail.
Linkadge
Posted by Sobriquet Style on March 17, 2006, at 11:08:40
In reply to Re: Never thought I'd hear this....., posted by linkadge on March 16, 2006, at 16:57:49
>For me, personaly, what I didn't like about the bipolar diagnosis was that the mood stabalizers just left me flat.
This is very common with anyone suffering from bipolar disorder - the flat effect. Many people report that their mood is left flat with treatment for bipolar dioorder, whether it be Bipolar 1, 2 3, or whatever it maybe suggested the type is.
I think this because some view this as a side effect. Personally I view this as "the effect" in so far as with manic depression, one of differences with the illness compared with other illness is the cycling. The person may cycle in days, but more often the cycles of depression will last months. The hypo/mania's usually last not as long as the depressions, sometimes days. Everyone different. But the flat effect is common.
I think this is because science has looked at manic depression similar how one would a graph when looking at the mood swings. They see the up and down nature of the cycles and so with the drugs used today they have flat-lined it.
I think in the general population of people without psychiatric illness, many do not always feel flat. Especially not on a dialy basis. Unfortunately for those with bipolar disorder the remission of symptoms that come with the use of a mood stabilizer, means that the flat effect is the way the medication works to make the patient "normally mentally fundctioning" Like I say though, normal people do not experience flat effects of their emotions, in the same way manic depressives are not genetically geared up for it either.
The first line medications which are considered the best because they can stop cyling, are also the ones that cause the worst kind of flat effect in my opinon. Now, does the future hold a treatment with the same level of effect that can stop the cyling without the flatness? If I invested in pharmaceuticals, I'd certainly invest in that bipolar medication..
~
Posted by detroitpistons on March 17, 2006, at 11:22:58
In reply to Re: Never thought I'd hear this....., posted by Sobriquet Style on March 17, 2006, at 11:08:40
Hi,
I've been taking Lamictal along with Effexor, and I don't feel flat at all. Perhaps this is just because the Lamictal didn't completely eliminate the hypomania, and I'm still in an "up" phase.
> >For me, personaly, what I didn't like about the bipolar diagnosis was that the mood stabalizers just left me flat.
>
> This is very common with anyone suffering from bipolar disorder - the flat effect. Many people report that their mood is left flat with treatment for bipolar dioorder, whether it be Bipolar 1, 2 3, or whatever it maybe suggested the type is.
>
> I think this because some view this as a side effect. Personally I view this as "the effect" in so far as with manic depression, one of differences with the illness compared with other illness is the cycling. The person may cycle in days, but more often the cycles of depression will last months. The hypo/mania's usually last not as long as the depressions, sometimes days. Everyone different. But the flat effect is common.
>
> I think this is because science has looked at manic depression similar how one would a graph when looking at the mood swings. They see the up and down nature of the cycles and so with the drugs used today they have flat-lined it.
>
> I think in the general population of people without psychiatric illness, many do not always feel flat. Especially not on a dialy basis. Unfortunately for those with bipolar disorder the remission of symptoms that come with the use of a mood stabilizer, means that the flat effect is the way the medication works to make the patient "normally mentally fundctioning" Like I say though, normal people do not experience flat effects of their emotions, in the same way manic depressives are not genetically geared up for it either.
>
> The first line medications which are considered the best because they can stop cyling, are also the ones that cause the worst kind of flat effect in my opinon. Now, does the future hold a treatment with the same level of effect that can stop the cyling without the flatness? If I invested in pharmaceuticals, I'd certainly invest in that bipolar medication..
>
> ~
>
>
Posted by Sobriquet Style on March 17, 2006, at 11:52:49
In reply to Re: Never thought I'd hear this..... » Sobriquet Style, posted by detroitpistons on March 17, 2006, at 11:22:58
>I've been taking Lamictal along with Effexor, and I don't feel flat at all. Perhaps this is just because the Lamictal didn't completely eliminate the hypomania, and I'm still in an "up" phase.
Sounds better than being left in a down phase :-)
I think you're probably right about Lamictal and the hypomania, Lamotrigine seems rare in the case that it is effectively good for treating depression and in some respects is therefore seen as an antidepressant rather than a mood stabilizer as its rarely effective (if at all) for acute mania and in some cases it doesn't look that good for preventing mania. That said bipolar depression is a disgusting depression to say the least, so its a great tool to fight it.
I'm currently taking Lamictal myself, it kind of feels more like an antidepressant to me compared to a mood stabilizer. It does stabilize, but I wouldn't say I feel protected from the high's too much and it appears to increase anxiety related symptoms. I'm only taking 12.5mg because when I push the dosage up it makes me feel pretty uncomfortable.
~
Posted by SLS on March 17, 2006, at 12:00:02
In reply to Re: Never thought I'd hear this....., posted by linkadge on March 17, 2006, at 9:55:15
> > My point is this: The cluster of behaviors that >we see with the administration of amphetamine, >and that you have listed, is not a sufficient >criterion for true mania such that these >investigators needed to find other models to use.
> Some of the models we have today may not be conclusive, but I don't think that is reason to ignore them.
The only thing these models demonstrate is that psychostimulants can produce in animals the same behaviors that they produce in man. My belief (currently) is that what psychostimulants produce in a healthy (not bipolar) man is not mania. Neither do antidepressants produce these behaviors in animals. They only produce them in man in association with affective disorder. There are probably exceptions, of course. I contend that the majority of antidepressant-induced manias are those produced in people whom have a bipolar disorder and not a unipolar disorder. The citations you produced links to seem to support this. Unfortunately no single study was designed to test the specific question that we are debating: Does an antidepressant-induced mania usually indicate bipolar disorder, despite a lack of previous spontaneous episodes?
> > They judged the validity of their models based >upon the capacity of mood stabilizers to reverse >them. The hyperlocomotive and hyperlibidinal >effects produced by psychostimulants are thus >not equivalent to mania, and the presence of >these behaviors is not sufficient to presume a >valid animal model.
> Psychosis and mania have been effectively treated with drugs that were active in these paradigms.
Yes, but they are also active in models of schizophrenic psychosis. They don't seem to me to be specific for mania. Despite this, I will concede that it is possible to "light up" the manic areas of the brain in a healthy individual if, as Dr. Manji said, the conditions are right. The key question is, what are these conditions? Does using an SSRI as monotherapy qualify? That is what we are talking about here, as we are also talking about numbers. What is the percentage of people whom experience mania as a reaction to an SSRI that are bipolar? How do we determine this? Again, I think this issue can be resolved by performing a longitudinal study of people whom have had this reaction using life charting and prospective observation. At this time, I would argue that if there are other features of bipolarity present (including family history), then a manic reaction to an antidepressant indicates treating the person as if they were bipolar. I believe the chances of getting them well is enhanced by doing so.
> We can aruge that these behaviors aren't identical to human mania, but we could argue the same thing for rodent depression. That doesn't negate the fact that the model is oftentimes highly predictive of drug sucess in humans.
Definitely. But does that answer the clinical questions being pursued here?
> > Otherwise, I imagine they would have used >cocaine. So far, I don't believe that they have >been able to reproduce mania in rodents using >SSRIs.
> I don't know.
> > Hopefully, they will develop a strain of rodent that exhibits such a reaction so as to serve as a model for mania. Of course, this would only go to reinforce the notion that there must be a genetic bipolar diathesis present to >display a manic reaction to antidepressants.
> It is my contention that long term rat studies may show things that the short term ones don't. Rat studies are brief, but in yours and my mothers case, a manic reaction was not evident right away.It took at least 6 months to emerge. This is in contrast to stimulant-induced hyperlocomotive or psychotic states.
> > My mania lasted for weeks after the >antidepressants were discontinued, despite >lithium treatment.
> Hey I've got a good one for you. An interesting phenomina, is that sometimes severe manic episodes can happen upon *discontinuation* of an antidepressant.Not news to me. Happened to me 3 times with Nardil. The abstracts on the web page you cited demonstrate this and refer to the patients as being bipolar. I also experience an improvement when tricyclics are withdrawn quickly.
> Now would these people be bipolar? I would argue no. They are undergoing a dopamine rebound. Regular people + dopamine overflow = strange behavior.
We might be getting just a little too theoretical here to attend to the clinical question being asked.
> >I think this is one factor
> >that leads me to believe that a manic reaction >to antidepressants is fundamentally different >from the acute behavioral states produced by >psychostimulants. Mania involves a self->perpetuating process, most likely effected by >kindling and probably facilitated through second >messenger events.
> Stimulants can cause seizures in no time at all. I guess that implies they can cause kindling in no time at all too?If the seizure threshold for subsequent exposures is reduced, it obviously can.
I think this question relates to matters of threshold (sensitivity) and inertia (length of episode). How much exposure (dosage; time) is necessary for the manic event to occur? I imagine the threshold is lower for someone who is bipolar. There might not even be a threshold (too high a threshold) for someone who is healthy. How long will the reaction persist after the provocative medication is discontinued? I should think that in someone who is bipolar, the longer the mania is allowed to continue, the greater is its inertia and tendency to persist after drug discontinuation. The interesting question is whether or not an inertia can be kindled in someone whom is not bipolar. I imagine the rodent studies can be used as a model for this.
> > Again, Depakote would have prevented this as my >mania are very responsive to it. It is also >responsive to Zyprexa, but not to the older APs. >I should think that combining Nardil and Zyprexa >would be a great combination for bipolar >depression.
> Depakote can be helpfull. It has a stronger anti-kindling effect than lithium. Lithium can actually be proconvulsant.
You are a wealth of knowledge and understanding. I only wish my inability to read and remember things were equal to yours.
> I think that the moment we understand how these drugs work, is the moment we can quantify (with any certainty) how and why they fail.
By saying "how these drugs work", are you admitting that they do indeed work?
:-)
- Scott
Posted by SLS on March 17, 2006, at 12:17:39
In reply to Re: Never thought I'd hear this....., posted by Sobriquet Style on March 17, 2006, at 11:08:40
> The first line medications which are considered the best because they can stop cyling, are also the ones that cause the worst kind of flat effect in my opinon.
> Now, does the future hold a treatment with the same level of effect that can stop the cyling without the flatness? If I invested in pharmaceuticals, I'd certainly invest in that bipolar medication.
Right now, Lamictal is considered by many to have anti-cycling properties and is recommended for ultra-rapid cycling. I'd like to see how this plays out with the passage of time. Maybe it only works this way in conjunction with other mood stabilizers. The combination of Lithium + Lamictal is supposed to be much more effective as a prophylaxis against bipolar I disorder than lithium alone.
12.5mg of Lamictal?
Isn't it funny how some people respond to such low dosages of drugs. I wish I could get that kind of mileage out of Lamictal. It would be a much less costly habit.
Actually, I had been taking 300mg for several years. I eventually was able to reduce it to 100mg and retain most of the benefit. My reason for reducing the dosage was that I found that the higher dosages impaired my memory and ability to learn new things above and beyond the impairments produced by the depression itself.
- Scott
Posted by SLS on March 17, 2006, at 14:29:49
In reply to Re: Never thought I'd hear this....., posted by SLS on March 17, 2006, at 12:00:02
> You are a wealth of knowledge and understanding. I only wish my <inability> to read and remember things were equal to yours.
I apologize. I didn't mean to play with words. I got mixed up.
"inability" should have been "ability".
:-(
- Scott
Posted by linkadge on March 17, 2006, at 15:22:04
In reply to Re: Never thought I'd hear this....., posted by Sobriquet Style on March 17, 2006, at 11:08:40
Very good point. Depakote made me a zombie. Lithium too. Tegretol and trileptal just me feel worthless. By zombie I mean that I didn't feel like a human being. I did not have a strong sence of self. I just was. Like a robot, nothing to look forward to, nothing to fear. No reason to live, yet no reason to kill myself. Nothing to work for, yet no reason to give up. No pleasure, no pain. It was the "little things" that were just wiped out. There was simply "no point", to doing the things that I once enjoyed.
I agree that normal people can still be alive and happy yet stable. Mood stabalizers always put me two knotches below where I wanted to be.
Linkadge
Posted by linkadge on March 17, 2006, at 16:16:11
In reply to Re: Never thought I'd hear this....., posted by SLS on March 17, 2006, at 12:00:02
>The only thing these models demonstrate is that >psychostimulants can produce in animals the same >behaviors that they produce in man. My belief
>(currently) is that what psychostimulants >produce in a healthy (not bipolar) man is not >mania. Neither do antidepressants produce these >behaviors in animals. They only produce them in >man in association with affective disorder.It totally depends on your definition of mania. If mania is defined simply by symptoms and behaviors then yes, stimulants can cause mania. If you define mania as being the result of a specific geneticly induced biochemical state, then no perhaps stimulants do not produce mania. But because your reaction took place while you were taking drugs, there is no conclusive way to tell if it was your genes or not. As soon as you introduce that new variable, your personal biochemisty has been altered, and you can never be 100 percent certain that this is the way you would have reacted drug free.
>There are probably exceptions, of course. I >contend that the majority of antidepressant->induced manias are those produced in people whom >have a bipolar disorder and not a unipolar >disorder. The citations you produced links to >seem to support this. Unfortunately no single >study was designed to test the specific question >that we are debating: Does an antidepressant->induced mania usually indicate bipolar disorder, >despite a lack of previous spontaneous episodes?
One of the reasons I contend that the drugs are to blame is that doctors have alreadly known that certain antidepressants are more likely than others to cause these reactions. There are people who have had manic reactions to say "wellbutrin", but then never had a similar reaction to an SSRI. The reverse holds true too. Some site that the TCA's are more likely to cause psychotic reactions than the SSRI's.
You need to come visit me, and see me in person some day. Get to know me, and the people who know me. My friends and family, teachers, and doctors have noticed absolutely no manic behavior since stopping offending agents. I have not had a similar reaction before or since. Only time will tell, but keep in touch, I hope to proove you wrong!
>Yes, but they are also active in models of >schizophrenic psychosis. They don't seem to me >to be specific for mania. Despite this, I will >concede that it is possible to "light up" the >manic areas of the brain in a healthy individual >if, as Dr. Manji said, the conditions are right. >The key question is, what are these conditions? >Does using an SSRI as monotherapy qualify? That >is what we are talking about here, as we are >also talking about numbers. What is the >percentage of people whom experience mania as a >reaction to an SSRI that are bipolar? How do we >determine this? Again, I think this issue can be >resolved by performing a longitudinal study of >people whom have had this reaction using life >charting and prospective observation. At this >time, I would argue that if there are other >features of bipolarity present (including family >history), then a manic reaction to an >antidepressant indicates treating the person as >if they were bipolar. I believe the chances of >getting them well is enhanced by doing so.
That may be the safest course to take, but I think there are a lot of peope who will fall through the cracks. Antidepressant treatments vary widely on their abilities to enhance dopaminergic function. TCA's show the strongest ability to increase the sensitivity of limbic dopamine receptors. They increase the sensitivity of d3 receptors in the neucleus accumbens, even in normal controll rats. Anticholinergics can also cause mania, and psychotic reactions in healthy people. In addition TCA's dose dependantly lower the seizure threshold in normal mice. So theres 3 reasons.
1. Anticholinergic, deleriant like effects.
2. Lowered seizure threshold
3. Increased limbic sensitivity to dopamine
in pleasure centres.
>It took at least 6 months to emerge. This is in >contrast to stimulant-induced hyperlocomotive or >psychotic states.TCA's effects on limbic dopamine receptors is acutally time dependant.
D2, and D3 expression often increases significantly after many months of treatment. This happened in normal mice. The receptors increased their expression well above baseline, these were not stressed or depressed rats. They were rats that were about to have robuslty enhanced dopaminergic response.
>The abstracts on the web page you cited >demonstrate this and refer to the patients as >being bipolar.Doctors just lable anything that resembles bipolar as being bipolar. It makes their lives easier. But does it make our lives easier. People just don't fit into these categories. Lets turn this arugment around. If I can induce depression in somebody with drugs, does that mean they have unipolar disorder? Of course not. How about a combination of PCPA, cyproheptadine, atenolol, haldol, and dilanin, and reserpine, valium, naltrexone, and acutaine :) That would make any normal person jump off the nearest bridge. Does that mean that these drugs unleashed a underlying unipolar disorder?
>I think this question relates to matters of >threshold (sensitivity) and inertia (length of >episode). How much exposure (dosage; time) is >necessary for the manic event to occur? I >imagine the threshold is lower for someone who >is bipolar.
No arguments there.
>There might not even be a threshold (too high a >threshold) for someone who is healthy. How long >will the reaction persist after the provocative >medication is discontinued?I think that in order for somebody to be considered "bipolar", their threshold needs to be low enough so that normal, life circumstances can trigger manic episodes.
>I should think that
>in someone who is bipolar, the longer the mania >is allowed to continue, the greater is its >inertia and tendency to persist after drug >discontinuation. The interesting question is >whether or not an inertia can be kindled in >someone whom is not bipolar. I imagine the >rodent studies can be used as a model for this.Normal rats can be kindled. And that kindling can go on for a long time unless intervention has occured.
>You are a wealth of knowledge and understanding. >I only wish my inability to read and remember >things were equal to yours.I don't aruge with fools :)
>By saying "how these drugs work", are you >admitting that they do indeed work?You got me! I think they must do something for somebody. I guess what I am saying is that if we don't exactly know how they help, than how can we know for sure that they don't harm?
Linkadge
Posted by Sobriquet Style on March 18, 2006, at 6:23:57
In reply to Re: Never thought I'd hear this....., posted by SLS on March 17, 2006, at 12:17:39
>Right now, Lamictal is considered by many to have anti-cycling properties and is recommended for ultra-rapid cycling. I'd like to see how this plays out with the passage of time.
Yes, this is promising.
>12.5mg of Lamictal?
Its a very small amount isn't it. I could be considered to be treatment resistant in some respects, although I hate to use the word treatment resistant, medication resistant is probably more accurate...I just hate the word risistant to be honest. I've found that as i'm not the best responder to psychiatric drugs (other drugs are a different story) I like to keep the dosages at a minimum. Before I've pushed dosages up high, only to be left with alot of increased and unwanted side effects, with really not much improvement for the condition I'm originally treating. It just gets so confusing with all the added side effects to deal with, I've found that keeping the dosage low, i manage to maintain the benefit that I was more or less getting at higher dosages, with less side effects.
>My reason for reducing the dosage was that I found that the higher dosages impaired my memory and ability to learn new things above and beyond the impairments produced by the depression itself.
I've found this aspect too. My learning and overall intelligence has been damaged enough by depressive episodes. I found too that being on the high end scale of the drugs and topamax and at any dosage! appeared to be leaving me the same level of loss of intelligence and learning that the illness was itself. Catch 22. The conclusion I've come to is to stick with the lower dosages.
~
Posted by Sobriquet Style on March 18, 2006, at 6:27:19
In reply to Re: Never thought I'd hear this..... » Sobriquet Style, posted by linkadge on March 17, 2006, at 15:22:04
>Mood stabalizers always put me two knotches below where I wanted to be.
I think replying on drugs alone to be exactly where you want to be, is a false hope in the long run, but I know exactly what you mean.
~
Posted by Sobriquet Style on March 18, 2006, at 6:36:25
In reply to Re: Never thought I'd hear this..... » Sobriquet Style, posted by linkadge on March 17, 2006, at 15:22:04
Posted by SLS on March 18, 2006, at 7:29:51
In reply to Re: Never thought I'd hear this....., posted by linkadge on March 17, 2006, at 16:16:11
> >The only thing these models demonstrate is that >psychostimulants can produce in animals the same >behaviors that they produce in man. My belief
> >(currently) is that what psychostimulants >produce in a healthy (not bipolar) man is not >mania. Neither do antidepressants produce these >behaviors in animals. They only produce them in >man in association with affective disorder.
> It totally depends on your definition of mania. If mania is defined simply by symptoms and behaviors then yes, stimulants can cause mania.There's the catch. Manji found that stimulants alone were not a valid model for mania because mood stabilizers would not attenuate the behaviors.
> If you define mania as being the result of a specific geneticly induced biochemical state, then no perhaps stimulants do not produce mania.
After reading Manji's work, I think that there are valid animal models for mania, but they have not been fully elucidated or evaluated yet. His adding of a BZD to AMPH probably works because the BZD produces disinhibition.
> But because your reaction took place while you were taking drugs, there is no conclusive way to tell if it was your genes or not.
I disagree. As in animal models, the specificity of a reaction to a given drug can be determined by producing strains sensitive to the assay.
> As soon as you introduce that new variable, your personal biochemisty has been altered, and you can never be 100 percent certain that this is the way you would have reacted drug free.
It is how the alteration is expressed that demonstrates state-specific or trait-specific reactions that are reflective of that state or trait.
You once wrote that MAOIs were most likely to produce a manic reaction. If my case is representative of the majority, I would have to agree with you.
> That may be the safest course to take, but I think there are a lot of peope who will fall through the cracks. Antidepressant treatments vary widely on their abilities to enhance dopaminergic function.
At this point, I think it is important to remember that the changes seen downstream of the primary site of action of a drug is only an association. In other words, the changes seen at secondary sites might be a facilitative or compensatory consequence for the activity produced by manipulating the primary site.
> TCA's show the strongest ability to increase the sensitivity of limbic dopamine receptors.
At this point, I think it is important to remember that the changes seen downstream of the primary site of action of a drug is only an association. In other words, the changes seen at secondary sites might be a facilitative or compensatory consequence for the activity produced by manipulating the primary site.
> They increase the sensitivity of d3 receptors in the neucleus accumbens, even in normal controll rats.
Sometimes, neuronal excitability increases rather than downregulating with increased activity. It is a positive feedback loop. Use it or lose it. The D3 receptors might show increased tone to reflect the increase in NE signaling from sites upstream.
> Anticholinergics can also cause mania, and psychotic reactions in healthy people.
Unless they are really occult bipolar. :-)
I'll have to take your word for it. Psychotic reactions I can see. I still have to question what criteria were used to determine the reactions to be manic rather than non-manic psychotic.
> >It took at least 6 months to emerge. This is in contrast to stimulant-induced hyperlocomotive or psychotic states.
> TCA's effects on limbic dopamine receptors is acutally time dependant.
> D2, and D3 expression often increases significantly after many months of treatment. This happened in normal mice. The receptors increased their expression well above baseline, these were not stressed or depressed rats. They were rats that were about to have robuslty enhanced dopaminergic response.This would be a good argument to support your contention that antidepressants can produce mania in non-bipolar individuals.
I don't see anything convincing enough to conclude one way or another based on the biological experiments and attendant inferences we have thusfar explored. I find your points compelling but not convincing. There is just so much to consider when it comes to the brain and behavior. I think if it were that easy to induce a true manic reaction in a non-bipolar subject with antidepressants, we would see much more of it. It is crucial to be able to differentiate mania from other forms of psychoses and hyperlocomotive states. If we see it happen to 5% of people diagnosed as being unipolar, that about matches the rate of bipolar disorder seen in the general population. However, I really don't know what that rate is. I doubt it has ever been studied, but it does seem to be rather low based upon the frequency with which it is reported.
I'm still processing all of this stuff. Thanks for sharing your knowledge and understanding.
- Scott
Posted by linkadge on March 18, 2006, at 9:07:30
In reply to Re: Never thought I'd hear this....., posted by Sobriquet Style on March 18, 2006, at 6:27:19
No not that I wasn't doing other things to try help my mood. I am saying that mood stabalizers locked me into a position 2 notches below where I wanted to be. Ie normal things that lifted my mood didn't do anything.
Linkadge
Posted by linkadge on March 18, 2006, at 9:40:22
In reply to Re: Never thought I'd hear this..... » linkadge, posted by SLS on March 18, 2006, at 7:29:51
>There's the catch. Manji found that stimulants >alone were not a valid model for mania because >mood stabilizers would not attenuate the >behaviors.
I would disagree with that statment.
The following was taken from:
----------------------------------------------
http://www.bpkids.org/site/PageServer?pagename=lrn_004
----------------------------------------------MANJI: Everything I said about antidepressants would apply to stimulants and maybe even more so. Enough stimulants seem to be capable of triggering manic-like episodes in anyone. In the lab, most of our animal models of mania are based on using stimulants. That is to say, we use repeated amphetamine administration to make the animal become sensitized so it shows high degrees of motor activity and hedonic [pleasure-seeking] behavior.
Interestingly, you can prevent this manic response to stimulants by pre-treating the animal with lithium. This is how we model human mania for our animal experiments. So if we have a new biochemical pathway that may work, one of the models we use is to treat animals with stimulants to make them hyperactive and then use this drug.
------------------------------------------------
>I disagree. As in animal models, the specificity >of a reaction to a given drug can be determined >by producing strains sensitive to the assay.
Sure you can produce animals more sensitive to the stimulant properties of a drug. But again, this does not conclude that the animal would have ever become manic without the drugs.
>It is how the alteration is expressed that >demonstrates state-specific or trait-specific >reactions that are reflective of that state or >trait.
We are just not smart enough yet to develop a concrete model of exactly how genes and drugs interact.
>You once wrote that MAOIs were most likely to >produce a manic reaction. If my case is >representative of the majority, I would have to >agree with you.
They are broad spectrum drugs, and they often cause profound changes in sleeping patterns.
>At this point, I think it is important to >remember that the changes seen downstream of the >primary site of action of a drug is only an >association. In other words, the changes seen at >secondary sites might be a facilitative or >compensatory consequence for the activity >produced by manipulating the primary site.
Ok so its an association, just like the association that some forms of severe psychosis are associated with similar biochemical alterations.
>Sometimes, neuronal excitability increases >rather than downregulating with increased >activity. It is a positive feedback loop. Use it >or lose it. The D3 receptors might show >increased tone to reflect the increase in NE >signaling from sites upstream.
Not saying I know why it happens.
>I'll have to take your word for it. Psychotic >reactions I can see. I still have to question >what criteria were used to determine the >reactions to be manic rather than non-manic >psychotic.Well they tend to make people giddy, euphoric, delerious, and can cause hallucinations.
>I find your points compelling but not >convincing.I'm sure you've naturally considered such possibilites before. :)
>There is just so much to consider when it comes >to the brain and behavior. I think if it were >that easy to induce a true manic reaction in a >non-bipolar subject with antidepressants, we >would see much more of it.We see an awefull lot of it. Enough of it that doctors are doing some of these stange things like revising the DSM, formulation new theories about the unification of bipolar and unipolar. Increase in SSRI/mood stabilizer combinations. New categories of bipolar. Statistically increased rates of suicide and agression in children treated with AD's. Bipolar has been called the "diagnosis du jour", this is a consequence of SSRI's inducing questionable behaviors. There is plenty of evidence available. Its just what picture you "want" to see.
>It is crucial to be able to differentiate mania >from other forms of psychoses and >hyperlocomotive states. If we see it happen to >5% of people diagnosed as being unipolar, that >about matches the rate of bipolar disorder seen >in the general population. However, I really >don't know what that rate is. I doubt it has >ever been studied, but it does seem to be rather >low based upon the frequency with which it is >reported.
I would disagree. I don't think that there would be multi-million doller research into the question as to whether SSRI's induce rapid cycling, if the statistics "fit nicely" into the presumed rate of bipolar.
>I'm still processing all of this stuff. Thanks >for sharing your knowledge and understanding.
Take Care
Linkadge
Posted by SLS on March 18, 2006, at 10:21:19
In reply to Re: Never thought I'd hear this....., posted by linkadge on March 18, 2006, at 9:40:22
> MANJI: Everything I said about antidepressants would apply to stimulants and maybe even more so. Enough stimulants seem to be capable of triggering manic-like episodes in anyone. In the lab, most of our animal models of mania are based on using stimulants. That is to say, we use repeated amphetamine administration to make the animal become sensitized so it shows high degrees of motor activity and hedonic [pleasure-seeking] behavior.
>
> Interestingly, you can prevent this manic response to stimulants by pre-treating the animal with lithium. This is how we model human mania for our animal experiments. So if we have a new biochemical pathway that may work, one of the models we use is to treat animals with stimulants to make them hyperactive and then use this drug.
I stand corrected!I still think the majority of manic reactions to antidepressants indicates bipolar diathesis.
I respect Dr. Manji enough to give him the last word. :-)
To be continued...
- Scott
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