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Dr. Bob is Robert Hsiung, MD,
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Posted by Phillipa on August 5, 2010, at 18:18:02
Very hopeful good news for those with treatment resistant bipolar Illness ketamine IV might be the treatment you've been waiting for per NiMH. Phillipa
From Medscape Medical News
Ketamine Yields Swift Antidepressant Effect in Treatment of Refractory Bipolar Depression
Megan BrooksAuthors and Disclosures
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August 3, 2010 A single intravenous dose of the N-methyl-D-aspartate (NMDA) antagonist ketamine hydrochloride produces a robust antidepressant effect within 40 minutes in patients with treatment-resistant bipolar depression (BPD), according to results of a controlled "proof-of-concept" study published in the August issue of the Archives of General Psychiatry."What is particularly noteworthy," Carlos A. Zarate, Jr., MD, told Medscape Medical News, "is that we demonstrated that it is possible to produce an onset of antidepressant effects in treatment-resistant BPD within 1 hour, which usually takes weeks or longer."
"In my opinion, these results and other related work raise the bar in drug development for BPD in that we should develop treatments that result in an antidepressant response in hours instead of weeks," added Dr. Zarate, who is chief of the Experimental Therapeutics & Pathophysiology Branch, Division of Intramural Research Program, National Institute of Mental Health, Bethesda, Maryland.
Several lines of evidence have recently converged to suggest that dysfunction in the glutamatergic system, particularly the NMDA receptor complex, plays a key role in the pathophysiology of BPD. The new study supports this line of thinking.
The randomized, placebo-controlled, double-blind, crossover, add-on study involved 18 adults with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, BPD resistant to lithium or valproate. The subjects had a mean age of 47.9 years and a mean length of illness of 27.6 years.
They were maintained at therapeutic levels of lithium or valproate and given either an infusion of ketamine hydrochloride (0.5 mg/kg) or placebo on 2 test days 2 weeks apart. Thirteen (72%) of the 18 subjects completed both study phases.
The Montgomery-Asberg Depression Rating Scale (MADRS) was used to rate subjects at baseline and at 40, 80, 110, and 230 minutes and on days 1, 2, 3, 7, 10, and 14 after infusion. Change in MADRS score was the primary outcome.
Robust, Rapid Effect
According to the investigators, within 40 minutes, depressive symptoms improved significantly in those receiving ketamine compared with those receiving placebo (d = 0.52; 95% confidence interval [CI], 0.28 0.76); this improvement was greatest at day 2 (d = 0.80; 95% CI, 0.55 1.04) and remained significant through day 3.
Twelve (71%) of 17 subjects responded to ketamine, and 1 (6%) of 16 responded to placebo at some point during the study, the researchers say, with response defined as 50% improvement from baseline on the MADRS. The median time to response was 40 minutes. Response to ketamine lasted for an average of 6.8 days (SE, 1.4 days); 4 patients responded for 1 week, and 3 additional patients had a response lasting 2 weeks or more.
In addition to the MADRS, statistically significant differences favoring ketamine were also evident on the Hamilton Scale for Depression, the self-rated Beck Depression Inventory, the visual analog scale for depression and anxiety, and the Hamilton Anxiety Rating Scale.
"These findings are particularly noteworthy because a substantial proportion of study participants had been prescribed complex polypharmacy regimens in the past with substantial treatment failures," Dr. Zarate and colleagues note in their report. The average number of past antidepressant trials was 7, and more than 55% of participants failed to respond to electroconvulsive therapy.
The drug was generally well tolerated; dissociative symptoms, only at the 40-minute time point, was the most common adverse effect, a finding "consistent with all published studies using ketamine," the study authors note. Manic symptoms developed in 1 subject receiving ketamine and 1 receiving placebo.
Landmark Contributions
Joseph R. Calabrese, MD, director of the Mood Disorders Program and codirector of the Bipolar Disorders Research Center, University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, Ohio, told Medscape Medical News that Dr. Zarate "continues to make landmark contributions to the field of mood disorders in general and bipolar disorder in particular.
"His work has shown that increased glutamatergic release results in an almost immediate acute antidepressant response in patients who are in the depressed phase of bipolar I and II disorder. It is the depressed phase of bipolar disorder where our patient live their symptomatic lives, suffer the most, and, in all too many instances, end their life by completing a suicide attempt," added Dr. Calabrese, who was not involved in the current study.
Dr. Zarate and colleagues note that the small size of the study and the inclusion only of the subgroup of patients with treatment-resistant BPD who were relatively late in their illness are 2 limitations of their study. The findings can therefore not be generalized to other patients with BPD with different illness and course characteristics (ie, rapid cycling course and current substance use disorders).
They also say it is possible, although unlikely, that the response seen was due to lithium or valproate rather than ketamine. It is also possible, although again unlikely, they say, that the patients who got better with ketamine had cycled out of their major depressive episode.
The transitory dissociative symptoms seen with ketamine could have compromised the study blinding.
"The primary shortcoming of this research that limits its clinical utility is the method by which ketamine needs to be administered, by intravenous infusions," said Dr. Calabrese. He is hopeful the pharmaceutical industry will "use Dr. Zarate's scientific thesis and now supportive data to develop new treatments that have not only robust short- and long-term efficacy in the depressed phase of bipolar I or II disorder, but now, with almost immediate onset."
The study was funded by the Intramural Research Program at the National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, and by a National Alliance for Research on Schizophrenia and depression Award to Dr. Zarate. A patent application for the use of ketamine in depression has been submitted, listing Dr. Zarate and a coinvestigator among the inventors; they have assigned their rights on the patent to the US government. Dr. Calabrese has disclosed no relevant financial relationships.
Arch Gen Psychiatry. 2010;67:793-802.
Posted by europerep on August 6, 2010, at 13:42:40
In reply to Ketamine IV yields swift AD Effect To Bipolar Pts, posted by Phillipa on August 5, 2010, at 18:18:02
> Very hopeful good news for those with treatment resistant bipolar Illness ketamine IV might be the treatment you've been waiting for per NiMH. Phillipa
>
hmm, that's true, but unfortunately it'll also be the drug patients will keep waiting for, probably permanently. its use in bipolar is interesting, wouldn't have thought they'd do that due to its "psychedelic" component, but there's lots of documentation on IV ketamine in TRD.. I contacted a researcher who was involved in an article published, and he said that ketamine is very unlikely to become a treatment in and of itself, due to the cognitive impairment it causes in long-term users. and if you read reports of "recreational" consumers there seems to be something to it. all the studies (except one) only gave one or a few injections to patients to see how they react. there are NMDAr antagonists in the making though, such as the EVT101 that I wrote about in a different thread. it's first phase II trial started in july 2010, but it'll be some years until it'll be available, IF it'll be available... :(
Posted by Phillipa on August 6, 2010, at 14:15:47
In reply to Re: Ketamine IV yields swift AD Effect To Bipolar Pts, posted by europerep on August 6, 2010, at 13:42:40
I actually got excited for some of the long term TRD bipolars from this article. Knew it is recreational and that's a shame if it couldn't help. Darn. Phillipa ps thanks for weighing in the article shows don't believe all you read or hear.
Posted by linkadge on August 7, 2010, at 22:39:42
In reply to Re: Ketamine IV yields swift AD Effect To Bipolar Pts » europerep, posted by Phillipa on August 6, 2010, at 14:15:47
Hard to know what the cognitive effects amount to. I know a lot of K users are polydrug abusers. The other issue is of dose and duration.
There may be a theraputic window. Lithium for instance can be highly neurotoxic above the theraputic level. It kills off brain cells when you go toxic.
I think there is a similar effect with NMDA antagonists. In lower doses, they are neuroprotective, in higher doses, they actually become excitotoxic. The effects in drug abusers therefore is hard to quantify.
Its just going to force many ill patients to the streets to obtain the drug in hopes of relief. It will be another 50 years till anything positive emerges from these studies.
Linkadge
Posted by Phillipa on August 7, 2010, at 23:59:33
In reply to Re: Ketamine IV yields swift AD Effect To Bipolar Pts, posted by linkadge on August 7, 2010, at 22:39:42
Isn't it a shame if it works? Only one Iv also they claim. Phillipa
Posted by Bob on August 8, 2010, at 0:02:36
In reply to Re: Ketamine IV yields swift AD Effect To Bipolar Pts, posted by linkadge on August 7, 2010, at 22:39:42
It will be another 50 years till anything positive emerges from these studies.
>
>
> Linkadge
>Yes, it will be a very, very long time. In the last decade or so I've become increasingly aware of the glacial pace at which true medical advances become available. I'm not sure why I had any other impression, but if you look at the treatments that are available today, they were often decades in development, if not longer. Even if a magical compound was discovered tomorrow, it would take years and years for the necessary experimental and approval processes to take place.
Bob
Posted by europerep on August 8, 2010, at 3:23:04
In reply to Re: Ketamine IV yields swift AD Effect To Bipolar Pts, posted by linkadge on August 7, 2010, at 22:39:42
yes and no. you're right about k abusers of course. also, the k you buy on the street is hardly pure, so the effect of cutting agents needs as well to be taken into account. I don't think the comparison with lithium is accurate though. every substance becomes toxic at some point, but that doesn't mean that every substance has the potential to do good at lower doses. then again, there are individual examples of maintenance treatment where it works:
http://www.primarypsychiatry.com/aspx/articledetail.aspx?articleid=2600
look at the number of ECT courses this poor woman has had.. it's a shame they didn't realize it wasn't working earlier.
still though, 50 years may be exaggerated. there is an NMDA antagonist in its first phase II trial, so maybe we'll be lucky...
Posted by europerep on August 8, 2010, at 9:33:21
In reply to Re: Ketamine IV yields swift AD Effect To Bipolar Pts » linkadge, posted by europerep on August 8, 2010, at 3:23:04
instead of "has the potential to do good" I should have said "is benign". of course it has the potential to do good, that's what the research shows.. sry, I was distracted..
Posted by Huxley on August 9, 2010, at 1:02:49
In reply to Re: Ketamine IV yields swift AD Effect To Bipolar Pts, posted by europerep on August 6, 2010, at 13:42:40
lol Ketamine.
Wow just wow. Cocaine and Heroin will also help you out with that pesky depression...
Posted by linkadge on August 9, 2010, at 9:05:15
In reply to Re: Ketamine IV yields swift AD Effect To Bipolar Pts » linkadge, posted by Bob on August 8, 2010, at 0:02:36
I was reading a book from 1985 which describes citalopram as a treatment for depression.
25 years ago, citalopram was already known to be an antidepressant.
Today, the top AD is escitalopram, which many docs think is essentially equal to citalopram.
So basically today, our top meds are 25-30+ years old.
Linkadge
Posted by linkadge on August 9, 2010, at 9:14:20
In reply to Re: Ketamine IV yields swift AD Effect To Bipolar Pts » linkadge, posted by europerep on August 8, 2010, at 3:23:04
>I don't think the comparison with lithium is >accurate though. every substance becomes toxic >at some point, but that doesn't mean that every >substance has the potential to do good at lower >doses.
Well I just don't think we have enough data on "theraputic" doses of ketamine to know that it causes permanant cognative dysfunction.
Also, there is (as I was mentioning) a biphasic effect for NMDA antagonists. You will notice studies for both the neuroprotective and neurotoxic effects of NMDA antagonists.
Even the NMDA atagonist Zinc has these properties. In low doses it has inhibitory effects, in higher doses it has excitotoxic effects.
I wouldn't equat this to the toxicity of any drug in general. Sure, citalopram will damage your brain at 1000 times the theraputic dose, but NMDA antagonists can cause neurotoxicity at say as little as 5x a dose which appears to be neuroprotective. Of course, I'm pulling those exact numbers out of nowhere, but the point I'm making is true - that there is a much narrower window for safety with NMDA antagonists then the average drug.
Posted by linkadge on August 9, 2010, at 9:20:49
In reply to Re: Ketamine IV yields swift AD Effect To Bipolar Pts, posted by Huxley on August 9, 2010, at 1:02:49
>lol Ketamine.
>Wow just wow. Cocaine and Heroin will also help >you out with that pesky depression...No, but there is a difference. Its true that cocaine can lift severe depression, but the depression returns as soon as the drug wears off. Ketamine is proving to be somewhat different.
It appears to provide prompt relief of depression at doses lower than what would typically be used to get high. The AD effect can occur independantly of a high. Also, the effect does not immediately wear of when the drug wears off.
Some reports suggest that patients remain symptom free for a week or more after a single treatment.
Also, other NMDA antagonists (devoid of hallucinogenic potential) have rapid acting antidepressant effects.
Posted by Huxley on August 9, 2010, at 19:12:04
In reply to Re: Ketamine IV yields swift AD Effect To Bipolar Pts » Huxley, posted by linkadge on August 9, 2010, at 9:20:49
Did you know that a massive trauma to the head can also provide a significant AD effect?Of course it has long lasting effects on important brain functions but apparently that is not a deterent in treating depression.
You speak of medications like you know what you are talking about, like you understand how the human brain functions and what intended and unintended effects these drugs have in the short and long term.
The leading scientists on the human brain confess to barely knowing how it functions yet psycho babble contains several resident experts that can diagnose you and give you an online pseudo prescription.
Posted by SLS on August 9, 2010, at 19:27:47
In reply to Re: Ketamine IV yields swift AD Effect To Bipolar Pts, posted by Huxley on August 9, 2010, at 1:02:49
Hi Huxley.
> lol Ketamine.
> Wow just wow. Cocaine and Heroin will also help you out with that pesky depression...Depression is quite a bit more painful and debilitating than it is "pesky" for many of its sufferers. For people who do not respond to standard treatments, the use of a drug representing a new paradigm represents hope. I'm glad ketamine is being investigated. Perhaps ketamine itself will be a disappointment. However, those properties that produce an antidepressant effect might be instructive in inspiring new paths to treating depression.
- Scott
Posted by ed_uk2010 on August 10, 2010, at 14:18:53
In reply to Re: Ketamine IV yields swift AD Effect To Bipolar Pts » Huxley, posted by SLS on August 9, 2010, at 19:27:47
>Perhaps ketamine itself will be a disappointment. However, those properties that produce an antidepressant effect might be instructive in inspiring new paths to treating depression.
Would you try ketamine Scott?
Posted by SLS on August 10, 2010, at 14:39:57
In reply to Re: Ketamine IV yields swift AD Effect To Bipolar Pts » SLS, posted by ed_uk2010 on August 10, 2010, at 14:18:53
> >Perhaps ketamine itself will be a disappointment. However, those properties that produce an antidepressant effect might be instructive in inspiring new paths to treating depression.
>
> Would you try ketamine Scott?I might if I knew more about it. Dosage is important and there is likely to be a narrow therapeutic window. It has been suggested that ketamine might "jump-start" the antidepressant responses to other agents. I would be interested in this.
Interestingly, the NIMH has studied the instantaneous antidepressant effects of procaine challenge. Infrequently, a patient would have a psychotic reaction to it. However, for others, this short response was the only experience of euthymia that they could recall ever having. There is much that could be learned from understanding the antidepressant response to procaine, even though it is impractical to use it clinically.
- Scott
Posted by ed_uk2010 on August 11, 2010, at 14:37:36
In reply to Re: Ketamine IV yields swift AD Effect To Bipolar Pts » ed_uk2010, posted by SLS on August 10, 2010, at 14:39:57
>I might if I knew more about it.
I know what you mean. Even if the antidepressant effect of a single dose lasted for several days, I have no idea what would happen in the long term after repeated doses.
Posted by Huxley on August 11, 2010, at 18:44:46
In reply to Re: Ketamine IV yields swift AD Effect To Bipolar Pts » Huxley, posted by SLS on August 9, 2010, at 19:27:47
> Hi Huxley.
>
> > lol Ketamine.
> > Wow just wow. Cocaine and Heroin will also help you out with that pesky depression...
>
> Depression is quite a bit more painful and debilitating than it is "pesky" for many of its sufferers. For people who do not respond to standard treatments, the use of a drug representing a new paradigm represents hope. I'm glad ketamine is being investigated. Perhaps ketamine itself will be a disappointment. However, those properties that produce an antidepressant effect might be instructive in inspiring new paths to treating depression.
>
>
> - ScottI think you have failed to detect my sarcasm.....
I am well aware of how painful and debilitating depression can be so don't bother taking that angle.I question psychiatry's methods, because they are directly effecting millions of peoples lives and they don't seem to answer to anybody when they get it wrong. They deserve to be questioned.
You seem to find this confronting and seem to be negative of anyone who doesn't accept the general wisdom of psychiatry.
If you are at all familiar with what ketamine can do... the wrong dose, to high or to low then you would understand why I am skeptical about it.
I have seen Ketamine leave people with permanent drug induced psychosis that resembles schizophrenia.
SLS you seem to offer a lot of advice to people here on what drugs to take.
Tell me this though, do you understand the human mind? Do you understand what effects the drugs that you are recomending have on peoples minds?
Posted by SLS on August 12, 2010, at 5:17:23
In reply to Re: Ketamine IV yields swift AD Effect To Bipolar Pts, posted by Huxley on August 11, 2010, at 18:44:46
> > Hi Huxley.
> > > lol Ketamine.
> > > Wow just wow. Cocaine and Heroin will also help you out with that pesky depression...> > Depression is quite a bit more painful and debilitating than it is "pesky" for many of its sufferers. For people who do not respond to standard treatments, the use of a drug representing a new paradigm represents hope. I'm glad ketamine is being investigated. Perhaps ketamine itself will be a disappointment. However, those properties that produce an antidepressant effect might be instructive in inspiring new paths to treating depression.
> I think you have failed to detect my sarcasm.....
Perhaps you failed to execute sarcasm in a way that would be obvious.
> I am well aware of how painful and debilitating depression can be so don't bother taking that angle.
I didn't know that I had an "angle". Perhaps you could detail what that angle is and what I might be attempting to prove to you.
> I question psychiatry's methods, because they are directly effecting millions of peoples lives and they don't seem to answer to anybody when they get it wrong. They deserve to be questioned.
That is exactly what the authors of ketamine studies are doing. They are questioning the status quo.
> You seem to find this confronting and seem to be negative of anyone who doesn't accept the general wisdom of psychiatry.I don't know how I effect negativism, but if you are accusing me of being more trusting than distrusting of the motivations of psychiatric medicine, I would agree with that statement.
> If you are at all familiar with what ketamine can do... the wrong dose, to high or to low then you would understand why I am skeptical about it.
You might want to review more closely the post that I submitted here:
http://www.dr-bob.org/babble/20100731/msgs/958161.html
> I have seen Ketamine leave people with permanent drug induced psychosis that resembles schizophrenia.
Would you care to provide more evidence of the irreversibility of a psychotomimetic reaction? Amantadine and memantine can produce psychosis infrequently, but I am not aware of these NMDA antagonists doing so irreversibly.
> SLS you seem to offer a lot of advice to people here on what drugs to take.
> Tell me this though, do you understand the human mind?Perhaps you could enlighten me as to where I am deficient in this.
> Do you understand what effects the drugs that you are recomending have on peoples minds?
Not as much as the understandings that modern biological psychiatry offers.
Any perspectives that you are willing to offer will be appreciated.
- Scott
Posted by Huxley on August 13, 2010, at 0:14:48
In reply to Re: Ketamine IV yields swift AD Effect To Bipolar Pts » Huxley, posted by SLS on August 12, 2010, at 5:17:23
I posted a reply to this but it seems to have been removed.
Posted by 10derHeart on August 13, 2010, at 1:33:28
In reply to Re: Ketamine IV yields swift AD Effect To Bipolar Pts » SLS, posted by Huxley on August 13, 2010, at 0:14:48
> I posted a reply to this but it seems to have been removed.
I don't know what happened to your reply to Scott, but I highly doubt it was removed. Only Dr. Bob or a deputy can remove a post, and there are no active deputies at this time. Dr. Bob rarely (if ever) removes posts unless a poster posts while blocked. I was a deputy for several years and he never did so, not even when posters pleaded with him to remove (their own) posts.
Possibly you closed the posting window without confirming? It's happened to me.
Posted by SLS on August 13, 2010, at 5:44:31
In reply to Re: Ketamine IV yields swift AD Effect To Bipolar Pts » SLS, posted by Huxley on August 13, 2010, at 0:14:48
> I posted a reply to this but it seems to have been removed.
I'm sorry that you lost all of your work. As 10derHeart indicated, Dr. Bob rarely, if ever, removes a post.
- Scott
Posted by Huxley on August 15, 2010, at 19:11:52
In reply to Re: Ketamine IV yields swift AD Effect To Bipolar Pts » Huxley, posted by SLS on August 13, 2010, at 5:44:31
> > I posted a reply to this but it seems to have been removed.
>
> I'm sorry that you lost all of your work. As 10derHeart indicated, Dr. Bob rarely, if ever, removes a post.
>
>
> - Scott
>
>Hi Scott,
I dont have enough energy to post it all again.
That argument was probably going nowhere interesting anyway so I guess we can just disagree.
Posted by europerep on August 16, 2010, at 3:24:45
In reply to Re: Ketamine IV yields swift AD Effect To Bipolar Pts, posted by Huxley on August 15, 2010, at 19:11:52
I did not know that ketamine as it is available now is a racemate:
Posted by paulk on August 22, 2010, at 16:14:10
In reply to Re: Ketamine IV yields swift AD Effect To Bipolar Pts, posted by Huxley on August 9, 2010, at 1:02:49
> lol Ketamine.
> Wow just wow. Cocaine and Heroin will also help you out with that pesky depression...
Actually, Cocaine is a SNRI.. not that it works any better than the pharmas. There may even be a place for the use of opiates as a head med.If water is abused, it also can kill you - sure hope the fact that ketamine is used as a street drug doesn't keep it from being considered in low dosage creams..
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