Does Seroquel plateau?

[393656]

Sorry guys I have found this great resource and have had to fire off some questions that otherwise I have really not been able to have answered and I actually read a lot of literature and am relatively savvy with the online journals but perhaps I am not as smart as some of you folks!

So from experience and some anedoctal evidence seroquel seems to be no more sedating after 300mg, meaning 300mg is about as sedating as it gets, then it plateaus. I have seen no evidence for its anti-histamine effects, alpha 1 effects or 5HT 2 antagonist effects plateauing but I suspect its histamine effects plateau around 300mg.

Does anyone else notice this or have evidence to the contrary? I like to increase seroquel quite quickly and I ALWAYS find its the hardest to get them to 300mg but after that you can rocket the dose with little problem. I am talking on the inpatient unit too so this isnt explained by someone "getting used to it" over weeks and falsley looking like the higher dose was not ass sedating as some people say about people who note remeron 45 is "less" sedating than 15, 30mg. Anyway back to topic at hand--anyone have any thoughts?

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[billypilgrim37]

Remeron isn't as sedating at higher doses, because unopposed histamine blockade is balanced by more excitatory NT systems at levels above 15 or 30mg. I explain it to patients with an awkward pantomime where I stick both my feet out like I'm driving. At low doses, the brake gets slammed on entirely. As the dose goes up, the brake can't go down any more, but I start pushing on the gas. At some point, the gas pedal overcomes the brake pedal and we start moving. People usually get it.

Histamine blockade maxes somewhere between 200 and 300mg for most patients on Seroquel, yes. You still have orthostasis to worry about after that, so if you jack up too fast after this dose, eventually you're going to be scraping their head off the floor for a stat CT scan.

 

[whopper]

In general, I don't like giving out Seroquel because per CATIE, it was the least efficacious antipsychotic (defintion of efficacy was the % of people who stopped it over time due to side effects).

Plenty of doctors prescribe it at lower dosages to help with sleep, but do not inform patients it's really an antipsychotic, nor do they inform them of the weight gain, cholesterol increase, and that it's really just acting as as antihistamine at the lower dosages for all intents and purposes.

There are studies out there describing the differential binding properties of the medication.

e.g. http://www.ncbi.nlm.nih.gov/pubmed/18032984

 

[Manicsleep]

In general, I don't like giving out Seroquel because per CATIE, it was the least efficacious antipsychotic (defintion of efficacy was the % of people who stopped it over time due to side effects).

Technically, efficacy is just the capacity/ability to produce an effect, usually under almost ideal conditions. When you add in things like side effects it becomes effectiveness (minute but important distinction in medicine, one the drug reps will use to trick you). Seroquel, even under ideal conditions...isn't so great, but also was noted to have lower effectiveness as you noted.

 

[Manicsleep]

I am not sure about the sedation plateau but there is a max dose plateau with seroquel. I think you aren't supposed to take more than 600mg at a time (per dose, not per day).

 

[393656]

In general, I don't like giving out Seroquel because per CATIE, it was the least efficacious antipsychotic (defintion of efficacy was the % of people who stopped it over time due to side effects).

Plenty of doctors prescribe it at lower dosages to help with sleep, but do not inform patients it's really an antipsychotic, nor do they inform them of the weight gain, cholesterol increase, and that it's really just acting as as antihistamine at the lower dosages for all intents and purposes.

There are studies out there describing the differential binding properties of the medication.

e.g. http://www.ncbi.nlm.nih.gov/pubmed/18032984

Thanks for the link but I cannot access it 👎 from my med center. If someone has access and can pm me the article that would be great!

Also I was not really talking the general binding of seroquel and its receptors but rather the specific point at which its h1 binding is saturated. Do not think that article addresses it by the name.

You also would be surprised that there is no data out there that remeron is less sedating at higher doses. I won't say its an urban legend but probably pretty close. The data that came from were a couple early long-term outpatient studies where they were given signifigant time between dose escalation. The more reasonable explanation and more common thought is the data set simply showed tolerability improve and a pleateau of the effect of histamine. Therefore 45 is no more less sedating than 15 and is probably about the same. However by the time anyone titrates to 30 or 45 it has generally been weeks on 15 where they have had time to adapt to the sedation.

Nobody knows the answer to this-Ill give you that. Those are the two schools and I believe the second one but that does not mean squat🙂

 

[whopper]

It's interesting and sometimes sad how some medications gain certain reputations.

Geodon, for years, long held a reputation as having terrible QT prolongation. In reality it was not found to have one more significant vs. the other atypicals per CATIE.

Neurontin was incorrectly described as a mood stabilizer and I still see several doctors give it out for that reason.

I see several doctors give out Topamax as a mood stabilizer as a first choice even though there have been no double-blinded placebo controlled studies backing it's use as one.

Seroquel is given out as a sleep medication even though it is an antipsychotic and and it's far more expensive than several other choices out there such as Zolpidem.

Seroquel has a warning on it that you're supposed to have the patient see an opthalmologist before and after it's use because it could cause glaucoma, despite that no doctor I know of does this, and despite that CATIE dispelled this problem, yet the warning is still there.

Wellbutrin has an FDA warning against it causing seizures even though the source of the data where this came from was highly suspect. Nonetheless, the FDA warning's still there.

 

[dl2dp2]

One of the psychopharm instructors here reports that Seorquel has been noted anecdotally to have a paradoxically effect on histaminergic action at higher than 300 doses, so once you reach the antipsychotic doses it actually gets less sedating.

The point about CATIE data is really good, and I haven't seen Seroquel used as a monotherapy for pretty much ANYTHING. Is there any situation where this would be appropriate? I guess other than a primary sleep disorder.

 

[Manicsleep]

I wouldn't go that far as to say its completely useless.
I have used it for bipolar depression at 300mg with success.

 

[Manicsleep]

It's interesting and sometimes sad how some medications gain certain reputations.

Geodon, for years, long held a reputation as having terrible QT prolongation. In reality it was not found to have one more significant vs. the other atypicals per CATIE.

Neurontin was incorrectly described as a mood stabilizer and I still see several doctors give it out for that reason.

I see several doctors give out Topamax as a mood stabilizer as a first choice even though there have been no double-blinded placebo controlled studies backing it's use as one.

Seroquel is given out as a sleep medication even though it is an antipsychotic and and it's far more expensive than several other choices out there such as Zolpidem.

Seroquel has a warning on it that you're supposed to have the patient see an opthalmologist before and after it's use because it could cause glaucoma, despite that no doctor I know of does this, and despite that CATIE dispelled this problem, yet the warning is still there.

Wellbutrin has an FDA warning against it causing seizures even though the source of the data where this came from was highly suspect. Nonetheless, the FDA warning's still there.

👍

Except that neurontin actually does cure everything.

 

[393656]

Great points about drugs and bad wraps! The geodon thing kills me everytime someone mentions it!

Seroquel as a sleeper always has bothered me. Not only for the obvious reason of putting someone at risk for TD (albeit probably small) and the whopping cost, but if the person prescribing it bothered to learn how it worked he would see that 2 alternatives offer the exact same receptor targeting and efficacy at a fraction of the cost.
1. remeron has good alpha 1 blockade, potent anti-histamine and potent 5HT2A activity. All 3 are what the derived benefit from seroquel is from.
2.Trazodone plus/minus hydroxyzine-potent 5ht2A and potent alpha 1 block (more than remeron) but a lot less anti-histamine. Still potent drug in and of itself but if necessary a low dose of hydroxyzine (non-anticholinergic anti-histamine I prefer also with inherent 5HT2A activity.
3.Or simply hyroxyzine plus/minus prazosin-5ht2a and anti-H1 from hyroxy and potent alpha 1 block from prazosin.

Not saying you have to get that creative but I think they are all smarter, cheaper and safer options to the patient than a seroquel sleeper! I am talking about people who otherwise do not need nor would benefit from seroquel.

I have to say I am quite a fan of seroquel in bipolar disorder. Do not bother in schizophrenia or psychotic illness unless in the context of bipolar disorder. Its efficacy in bipolar depression is actually pretty solid if you look at the studies. By far better than anything else we have and clinical experience I have had confirms this. Many many bipolar patients have had their depression treated or kept in remission with Lith/dep plus seroquel-that is my go-to bipolar treatment

 

[whopper]

I mentioned this before but I rarely give out Seroquel unless unless the person has Parkinson's or has D2 sensitivity and is in need of an antipsychotic.

Why? It does not have a favorable metabolic side effect profile, it's not cheap, I've found the sedation overwhelming for several unless the person had terrible insomnia, it has a street value, and per CATIE, it was the least efficacious antipsychotic.

Of course it has it's place. IMHO, I've determined where in the scheme I'd give it, and I mentioned it above.

I've never yet had a bipolar depression case where I gave Seroquel but I'm open to doing that. I've usually resorted to Lamictal possibly with an SSRI added.

Strangely, I had a patient with bipolar disorder who is only on Seroquel XR 50 mg QHS. I told her that by studies this is not where the medication is supposed to work for bipolar disorder at that dosage. She insists on staying on it, and since it's an informed decision, with my warning, I'm allowing her to go for it. I double checked to make sure she has bipolar disorder, and she met the DSM criteria, she made it clear that she believes she has the disorder, and for all I know she's an outlier where the medication actually works at the dosage.

 

[393656]

Whopper, not trying to attack or question you but honestly am curious as you cite the catie trial and using evidenced base prescribing, you then tell us that you use treatments that have proven to have zero efficacy and even the potential to worsen symptoms (ssri).... Seroquel has the most and really only evidence aside from lithium to have efficacy in bipolar depression. Abilify probably has as much data as lamictal-some positive, some inconclusive studies but a reasonable choice..

Just curious that is all-always like to get others strategies to steal and use as my own 🙂 jk

 

[whopper]

When I have a patient with bipolar depression, I don't direct them away from Seroquel based on my own preferences.

I tell them the options including Seroquel. I go over the side effects of the meds including that the STEP-BD showed that antidepressants for bipolar depression did not seem to work.

I've never demanded someone stop Seroquel in regards to bipolar depression. The only time I've told someone to stop Seroquel was when I noticed someone get TD from it. The weight gain data is usually enough for anyone to want to stop it from my own experience. What usually ends up happening is the patient does not want to gain weight, and I tell them it's a side effect. Another factor is that Lamictal is about $20 for a month's supply while Seroquel XR is $551.01 per month. That usually is the factor in the patient's decision.

Now, I have mentioned that I don't like giving out Seroquel because of reasons stated above. That said, I will not limit it's use if someone does not have an abuse history, and knows the risks. In PP, I rarely have dangerously manic or psychotic patients. In that setting the patients opt for things aside from Seroquel when I tell them the risks and price.

In the forensic unit setting I also work in, most of the patients are extremely psychotic and manic, and Seroquel usually doesn't cut it, and in that setting most of the patients do have an abuse history and eventually end up discharged to places where Seroquel has a much higher liquid street value such as jail, prison, homeless shelters, or group homes.

When the STEP-BD came out, I informed every patient I had with bipolar depression the study and we agreed to stop the antidepressant if they were on one. Guess what? They all became depressed within a few weeks. After putting them back on the antidepressant their depression stopped. Not just me but pretty much every single psychiatrist I know who did the same had similar results.

I know. WTF? Personally I don't know what explains this because the STEP-BD was a very good study. It was the only time I've seen what I felt was a great study and it didn't match what I was seeing in the real life clinical setting. My own theory is the bipolar depression is due to at least two phenomenon, and that may have affected the study: Bipolar disordered people likely get depressed due to the physiological processes going on in bipolar disorder and because they get depressed just like any other person. Depending on what factor causes the depression, antidepressants may or may not work.

That said, the STEP-BD, if I remember correctly addressed this to some degree, but IMHO it did not completely dispel my theory. That's the only explanation I could give to this phenomenon.

Don't take my opinion on Seroquel as a criticism of you. So long as someone practices under evidenced-based standards that's fine by me. E.g. Someone's psychotic, and the doctor gives an antipsychotic--but which one? The data can only direct us so much. I only am bugged by those that give the same med for the same disorder every single time when IMHO other factors such as the patient's metabolic status, prior experiences with meds, abililty to pay for the medication, etc. should be considered. Even with that 2 doctors could still pick different meds. E.g. for a diabetic, overweight, and psychotic patient, one might pick Abilify, the other Geodon.

 

[dl2dp2]

I think STEP-BD doesn't necessarily directly address the question that you have (or is contradictory of your practice thereof), which is that suppose someone FAILS mood stablizer monotherapy, is adding an antidepressant conferring additional advantage, which I bet you the answer is yes (i.e. look at STAR*D).

STEP-BD simply says that if someone has bipolar depression, there's no reason to START with a combination antidepressant, because on average these people do as well as on a placebo. The other issue is the question of switching. I.e. bipolar initially manifest as depression, were treated with antidepressant, then subsequently diagnosed with bipolar. In these cases, does STOPPING the antidepressant he's on make a difference--or switching to Lamictal, for example. This is also thus far inadequately addressed by STEP-BD.

When I have a patient with bipolar depression, I don't direct them away from Seroquel based on my own preferences.

I tell them the options including Seroquel. I go over the side effects of the meds including that the STEP-BD showed that antidepressants for bipolar depression did not seem to work.

 

[whopper]

STEP-BD simply says that if someone has bipolar depression, there's no reason to START with a combination antidepressant, because on average these people do as well as on a placebo

Yep. And it's not working better than placebo, then it shouldn't really do anything for bipolar depression. If something does not worksignificantly better than placebo, the argument is that it's not doing anything significant with what's being measured.

 

[393656]

Yep. And it's not working better than placebo, then it shouldn't really do anything for bipolar depression. Get it?

Not only does it not do anything but adds a risk of switching (albeit much smaller with new drugs than previously thought)

I avoid AD at all cost as there are too many other treatments out there including lithium, depakote, lamicatal, tegretol, all the atypicals. If you get through all of that and no dent in depression you should be looking at other life changes or psychosocial stressors. The one exception is I truly believe MAOi's remaining place in the psychiatric world is treatment of bipolar disorder. Atypical depression is really what bipolar's experience 90 percent of the time and when MAO'is were initially shown to be more effective in atypical depression, they likely were looking at a lot of bipolar patients who were depressed as they did not screen them out very well.

Every patient with severe depression will get some conbmo of lithium, seroquel, MAOI-sometimes 1 alone, 2 or all 3 depending on severity. I then go to second line stuff like lamictal, depakote, tegretol and other atypicals. Usually starting with abilify and depakote.

Of course psych is not black and white and just my own personal preferences based on evidence of course!

 

[Suedehead]

I know. WTF? Personally I don't know what explains this because the STEP-BD was a very good study. It was the only time I've seen what I felt was a great study and it didn't match what I was seeing in the real life clinical setting. My own theory is the bipolar depression is due to at least two phenomenon, and that may have affected the study: Bipolar disordered people likely get depressed due to the physiological processes going on in bipolar disorder and because they get depressed just like any other person. Depending on what factor causes the depression, antidepressants may or may not work.

another possibility is that STEP-BD bipolar subjects were mixed with borderlines. If so, this would not be a problem with the study, but rather with the DSM (over-inclusive criteria). borderlines may very well have responded to the AD. a TRUE bipolar can switch into mania (scary business).

 

[whopper]

Not only does it not do anything but adds a risk of switching (albeit much smaller with new drugs than previously thought)

I avoid AD at all cost

Yeah, but like I said, I did take in STEP-BD, and when I took patients off of SSRIs with bipolar depression, they got worse. They got back on them, they got better. I still do become hesitant to give out SSRIs in the bipolar depressed for the same reasons you mentioned and because I thought STEP-BD was a very well done study...(JUST WTF happened and why is what I'm seeing different!?!?!)

I do though respect your own opinion, especially since you have evidenced-based data to back it up.

another possibility is that STEP-BD bipolar subjects were mixed with borderlines

Another theory that did cross my mind but I felt the study was well-done to the point that it's investigators would've factored this in and made sure borderlines weren't in it. I could of course be wrong. I've seen some of the most respected researchers make mistakes I considered not worthy of a PGY 1.

 

[Encephalopathy]

I can find the reference if anyone is interested, but one study I read showed Seroquel had the highest all-cause mortality of all the atypicals, though it wasn't significant. What was significant was clozapine, which had the lowest all-cause mortality.

Still, I think the data supports Seroquel for bipolar depression, and definitely moreso than lamotrigine. In fact, lamotrigine has never been shown to have any acute antidepressant effect, only "prophylaxis of mood states". The hiding of the negative lamotrigine studies is a good example why "evidence-based" medicine must be taken with a grain of salt: http://www.be-md.ncbi.nlm.nih.gov/pmc/articles/PMC2580079/

 

[Suedehead]

Another theory that did cross my mind but I felt the study was well-done to the point that it's investigators would've factored this in and made sure borderlines weren't in it. I could of course be wrong. I've seen some of the most respected researchers make mistakes I considered not worthy of a PGY 1.

I agree. the study was well done, and by smart people. again, the problem isn't the study but rather our grossly inadequate conceptualization of bipolar disorder.

Bipolar disorder is our generation's psych dx fad. 20 years ago it was multiple personality disorder. before that everyone was schizophrenic.

Not meaning to hijack the thread, but we're talking about the indications of these medicines. seroquel's multiple mechanisms of action could be useful in multiple scenarios, if the benefits outweighed the risks. But relying on evidence based reasoning limits us because our evidence is generally poorly conceived.

 

[393656]

I can find the reference if anyone is interested, but one study I read showed Seroquel had the highest all-cause mortality of all the atypicals, though it wasn't significant. What was significant was clozapine, which had the lowest all-cause mortality.

Still, I think the data supports Seroquel for bipolar depression, and definitely moreso than lamotrigine. In fact, lamotrigine has never been shown to have any acute antidepressant effect, only "prophylaxis of mood states". The hiding of the negative lamotrigine studies is a good example why "evidence-based" medicine must be taken with a grain of salt: http://www.be-md.ncbi.nlm.nih.gov/pmc/articles/PMC2580079/

THis is schiophrenia so keep that in mind as seroquel is now used in many other disorders.

Whopper-I defer to your expereince and I am probably way less experienced than you so mine is all hypothetical evidenced based thoughts. As with other things I notice that changes very quickly so I do not doubt a word yo are saying! Was just curious to hear your point of view that is all! Dont disagree with you one bit!

 

[whopper]

No problem. In my opinion, so long as a doctor has a differing opinion based on good data, so be it. I just get ticked off with the doctors, for example, giving Neurontin to treat depression or things to that effect.

In fact, our "disagreement" on the issue may, with more time and research, ulitimately yield that your opinion was more correct than mine. This is certainly something where the research, and what people are experiencing clinically just begs more questions. I think you were well within the science to bring up your points and stand on your own if this were a heated debate.

When I do have other medical people with me, and I do something that's a bit unorthodox, I try to specifically mention my reasoning and the data to support it. Unfortunately we all know this happens. E.g. when CATIE came out, I stopped being so cautious with Geodon and QT prolongation and others were shocked with that. Now it seems, the consensus, at least where I am, have finally caught up with CATIE. Took about 3 years for it to happen.

With the antidepressant thing in bipolar depression, this is definitely a weird issue given all that's been mentioned above. For person X find fault in person Y for a differing opinion, when person Y has very good empirical data to support him shows weak character on X's part.

 

[393656]

For sure!! Stuff we are doing now, in 10 years will look like we were totally wrong and naive I am sure. Gotta go with the data and experience even when our data often isnt all that great!

Great points!