I agree with Mr. Dawdy here -- atypicals are vastly overprescribed, especially among the elderly and children.

Still, I think they still have a limited place in the treatment of some non-psychotic conditions. As low-dose, adjunct medications they can work quite well. I take 50-75 mg of Seroquel a day as an adjunct to Depakote, and together they keep my aggressive/agitated/impulsive manic symptoms at bay.

here here!

it's one thing I think to use that stuff in the dark corners of state psychiatric institutions on violent murders or paedophiles,

it's quite another to force children and the elderly to take that shit just to shut them up

the latest attempts to market them as antidepressants is just sick

I can't think of anything more depressing than watching your own personality and cognitive abilities be erased a little bit every day

these drugs have been proven to damage both mind and body

I don't think there exists any psychiatric drug that will put you further away from real mind-body health and wholeness that those poisons

this is not a 'maintenance' drug it's a chemical that should be left in reserve for the worst cases of derangement and violent psychosis that will not respond to anything more humane

the time has come for this whole antipsychotic machine to grind to a halt

Thanks, Phillip. I've been waiting since 2002 for the docs to stop drooling over this lethal class of drugs. Let's hope the trend continues, and the use goes down, as people are still dying, getting diabetes, boobs, and turning into little blank robots.

There's no clear cut diagnostic criteria for anything from schizophrenia to post traumatic stress disorder to ADHD so it's impossible to determine whether these drugs are treating such diseases.

However if we consider these drugs to be drugs that like other drugs before them and other drugs after them are taken by people to feel better, then we can get useful information.

This is an important piece. We don't know the diseases are but we can see symptoms and effects of drugs. What happens to somebody who takes zyprexa is a better question to ask than does zyprexa cure depression or schizophrenia because those are vague non medical terms.

No one pretends that alcohol treats anything but there on numerous studies on what happens good and bad when one drinks it. Look at the effects of these drugs on people, not on vague, pseudo scientific maladies and we might discover things like, if someone is so sad they don't want to get out of bed, what sort of effect, if any, does doping them up like crazy so they start movign around going to have on their mental and physical health. Ask people who have auditory hallucinations what sort of relief they want, don't zombie them out and talk to their guardians.

Jane, you write: "it's one thing I think to use that stuff in the dark corners of state psychiatric institutions on violent murders or paedophiles,"

and

"this is not a 'maintenance' drug it's a chemical that should be left in reserve for the worst cases of derangement and violent psychosis that will not respond to anything more humane"

Are you equating mental distress with a violent crime? Saying it's okay to use these drugs as punishment for the guilty? Saying that a person labeled as severely mentally ill is guilty of something?

Is it just me, or did the Lancet meta-analysis actually find that some atypicals were superior to typicals with small to moderate effect sizes? At least, that's what it says in the abstract. I'm still waiting for the full article to be available to comment properly, but the abstract seems to contradict the overall thrust of the post above. I don't think anyone thinks that atypical antipsychotics are miracle drugs, but they are superior to placebo in treating psychosis and mania. There isn't much doubt about that.

There's no clear cut diagnostic criteria for anything from schizophrenia to post traumatic stress disorder to ADHD so it's impossible to determine whether these drugs are treating such diseases.

...What happens to somebody who takes zyprexa is a better question to ask than does zyprexa cure depression or schizophrenia because those are vague non medical terms.

...Look at the effects of these drugs on people, not on vague, pseudo scientific maladies...

I'm very curious, Sally, as to what you consider valid diagnostic criteria for any disease. I'm also curious as to why you don't consider depression and schizophrenia medical terms, and what sort of bar a malady must clear before it's considered scientific.

And from Jane:

I can't think of anything more depressing than watching your own personality and cognitive abilities be erased a little bit every day

This hasn't happened to me, and I credit it to keeping the dosage down to the bare minimum needed to achieve the desired effect.

dguller: no it doesn't. yes, there are small effects sizes in the abstract, but it was the view of the two editorial writers (and i think at least one is a research psychiatrist) that it didn't amount to much and called into question to use of this class of drugs at 10 to 20 times the price and a whole different host of side effects. if they are on the record saying that, then i'm okie dokie with what i wrote.

what i sort of pick up from the abstract is that the effect sizes vs. older drugs depend on which older drug the atypicals were trialed against....haldol or perphenazine, etc. i'll know more when i read the entire paper.

Philip:

Whether their mild to moderate increased efficacy is worth the extra price is another matter. The fact remains that the meta-analysis did show their superiority, even if it was not as dramatic as the drug companies would like. Look at Clozapine, which had an effect size of around 0.5, for example. That is quite significant, but then again, Clozapine has always demonstrated good efficacy, but with significant risks.

Sally: "Are you equating mental distress with a violent crime? Saying it's okay to use these drugs as punishment for the guilty? Saying that a person labeled as severely mentally ill is guilty of something?"

that was exactly what happened to me for my crime of mental illness.

that is how they are used now. punishment for those guilty of malfunctioning and daring to bring personal problems to someone's attention

Ikhllwd: "This hasn't happened to me, and I credit it to keeping the dosage down to the bare minimum needed to achieve the desired effect."

that's called tolerance, you can take many poisons into your system for a long time and get used to them and function more or less without debilitation as long as the dose is low enough

for example, you can smoke cigarettes and drink alcohol in moderation every day and be just fine. You can also ramp up the alcohol and nicotine to levels where it would effect you noticeably, you can ramp that up until it kills you

I experienced the death of personality from the strongest possible dose of liquid trilafon, I was put on the same dose that are used on serial killers when I was 14.

I nearly killed myself while on that drug to escape it

Seeking out psychiatric help for my problems was one of the biggest mistakes of my entire life

like so many other psychiatric survivors I had no idea what 'treatment' entailed. I had faith in science.

Six months of my life were lost to antipsychotics. Six months I can never get back. All for what?

I was right back to where I was when I started. All my issues intact waiting for me like someone on the other line.

I am not very good at math so I always struggled before I was on neuroleptics. I completely bombed my freshman year college prep math class because of trilafon. My thoughts just would not gell.

You should be glad I am not in charge of these things. If it were up to me those poisons would be banished from the face of the earth

To all who would cry, what are they to do about the noise in their head when it comes back?

To them I would say learn how to control it like I did.

There is no getting around sounding like a self righteous, sanctimonious bitch about it but, it can be done.

dguller: it's interesting that you chose to highlight clozaril to make your point. clozaril is only very rarely prescribed, regardless of its efficacy, so i'm surprised the authors' included it in their study (which i probably won't get a copy of until monday). clozaril may be one of the deadliest psych meds of all time.

from 1998 to 2005, the fda adverse events database reports 3,277 Americans were killed by clozaril. and by 1998, the drug was barely being used. how many it killed between 1989 (year of introduction) and 1997 is unknown.

my own sources at a very large teaching hospital out here tell me that they had virtually stopped using the drug by 1998 and even before then they had only used it in very aggressive cases of sz due to the blood problems associated with the drug.

so like i said at the top, it's a bit weird they included it at all. you don't see too many studies including thorazine these day do you? or mellaril?

Jane,

You write:

"that was exactly what happened to me for my crime of mental illness.

that is how they are used now. punishment for those guilty of malfunctioning and daring to bring personal problems to someone's attention."

I agree and it's not fair and shouldn't be legal.

that's called tolerance, you can take many poisons into your system for a long time and get used to them and function more or less without debilitation as long as the dose is low enough

Well, no...tolerance, as I understand it, is either an ability to endure especially large doses of a drug, or the decreased response to a drug which results in the need for increasingly large doses. I'm just keeping the dosage low.

To all who would cry, what are they to do about the noise in their head when it comes back?

To them I would say learn how to control it like I did.

And to you I would say that how people handle the noise in their heads isn't any of your business. It's wonderful that you have the fortitude to deal with whatever it is that ails you, but others just don't.

There is no getting around sounding like a self righteous, sanctimonious bitch about it but, it can be done.

There are many ways of getting around sounding like a self-righteous, sanctimonious bitch about it.

I agree and support Philip's response to dguller's first comment. That seems rather acceptable especially in light of the accompanying editorial. I have not looked at most of the papers Philip linked to about the atypicals, but it would be interesting to know if some of the papers mentioned showed no effect over the typicals, when, in this meta-analysis, some apparently did.

And clozaril. See LastPsychiatrist: According to the FDA more people die of myocarditis on clozaril than agranulocytosis. I also read a case report where a group of internists and psychiatrists recommended that clinician's pay attention to some of the early nonspecific signs of heart failure that have traditionally been attributed to benign transient effects of starting clozaril -- fever, for instance.

Philip's post is especially on the money, in my opinion.

"There are many ways of getting around sounding like a self-righteous, sanctimonious bitch about it."

Posted by: lkhllywd at December 5, 2008 03:01 PM

I think this comment section has had some ups and downs but this is ridiculous.

First, the fact that Clozapine is dangerous is independent of its efficacy in treating psychosis in schizophrenia, which is clearly evident in the meta-analysis in the Lancet. Its significant risks are the reason that it is only recommended in treatment-resistant forms of schizophrenia, and require thorough forms of monitoring, which in my neck of woods includes weekly bloodwork for several months, which can then be changed to be more lax, if possible.

Second, I am not too sure what people are reading in the article, because the abstract clearly states that Clozapine, Risperidone, Olanzapine and Amisulpride all had greater efficacy than typicals in the meta-analysis. I think the valid criticism being made is their marketing as being MUCH better than typicals when they are MARGINALLY better. That is the chimeric and spurious aspects of the situation, as far as I am concerned.

However, like Philip, I am waiting for the full article to become available online to read for myself.

oops, re-reading this thread i see that phrase was written other places, never mind.

---

Philip:

I looked at the article that you got your 3,277 number from (Arch Intern Med. 2007;167(16):1752-1759). On p. 1755, there is a table that lists the following drugs and their fatalities between 1998 and 2005:

Oxycondone -- 5,548 (opiate)
Fentanyl -- 3,545 (opiate)
Clozapine -- 3,277 (antipsychotic)
Morphine -- 1,616 (opiate)
Acetaminophen -- 1,393 (analgesiac)

By your reasoning, we should also ban Oxycodone and Fentanyl, because they have killed more people than Clozapine.

Furthermore, there is more information on that chart in terms of the number of cases of "disability or other serious outcome". In that chart, Clozapine has 4,388 cases, and ranks 12th. 1st is Estrogen with 11,514 cases and 2nd is Insulin with 9,597 cases. I suppose we should ban those medications too as toxic substances that destroy the lives of patients.

dguller, i stand by my assessment of the study abstract and the editorial. it's clearly the editorial that is driving others' assessment of the study. once i access the full paper some of these issues will become a bit clearer, but i trust that the docs who wrote the editorial read the paper in whole and are in a position to offer an assessment of its contents. i was/am certainly relying upon their reading of the paper.

speaking as a patient, mental health reporter and former shelter worker, any drug could be the most effective drug on the planet in treating psychosis (or any other disorder), but if it's too dangerous for patients to take or for docs to prescribe except in very limited circumstances, then its efficacy is kind of beside the point in anything other than an academic sense. i still wonder why the study authors bothered including it in their meta-analysis. it's an interesting choice they made.

but anyway, we'll have to see what the full study says. and then i can hopefully figure out how the atypicals rank vs. haldol and vs. lighter old antipsychotics.

maybe you are right and there's tons of efficacy for atypicals and i am being grossly unfair to a much maligned class of drugs. but i doubt it, especially after the catie study and cutlass study--both examining atypicals vs. older anitpsychotics--found no advantage for the atypicals in efficacy or side effects.

dguller, i don't think i have called for a ban on clozaril or the other atypicals. i have called for a radical curtailment in their use for non-psychotic disorders. i don't particularly think their use in sz is justified by their efficacy and expenses and side effects. maybe in some cases where they work. in other disorders, i think the long term use of these drugs should be completely avoided by patients and should be discouraged by docs. there will be exception of course, but i think the rule of thumb with the atypicals for non-psychotic disorders should be the same as it was in the 90s for the use of the old antipsychotics in non-psychotic disorders: to be avoided long term and to be used only very short term.

i do think their use in children should be limited to psychotic disorders only.

sorry but i've seen too many people harmed by these drugs used for non-psychotic disorders and i've seen people with sz utterly messed up by the drugs. for the record, i was someone allegedly with bipolar disorder who got messed up by the atypicals in long term use. call me biased and non-scientific in my views, but i think the available evidence (all those studies i linked to earlier in the post itself) and the word on the street argue against their casual use.

as for oxycontin and other opiates, their prescribed uses are controlled by the dea and various state health depts (esp in wash state) and while doctors can rx them, if they overdue it they'll be getting a visit from a govt official. docs have to put their dea number on rx forms and so on. oxy and other opiates can be very good and very debilitating pain killers. i personally know people who have been hurt by them, using them as instructed by their docs. i wouldn't want to ban them and i trust docs and patients to work together to figure out how to manage the trade offs, which is sadly something psychiatrists almost never do with sz patients.

as to the casual use of opiates in american cuture through black market sources, it is totally unacceptable and needs to stop. i've seen several people try to plat around with oxy and have their lives ruined.

dguller: I don't want to presume to speak for Philip. But I sincerely doubt that is his "reasoning". So don't put it forth as such. That's just silly. Again, can't speak for Philip or anyone else, but I'm sure Philip doesn't approve of the whole world living in pain, or setting anesthesia back by decades. You say thats his "reasoning" and it sounds ridiculous, but you neglect to remind us all of the obvious fact that oxycodone and fentanyl are highly addictive and highly abused drugs. Of-goddamn-course they kill that many people. Oxycodone and fentanyl have legitimate purposes in pain relief and anesthesia and are highly effective. Clozaril may be effective for treatment resistant schizophrenia, but it is not addictive and not highly abused. Therefore the likelihood that legitimate prescription of these drugs caused a majority of these deaths is much higher.

Who the hell would get rid of pain relief? No surgery? Is that a serious way to characterize someone else's reasoning? A monkey maybe?

My daughter is on Clozaril. She goes every 2 weeks for a blood draw to make sure her white cell count is normal, and in the mean time she could die of a heart attack, her heart could explode.

She is the poster child now an adult of why antipsychotics should not be used except in extreme cases, and even then I have a hard time defining that.

Over the last decade there has been discussion about my daughter's brain becoming damaged and basically unable to function without an antipsychotic.

For a dozen psychiatrists who have seen her (and mostly as a result of being bounced around in an adult defunct mental health system)no one has answers.

Because, no one will ever know what her story would be now if she had not been placed on psych meds at age 11 for bed wetting.

There is no reason antipsychotics should be used for depression and anxiety and all of the rest of the new "SSRI replacement-patent-ran-out" diagnoses.

I've witness horrific results in dozens and dozens of people and it is not a pretty sight.

Diabetes, permanent tremors, quivering lips, shuffling walks, I say take these at your own risk. (I see these ppl daily and it's awful, this is just nothing to take lightly, these drugs).

The whole thing gives me nightmares.

Philip:

Thank you for your comments. I think we are almost in total agreement here. :)

JC:

I suppose I was too rash in my interpretations, and Philip has wonderfully clarified things so that we are mainly in agreement.

His main point is that antipsychotics, such as Clozapine, can be very dangerous, and that does not necessarily preclude their use in patients, especially if they have been shown to be effective, such as Clozapine has. However, a frank discussion of their risks and benefits must be engaged in before they are used.

Now, regarding your point that the opiates I mentioned are addictive and often abused by people dependent upon them. I don't see how that supports your position, because I think that would be an argument AGAINST their use, especially since they have a substantially larger death toll than Clozapine does. Also, from what I understand, and I'll check the figures, but the incidence of deadly adverse effects with Clozapine is actually quite rare (less than 0.5% of cases), and thus it is quite safe with the proper precautions in place, I think.

Dguller,

I've never had a physician prescribe Oxycondone, Fentanyl, or Morphine for SSRI induced insomnia. I have, however, had a physician prescribe antipsychotics for insomnia. How many patients would accept the risks of antipsychotics for insomnia or depression if they were aware of them? Having seen a debridement of a diabetic's foot - I vote no thanks. To those who are okay with these risks & want to take them, fine by me.

Lisa:

Well, they wouldn't because opiates are useful for analgesia, and not as sedatives. So, they wouldn't prescribe opiates for SSRI-induced insomnia.

Low-dose atypical antipsychotics have been shown in multiple studies to be useful as augmenting agents with antidepressants, hypothetically due to their impact on both serotonin and dopamine receptors. They can be especially useful, for example, in treatment resistant depression (J Clin Psychiatry 2007; 68(6):826-31).

There is no current evidence for how long they should be used, but it stands to reason that they should be discontinued soon after remission is attained with antidepressants. Even antidepressants should be discontinued 6-9 months after remission is attained, and maintenance use should only be considered in those who have had several major depressive episodes, because they are risk of further relapse.

Exactly Lisa. People need to be told these drugs are antipsychotics, and as a consumer we both know PCP's as well as psychiatrist's do not often tell a patient this, especially when walking out of a PCP office with insomnia meds or depression meds...that's my concern, same as Abilify for kids, that parents are not being told.

In the decade I have been in the system with my daughter she was and I was never told risks of these drugs.

Even with Clozaril. Inpatient psych docs don't tell patients much of anything in that regard, but those drug reps are swarming. My daughter came home with a Zyprexa costmetic kit for example, and the Seroquel rep was there to "teach" a lunch-and-learn for Seroquel rx for Borderline.

Neuroleptics are sedating because they bind strongly to histamine, not due to 5HT or D. At low dose, neuroleptics are no more effective for sleep than say benadryl.

IMO, if you were prescribed a major tranquilizer for insomnia you should find another doctor, quickly.

"Low-dose atypical antipsychotics have been shown in multiple studies to be useful as augmenting agents with antidepressants, hypothetically due to their impact on both serotonin and dopamine receptors. They can be especially useful, for example, in treatment resistant depression."

Useful in what way? (I need to read this study). I would imagine most people who are sedated are less aware they're depressed, and pretty much less aware of a whole lot of things. At what cost? Why not recommend that they stay stoned on pot? What's the difference (besides the legal issue, of course)?

"My daughter came home with a Zyprexa costmetic kit for example, and the Seroquel rep was there to "teach" a lunch-and-learn for Seroquel rx for Borderline."

I guess they have now replaced the Zyprexa cosmetic kit with a blood sugar test kit?

Lisa:

Useful in the sense that subjects given antidepressants plus low-dose atypical antipsychotics versus those given antidepressants plus placebo over 4-12 weeks had a higher rate of response (57.2% vs 35.4%) and remission (47.4% vs 22.3%) in treatment-resistant depression, as recounted in the meta-analysis I cited. You should absolutely read the article, and please tell me what you think about it.

With regards to marijuana, I am unaware of any studies that show it to be useful as an augmenting agent in treating depression.

Useful?

I can only wonder in what sense a major tranquilizer can be "useful" in treating a person suffering from emotional distress. Whilst I think it's "useful" to look at the criteria and measures used that define response, I can only wonder what happens to these people long beyond the 4-12 weeks. The risk on NMS or permanent TD seem to outweigh, in my mind, very modest increases in scores.

It still amazes me that major tranquilizers would be considered as a treatment, add on or otherwise, for depression. Tranquilizers are needed for very narrow, specific purposes - not chronic conditions. It's akin to shooting ants with a howitzer.

Paul:

I'm not too sure why you are using the scare quotes around "useful", except to denigrate the usefulness of atypical antipsycotics as augmenting agents in treatment-resistant depression. That is certainly your prerogative, but the meta-analysis clearly shows its usefulness in that situation for the duration mentioned. As for what happens beyond 12 weeks, there is no evidence there.

Also, I would say that the dosages were low and thus the risk of EPS and TD are very low. For those who are suffering from depression and have failed multiple treatments, they should be offered this as an option with full disclosure of the risks, as should be standard practice.

Dguller,

If I wanted to denigrate something I would do so directly and deliberately. Please don't presume to know my mind or project whatever is in yours.

A more "useful" question is how do low dose tranquilizers fare against a decent antihistamine. How or why should sedation improve AD response? Is it due to a reduction in insomnia or just getting better sleep or some other knock on effect? What exactly gets "better" for treatment resistant depression?

I'm not going to write an essay on receptor binding and such so the following is a simplification. Low dose neuroleptics almost exclusively bind to histamine. It's only at higher doses when histamine is "saturated" that 5HT, D2, and others act. The point is that at low doses neuroleptics behave as anti-histamines with perhaps some orthostasis depending on a1 affinity. They do nothing in terms of 5HT or D2 - you need the higher therapeutic dosage for that and we know the effects of these drugs at these levels. Obviously, there is variation within this class of drugs, but there it is. If you take 25-100 mg of Seroquel you're taking a very expensive and powerful dose of an otherwise OTC available anti-histamine - nothing more.

So what exactly is going on here that's useful? Is the takeaway to sedate AD treatment resistant depressed people?

Please note any and all uses of quotes were not used to scare any readers aside those already predisposed.

Paul:

First, I "apologize" about the comment about scare quotes. :)

Second, I am unaware of any studies that used an antihistamine exclusively as an augmenting agent to treat depression. That would be an interesting study. If you find one, please let me know.

Third, the doses used in the studies cited in the meta-analysis that I mentioned above would certainly block a significant portion of D2 and 5-HT2 receptors. One study found the following saturation rates:

-- Risperdal 2 mg daily: D2 70%, 5-HT2 70%.
-- Olanzapine 5 mg daily: D2 40-60%, 5-HT2 90-100%.
-- Clozapine 75 mg daily: D2 20%, 5-HT2 100%.

These figures are from Am J Psychiatry. 1999; 156(2):286-93. The current understanding is that blocking 5-HT2 receptors in the brainstem leads to an increase in dopamine and norepinephrine release in the PFC, which can help with attention, concentration and executive function, as well as improve top-down regulation of unstable emotions. That's the theory anyway, and it does help explain why low dose atypical antipsychotics that do block 5-HT2 receptors would be helpful in depression, independent of their sedating properties.

I can only wonder in what sense a major tranquilizer can be "useful" in treating a person suffering from emotional distress.

Why do you conflate atypicals with major tranquilizers? The side effects of the various atypicals vary, and any degree of somnolence is often dosage-related.

Okay.

So, I finally got access to the Lancet article that Philip cited, and have read it. Irrespective of what the editorial says, the actual meta-analysis does not say that atypical antipsychotics are no better than typical antipsychotics.

Figure 1 on p. 2 clearly shows that atypicals did better than typicals in terms of overall symptoms, positive and negative symptoms, but that the difference was small to moderate in terms of effect size.

With regards to the individual drugs some were better than others depending on whether they were looking at overall symptoms, positive symptoms, negative symptoms or depression. If you look at Figure 2 on p. 3, you find the following:

-- Amisulpride did better across all domains.
-- Aripiprazole was very mildly better in terms of depression.
-- Clozapine did better across all domains.
-- Olanzapine did better across all domains.
-- Quetiapine did better across all domains.
-- Risperidone did better in overall, positive and negative symptoms, but not depression.
-- Sertindole did not do better in any domain.
-- Ziprasidone did not do better in any domain.
-- Zotepine did not do better in any domain.

With regards to EPS, Figure 4 on p. 6 shows that atypicals were better than Haldol, but no better than low dose typicals. They also found that atypicals did better in terms of lower EPS than low dose Haldol (

With regards to sedation and weight gain, Figures 5 and 6 on pages 7 and 8 show that atypicals are better than Haldol, but not much better than low dose typicals.

So, the meta-analysis clearly concludes that atypicals are better than typicals in multiple symptom domains, but only to a mild to moderate degree, which is exactly what the abstract stated.

So, why the extremely hostile editorial? Well, for those who sold these medications as being SUBSTANTIALLY better than typical antipsychotics and as some kind of godsend, then this is a wake-up call. They are better, but only marginally so. Given that fact, plus their significant side effect burden, their extremely high costs should be reassessed, and cheaper alternatives should start to make a comeback.

Dguller,

No need to apologize. I was being a bit cheeky.

I doubt you'll find any such studies nor expect anyone to fund one.

I also wouldn't agree that 5 mg Zyprexa is an especially low dose. 5 mg zyprexa is more similar to 250-300 mg of Seroquel - neither would I consider a low dose.

If the AD is already providing significant 5HT blockade, then adding a neuroleptic won't obviously provide an additional useful effect. Yes, yes, different receptors might be involved so it's rather messy which is among my major objections. I can't see how you can tease out exactly what's going on to claim utility given the safety profile of neuroleptics.

lkhllywd,

No conflation, these terms are synonymous: neuroleptic = (atypical) anti-psychotic = major tranquilizer.

Yes, sedation varies based on histamine binding/binding rate/blockade, which does vary within this class of drugs. The largest perceived effect is at the lower doses because of a greater affinity for histamine compared to other receptors these drugs target. Once saturated, additional drug won't result in greater sedation but rather other receptors will now start to bind (vast oversimplification alert...) Doubling the dose does not necessarily result in greater sedation - it depends on how much drug is needed to reach maximal effect which is not necessarily 100% blockade.

Regardless, it's important to realize that the dose you take actually changes the action of the drug. If you take low dose seroquel, below 100 mg for example, it has ZERO effect on 5HT and D2 - meaning it does nothing physiologically other than to sedate. At higher doses (above 250mg) you'll experience the effects from serotonin and dopamine blockade.

Paul:

No problem about the cheekiness. :)

First, you are correct that at low doses, particularly of Seroquel, the antihistamine properties will dominate until the histamine receptors are almost or fully saturated, and then the other properties will kick in.

Our discussion of the theoretical receptor profiles of these drugs is actually incidental, because studies have shown the atypicals to be useful augmenting agents for treatment-resistent depression. The underlying mechanisms are secondary to the fact that the medications do work in that setting, as has been demonstrated in research studies.

Also, from what I understand, most antidepressants do not block 5-HT receptors, but rather activate them as part of their therapeutic action. Prozac, on the other hand, does block 5-HT2A/C receptors in the brainstem, which leads to the boost in DA and NE in the PFC, in a similar fashion as the atypicals are hypothesized to do.

Take care.

No conflation, these terms are synonymous: neuroleptic = (atypical) anti-psychotic = major tranquilizer.

No.

Neuroleptics and tranquilizers (otherwise known as sedative-hypnotics) are two separate classifications of drugs. Though some neuroleptics may cause somnolence, they are not classified as tranquilizers, no matter how many times you insist that they are.

Regardless, it's important to realize that the dose you take actually changes the action of the drug. If you take low dose seroquel, below 100 mg for example, it has ZERO effect on 5HT and D2 - meaning it does nothing physiologically other than to sedate. At higher doses (above 250mg) you'll experience the effects from serotonin and dopamine blockade.

I don't really care if my dosage of Seroquel (50 - 75 mg) isn't keeping my 5HT and D2 receptors occupied. I do care if it's helping to keep me stable.

And it is.

lkhllywd,

Note I said MAJOR tranquilizer, minor tranquilizers such as benzos are what you referred to. You can look this up virtually anywhere - even wiki.

If taking a histamine blocker helps you, great. We all wish to feel well. However, do not be mislead in thinking that dose provides any D2 or serotonin effect. It doesn't. Don't take my word for it, ask any competent pharmacologist.

"The current understanding is that blocking 5-HT2 receptors in the brainstem leads to an increase in dopamine and norepinephrine release in the PFC, which can help with attention, concentration and executive function, as well as improve top-down regulation of unstable emotions."

Dguller, if antipsychotics improve attention, concentration & executive function they why are they being prescribed for insomnia in people with treatment resistant depression? How can it both improve depressed patients' concentration and make them sleepy?

Also, you guys need to do some studies on the effects of weight gain on mood. Please do tell your patients that they are risking significant weight gain which puts them at risk for diabetes & metabolic syndrome before putting them on these drugs for major depression. As someone who has been in the treatment resistant depression category, nothing would have depressed me more than to have gained a lot of weight.

Any studies in the works to look at antipsychotic med compliance among people with major depression? Good luck with that.

Paul:

I thought you might be interested in this information. A PET study published in Arch Gen Psychiatry (2000; 57:553-559) found that Seroquel 150 mg had no D2 occupancy, but did have 20% 5-HT2 occupancy, and that Seroquel 300 mg had about 5% D2 occupancy, but did have 50% 5-HT2 occupancy. So, there is some serotonergic activity even at low doses of Seroquel.

Take care.

Dguller,

Yes, that's correct. Q has basically no "anti-psychotic" effect below 300 mg, but sure is sedating.

Lisa:

That is an excellent point, which was actually mentioned in the meta-analysis that I cited above. The authors found that there was no difference between atypical antipsychotic augmentation versus placebo augmentation in terms of overall discontinuation rate or discontinuation due to inefficacy. However, there was a higher rate of discontinuation due to side effects in the antipsychotic group versus placebo (RR 3.38, 1.98-5.76, p

So, it appears that there is a side effect burden with using atypical antipsychotics as augmenting agents, which should not be surprising. However, overall, they were well tolerated, based on the overall discontinuation rate between the two groups.

Lisa:

The sedating properties are predominantly due to blocking histamine receptors in the brain. This is why the medications are given at bedtime, so that sedation will not be a problem.

I know that the boost in DA and NE in the PFC occurs following the blockage of 5-HT2A/C in the brainstem, and that there might be a delay in that effect, which could kick in during the daytime. However, this is just me speculating.

Regarding weight gain, you are correct that obesity is correlated with depression, and so it would be counterproductive to induce it in depressed individuals. Fortunately, the dosages do not have to be high, and the duration of treatment is also short-term, which should help reduce the chances of a metabolic syndrome occurring.

Sorry, forgot to add that this a very complicated question to answer. When you have 2 drugs competing for the same receptor(s) the results can be unpredictable. You just can't add the two numbers together. I've been trying to get my head around this for some time, but I haven't a defensible position because there is just too much uncertain and unknown.

My suspicion is that neuroleptics have been proven are too dirty to use except in extremis and only acutely. AD therapy is anything but acute in practice and so probably is an inappropriate course for neuroleptics imo.

Thanks for the debate!

"Fortunately, the dosages do not have to be high, and the duration of treatment is also short-term, which should help reduce the chances of a metabolic syndrome occurring."

Well, call me skeptical but I seriously doubt antipsychotics will be used short term. Also, what about the impact on mood when the drug is taken away?

Lisa:

I do not have the answer to those questions, unfortunately. Sorry.

Paul:

Excellent points, as always. Thank you, as well, for the engaging discussion. :)

"I do not have the answer to those questions, unfortunately. Sorry."

Dgueller, with all due respect shouldn't you have information on the impact of withdrawing antipsychotics from depressed patients - especially since you're advocating their use short term? It seems like it would be important to know the impact of this on mood.

Lisa:

I was actually referring to your statement that you doubt whether the antipsychotics will be used by clinicians short term. I do not have the information about the future use of these medications by clinicians.

Regarding the impact on mood of withdrawing atypical antipsychotics after short-term use, I have never encountered any problems during my training, as long as the medication is discontinued properly. I am also unaware of any literature that demonstrates any lasting negative impact on mood following atypical antipsychotic discontinuation, if done properly, especially not after a short-term use of a few months. However, if you are aware of anything, then please let me know.

Thanks!

Are you aware of any studies that look at those with treatment resistant depression who received antipsychotics short term & how they're doing a year or two later? It would be interesting to know.

Lisa:

There is a study (Neuropsychopharmacology 2006;31: 2505-13) that looked at Risperdal augmentation of Celexa. After 4-6 weeks of open use of Celexa, those who failed to respond to it were put on low-dose Risperdal for 4-6 weeks, and then randomized to either continue with Risperdal or placebo for 24 weeks in a continuation phase.

They found that there was a significant improvement with Risperdal augmentation of subjects non-responsive to Celexa after 4-6 weeks, but found no benefit to continuing the Risperdal for the 24 week continuation phase compared to placebo.

Regarding your question of what the adverse effects are for those who use Risperdal short-term, and then discontinue it a year or two later, this study looked at what happens over a 6 month period. They found that the subjects tolerated the change well without any significant adverse effects. The only clinically significant adverse effects were elevated prolactin levels (35 vs 7), galactorrhea (2.5% vs 0.0%), and weight gain (1.3 kg vs -0.5 kg) in the Risperdal group compared to placebo.

So, to answer your question, at least with regards to Celexa augmented with low-dose Risperdal in treatment-resistant depression, the Risperdal should be used short-term and discontinued, and there does not appear to be any significant adverse effects to that strategy over the subsequent 6 month period.

If I find any other studies, I'll let you know, but this is the closest one that partially answers your question.

I hope this helps. :)

I don't have access to read the study at the moment, so I am unable to find out what significant improvements they've had. As soon as I'm able I will read it and get back to you. However based upon what you have posted, it still doesn't answer my question about how these patients are doing a year or two later? Has anything changed for them?

Lisa:

Sorry, that's all that's in the literature for now, as far as I know. I'm sure that they'll be doing more long-term studies that look at the issues that you've raised.

For now, it is fairly clear that in treatment-resistant depression, short-term, low-dose atypical antipsychotic augmentation is a viable strategy to improve response and remission rates.

http://bipolarsoupkitchen-stephany.blogspot.com/2009/07/40-million-dollar-nimh-schizophrenia.html

Another study on the horizon:

$40 million dollar RAISE schizophrenia study funded by NIMH