Seroquel--the worst antipsychotic?

[Celexa]

People seemed to like my Sunday morning musings last week so here's another.

I dislike seroquel intensely. Which doesn't mean I don't use it. But, reasons I hate it--

1. Makes people fat. Recently was looking through data on metabolic effects and was shocked in the literature it's not shown to be one of the worst. My experience is people gain tons of weight.

2. Orthostatic hypotension. I do a lot of geri and CL, so seroquel is obviously often a theoretical first line for pts with Parkinson or LBD. But goddam the orthostatic hypotension is real and dangerous. And you also get people who have been on it for decades who become vasculopaths as they get older and its a real problem.

3. It's so hard to wean. Even with cooperative patients it's hard. Sometimes I'd rather be weaning a benzo.

4. Related to #3, seroquel is the only non-controlled med I've been SCREAMED at when a patient needed a refill or wanted restarted in the hospital. The other times that happens are benzos and Adderall. Really makes one think, no? We know it has "abuse potential" but that's said of wellbutrin too and no one has ever melted down at me to get their wellbutrin. Or gabapentin.

5. Does it even antipsychotic? Yeah, yeah, we all know that doses need to be high to get dopamine blockade. I just can't shake the feeling it doesn't do its job on that front. If I am going to make someone gain a ton of weight I may as well give them olanzapine. At least that's an effective antipsychotic.

6. I want to be able to put people straight on latuda and vraylar for bipolar depression but get stuck in prior Auth hell unless they've tried seroquel. Hate.

What's your experience been?

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[MedMan80]

I like it, really good for insomnia. Adolescent populations with bipolar spectrum + anxiety + insomnia, it's almost a go-to for me apart from Abilify. Weight gain is variable, not really worse than risp in my experience. Low incidence of EPS. Don't rag on it!

 

[Fan_of_Meehl]

I like it, really good for insomnia. Adolescent populations with bipolar spectrum + anxiety + insomnia, it's almost a go-to for me apart from Abilify. Weight gain is variable, not really worse than risp in my experience. Low incidence of EPS. Don't rag on it!

Just a question from a non-prescriber...does it really effectively treat insomnia long-term (with daily use?). Same question with respect to anxiety? I know I could research the basic literature but I'm always interested in prescribers/practitioners on the 'front lines' so to speak and their experiences.

 

[clozareal]

It's one of the few that can treat bipolar mania, bipolar depression, and mixed states. It's great for anxiety and insomnia which go with bipolar disorder. The effect size is also higher than other antipsychotics. I tend to go for 300mg as the max for bipolar disorder since there doesn't seem to be that much more benefit to going to 600mg.

To your points:
1. Olanzapine and risperidone are much more likely to cause weight gain. I've had patients get precipitous insulin resistant and gain lots of weight (40 lbs in 6 months) on ziprasidone monotherapy. Start quetiapine with metformin or use topiramate along with it. If BMI > 30 then you can try a GLP-1 agonist if you can get it approved.

2. Orthostatic hypotension resolves for most people with slow titration. The alpha-1 receptors on arterioles that leads to orthostatic hypotensive symptoms takes about 2-3 days to re-regulate.

3. I feel like this is the case with most antipsychotics.

4. I've never had this. I've been yelled at for stimulants, benzos, z-drugs, and gabapentin during residency, especially at CMHC and VA settings. I have not been yelled at since graduating from fellowship thankfully.

5. I tend not to use it as an antipsychotic.

6. Lurasidone is now generic! I use lithium and lamotrigine for bipolar depression more than an atypical antipsychotic, despite the literature showing the effect size is highest for cariprazine and quetiapine mainly because of side effect profile.

 

[PikminOC]

It's one of the few that can treat bipolar mania, bipolar depression, and mixed states. It's great for anxiety and insomnia which go with bipolar disorder. The effect size is also higher than other antipsychotics. I tend to go for 300mg as the max for bipolar disorder since there doesn't seem to be that much more benefit to going to 600mg.

To your points:
1. Olanzapine and risperidone are much more likely to cause weight gain. I've had patients get precipitous insulin resistant and gain lots of weight (40 lbs in 6 months) on ziprasidone monotherapy. Start quetiapine with metformin or use topiramate along with it. If BMI > 30 then you can try a GLP-1 agonist if you can get it approved.

2. Orthostatic hypotension resolves for most people with slow titration. The alpha-1 receptors on arterioles that leads to orthostatic hypotensive symptoms takes about 2-3 days to re-regulate.

3. I feel like this is the case with most antipsychotics.

4. I've never had this. I've been yelled at for stimulants, benzos, z-drugs, and gabapentin during residency, especially at CMHC and VA settings. I have not been yelled at since graduating from fellowship thankfully.

5. I tend not to use it as an antipsychotic.

6. Lurasidone is now generic! I use lithium and lamotrigine for bipolar depression more than an atypical antipsychotic, despite the literature showing the effect size is highest for cariprazine and quetiapine mainly because of side effect profile.

I had one patient who was a drug user get very mad about stopping Seroquel as it made withdrawal smoother for him. But that was in my history of practice

 

[SmallBird]

It is under appreciated that quetiapine actually has multiple RCTs supporting its utility for anxiety. It is also an evidence based treatment for mood lability and is my go to for patients with a common mix of anxiety and affective instability who don't meet criteria for bipolar mood disorder. I use it instead of a benzo for acute anxiety especially in hospital settings with great effect.

 

[wolfvgang22]

Everyone else already replied what I think about quetiapine. Risperidone causes a lot more weight gain and I see more tardive dyskinesia with Risperidone. No one has ever yelled at me about weaning any antipsychotic. I've had prison inmates ask for quetiapine and trazodone because they wanted to snort them, but they didn't yell at me or anything.

I do use quetiapine a lot off label for Chronic, severe PTSD patients who have a lot of anxiety and anger. It's seems to help with these issues when SSRIs, SNRIs, and alpha 2 medications are only partially effective. It has drastically reduced road rage and domestic violence behavior in some of my VA patients, who are nearly always armed. Sometimes I also use low dose Haldol PRNs to help those patients. I must be careful to avoid polypharmacy, however.

 

[forchinet121]

I like Seroquel I think it’s helpful for anxiety, sleep, depression, PTSD, mood instability, lots of different uses. The fact it causes less TD and acute EPS is also a bonus

 

[mistafab]

I’m adding that sleep wise, trazodone (best) and doxepin (second best) are better in non bipolar folks for actually improving sleep architecture and increase deep sleep states. Seroquel acts like Benadryl, no deep sleep gains. These findings haven't been fully translated/explored clinically though, but i'd wager that benadryl/seroquel don't actually improve restful sleep - but in bipolar it may not matter as much.

Seroquel however I feel gets better mileage in Geri pts. Also good in TBI behavior problems.

 

[SmallBird]

I’m adding that sleep wise, trazodone (best) and doxepin (second best) are better in non bipolar folks. They actually change sleep architecture and increase deep sleep states. Seroquel acts like Benadryl, no deep sleep gains.

Seroquel however I feel gets better mileage in Geri pts. Also good in TBI behavior problems.

Do you have any papers? Not saying you are wrong, that just seems important and genuinely interesting.

 

[docksan]

I’m adding that sleep wise, trazodone (best) and doxepin (second best) are better in non bipolar folks. They actually change sleep architecture and increase deep sleep states. Seroquel acts like Benadryl, no deep sleep gains.

Seroquel however I feel gets better mileage in Geri pts. Also good in TBI behavior problems.

Dunno, in my experience doxepin is actually more effective than trazodone and Seroquel tends to be less helpful for sleep because of its partial indirect activation of cortical dopamine.

 

[annoyedpsychiatrist]

i only use seroquel in very specific patients such as dementia patients or bipolar with severe sleep issues.

Its very easy to get caplyta and vraylar now through the patient support program via the manufacturer. Most bipolar patients that I see tend to not be very affluent and qualify. I utilize this program very frequently, and patients can get the meds delivered to their door for free.

I like both caplyta and vraylar because of the metabolic profiles. Also no titration period is nice, being able to start an effective dose makes things more succinct. Ill use lithium in some people problem here is a lot of people i see are older/more medical issues so SGAs end up being the more tolerated med, though i wont deny lithium is good at what it does in the right person.

 

[Merovinge]

Started my time in medicine assuming any doctor who used it regularly was a bad psychiatrist

Generally felt that way through residency

Became an attending and realized how effective the medication is in bipolar disorder. Now I still don't prescribe it too often due to the weight gain, but the combination of controlling mania and depression, anxiety, and sleep is pretty unreal from a single medication. Somehow nuanced understanding was the right conclusion rather than medicine = good or medicine =bad.

 

[comp1]

Suzy-Q can be a pretty useful med. It's also abusable. I'm sure it causes weight gain. I don't think it causes more than olanzapine... I would have thought it caused more than risperidone which is so near a typical in terms of receptor binding profile.

 

[clozareal]

Started my time in medicine assuming any doctor who used it regularly was a bad psychiatrist

Generally felt that way through residency

Became an attending and realized how effective the medication is in bipolar disorder. Now I still don't prescribe it too often due to the weight gain, but the combination of controlling mania and depression, anxiety, and sleep is pretty unreal from a single medication. Somehow nuanced understanding was the right conclusion rather than medicine = good or medicine =bad.

I felt this way too because it was used way too often on the inpatient non-psychiatric services, being used in insomnia in those without bipolar, and being used in the elderly despite the risk of alpha blockage and anticholinergic side effects.

 

[ObsequiousAplomb]

Suzy-Q can be a pretty useful med. It's also abusable. I'm sure it causes weight gain. I don't think it causes more than olanzapine... I would have thought it caused more than risperidone which is so near a typical in terms of receptor binding profile.

I'd agree with the experience regarding Risperdal. Maybe Risperdal causes more weight gain above the navel? Either way, my med naïve patients do tend to get fatter with any antipsychotic

 

[whopper]

No one mentioned on CATIE Trial Quietiapine had the most amount of QT prolongation vs any of the other antipsychotics in the trial.

I don't like giving it out in general but as with all meds there's exceptions where the patient did find it a good beneficial option.

Lurasidone is now generic but the problem is several pharmacies still don't have the generic in stock and it could be several months before they do get it in stock.

 

[mistafab]

Dunno, in my experience doxepin is actually more effective than trazodone and Seroquel tends to be less helpful for sleep because of its partial indirect activation of cortical dopamine.

I miswrote my original post. I meant "best" in terms of effect on altering sleep architecture for the better. No other drugs tested seem to do that besides trazodone and doxepin (melatonin wasn't tested, ramelteon either). Interestingly, a single dose of propofol also seems to have the same effect... Maybe Michael Jackson's doctor was onto something 🤣

I'm sure down the pipeline we will start seeing single dose propofol get looked at more for insomnia r/t depression/bipolar.

 

[MacDonaldTriad]

I wasted too much of my time trying to find the effective dose of Zeroquel. I stopped trying a while ago.

 

[Candidate2017]

I don't prescribe Seroquel much, but it is very effective for schizophrenia and bipolar. My hypothesis for why it appears less effective in the real world for schizophrenia is because it has a short half life (IR and XR), and if patients have trouble with the IR titration or miss a dose, it becomes less effective than other antipsychotics.

The people who get mad about tapering off Seroquel are the ones who I inherit with comorbid substance issues and have a history of "losing" their Seroquel.

 

[Stagg737]

What's your experience been?

It's a great med for the right patients but is basically a messier version of lamotrigine in terms of people just throwing it at patients when they're not sure what to do. Also makes a lot of people fat.

 

[mistafab]

Do you have any papers? Not saying you are wrong, that just seems important and genuinely interesting.

There are a lot of papers. If you just pubmed “trazodone sleep architecture” you’ll find myriad - even meta analysis looking at this stuff.

Basically, anesthesiologists have been quietly doing this kind of research for years. Often in healthy controls, but now more intently in depression. At some point in the future, again, I think we’ll see some sleep-related anesthesia/psychiatry interventions. Ketamine was just such a hot find that it is spurring a lot of interest in these agents. My money is on propofol.

 

[Stagg737]

People seemed to like my Sunday morning musings last week so here's another.

I dislike seroquel intensely. Which doesn't mean I don't use it. But, reasons I hate it--

1. Makes people fat. Recently was looking through data on metabolic effects and was shocked in the literature it's not shown to be one of the worst. My experience is people gain tons of weight.

2. Orthostatic hypotension. I do a lot of geri and CL, so seroquel is obviously often a theoretical first line for pts with Parkinson or LBD. But goddam the orthostatic hypotension is real and dangerous. And you also get people who have been on it for decades who become vasculopaths as they get older and its a real problem.

3. It's so hard to wean. Even with cooperative patients it's hard. Sometimes I'd rather be weaning a benzo.

4. Related to #3, seroquel is the only non-controlled med I've been SCREAMED at when a patient needed a refill or wanted restarted in the hospital. The other times that happens are benzos and Adderall. Really makes one think, no? We know it has "abuse potential" but that's said of wellbutrin too and no one has ever melted down at me to get their wellbutrin. Or gabapentin.

5. Does it even antipsychotic? Yeah, yeah, we all know that doses need to be high to get dopamine blockade. I just can't shake the feeling it doesn't do its job on that front. If I am going to make someone gain a ton of weight I may as well give them olanzapine. At least that's an effective antipsychotic.

6. I want to be able to put people straight on latuda and vraylar for bipolar depression but get stuck in prior Auth hell unless they've tried seroquel. Hate.

What's your experience been?

It's one of the few that can treat bipolar mania, bipolar depression, and mixed states. It's great for anxiety and insomnia which go with bipolar disorder. The effect size is also higher than other antipsychotics. I tend to go for 300mg as the max for bipolar disorder since there doesn't seem to be that much more benefit to going to 600mg.

To your points:
1. Olanzapine and risperidone are much more likely to cause weight gain. I've had patients get precipitous insulin resistant and gain lots of weight (40 lbs in 6 months) on ziprasidone monotherapy. Start quetiapine with metformin or use topiramate along with it. If BMI > 30 then you can try a GLP-1 agonist if you can get it approved.

2. Orthostatic hypotension resolves for most people with slow titration. The alpha-1 receptors on arterioles that leads to orthostatic hypotensive symptoms takes about 2-3 days to re-regulate.

3. I feel like this is the case with most antipsychotics.

4. I've never had this. I've been yelled at for stimulants, benzos, z-drugs, and gabapentin during residency, especially at CMHC and VA settings. I have not been yelled at since graduating from fellowship thankfully.

5. I tend not to use it as an antipsychotic.

6. Lurasidone is now generic! I use lithium and lamotrigine for bipolar depression more than an atypical antipsychotic, despite the literature showing the effect size is highest for cariprazine and quetiapine mainly because of side effect profile.

1. Agree with the weight gain. Data may show that other medications cause more weight gain, but I've never seen someone gain 200+ pounds on risperidone. I have seen multiple patients gain that kind of weight on Seroquel. Only meds I've seen come close to that are clozapine and Abilify once or twice in kids with severe ID/genetic disorders (which may have been the actual reason they gained weight).

2. I've actually seen this more with risperidone than seroquel.

3. The only times I've had patients have issues with weaning any antipsychotics were d/t significant anxiety, especially if they have sleep issues.

4. This is pretty inline with my experience as well. I've had a couple patients yell about gabapentin as well, but I've had a few patients get physically aggressive (posturing, throwing stuff, never stuck around to get assaulted) blow-ups from patients who I didn't feel seroquel was appropriate for. This is almost always in patients with severe substance problems as it does significantly assist with withdrawal symptoms, especially stimulant withdrawal.

5. It's a meh antipsychotic. When I use it it there's almost always a (hypo)manic component and it's never my first, or second, or third, etc choice, but I've had a couple of patients where that's just what worked. Shrug.

It is under appreciated that quetiapine actually has multiple RCTs supporting its utility for anxiety. It is also an evidence based treatment for mood lability and is my go to for patients with a common mix of anxiety and affective instability who don't meet criteria for bipolar mood disorder. I use it instead of a benzo for acute anxiety especially in hospital settings with great effect.

For short term for anxiety, sure. But longer term it's still going to carry a very heavy side effect burden which is questionably dose-dependent. I do think it has a place for some PTSD patients, but for more general anxiety the side effects almost always outweigh the benefits for longer-term use imo. I can see its use for the bolded, but I'd guess that there's a certain personality component going on there that any med that would blunt cognitive/affective lability could help with.

 

[erg923]

I do use quetiapine a lot off label for Chronic, severe PTSD patients who have a lot of anxiety and anger. It's seems to help with these issues when SSRIs, SNRIs, and alpha 2 medications are only partially effective. It has drastically reduced road rage and domestic violence behavior in some of my VA patients, who are nearly always armed.

Interested in these posts. But have to say... attributing Seroquel prescription/dosage to a decrease of wife and motorist beating events is a gross empirical leap.

"Seems" "drastically" and faulty casual inference are all over the place in your statement, no?

 

[G Sheb]

The data doesn't support very high doses for seroquel for antipsychotic effect. 300-450mg is the sweet spot. Higher doses don't seem to work any better.

Just by virtue of it being the go to antipsychotic in PD (second to clozapine) or LBD , I think that makes it already special.
Very useful in dementia as well.

 

[annoyedpsychiatrist]

its also abused like crazy in the prison and community health setting. if i had 1 dollar for every time someoneone asked for seroquel id be rich

 

[docksan]

The data doesn't support very high doses for seroquel for antipsychotic effect. 300-450mg is the sweet spot. Higher doses don't seem to work any better.

Just by virtue of it being the go to antipsychotic in PD (second to clozapine) or LBD , I think that makes it already special.
Very useful in dementia as well.

But I was taught that if something doesn't work just go higher, damned be to evidence!

 

[whopper]

Olanzapine and risperidone are much more likely to cause weight gain.

Risperidone per the data and most people's clinical experience is no where as bad vs Quetiapine in weight gain.

 

[Stagg737]

The data doesn't support very high doses for seroquel for antipsychotic effect. 300-450mg is the sweet spot. Higher doses don't seem to work any better.

Just by virtue of it being the go to antipsychotic in PD (second to clozapine) or LBD , I think that makes it already special.
Very useful in dementia as well.

Is it though?

Pimavanserin seems to have taken over as the go-to for PD/LBD related psychosis and I've had little to no success with quetiapine for PD/LBD related psychosis. I've also never talked to anyone who strongly recommended it for any reason other than it's less dopaminergic at low doses and is less likely to cause exacerbation of movement symptoms, and we have a fairly well-known movement disorder clinic where I'm at...

 

[G Sheb]

But I was taught that if something doesn't work just go higher, damned be to evidence!

I was also 'taught' that you should go to 600 of seroquel for 'antipsychotic effect'. It's all bs. There's so much crap in our field that gets tolerated and that is based on nothing but the whims and inclinations of so-called 'experts'.

Is it though?

Pimavanserin seems to have taken over as the go-to for PD/LBD related psychosis and I've had little to no success with quetiapine for PD/LBD related psychosis. I've also never talked to anyone who strongly recommended it for any reason other than it's less dopaminergic at low doses and is less likely to cause exacerbation of movement symptoms, and we have a fairly well-known movement disorder clinic where I'm at...

I agree the evidence is not entirely there for anitpsychosis efficacy, but if you have to go for an antipsychotic to treat psychosis in these conditions, it is the go-to. Along with clozapine in PD and for LBD as well, I believe it's the only one shown to be well tolerated and not to exacerbate movement disorders.
I did not say it's the first line medication for these conditions. You're right, pimavanserin is the first line for LBD.

edit: Nevermind, for some reason I thought pimavanserin is an cholineesterase inhibitor.

 

[whopper]

But I was taught that if something doesn't work just go higher, damned be to evidence!

I remember patients being given literally doses of Haloperidol over 50 mg in a day. Rare but it happened.

Turns out several meds could work better than their FDA recommended dosages. Some meds such as Olanzapine, later data showed much higher efficacy while still being safe at higher dosages. Problem is once the FDA puts their guidelines into writing they almost NEVER change them. E.g. Zyprexa was recommended to be given at up to 30 mg daily on CATIE by the manufacturer despite that the FDA maximum is 20 mg daily.

For this reason, outside the FDA, some pharmacological guides recommend dose ranges that do not match the FDA recommended dosages. Add in that the patient could be a super or slow metabolizer.

 

[ObsequiousAplomb]

I remember patients being given literally doses of Haloperidol over 50 mg in a day. Rare but it happened.

Within the past several years I took care of plenty of patients taking more Haldol than this (granted, the attendings doing this were old enough to have been ancient back you trained). Saw lots of 40 BID.

 

[whopper]

Worst case scenario I remember was as a resident, a guy with a severe TBI who was bashing his head into the wall (after the TBI) pretty much daily and didn't sleep at all, only thing that reduced his self-destructive behavior was Haloperidol in dosages about 80mg + a day. Nothing else did anything. Yes everything was tried.

Add to this problem his family was highly litigious, trying to spot anything to sue the doctor on. So whoever treated him was in the impossible position of not being able to give anything conventional that worked, and a family where anything unconventional has them mad at you and willing to make your life a legal hell.

I wouldn't touch this type of case with a 10 foot pole. Call me a coward. I call it wanting to actually raise my family without having to live in fear.

 

[Stagg737]

I was also 'taught' that you should go to 600 of seroquel for 'antipsychotic effect'. It's all bs. There's so much crap in our field that gets tolerated and that is based on nothing but the whims and inclinations of so-called 'experts'.

I've always been taught 400-600mg is the target antipsychotic dose for seroquel as it generally doesn't have much D2 antagonism until around 400mg. I've seen it as high as 1200mg, but never gone above 800mg myself, and that was only because that was a patient's previous effective dose. I have gone above 600mg on occasion, but usually there's some split dosing involved at that point. I still don't like it as a general antipsychotic though. If you're going to target dopamine, may as well actually give it a solid hit.

I agree the evidence is not entirely there for anitpsychosis efficacy, but if you have to go for an antipsychotic to treat psychosis in these conditions, it is the go-to. Along with clozapine in PD and for LBD as well, I believe it's the only one shown to be well tolerated and not to exacerbate movement disorders.
I did not say it's the first line medication for these conditions. You're right, pimavanserin is the first line for LBD.

edit: Nevermind, for some reason I thought pimavanserin is an cholineesterase inhibitor.

It's a non-dopaminergic antipsychotic that did poorly in treating primary psychotic disorders but did show some efficacy for PD psychosis. There was a big hullaballoo over it for a while when some phase 4 studies showed increased all-cause mortality which seems to have been a whole bunch of nothing because they didn't account for increased risk of mortality directly attributable to Parkinson's. When that was accounted for seems like there wasn't any increased risk associated with it.

 

[Merovinge]

I've always been taught 400-600mg is the target antipsychotic dose for seroquel as it generally doesn't have much D2 antagonism until around 400mg. I've seen it as high as 1200mg, but never gone above 800mg myself, and that was only because that was a patient's previous effective dose. I have gone above 600mg on occasion, but usually there's some split dosing involved at that point. I still don't like it as a general antipsychotic though. If you're going to target dopamine, may as well actually give it a solid hit.

I don't like it as a general antipsychotic either, but not for some Stahl based receptor reasons. Clozapine and olanzapine are almost universally regarded as the most effective antipsychotics and are both structurally cousin to Seroquel and have very limited dopamine blockade. Seroquel just doesn't work as well as those medications for psychosis.

 

[G Sheb]

I don't like it as a general antipsychotic either, but not for some Stahl based receptor reasons. Clozapine and olanzapine are almost universally regarded as the most effective antipsychotics and are both structurally cousin to Seroquel and have very limited dopamine blockade. Seroquel just doesn't work as well as those medications for psychosis.

True, but it is also not any worse than all other antipsychotics, including the famed "dopamine blockers".
The data we have so far, as limited as it is, does not suggest one needs to go very high for the antipsychotic effect to take place.

I know some will mentions their 'experience', but to my view anecdotal evidence might as well be tossed in the trash and it should not be prioritized over published data.
We are probably better practicing astrology in that case. Seems to work best for Leo's and Virgo's as long as Jupiter is in their orbit.

 

[Stagg737]

I don't like it as a general antipsychotic either, but not for some Stahl based receptor reasons. Clozapine and olanzapine are almost universally regarded as the most effective antipsychotics and are both structurally cousin to Seroquel and have very limited dopamine blockade. Seroquel just doesn't work as well as those medications for psychosis.

I'm a clozapine advocate, but I think there are some significant confounding factors which make me hesitant to fully acknowledge cloazapine as the king in terms of efficacy. I've never heard anyone argue that olanzapine is significantly more effective than any others. I'd be interested if you've got articles/sources, or better yet data, making that claim. It's also important to note that small structural changes can have massive impacts on molecular action. Fluoxetine and atomoxetine are nearly identical molecular compounds, but act very differently and appear to have significantly different clinical effects.

Saying that we should use a med that solidly hits dopamine isn't based on Stahl-logic or some Pub Med StatPearl. The prevailing evidence-based theory for most forms of psychosis is still that there is dysregulation in striatal dopamine signaling and that inhibition of D2 receptors should be the first priority in treatment. That includes clozapine despite it's semi-false reputation for limited to no D2 activity. Good reading from one of the former giants of neuropsychiatry regarding clozapine and D2 inhibition:

Clozapine, a Fast-Off-D2 Antipsychotic - PMC

Ever since clozapine was first synthesized and tested, it showed the unique property of having antipsychotic action but no Parkinson-like motor side effects. The antipsychotic basis of clozapine is to transiently occupy dopamine D2 receptors in the ...

www.ncbi.nlm.nih.gov

True, but it is also not any worse than all other antipsychotics, including the famed "dopamine blockers".
The data we have so far, as limited as it is, does not suggest one needs to go very high for the antipsychotic effect to take place.

I know some will mentions their 'experience', but to my view anecdotal evidence might as well be tossed in the trash and it should not be prioritized over published data.
We are probably better practicing astrology in that case. Seems to work best for Leo's and Virgo's as long as Jupiter is in their orbit.

Which is why targeting dopamine should continue to be the first goal for what we suspect are primary psychotic disorders. The evidence is that meds that don't act on dopamine (specifically D2) don't work for most primary psychotic disorders.

We can counter that by pointing to all the TR cases where multiple antipsychotics fail, but I'd argue when we're hitting true treatment resistance we need to start asking if we're actually dealing with a primary psychotic disorder. How many "medical" psychoses are we still calling "schizophrenia"? We didn't know about autoimmune encephalitides until the 1960's and anti-NMDA was just discovered 15 years ago. Today we know it's more prevalent than most viral forms of encephalitis and that dopamine blockade is likely to just make it worse.

I agree that many people still jump to high doses too quickly, but my biggest issue with seroquel is the awful side effect profile even at very low doses. Even without the EPS, I still think it's just so much worse than most other antipsychotics.

 

[G Sheb]

I'm a clozapine advocate, but I think there are some significant confounding factors which make me hesitant to fully acknowledge cloazapine as the king in terms of efficacy. I've never heard anyone argue that olanzapine is significantly more effective than any others. I'd be interested if you've got articles/sources, or better yet data, making that claim. It's also important to note that small structural changes can have massive impacts on molecular action. Fluoxetine and atomoxetine are nearly identical molecular compounds, but act very differently and appear to have significantly different clinical effects.

Saying that we should use a med that solidly hits dopamine isn't based on Stahl-logic or some Pub Med StatPearl. The prevailing evidence-based theory for most forms of psychosis is still that there is dysregulation in striatal dopamine signaling and that inhibition of D2 receptors should be the first priority in treatment. That includes clozapine despite it's semi-false reputation for limited to no D2 activity. Good reading from one of the former giants of neuropsychiatry regarding clozapine and D2 inhibition:

Clozapine, a Fast-Off-D2 Antipsychotic - PMC

Ever since clozapine was first synthesized and tested, it showed the unique property of having antipsychotic action but no Parkinson-like motor side effects. The antipsychotic basis of clozapine is to transiently occupy dopamine D2 receptors in the ...

www.ncbi.nlm.nih.gov

Which is why targeting dopamine should continue to be the first goal for what we suspect are primary psychotic disorders. The evidence is that meds that don't act on dopamine (specifically D2) don't work for most primary psychotic disorders.

We can counter that by pointing to all the TR cases where multiple antipsychotics fail, but I'd argue when we're hitting true treatment resistance we need to start asking if we're actually dealing with a primary psychotic disorder. How many "medical" psychoses are we still calling "schizophrenia"? We didn't know about autoimmune encephalitides until the 1960's and anti-NMDA was just discovered 15 years ago. Today we know it's more prevalent than most viral forms of encephalitis and that dopamine blockade is likely to just make it worse.

I agree that many people still jump to high doses too quickly, but my biggest issue with seroquel is the awful side effect profile even at very low doses. Even without the EPS, I still think it's just so much worse than most other antipsychotics.

I think you're putting the cart before the horse here.
The best evidence is the data you collect in a systematic and scientific way about which medicine actually results in improvement of symptoms.
Not theoretical mechanisms of how they work. That information is valuable but there's ample evidence, evidence that is as good as pretty much for any other antipsychotic including D2 blockers, that seroquel works on decreasing psychotic symptoms in patients diagnosed with schizophrenia.
Prioritizing "D2 blockers" doesn't make much sense when it comes to efficacy. There's no good evidence that in a head to head the typical or stronger "D2 blockers" have better efficacy than the 'lesser' D2 blockers. Even seroquel has D2 blocking abilities; all of the antipsychotics do.

 

[Merovinge]

I'm a clozapine advocate, but I think there are some significant confounding factors which make me hesitant to fully acknowledge cloazapine as the king in terms of efficacy. I've never heard anyone argue that olanzapine is significantly more effective than any others. I'd be interested if you've got articles/sources, or better yet data, making that claim. It's also important to note that small structural changes can have massive impacts on molecular action. Fluoxetine and atomoxetine are nearly identical molecular compounds, but act very differently and appear to have significantly different clinical effects.

Saying that we should use a med that solidly hits dopamine isn't based on Stahl-logic or some Pub Med StatPearl. The prevailing evidence-based theory for most forms of psychosis is still that there is dysregulation in striatal dopamine signaling and that inhibition of D2 receptors should be the first priority in treatment. That includes clozapine despite it's semi-false reputation for limited to no D2 activity. Good reading from one of the former giants of neuropsychiatry regarding clozapine and D2 inhibition:

Clozapine, a Fast-Off-D2 Antipsychotic - PMC

Ever since clozapine was first synthesized and tested, it showed the unique property of having antipsychotic action but no Parkinson-like motor side effects. The antipsychotic basis of clozapine is to transiently occupy dopamine D2 receptors in the ...

www.ncbi.nlm.nih.gov

Which is why targeting dopamine should continue to be the first goal for what we suspect are primary psychotic disorders. The evidence is that meds that don't act on dopamine (specifically D2) don't work for most primary psychotic disorders.

We can counter that by pointing to all the TR cases where multiple antipsychotics fail, but I'd argue when we're hitting true treatment resistance we need to start asking if we're actually dealing with a primary psychotic disorder. How many "medical" psychoses are we still calling "schizophrenia"? We didn't know about autoimmune encephalitides until the 1960's and anti-NMDA was just discovered 15 years ago. Today we know it's more prevalent than most viral forms of encephalitis and that dopamine blockade is likely to just make it worse.

I agree that many people still jump to high doses too quickly, but my biggest issue with seroquel is the awful side effect profile even at very low doses. Even without the EPS, I still think it's just so much worse than most other antipsychotics.

A meta-analysis of effectiveness of real-world studies of antipsychotics in schizophrenia: Are the results consistent with the findings of randomized controlled trials? - Translational Psychiatry

Randomized controlled trials (RCTs) have been considered as gold standard for establishing the efficacy and safety of investigational new drugs; nonetheless, the generalizability of their findings has been questioned. To address this issue, an increasing number of naturalistic studies and...

www.nature.com

A meta-analysis of head-to-head comparisons of second-generation antipsychotics in the treatment of schizophrenia - PubMed

The findings suggest that some second-generation antipsychotics may be somewhat more efficacious than others, but the limitations of meta-analysis must be considered. In tailoring drug treatment to the individual patient, small efficacy superiorities must be weighed against large differences in...

pubmed.ncbi.nlm.nih.gov

Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis

There are some efficacy differences between antipsychotics, but most of them are gradual rather than discrete. Differences in side-effects are more marked. These findings will aid clinicians in balancing risks versus benefits of those drugs available in their countries. They should consider the...

www.thelancet.com

I've always thought efficacy tiers by psychosis experts I worked with were pretty consistent.

Tier 1 Clozapine
Tier 2 Olanzapine
Tier 3 Risperidone, Invega
Tier 4 Seroquel, Abilify
Tier 5 Geodon, Latuda

I am so old that all the other new antipsychotics I don't even have a feel for antipsychotic effect but I think quite low is the answer.

 

[J ROD]

Seroquel works well for Borderpolar disorder.

 

[futureapppsy2]

Just popping in to say that I'm appreciating all the nicknames for Seroquel in this thread.

 

[clausewitz2]

A meta-analysis of effectiveness of real-world studies of antipsychotics in schizophrenia: Are the results consistent with the findings of randomized controlled trials? - Translational Psychiatry

Randomized controlled trials (RCTs) have been considered as gold standard for establishing the efficacy and safety of investigational new drugs; nonetheless, the generalizability of their findings has been questioned. To address this issue, an increasing number of naturalistic studies and...

www.nature.com

A meta-analysis of head-to-head comparisons of second-generation antipsychotics in the treatment of schizophrenia - PubMed

The findings suggest that some second-generation antipsychotics may be somewhat more efficacious than others, but the limitations of meta-analysis must be considered. In tailoring drug treatment to the individual patient, small efficacy superiorities must be weighed against large differences in...

pubmed.ncbi.nlm.nih.gov

Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis

There are some efficacy differences between antipsychotics, but most of them are gradual rather than discrete. Differences in side-effects are more marked. These findings will aid clinicians in balancing risks versus benefits of those drugs available in their countries. They should consider the...

www.thelancet.com

I've always thought efficacy tiers by psychosis experts I worked with were pretty consistent.

Tier 1 Clozapine
Tier 2 Olanzapine
Tier 3 Risperidone, Invega
Tier 4 Seroquel, Abilify
Tier 5 Geodon, Latuda

I am so old that all the other new antipsychotics I don't even have a feel for antipsychotic effect but I think quite low is the answer.

Adding to this CUTLASS back in the day showed olanzapine separated out with a lower rate of treatment discontinuation due to a lack of efficacy.

 

[SmallBird]

I'm a clozapine advocate, but I think there are some significant confounding factors which make me hesitant to fully acknowledge cloazapine as the king in terms of efficacy. I've never heard anyone argue that olanzapine is significantly more effective than any others. I'd be interested if you've got articles/sources, or better yet data, making that claim. It's also important to note that small structural changes can have massive impacts on molecular action. Fluoxetine and atomoxetine are nearly identical molecular compounds, but act very differently and appear to have significantly different clinical effects.

Saying that we should use a med that solidly hits dopamine isn't based on Stahl-logic or some Pub Med StatPearl. The prevailing evidence-based theory for most forms of psychosis is still that there is dysregulation in striatal dopamine signaling and that inhibition of D2 receptors should be the first priority in treatment. That includes clozapine despite it's semi-false reputation for limited to no D2 activity. Good reading from one of the former giants of neuropsychiatry regarding clozapine and D2 inhibition:

Clozapine, a Fast-Off-D2 Antipsychotic - PMC

Ever since clozapine was first synthesized and tested, it showed the unique property of having antipsychotic action but no Parkinson-like motor side effects. The antipsychotic basis of clozapine is to transiently occupy dopamine D2 receptors in the ...

www.ncbi.nlm.nih.gov

Which is why targeting dopamine should continue to be the first goal for what we suspect are primary psychotic disorders. The evidence is that meds that don't act on dopamine (specifically D2) don't work for most primary psychotic disorders.

We can counter that by pointing to all the TR cases where multiple antipsychotics fail, but I'd argue when we're hitting true treatment resistance we need to start asking if we're actually dealing with a primary psychotic disorder. How many "medical" psychoses are we still calling "schizophrenia"? We didn't know about autoimmune encephalitides until the 1960's and anti-NMDA was just discovered 15 years ago. Today we know it's more prevalent than most viral forms of encephalitis and that dopamine blockade is likely to just make it worse.

I agree that many people still jump to high doses too quickly, but my biggest issue with seroquel is the awful side effect profile even at very low doses. Even without the EPS, I still think it's just so much worse than most other antipsychotics.

I don't think the evidence for olanzapine superiority is compelling but if you stick around you will hear the argument for sure. The NICE guidelines in the UK at one point (maybe still?) required that patients fail olanzapine before a clozapine trial could be done.

 

[Merovinge]

Adding to this CUTLASS back in the day showed olanzapine separated out with a lower rate of treatment discontinuation due to a lack of efficacy.

Funny I was actually recalling that study initially but trying to pull up articles during a Zoom call and didn't recall the name. Thank you for adding that one.

In other thoughts, how did people actually use forums before you could do it as the same time as a video meeting??

 

[ChudsMgee]

Does anyone prescribe Perphenazine (Trilafon)? Its something I still write with great success and dont see it much

 

[clausewitz2]

Does anyone prescribe Perphenazine (Trilafon)? Its something I still write with great success and dont see it much

It's been a while. The only old-school neuroleptic I use apart from haldol is fluphenazine once in a while, to be honest.

 

[Stagg737]

I think you're putting the cart before the horse here.
The best evidence is the data you collect in a systematic and scientific way about which medicine actually results in improvement of symptoms.
Not theoretical mechanisms of how they work. That information is valuable but there's ample evidence, evidence that is as good as pretty much for any other antipsychotic including D2 blockers, that seroquel works on decreasing psychotic symptoms in patients diagnosed with schizophrenia.
Prioritizing "D2 blockers" doesn't make much sense when it comes to efficacy. There's no good evidence that in a head to head the typical or stronger "D2 blockers" have better efficacy than the 'lesser' D2 blockers. Even seroquel has D2 blocking abilities; all of the antipsychotics do.

I realize this and was simply pointing out that if one of your reasons for prescribing a med is strong dopamine inhibition, quetiapine is a poor choice. To the first bolded part, that was also my point and I was confused about your use of the term "D2 blockers" which I assumed you just meant meds with more potency at that receptor. Sure, quetiapine can be effective for psychosis, but anecdotally (and evidently per EBM), there are many better choices. As I stated, I personally don't like it because of the potential side effect profile and the fact that a lot of prescribers use it like a shotgun for whatever they feel like, including snowing the elderly in facilities. It's a med that you have to be thoughtful about prescribing and many people just are not.

To the second part of the bolded is only partially true. Currently, only the effective antipsychotics are (at least partial) D2 antagonists. Pimavanserin is an atypical antipsychotic with no notable dopamine effects, and it also doesn't work for primary psychosis/schizophrenia. There are TAAR1 agonists in development which do appear to show efficacy for schizophrenia/psychosis and primarily act directly on TAAR1 as well as 5HT-1A with no appreciable direct effects on D2 or other dopamine receptors. I've been keeping an eye out for updated trials/data, but haven't seen any in the past few months.

A meta-analysis of effectiveness of real-world studies of antipsychotics in schizophrenia: Are the results consistent with the findings of randomized controlled trials? - Translational Psychiatry

Randomized controlled trials (RCTs) have been considered as gold standard for establishing the efficacy and safety of investigational new drugs; nonetheless, the generalizability of their findings has been questioned. To address this issue, an increasing number of naturalistic studies and...

www.nature.com

A meta-analysis of head-to-head comparisons of second-generation antipsychotics in the treatment of schizophrenia - PubMed

The findings suggest that some second-generation antipsychotics may be somewhat more efficacious than others, but the limitations of meta-analysis must be considered. In tailoring drug treatment to the individual patient, small efficacy superiorities must be weighed against large differences in...

pubmed.ncbi.nlm.nih.gov

Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis

There are some efficacy differences between antipsychotics, but most of them are gradual rather than discrete. Differences in side-effects are more marked. These findings will aid clinicians in balancing risks versus benefits of those drugs available in their countries. They should consider the...

www.thelancet.com

I've always thought efficacy tiers by psychosis experts I worked with were pretty consistent.

Tier 1 Clozapine
Tier 2 Olanzapine
Tier 3 Risperidone, Invega
Tier 4 Seroquel, Abilify
Tier 5 Geodon, Latuda

I am so old that all the other new antipsychotics I don't even have a feel for antipsychotic effect but I think quite low is the answer.

Interesting, and don't completely disagree. My "tiers" in terms of preference/efficacy are pretty in line with this but I'd just lump tiers 2 and 3 together and move geodon into tier 4. I just haven't heard olanzapine touted as being "better" than the other "good" antipsychotics. I've the the last study, but will look at the first two, thank you for sharing.

 

[SmallBird]

I realize this and was simply pointing out that if one of your reasons for prescribing a med is strong dopamine inhibition, quetiapine is a poor choice.

I would say if you are going to pick a reason for prescribing a medication, doing so based on expected activity at a single receptor is a poor choice.

 

[Stagg737]

I would say if you are going to pick a reason for prescribing a medication, doing so based on expected activity at a single receptor is a poor choice.

I don't disagree, but as pointed out by myself and even those arguing against me, our understanding of "schizophrenia" and effective pharmacologic treatment essentially revolves around the D2 receptor and medications that inhibit it at this time.

 

[docksan]

Which is interesting when you think about the role of 5HT2A in neuromodulation.