Seroquel (Quetiapine) - Drugs, Sex, Money and Psychopharm

In this episode, I discuss a medication that patients who saw a psychiatrist or their primary care provider between about 1997 and 2015 were very likely to find themselves prescribed.  More recently, it has been taken down a notch or two on prescribers lists of preferred meds.  This medication is quetiapine, marketed as Seroquel by AstraZeneca in the US.  Whether you were diagnosed with schizophrenia, bipolar disorder, depression, anxiety, an eating disorder, insomnia, PTSD, borderline personality disorder, obsessive compulsive disorder, and many others it appeared in the mid 2000s that Quetiapine was just the thing for you.  Was it ever?

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References and readings (when available) are posted at the end of each episode transcript, located at psydactic.buzzsprout.com. All opinions expressed in this podcast are exclusively those of the person speaking and should not be confused with the opinions of anyone else. We reserve the right to be wrong. Nothing in this podcast should be treated as individual medical advice.

Transcript

Quetiapine (aka Seroquel) - Drugs, sex, and money

Welcome to PsyDactic, I am Dr. O’Leary, a 4th year psychiatry resident in the National Capital Region.  I make this podcast primary for physicians, especially psychiatry residents and grown up psychiatrists, but I hope anyone listening can benefit.  I need to inform you that when I make this podcast, I speak only for myself.  Nothing I say here should be mistaken for anyone else's opinions, especially those of Ely Lilly or AstraZeneca.

Today I am going to discuss a medication that patients who saw a psychiatrist between about 1997 and 2015 were likely to find themselves prescribed.  However, more recently, it has been taken down a notch or two on prescribers lists of preferred meds.  This medication is quetiapine, marketed as Seroquel by AstraZeneca in the US.  Whether you were diagnosed with schizophrenia, bipolar disorder, depression, anxiety, an eating disorder, insomnia, PTSD, borderline personality disorder, obsessive compulsive disorder, and many others it appeared in the mid 2000s that Quetiapine was just the thing for you.  By 2010, Seroquel was raking in about 6.8 billion dollars annually in sales.  That same year, AstraZeneca was fined a half of a billion dollars for clandestinely promoting the off-label use of quetiapine while covering up data on its side effects.

The quetiapine global market in 2023 was only 160 million dollars. This in part has to do with it coming off patent.  I do not have a degree in math, but if quetiapine had only been prescribed for what it had been thoroughly researched to treat with some spillover due to expected levels of off-label prescribing, I imagine it probably would not have broken about 500 million dollars annually. Some data I perused showed it was prescribed more for depressive disorders and if you add depressive, anxiety, and sleep disorders, psychotic disorders were dwarfed in comparison.  There are two 500 millions in a billion and 2 times 6.8 is 13.6.  That means that in one year alone, AstraZeneca made at least 12 times what it may have made, and then paid out only 1 of those 12 times in fines.  That was in only one year!  The math is telling me that it is at least an order of magnitude more profitable to get caught encouraging poor prescribing practices than to do the right thing.  There was also some sex scandal where a pharmaceutical rep may have been trading sexual favors for industry secrets.  Now that I have your attention, I am going to disappoint you by not talking about the sex scandal.

AstraZeneca also gets to benefit from a decade of exaggerated or hidden information making its indelible mark on the institution of psychiatry and family medicine doctors.  While prescriptions of quetiapine have waned (at least in part to newer agents coming on the market), they may be substantially higher still than they would have been without that decade of market manipulation.  I have met a prescriber who uses quetiapine even in lieu of well established, and evidence based practices because he insists that it works on everything.  And it might work for everything as he proposes, but I have seen little evidence that it does a good job of most of it, and Seroquel comes with far more side effects than our normal first and second-line therapies.

The reason that quetiapine has been used for so many indications is that it has a broad receptor profile that hits all kinds of receptors including histamine, acetylcholine, norepinephrine, serotonin, and dopamine receptors.  Quetiapine was developed in 1985 by AstraZeneca in an effort to create a compound that was as effective as clozapine for psychotic disorders, but didn’t have the pesky side effect of agranulocytosis.  In fact, clozapine had been taken off the market in 1975 and wasn’t put back on the market until 1990 after establishing strict tracking and monitoring criteria.  Quetiapine and its sister medication, olanzapine, which was patented by Eli Lilly in 1991, were both developed to fill this gap.  Neither proved as effective for psychosis, but both were effective and they were both approved by the FDA.  Eli Lilly beat AstraZeneca to the punch by securing an FDA approval for olanzapine for schizophrenia in 1996.  Quetiapine was not approved until 1997.

There is somewhat of a myth that “first generation antipsychotics are strong D2 blockers and second generation antipsychotics are strong 5HT2A blockers that also block D2 receptors, so that makes them better.”  This vast oversimplification gives us a highly misleading concept about the various antipsychotics.  I am not sure if this is the case, but it would also certainly benefit pharmaceutical companies to promote this myth.  “The new drugs we developed are better and have fewer side effects, so use them instead.”  In my literature searches, I have found very little evidence of this.  I don’t think that psychiatry has insisted on better neuroscience of their antipsychotics because, primarily, we are not neuroscientists, and secondarily, we think we know more than we actually do.  This is a bit of a dangerous combination.  We are getting better.

Despite pharmaceutical company cover-ups, disinformation, and a culture of credulous gullibility, we have now over two decades of experience with quetiapine and some longitudinal evidence to draw from.  Quetiapine is currently approved for schizophrenia, for acute manic episodes, and is among five antipsychotics approved for adjunctive treatment for major depressive disorder.  There is evidence that it can also treat bipolar depression.  It is also often given among many other things for maintenance in bipolar type 2, anxiety disorders, post-traumatic stress disorder, various kinds of insomnia, disorders in the obsessive and compulsive chapter of the DSM, and various personality disorders, especially borderline personality disorder.  This is a very short list.  I haven’t seen studies that give strong evidence for any of the off label indications, and I haven’t seen studies that show that it is on average better than anything else for anything it is prescribed for.  Of course, that doesn't mean it isn’t effective.  I just am having a hard time confirming that.

Its broad range of uses are likely related to how messy of a medication it is.  It coats dozens of receptor types on neurons at various affinities.  To complicate things, one of its metabolites, norquetiapine, has its own receptor profile, distinct from quetiapine.  After taking this medication, receptors all over the place end up blocked and at higher levels you also get substantial blockade of the norepinephrine transporter, but I’ll get back to that.  Psychiatrists will know what I am talking about when I mention Stahl’s Illustrated Guides.  They do a great job of helping physicians understand the proposed mechanisms of psychotropics, including antipsychotics, but their illustrations are somewhat misleading.  To demonstrate receptor profiles, they show a crude circular cell with the various receptors sticking out that, for example, quetiapine hits.  The two largest for quetiapine are 5HT2A and D2.  This may be because these are thought to be the most important receptors for its approved indications.

If you were to list the receptors for which quetiapine, itself, has the highest affinity in order, then the top 5 would be H1, α1A, α1B, 5-HT2A, D2.  For norquetiapine the top 5 were H1, 5-HT2B, M5, M3, M1.  Norquetiapine has a moderately higher affinity for D2 than quetiapine, but to get there it needs first to fill 5-HT1A, 5-HT2A, NET, 5-HT7, α1B, 5-HT1E, 5-HT2C, M4, and α1A.  I could not find a good estimate of the relative plasma levels of quetiapine versus norquetiapine after stable dosing.  One paper reported that only 1-2% of quetiapine is excreted unchanged, which suggests a lower concentration of quetiapine than its metabolites.  Another paper reported a concentration of about 12% for the metabolites of quetiapine versus the unchanged compound.  These things seem to be in conflict.

One paper noted the mean NET occupancy in the thalamus was 19 and 35%, respectively, after doses of quetiapine XR of 150 and 300 mg/d respectively.  I found that the dose of venlafaxine necessary for a 35% occupancy rate at the NET is about 150mg, so it may be that a dose of 300MG of quetiapine would end up having clinically significant activity there, which means that it could be anxiolytic and promote cognition and attention.  Another potential anxiolytic action of norquetiapine is its partial agonist activity at 5HT1A, which it has a higher affinity for than the NET.

But let’s not forget what else norquetiapine and quetiapine hit.  Long before they have significant action blocking NETs or partially agonizing 5HT1A, they are blocking H1, and α1A and α1B, which could be sedating or drop someone's blood pressure.  I feel like the action it has at NET may be counteracting its hypotensive effects, but this likely takes some time.  When first starting quetiapine, it is best not to give doses above 50MG because it might put someone on the floor with a syncopal event, after which they won’t want to take it again.  Once they get used to it, and norquetiapine is at more stable levels hitting that NET, this may be less likely to happen.

However, what patients continue to feel are the sedating effects of quetiapine.  This is the most commonly reported side effect and doesn’t appear to go away with time.  This makes sense because its highest affinity is for histamine 1 receptors.  This sedating effect is what made people excited to give Seroquel for insomnia, but this has proved to be a risky strategy.  Doses up to 300MG have been studied, and quetiapine will sedate you.  The problem are the numerous other side effects, which I will cover in a second.

But first I want to talk about its use as an antipsychotic and adjunct for depressive disorders.  The 5HT2A blocking activity of quetiapine doses is also augmented to a great extent by norquetiapine, as its affinity for 5HT2A is about twice that of quetiapine.  The blockade of 5HT2A likely contributes to the antipsychotic properties of quetiapine use, but blocking 5HT2A alone is generally not sufficient.  You really need to start blocking D2 receptors.  For norquetiapine D2 is the 15th receptor in order of known affinities. For quetiapine it is the 5th.  However, norquetiapine still has a higher affinity than quetiapine for this receptor.  One of the reasons that drugs like quetiapine have lower rates of extrapyramidal symptoms is because its affinity for D2 is about 20-50 times less than more strong D2 blocking agents.  I have heard this called “kiss and run” because it doesn’t hug tightly to the D2 receptor, but still reduces its overall activity.

I am not sure why Quetiapine is effective as an adjunct in major depressive disorder, but to be fair, this is a low bar to meet.  Between it and norquetiapine, they are partial agonists at 5HT1A, and antagonists at 5HT1D, 1E, 2A, 2B, and 2C.  There are so many drugs with various mechanisms of actions as adjuncts for MDD, that I am reminded of something a surgeon once said to me.  “If there are many different ways to do something, it means none of them work very well.”

Some of the most worrisome side effects of antipsychotic drugs are their metabolic effects, such as weight gain, insulin resistance, increased fasting glucose levels, high cholesterol, and generally reduced levels of activity.  This metabolic syndrome may be due to  muscarinic, histaminic, and 5HT2C blocking properties.  I am not going to go into a deep dive here, but M3 receptors in regions of the brain control food intake and insulin secretion.  M3 is also present in pancreatic beta-cells that secrete insulin.  Over time, blocking these receptors in the brain can dysregulate appetite and blood glucose metabolism.  H1-favoring antihistamines also increase appetite and cause weight gain, and quetiapine has its highest affinity for H1.  Blocking 5HT2C, which norquetiapine has a high affinity for, also increases appetite and food intake.  The weight gain caused by quetiapine was something AstraZeneca was accused of covering up.  Olanzapine, quetiapine’s cousin from Eli Lilly, is notorious for weight gain.  If people were to think that quetiapine didn’t cause weight gain it could tip the prescriber toward AstraZeneca.  Here I am just speculating.

The additional side effect profile for quetiapine, like any psychotropic, can be very long.  If you think about the antihistamine and anticholinergic actions, you could expect things like dry mouth, dry skin, blurry vision, or in a toxidrome: urinary retention, hyperthermia, tachycardia, mydriasis, delirium; all those mad as a hatter, high as a kite, dry as bone, red as a beat, full as a flask, hot as a desert things.  The full as a flask part is not just your bladder.  You may also be severely constipated or have an ileus, which is basically when your bowel gives up trying to move food forward.  This can be deadly.  Ileus is a very common side effect of clozapine (although clozapine gets most of its attention for agranulocytosis), and ileus is possible, though less so in quetiapine.  Regular old constipation is far more common.  Agranulocytosis is also possible with quetiapine, but the incidence is so low that it does not require monitoring.

Quetiapine, in addition to sedating people, which is why it is given at night, may also result in brain fog, but some people report improvement in cognitive function, so I think it depends on where you start from.  If you are psychotic, then cognitive function will likely improve substantially.  It was hoped that quetiapine may be beneficial for the negative symptoms of psychosis, and while it is less likely to worsen them substantially, it is not likely to help much.

There are some special places where quetiapine may be the best choice among other not very good choices.  For example, psychosis in the alpha-synucleinopathies like Parkinson’s or Lewy Body Dementia may benefit from quetiapine or clozapine or pimavanserin, but other antipsychotics should be avoided.  I’ve seen low dose quetiapine being used for delirium as a second line agent (only after all of the environmental and behavioral interventions have been implemented) with some good effect.

As a psychiatric practitioner young in my career, it is difficult for me to distinguish between the mythology of quetiapine that was weaved together in the early 2000s and its actual efficacy.  There is too much noise in the signal.  I think quetiapine is a good choice, especially for some patients with schizophrenia or bipolar type 1 disorder.  The risk versus benefit analysis leans more toward taking quetiapine in those disorders.  In others, I feel like the jury is still out, especially because in the race to the top, quetiapine has not been shown to be more effective than other drugs for its indications.

Thank you for listening. I am Dr. O’Leary, and this has been an episode of PsyDactic.

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https://www.psychdb.com/teaching/pharmaceutical-industry-influence#quetiapine

History of development…

https://www.cbsnews.com/news/seroquel-trial-allegations-of-sex-for-secrets-az-wants-papers-sealed/ 

Brett J. Concerns about quetiapine. Aust Prescr. 2015 Jun;38(3):95-7. doi: 10.18773/austprescr.2015.032. Epub 2015 Jun 1. PMID: 26648630; PMCID: PMC4653966.

Riedel M, Müller N, Strassnig M, Spellmann I, Severus E, Möller HJ. Quetiapine in the treatment of schizophrenia and related disorders. Neuropsychiatr Dis Treat. 2007 Apr;3(2):219-35. doi: 10.2147/nedt.2007.3.2.219. PMID: 19300555; PMCID: PMC2654633.

Seroquel Fountain

https://www.youtube.com/watch?v=loW237oMWe0 

Naji A, Gatling JW. Muscarinic Antagonists. [Updated 2023 May 8]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK557541/

Xiang Z, Thompson AD, Jones CK, Lindsley CW, Conn PJ. Roles of the M1 muscarinic acetylcholine receptor subtype in the regulation of basal ganglia function and implications for the treatment of Parkinson's disease. J Pharmacol Exp Ther. 2012 Mar;340(3):595-603. doi: 10.1124/jpet.111.187856. Epub 2011 Dec 1. PMID: 22135383; PMCID: PMC3286317.

Maglione M, Maher AR, Hu J, Wang Z, Shanman R, Shekelle PG, Roth B, Hilton L, Suttorp MJ, Ewing BA, Motala A, Perry T. Off-Label Use of Atypical Antipsychotics: An Update [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2011 Sep. Report No.: 11-EHC087-EF. PMID: 22132426.

Che-Yin Lin, Cheng-Hen Chiang, Mei-Chih Meg Tseng, Ka-Wai Tam and El-Wui Loh. Effects of quetiapine on sleep: A systematic review and meta-analysis of clinical trials.  European Neuropsychopharmacology, 2023-02-01, Volume 67, Pages 22-36, Copyright © 2022 Elsevier B.V. and ECNP

López-Muñoz F, Alamo C. Active metabolites as antidepressant drugs: the role of norquetiapine in the mechanism of action of quetiapine in the treatment of mood disorders. Front Psychiatry. 2013 Sep 12;4:102. doi: 10.3389/fpsyt.2013.00102. PMID: 24062697; PMCID: PMC3770982.

Mauri MC, Volonteri LS, Colasanti A, Fiorentini A, De Gaspari IF, Bareggi SR. Clinical pharmacokinetics of atypical antipsychotics: a critical review of the relationship between plasma concentrations and clinical response. Clin Pharmacokinet. 2007;46(5):359-88. doi: 10.2165/00003088-200746050-00001. PMID: 17465637.

Svante Nyberg, Aurelija Jucaite, Akihiro Takano, Matts Kågedal, Zsolt Cselényi, Christer Halldin, Lars Farde. Norepinephrine transporter occupancy in the human brain after oral administration of quetiapine XR. International Journal of Neuropsychopharmacology, Volume 16, Issue 10, November 2013, Pages 2235–2244, https://doi.org/10.1017/S1461145713000680

Weston-Green K, Huang XF, Lian J, Deng C. Effects of olanzapine on muscarinic M3 receptor binding density in the brain relates to weight gain, plasma insulin and metabolic hormone levels. Eur Neuropsychopharmacol. 2012 May;22(5):364-73. doi: 10.1016/j.euroneuro.2011.09.003. Epub 2011 Oct 6. PMID: 21982116.

https://en.wikipedia.org/wiki/Quetiapine 

Site | QTP | NQTP | Action
5-HT1A | 320 | 45 | Partial agonist
5-HT1D |
| 249 | ND
5-HT1E | 2,402 | 97 | ND
5-HT1F | 2,240 | ND | ND
5-HT2A | 96–101 | 48 | Antagonist
5-HT2B |
| 14 | Antagonist
5-HT2C | 2,502 | 107 | Antagonist
5-HT3 |
| 394 | Antagonist
5-HT6 | 1,865 | 503 | Antagonist
5-HT7 | 307 | 76 | Antagonist
D1 | 712 | 214 | Antagonist
D2 | 245 | 196 | Antagonist
D2L | 700 | ND | Antagonist
D2S | 390 | ND | Antagonist
D3 | 340 | 567 | Antagonist
D4.2 | 1,600 | ND | Antagonist
D5 | 1,738 | 1,419 | Antagonist
H1 | 11 | 3.5 | Antagonist
H2 |
| 298 | Antagonist
M1 | 858 | 39 | Antagonist
M2 | 1,339 | 453 | ND
M3 |
| 23 | Antagonist
M4 | 542 | 110 | ND
M5 | 1,942 | 23 | Antagonist
NET |
| 58 | Blocker
α1A | 22 | 144 | Antagonist
α1B | 39 | 95 | Antagonist
α2A | 3,630 | 237 | Antagonist