12 clinically relevant findings from the past 3 years on quetiapine (Seroquel), including new side effects, dosing strategies, withdrawal phenomena, and new uses in bipolar with OCD.

Published On: 06/6/2022

Duration:  20 minutes, 27 seconds

Referenced Article: “Quetiapine Reconsidered,” The Carlat Child Psychiatry Report, June 2022

Chris Aiken, MD, Kellie Newsome, PMHNP, have disclosed no relevant financial or other interests in any commercial companies pertaining to this educational activity.

Transcript:

10 years ago quetiapine went generic, but that hasn’t stopped the flow of knowledge on this antipsychotic, and today we bring you 12 updates from recent research.

Welcome to the Carlat Psychiatry Podcast, keeping psychiatry honest since 2003. I’m Chris Aiken, the editor in chief of the Carlat Report. And I’m Kellie Newsome, a psychiatric NP and a dedicated reader of every issue.

It is the best of drugs, it is the worst of drugs, so begins Paul Riordan’s review of quetiapine (Seroquel) in this month’s Carlat Report. As we combed through the research on quetiapine, it kept standing out – sometimes for extraordinary benefits that are shared by no other antipsychotics – and other times for extraordinary risks. In bipolar disorder, it stands alongside lithium for its large effect size in all phases of the illness – mania, depression, and maintenance. Yet it also tops the list of psychiatric medications that prompt visits to the emergency room – a fact that’s probably explained by its high rate of side effects – sedation, orthostasis, falls, and – over the long-term – weight gain.  

KELLIE NEWSOME: In this companion podcast we’re going to bring you the latest research updates on quetiapine. Here’s the methodology. We go to pubmed, type in quetiapine[ti] for all papers with quetiapine in the title: 247 papers in the past 3 years. Then, we read all the abstracts to narrow it down to the ones that are most informative for everyday practice. You’ll learn new uses and new side effects for this old drug, and get a better sense for where it fits in schizophrenia and mood disorders. We’ll weave all that in as we walk you through the history of this antipsychotic.

CHRIS AIKEN: Quetiapine was developed in the early 1980’s by Edward Warawa, a chemist working at the small pharmaceutical company ICI in Wilmington Delaware. His goal was to modify clozapine so it wouldn't cause agranulocytosis, so modified clozapine by adding a piperazine structure that cleaved off the antihistamine hydroxyzine to it. He then altered the atoms on the rings – replacing them with sulfur, oxygen, and nitrogen and testing the new compound out in rats until he found quetiapine – which had the best antipsychotic effects. 

ICI was bought by Zeneca, a precursor of AstraZeneca, which launched quetiapine in 1997 for schizophrenia, joining risperidone and olanzapine in this early crop of atypical antipsychotics. At the time, no one was talking about weight gain or diabetes on these meds – those studies were buried by the pharmaceutical industry – but what did have everyone concerned was a risk that seemed unique to this drug: It caused cataracts in beagles at high doses.  

KELLIE NEWSOME: That worry faded over the next few years, and a 2015 study finally put it to rest. They compared ophthalmologic outcomes for quetiapine and risperidone over two years in 1000 patients with schizophrenia. The ophthalmologists were blinded to the treatment arms, but they could still see through the slit lamp to test for lens obfuscation in the patients’ eyes. The result: both antipsychotics had similar effects, and quetiapine actually had a lower risk of cataracts on some of the measures. 

CHRIS AIKEN: The other side effect that stood out for quetiapine was QTc prolongation, and you’re still likely to see this risk emphasized in textbooks even though the latest data is reassuring. The QTc interval is a marker for arrhythmias like torsades de point – and that’s the point – it’s just a marker, much like gray hair is a marker for age. But we know lots of people who turn gray in their 30’s, and others who keep their color into their 50’s. In the case of quetiapine, the drug does prolong the QTc, but it doesn’t seem to raise the risk of arrhythmias very much even when given in the ICU. This is a complicated subject, and we cover it in our textbook prescribing psychotropics. But suffice it to say that some of the antipsychotics that have a high risk of prolonging the QTc – like quetiapine and ziprasidone – have a low risk of causing torsades de point, while others with minimal QTc effects – like aripiprazole  - have a higher risk of causing this potentially fatal arrhythmia. That doesn’t mean quetiapine is free of the problem – no antipsychotic is – and the patients you need to watch out for are those with electrolyte disturbances, cardiac disease, or on multiple drugs that prolong the QTc including cocaine and stimulants. 

KELLIE NEWSOME: Even as psychiatrists got more comfortable about these risks, they were slow to adopt quetiapine. First, the dosing was not clear. We now know that you need at least 400mg/day to treat schizophrenia and mania, but at first no one knew where to land in the 25-800 mg range. The second problem was that people were dosing it 2-3 times a day, which makes patients very groggy. Later, studies compared once-at-night dosing to twice a day dosing and have found no difference in outcomes – but a big reduction in side effects. The third obstacle that held quetiapine back was the perception that it just wasn’t very effective as an antipsychotic. That one may have a ring of truth to it – when antipsychotics are lined up by their effect size in schizophrenia quetiapine lands in the middle or low-middle – not bad, but not good – but olanzapine and risperidone rank near the top – and those are the two that quetiapine was competing with when it first came out.

CHRIS AIKEN: In mood disorders we see a very different pattern – quetiapine stands out as one of the more effective ones in its class, and that brings us to our next study. In 2021, researchers in Germany compared outcomes of 5,000 patients with bipolar disorder over 13 years on various meds in their outpatient clinic. As in most studies like these, lithium had the best outcomes, but quetiapine was a close second. They used a rough measure of bad outcomes – having to stop the drug or add in a new one – and outcomes were the worst for olanzapine. 

KELLIE NEWSOME: But when we turn to schizophrenia we see the opposite pattern. In 2020, a randomized trial from Spain compared discontinuation rates for 6 antipsychotics over a 3 year period in schizophrenia. Quetiapine had the highest rate of discontinuation – even higher than haloperidol. So which antipsychotic were patients most likely to stick with? Olanzapine – the same one they stayed with in the Catie trial – but notice olanzapine was the one they were least likely to stay in the bipolar study.

KELLIE NEWSOME: And if your patient does discontinue quetiapine, a new study from 2021 suggests that abrupt discontinuation may cause withdrawal symptoms. They reviewed 13 papers on quetiapine withdrawal and concluded the drug does have rare but real withdrawal effects: nausea, restlessness, sweating, insomnia, irritability, anxiety, racing heart, high blood pressure, and dizziness. As well as withdrawal dyskinesias – a problem with most antipsychotics.

CHRIS AIKEN: AstraZeneca knew that quetiapine had a reputation problem – lots of side effects made patients stop it, and it didn’t seem to work so well in schizophrenia. Over the years they tried to find creative ways to improve on the quetiapine’s efficacy and tolerability. On the inpatient side, they had to convince doctors that quetiapine could act quickly, but the titration schedule in the PDR was slow, starting at 50mg/day and raising to 300-400mg/day by day 4. So they tested a more rapid titration for mania and psychosis, starting at 200mg/day on day 1 and raising by 200 mg increments every day so that you could get to a full dose of 600-800mg in 3-4 days. This strategy probably got more docs to give quetiapine a try, but did it really improve outcomes?

In 2019 a meta-analysis of these rapid titration studies came out, and the answer they came up with: “No.” Rapidly titrating the drug didn’t get patients better any faster, but it did cause more sedation.

KELLIE NEWSOME: Sedation was a particular barrier in outpatient practice, and the company developed a few dosing strategies to try to get around that. Giving it once a day – all at night – helped – but it also increased the risk of orthostasis – low blood pressure and falls – especially at doses above 300mg. So they developed an XR form that smoothed over those orthostatic-inducing peak levels. The XR form also gave the company new data, which they used to create a new game of smoke and mirrors.

CHRIS AIKEN: Here’s how it worked. The AstraZeneca rep would come and try to convince you to switch patients from instant release quetiapine to XR. “But wait,” you’d say, “I dose quetiapine for depression all at night, and the biggest complaint I get is morning fatigue, so isn’t that going to be worse on the XR.”

Then the rep would pull out data showing the rate of sedation is actually worse with the instant release. “You see,” they’d explain, “We give the XR in the early evening, and it takes a couple hours to release so your patient can still go about their business until bedtime. Then, because you gave it early, it wears off faster, leaving them less groggy in the morning.”

The problem is this explanation did not exactly match the facts. The studies showing less sedation on quetiapine XR were comparing XR all-at-night with instant release given twice a day – which of course is going to cause more daytime sedation.  And that brings us to our next study, a 2019 meta-analysis of quetiapine in bipolar depression. They concluded that the XR was more likely to cause morning sedation than the instant release when both were dosed once-at-night. This analysis also provides some reassurance for those who fear off-label prescribing. Quetiapine is FDA approved for unipolar depression in both the instant-release and XR forms, but it is only approved in bipolar depression as an XR drug. That approval came later, when the company was dropping its investment in instant release quetiapine, but fear not: They had conducted studies in bipolar depression with the instant release. This meta-analysis concluded that both XR and instant release were equally effective in bipolar depression, and the optimal dose was 300mg at night. The 600mg dose proved no more effective and caused more side effects.

KELLIE NEWSOME: But where did AstraZeneca get the idea to test quetiapine in depression? Schizophrenia. In the 1990’s, psychiatrists noticed that mood improved when they treated psychosis with quetiapine and the other atypical antipsychotics. That early observation has held up, and particularly with quetiapine – we found several head-to-head comparisons where quetiapine relieved depression and anxiety better than haloperidol or risperidone when used in schizophrenia:

https://pubmed.ncbi.nlm.nih.gov/25356632/

https://pubmed.ncbi.nlm.nih.gov/24681810/

https://pubmed.ncbi.nlm.nih.gov/12870569/

https://pubmed.ncbi.nlm.nih.gov/12523876/

CHRIS AIKEN: Studies in mood disorders started coming out in the 2000’s, and quetiapine went on to gain FDA approval in bipolar mania, bipolar depression, and as an augmentation to antidepressants in unipolar depression. It was the first medication to gain FDA approval for both manic and depressive episodes in bipolar disorder – and until recently it was the only one – it is now joined by cariprazine (Vraylar). All this history is well known, but you may not know about two indications that it failed to gain approval in: as monotherapy in Generalized Anxiety Disorder and in Major Depression.

KELLIE NEWSOME: In the late 2000’s, AstraZeneca submitted trials showing a large effect size for quetiapine in generalized anxiety disorder. They also had proof that the drug works as monotherapy in major depression – not just as an augmentation of antidepressants – they ran 4 trials; in 3 it worked and the 4th was a failed trial because the active antidepressant arm failed to separate from placebo. Ultimately, the FDA denied these indications because the drug was considered too risky to justify its use, and they knew if it was approved as monotherapy that clinicians might start using it first line without even trying a safer antidepressant. It did gain approval as monotherapy in depression in other countries though, like Australia and Canada.

CHRIS AIKEN: This is surprising, because every other antipsychotic requires an antidepressant – antipsychotics don’t treat depression on their own, and there’s even some evidence that antipsychotics might cause depression. So what makes quetiapine different? One reason may be that it is metabolized into norquetiapine, which has antidepressant qualities of its own – it acts a bit like an SNRI. We don’t recommend using quetiapine on its own in unipolar depression, but if the patient is unable to take an antidepressant for any reason it’s good to have this option in your back pocket.

KELLIE NEWSOME: Actually there is one other antipsychotic that might work as monotherapy in unipolar depression – lurasidone (Latuda) – but that is only in depression with mixed features – a new diagnosis in DSM-5 that captures patients whose depressions have a few manic features but don’t meet full criteria for bipolar disorder. 

CHRIS AIKEN: Unlike lurasidone, quetiapine failed to gain approval in pediatric bipolar depression, even though the drug is approved in pediatric mania for ages 10 and above. In 2020, a meta-analysis looked at all the studies in pediatric bipolar depression – all 2 of them – and concluded that quetiapine does not work there.

KELLIE NEWSOME: And on the subject of “Quetiapine does not work” – we’ll add a few more. It missed the mark in delirium in 2 randomized trials from 2021, one where it was tested in active delirium, and another that looked at whether it could prevent delirium. This is not unique to quetiapine – most antipsychotics are turning up negative findings in delirium, and the general consensus is that their risks rarely outweigh their benefits there.

CHRIS AIKEN: But we can also add a new use for quetiapine: Bipolar with OCD.  In a randomized controlled trial from 2021, Quetiapine outperformed placebo in stable bipolar patients with active OCD at a mean dose of 325 mg/day. Although the study was small, the results were impressive, with a positive response in half the patients, compared to only 5% who responded to placebo.

KELLIE NEWSOME: We close with a new risk for quetiapine: hypothyroidism. This is one of those side effects that’s buried in the PDR – yes, it’s actually mentioned there – and rarely gets talked about, even though the Maudsley guidelines recommend an annual thyroid function test for patients on the drug. A new review looked at all the evidence: 32 papers, mostly observational studies, and concluded that this adverse effect is likely real, but it’s rare, and the causation has not been definitively proven. 

CHRIS AIKEN: Read more about quetiapine, including dosing strategies and a little-known drug interaction with lamotrigine in our online issue.And while you’re there, get $30 off your first year’s subscription with the promo code PODCAST

And now for the word of the day…. Witzelsucht

KELLIE NEWSOME: Witzelsucht is a symptom of inappropriate humor seen in neurologic and psychotic disorders.  These patients make puns, or tell inappropriate jokes or pointless stories in socially inappropriate situations. Like a good straight man, the patients are usually immune to other people’s jokes – not even cracking a smile while their own off-color wit sends others into laughter. Witzelsucht is among the many signs of psychosis that Conrad Swartz detailed in our interview on psychotic depression, which we’ll feature when we return in 2 weeks.

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