Quetiapine is a second-generation antipsychotic approved by the FDA for schizophrenia, bipolar
disorder, and as an add-on therapy for depression.
It's widely used for other conditions, including insomnia, anxiety, delirium, and as a single
therapy for depression.
Before discussing specific uses, it's important to know the research on quetiapine, like many
drugs, is far from ideal.
The results can be biased, perhaps due to the influence of pharmaceutical companies,
and high drop-out rates produce a lot of missing data.
Saying how effective it is or what the adverse effects are is difficult.
It's been studied for multiple conditions, including schizophrenia, bipolar disorder,
insomnia, depression, anxiety, borderline personality disorder, and substance use disorders.
The effects can be separated based on dose.
At low doses of 25 to 50 mg, it's primarily a sleep medication.
As the dose increases, it may become helpful for conditions like depression and anxiety.
And once you're over 300 mg, it has more overt antipsychotic and mood stabilizing effects.
For schizophrenia, second-gen antipsychotics like quetiapine tend to have similar efficacy
to antipsychotics like haloperidol.
They might be superior for certain patients and they could offer more alleviation of cognitive
and negative symptoms, like impaired emotion, low motivation, and apathy.
But the evidence that quetiapine far exceeds first generation drugs isn't substantial.
It seems other second-gen antipsychotics like risperidone and olanzapine could have a higher
or similar efficacy.
It's not uncommon for studies to have dropout rates over 50%, which makes figuring out the
effects even more difficult.
Overall, the drug reduces delusions, hallucinations, disordered thinking, and mood issues in schizophrenia.
The cognitive symptoms of psychotic disorders often don't respond to antipsychotics.
That's true even with quetiapine, but there's evidence it helps with attention and executive
function.
There's mixed evidence suggesting unmedicated patients sometimes retain better memory performance
and verbal fluency.
The sedative effects alone could in some cases reduce performance.
Compared to first-gen drugs, it may cause fewer movement disorders like extrapyramidal
symptoms and tardive dyskinesia.
And it may cause less sexual dysfunction and cardiovascular problems.
Yet it has adverse effects like significant sedation, drowsiness, and metabolic problems.
Bipolar disorder is broken into two core categories, Bipolar 1 and Bipolar 2.
Bipolar 1 involves depression with full manic episodes.
While Bipolar 2 involves depression alongside at least one hypomanic episode.
Mania is characterized by hyperactivity, impulsivity, mood elevation, reduced sleeping, and even
psychotic symptoms, which has led people to group aspects of bipolar with classic psychotic
disorders.
There's evidence quetiapine can help with all phases of the disorder.
It might be useful when someone is experiencing depression or mania.
And it could be a good add-on or single therapy for maintenance.
Even though the use of antipsychotics for long-term maintenance isn't heavily supported,
it's common.
Many patients end up on multiple medications, including antipsychotics like quetiapine.
It's recommended people with severe manic episodes receive a combination of lithium
or valproate with an antipsychotic.
Milder cases can be treated with a single drug.
If you're just suffering from insomnia, quetiapine probably isn't ideal despite it having verified
effects on sleep, like increased sleep time, a reduction in REM, and an increase in Stage
2.
Though it's frequently used for insomnia, the effects may decline over time, there's
not much evidence supporting its use, and it comes with potential adverse effects like
daytime sedation and long-term metabolic issues.
Someone with a disorder like depression or anxiety that's accompanied by insomnia could
benefit more from quetiapine.
If we're just looking at acute use for sleep, it is helpful.
Some people use it to sleep after stimulant or psychedelic use for this reason.
But acute use comes with a pretty high chance of feeling groggy the next day.
The creator of quetiapine, AstraZeneca, pushed the FDA to approve it for major depression
and generalized anxiety disorder, but the FDA didn't agree with those uses.
Even though some evidence supports its efficacy alone or with other treatments, more studies
would be helpful.
Exposing people to side effects like a higher risk of diabetes, cardiovascular issues, and
movement disorders doesn't make sense unless it's truly needed.
Of course the typical treatments for these conditions, like SSRIs, SNRIs, and benzodiazepines,
also come with adverse effects.
Despite it not being approved as a single therapy, many people receive quetiapine for
depression and anxiety.
Given the evidence is mixed, with some studies failing to show a benefit and others showing
efficacy similar to first-line treatments, it's hard to say if quetiapine should be recommended.
Some of its antipsychotic uses, such as for delirium in hospitals or for psychosis in
dementia and Parkinson's, haven't been adequately studied.
It's used for those conditions, but it's not clear that it's reliably beneficial or better
than other antipsychotics.
Quite a few articles have been written about the alleged "abuse potential" of quetiapine.
There are cases of people using it non-medically, faking symptoms to receive prescriptions,
and buying it in prisons and other restrictive settings.
When analyzing those cases, it doesn't seem to actually have recreational effects.
Instead, people are using it for sedation and sleep, either on its own, to come down
from other drugs, or mixed with other substances.
At most it could offer some anxiety reduction and relaxation, but it doesn't have a significant
recreational potential.
Quetiapine is a dibenzothiazepine derivative with structural similarities to clozapine,
the first second-gen antipsychotic.
They contain a similar tricyclic heterocycle structure.
One of the nitrogen heteroatoms within clozapine's dibenzodiazepine ring has been replaced with
a sulphur in quetiapine, yielding a dibenzothiazepine ring.
Both drugs also have a piperzine ring substituted at the 4 position of their main tricyclic
heterocycle.
It interacts with multiple receptors, including dopamine D2, serotonin 2A, serotonin 1A, histamine
H1, and adrenergic A1.
There's also some antagonism at muscarinic M1 receptors.
That doesn't do much at typical doses, but it could contribute to increased heart rate
and delirium in overdose.
Unlike a first-gen antipsychotic, it has a higher affinity for 5-HT2A, a1-adrenergic,
and H1 receptors than for D2.
Lower D2 affinity and fast dissociation might be the reason movement disorders are less
common.
It could also be biased away from activity in pathways that produce movement issues.
D2 antagonism is likely a key part of the antipsychotic effects when sufficient doses
are used.
A role for 5-HT2A also seems possible.
Though this reduction in dopamine activity is thought to be important for schizophrenia,
the condition isn't just one of high dopamine activity.
Other systems are involved and a lack of dopamine activity in some regions is linked to the
cognitive and negative symptoms.
Quetiapine addresses those symptoms by increasing dopamine in the prefrontal cortex.
This could be from 5-HT1A agonism and from effects on the norepinephrine system.
Extended treatment with quetiapine increases prefrontal cortex activity triggered by emotional
input and it increases activation during cognitive tasks.
So its relief of blunted affect and cognitive deficits might be connected to improved cortical
activity.
For depression, anxiety, and mood disorders, interactions with serotonin 2A and 1A receptors,
along with effects on norepinephrine activity, could be important.
5-HT2A is implicated in depression and anxiety, so blocking that site provides a basis for
antidepressant and anxiolytic properties.
For insomnia, H1 and serotonin antagonism are probably responsible for the beneficial
effects.
It's been speculated based on research with other antipsychotics that a rise in allopregnanolone,
a neuroactive steroid with effects on GABAergic activity, might be contributing.
The drug has interesting antioxidant and neuroprotective properties, based on in vitro and animal studies.
It's useful in models of Alzheimer's disease, chronic stress, methamphetamine toxicity,
and blood supply reduction.
This opens up another pathway for beneficial effects in certain neurotoxic and psychiatric
conditions.
Its ability to block a reduction in cellular proliferation and BDNF expression caused by
stress is of particular interest for mood disorders and anxiety.
Some other relevant actions could include modulation of inflammatory responses and inhibition
of nitric oxide.
At the genetic level, stress can alter the genetic profile of the frontal cortex and
those alterations are inhibited by quetiapine.
Other genetic effects, like increased expression of circadian clock genes, which may be disrupted
in psychiatric conditions, could be playing a role.
Quetiapine reaches its max concentration in 1 to 2 hours and its half-life is 7 hours.
It's mainly metabolized via CYP3A4, with the greatest metabolites being quetiapine carboxylic
acid and quetiapine sulfoxide.
Though it was long believed metabolites don't contribute to its pharmacology, at least one
metabolite, norquetiapine, appears important.
Norquetiapine has its own pharmacological profile that overlaps significantly with antidepressants,
anxiolytics, and antipsychotics.
It also works as an antagonist at D2 and 5-HT2A, and it has a significantly higher affinity
for the norepinephrine transporter, 5-HT1A, and 5-HT7.
Its affinity at the norepinephrine transporter and agonism at 5-HT1A likely contribute to
quetiapine's activity.
Both of those are targets for known antidepressant and anxiolytic drugs.
Indeed, norquetiapine has antidepressant and anxiolytic effects in animals.
It's also a more potent antagonist at 5-HT2C, which could be relevant.
The dose is usually between 300 and 800 mg, though some people end up on higher doses.
Doses over 800 mg have less evidence behind them, so it's not clear if those amounts are
wise when treating psychotic symptoms or bipolar disorder.
Lower doses may be used for depression and bipolar depression.
The actual dose used in clinical settings can vary significantly between patients.
Quetiapine was developed by AstraZeneca, a British pharmaceutical company, in 1985.
Four years later, the first second-gen antipsychotic, clozapine, entered the US market.
It would take until 1997 for quetiapine to become available.
By 2006 it was approved and available in over 80 countries worldwide.
Sales grew to $4.5 billion in 2008, driven in large part by off-label prescribing.
In 2009, the FDA asked an advisory committee if it should be approved for depression and
anxiety.
AstraZeneca had been developing the drug for those conditions and argued it was effective.
The committee endorsed its approval as an add-on drug for depression, but they weren't
comfortable with a general approval for depression or anxiety.
Despite the existence of efficacy, concerns about metabolic issues, cardiac problems,
and tardive dyskinesia were highlighted.
Quetiapine has only ever been approved for a small set of conditions, but AstraZeneca
wasn't satisfied with those approvals.
In 2010, it paid a $520 million settlement for off-label marketing and improper handling
of clinical trials.
Because of lawsuits filed against the drug maker, it was discovered the company knew
about efficacy issues and side effects without adequately informing the public.
The company intentionally misled people about the risk of weight gain and diabetes.
It buried studies showing worse side effect profiles and it misrepresented studies that
found it wasn't superior to first-gen antipsychotics.
In one case, AstraZeneca learned of clinical data showing significant weight gain potential,
yet it presented data at a conference that showed weight loss instead.
Even now in 2017, the company is still facing lawsuits over its handling of clinical data
related to side effects.
Though the side effect profile isn't unreasonable, it's worse than what AstraZeneca told doctors
and patients.
In 2013 it was the most frequently prescribed second-gen antipsychotic in the US, with over
14 million prescriptions dispensed.
It's prescription-only in the US.
Similar prescription-only restrictions exist in Australia, Canada, and the UK.
This means sales are only allowed in approved settings, and possession may or may not be
illegal depending on your country.
A large portion of patients will encounter side effects, but they're usually mild and
may decline over time.
The most common ones include drowsiness, dizziness, dry mouth, and sexual dysfunction.
Sexual dysfunction usually isn't severe and it's less significant than many other antipsychotics
and antidepressants.
Nevertheless, diminished libido is pretty common.
Less common are cardiovascular, metabolic, and movement disorders.
Quetiapine was thought to have a very minimal connection to heart rhythm issues, but it
appears the risk of sudden cardiac death is similar to first-gen antipsychotics.
The risk is dose-dependent, so this barely applies to people taking under 100 mg.
Major cardiac issues are rare, but care should be taken if you have a preexisting cardiovascular
disorder or are taking medications that can prolong the QT interval.
For metabolic effects, it has a pretty minimal connection to cholesterol changes and a greater
connection to increased fasting triglycerides and glucose.
Quetiapine is a risk factor for obesity, diabetes, cardiovascular disease, and hyperlipidemia
in the long-term.
It's rare for someone to develop diabetes seemingly due to quetiapine, but it's somewhat
common to have weight gain.
Very different levels of weight gain have been reported in the literature.
Some studies show no increase.
Most show a modest average increase of 1 to 5 lbs over a period of a few months.
Many studies find no significant link to movement disorders.
Yet opposing evidence exists showing some people will experience extrapyramidal symptoms
and potentially tardive dyskinesia.
Quetiapine is pretty safe in overdose, with very few deaths coming from direct toxicity.
That's despite countless people attempting suicide with the drug, which is common for
medications used in people who have a substantially heightened suicide risk.
Increased heart rate and drowsiness are two of the top symptoms.
Hypotension, respiratory depression, delirium, arrhythmias, rhabdomyolysis, and seizures
occur rarely.
Coma is possible with large overdoses.
Other depressants or drugs affecting the QT interval increase the risks.
Withdrawal symptoms can occur when you stop it.
Those are worst if you abruptly stop it instead of tapering.
The symptoms can include increased blood pressure, vomiting, nausea, nervousness, insomnia, anxiety,
increased heart rate, and sweating.
If you have any questions, feel free to put them in the comments.
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