I made the mistake of suggesting that we need a better version of quetiapine for insomnia on Twitter. That triggered the usual comments that basically suggested that I did not know anything about quetiapine or what I was doing in general. This post is for cooler heads. Let me start out by saying quetiapine came out early in my career. The early concern was ocular side effects and of course cardiac conduction problems (prolonged QTc). Since that time the ocular side effects are not a primary concern (both retinal hyperpigmentation and cataracts were a concern with phenothiazines). Since I was in acute care psychiatry, the main concern was that this medication did not work fast enough for acute mania or psychosis. There was a time lag of days to weeks relative to more potent atypical antipsychotics (AAP). And not too long after they were released the metabolic problems were noted including dyslipidemia, insulin resistance and overt diabetes mellitus, metabolic syndrome, and weight gain. Since most Americans are overweight and have a moderate risk of diabetes mellitus Type 2 in middle age – this is the primary reason to avoid using most medications in this class. Theoretical considerations suggest that the newer AAPs – aripiprazole, lurasidone, and brexpiprazole have less risk, but I have certainly seen people who gained substantial amounts of weight on these agents. I have also seen several people develop diabetes without gaining a pound. That risk is clearly there and it is significant.
Indications for both olanzapine and quetiapine include
schizophrenia and mood disorders typically bipolar variants or psychotic
depression. Ideally the medication will also work for any associated sleep
disturbance but that is not always the case. Sleep is important in primary
psychiatric disorders because the person with the disorder generally does
better if they are sleeping well. In the real world that ideal solution is not
always there. As an example, the patient may be responding well to a non-sedating
AAP like aripiprazole but continuing to not sleep. They do not want to take the
chance of significant weight gain, but at the same time practically all the
other medications in the above table have been tried and are ineffective. In
that case low doses of quetiapine are often added to the primary AAP, not for
additional treatment of psychotic or mood symptoms, but in the hope of
normalizing sleep. That can make a significant difference even though the risk
of metabolic problems remains.
The above table was constructed to look at non-benzodiazepine
drugs for sleep. I plan to revisit the benzodiazepine issue again this year and
am working on a table. For the purpose of this post, I am referring to all high
potency and low potency benzodiazepines as well as the z-drugs (zolpidem,
eszopiclone, and zaleplon). As I wrote about a few years ago, this class of
medications poses a significant risk of the term the side effects and also dose
escalation and uncontrolled use. Since they were invented to replace
barbiturates and were clearly safer than that class of medications, there was a
lag time before physicians found that they also posed unique risks. Benzodiazepines are also extremely risky for
patients with diagnosed substance use problems and should generally be avoided
in that population. The population also has very significant sleep problems as
well as problems with anxiety and depression.
In treating this population, insomnia can be related
to intoxication and withdrawal states, the chronic sleep effects of intoxicants,
circadian rhythm disturbances due to patterns of substance use, secondary to a
substance induced psychiatric disorders, as well as an ongoing primary insomnia
that has never been addressed. Some withdrawal states most notably opioids,
benzodiazepines, and alcohol can produce long-standing severe insomnia that can
last for weeks or more. That insomnia can be considered life-threatening if it
perpetuates the cycle of ongoing substance use. I often hear: “If you can't give
me something that will help me sleep, I know what will do it.” That discussion
invariably comes back to using heroin or alprazolam or alcohol or possibly a
combination of all three in order to get to sleep. The sleep does not have to
be “normal” in any way. It might only involve 3 to 4 hours of interrupted sleep
but that is considered better than nothing or one or two hours. This is typically referred to as "self-medication" and it illustrates that this concept has very little to do with normalization of function. Self medication with addictive compounds is a semi-rational process that only partially addresses the problem.
With the exception of the above orexin receptor antagonists, amitriptyline, and trimipramine, I use all of the compounds in the above table for the treatment of insomnia. The most commonly used medication is trazodone. It is generally well tolerated and effective. Like all medications it is not 100% effective and most common reasons people request changes are excessive morning sedation, daytime drowsiness, excessive dreaming, and nasal congestion. The remaining sedating antidepressants all depend heavily on anti-histaminergic effects enter probably as well tolerated but have unique side effects that need to be monitored. The only antidepressant that has an FDA indication for sleep is doxepin and that is in a proprietary dosage form of 3 and 6 mg. According to the Ki values, doxepin is the highest affinity for H1 receptors. Insurance company constraints usually result in people getting low-dose generic doxepin rather than the FDA approved proprietary version Silenor. Silenor comes in 3 mg and 6 mg tabs and the smallest generic dose of doxepin that I can typically prescribe is 10 mg.
Antihistamines are typically over-the-counter sleep
medications - usually diphenhydramine or doxylamine. In the table, hydroxyzine seems to have a
comparative advantage due to the lower Ki value, but the metabolism of this
compound is extensive and one of the metabolites cetirizine has a high affinity
for H1 receptors but also no brain penetration – so it is ineffective for
sleep. There is also a concern about
prolonged QTc interval with hydroxyzine that has led European regulators to
limit the total daily dose of hydroxyzine to 100 mg. I typically see hydroxyzine prescribed for
anxiety and insomnia in patients with substance use problems. It is generally not very effective for either
anxiety or sleep.
In the clinical population I see practically everyone has access to melatonin. It appears to be much less effective than trazodone but has the appeal that it is a “natural” supplement. That also means it is not monitored by the FDA in terms of bioequivalence. The dose of melatonin that most people take is many times the amount that is produce physiologically. I was told by one of the top sleep experts in the country several years ago that the appropriate way to take it is taking 1 or 2 mg at five or 6 PM to mimic the physiological release of melatonin. I often make that suggestion people who tell me they feel like they are taking too much with a 5 to 10 mg dose at bedtime. Ramelteon is available as melatonin receptor agonist and seems to be effective for sleep onset in about 30% of the people I see.
Gabapentin and pregabalin are unique compounds in that
their primary action is through N-Type Voltage Gated Calcium Channels (VGCC). A small segment of the population will
experience these medications as very sedating.
Most people do not. In addiction
psychiatry, there was a trial of gabapentin in alcohol use disorder that showed
that the treatment group (600 mg TID) had less insomnia, less anxiety, fewer
cravings, and were less likely to relapse to alcohol use. In the sleep literature, both are used for
restless leg syndrome (RLS) and I have seen patients who experienced significant
relief from these compounds when nothing else seemed to work. These medications are currently controversial
because of some concern of overuse in the context of limited efficacy. In addiction, they are prescribed mostly for
off label indications and sleep is one of those indications. Even though I work in one of the strictest
prescribing environments with regard to controlled substances, I do prescribe
gabapentin for sleep, anxiety, chronic pain, and protracted benzodiazepine
withdrawal (all off-label) but generally to patients with alcohol use disorders
(per the clinical trial). I generally
avoid prescribing gabapentinoids for people with opioid use disorders because there
is some evidence that they may escalate the dose and try to enhance the
euphorigenic effects of opioids. I also
advise people ahead of time about these potential effects and encourage them to
self-monitor for either euphorigenic effects or a tendency to escalate the
dose. Gabapentinoids should be
discontinued in those circumstances.
I have not started using the orexin receptor antagonists
yet. Based on my previous review they look
like very interesting compounds, but their clinical effects do not seem to
match the theoretical effects at this point.
I think a clinical trial is needed to see if they can be safely used in
populations with substance use disorders.
I hope to be of assistance designing and working on that trial.
In my capacity as a tertiary consultant, I am in the
position of seeing large numbers of people for evaluations who are already
taking quetiapine for sleep. There is a selection
bias in place because 100% of the people I see have a substance use disorder. A substantial number overuse benzodiazepines
and in some cases have been using very high doses for years before I see them. If I am discussing treatment with a person at
the end of my initial assessment and they are taking quetiapine, my first order
of business is to inform them that according to Minnesota State Statutes – they
need to sign a written consent form to take it and I review the sections on
general side effects, metabolic effects (increased appetite, weight gain,
diabetes, dyslipidemia) and the neurological effects – some of which may be
irreversible (tardive syndromes). That
point is typically a defining point in the interview and I hear one of two
things:
“Nobody ever told me about that before.”
“I have tried everything else for sleep and it doesn’t
work. And you know I can’t take
benzodiazepines.”
In the case of the first response, additional details
will depend on whether or not the patient has gained weight. In some of those cases they will be irate. Some will respond on the basis of a family history
of diabetes and tell me there is no way they want to get it. The majority of these patients will want to
stop the quetiapine and in many cases they have never tried medications from
the above table and one of them will work. Those responses indicate to me that quetiapine was probably prescribed prematurely - before some of the other alternatives were tried.
In the case of the second response, I get very interesting histories of severe treatment refractory insomnia associated with substance use. Most people take 25-150 mg of quetiapine for sleep but some take doses that are typically used for the stabilization of bipolar disorder (300-800 mg at night). And they have been taking it for years. My basic job is to make sure they do not have tardive dyskinesia, diabetes mellitus, or cardiac conduction problems but things can get even more complicated than that. For example, what about the person who already has diabetes mellitus Type II, hypertension, dyslipidemia, heart disease and a severe alcohol use problem? What if they tell you: “Look doc – if I can’t use quetiapine for sleep my go to is alcohol and I know that alcohol is killing me. You have to let me use that quetiapine or I will end up drinking myself to death”.
In the case of the second response, I get very interesting histories of severe treatment refractory insomnia associated with substance use. Most people take 25-150 mg of quetiapine for sleep but some take doses that are typically used for the stabilization of bipolar disorder (300-800 mg at night). And they have been taking it for years. My basic job is to make sure they do not have tardive dyskinesia, diabetes mellitus, or cardiac conduction problems but things can get even more complicated than that. For example, what about the person who already has diabetes mellitus Type II, hypertension, dyslipidemia, heart disease and a severe alcohol use problem? What if they tell you: “Look doc – if I can’t use quetiapine for sleep my go to is alcohol and I know that alcohol is killing me. You have to let me use that quetiapine or I will end up drinking myself to death”.
An equally compelling situation occurs in the person
with opioid use disorder who refuses agonist treatment with buprenorphine of
methadone. After years of opioid use,
severe insomnia generally does not resolve very easily and it can last for
weeks or months. Can a physician not
prescribe a medication that can typically work for this insomnia based on the idea
that some people consider the medication to be “bad”? I think the answer is that the physician cannot. If an assessment has been made that none of
the other medications in the table are suitable, and the patient has a
potentially life-threatening illness associated with insomnia and they have
given adequate informed consent, then the medication must be prescribed. Not sleeping and risking relapse to alcohol
and drug use is a life threatening problem for most of the people I see. In short, quetiapine should not be used casually for insomnia but there are situations where it may be required.
These are a couple of things I am working on with
regard to sleep right now. The Kis in
the above table are only part of the story.
Coming up with better theories about quetiapine will hopefully lead to
better ideas about sleep medications.
George Dawson, MD, DFAPA
Supplementary:
Supplementary:
Table added to clarify the muscarinic acetylcholine receptor (mAChR) functions and the subtype most implicated in delirium. (click to enlarge).
References:
1. Fukasawa H, Muratake H, Ito A, et al. Silicon-containing GABA derivatives, silagaba compounds, as orally effective agents for treating neuropathic pain without central-nervous-system-related side effects. ACS Chem Neurosci. 2014;5(7):525-532. doi:10.1021/cn500053d
2. Kroeze WK, Hufeisen SJ, Popadak BA, et al. H1-histamine receptor affinity predicts short-term weight gain for typical and atypical antipsychotic drugs. Neuropsychopharmacology. 2003;28(3):519-526. doi:10.1038/sj.npp.1300027
3. Nishiyama K, Shintani Y, Hirai K, Yoshikubo S. Molecular cloning and pharmacological characterization of monkey MT1 and MT2 melatonin receptors showing high affinity for the agonist ramelteon. J Pharmacol Exp Ther. 2009;330(3):855-863. doi:10.1124/jpet.109.155283 (monkey receptors)
4. Ancizu S, Castrillo N, Pérez-Silanes S, et al. New quinoxaline derivatives as potential MT₁ and MT₂ receptor ligands. Molecules. 2012;17(7):7737-7757. Published 2012 Jun 25. doi:10.3390/molecules17077737
5. Taylor CP, Angelotti T, Fauman E. Pharmacology and mechanism of action of pregabalin: the calcium channel alpha2-delta (alpha2-delta) subunit as a target for antiepileptic drug discovery. Epilepsy Res. 2007;73(2):137-150. doi:10.1016/j.eplepsyres.2006.09.008 (human recombinant n 2— Type 1 subunit proteins)
6. Salvi V, Mencacci C, Barone-
Adesi F. H1-histamine receptor affinity predicts weight gain with antidepressants. Eur Neuropsychopharmacol. 2016;26(10):1673-1677. doi:10.1016/j.euroneuro.2016.08.012
7. Gillard M, Van Der Perren C, Moguilevsky N, Massingham R, Chatelain P. Binding characteristics of cetirizine and levocetirizine to human H(1) histamine receptors: contribution of Lys(191) and Thr(194). Mol Pharmacol. 2002;61(2):391-399. doi:10.1124/mol.61.2.391
8. Roth, BL; Driscol, J. "PDSP Ki Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved July 5, 2020.
9. Hshieh TT, Fong TG, Marcantonio ER, Inouye SK. Cholinergic deficiency hypothesis in delirium: a synthesis of current evidence. J Gerontol A Biol Sci Med Sci. 2008;63(7):764-772. doi:10.1093/gerona/63.7.764
9. Hshieh TT, Fong TG, Marcantonio ER, Inouye SK. Cholinergic deficiency hypothesis in delirium: a synthesis of current evidence. J Gerontol A Biol Sci Med Sci. 2008;63(7):764-772. doi:10.1093/gerona/63.7.764
