One More Dream…..

 

One More Dream…

The purpose of this post is an illustration of a strategy I use to improve my sleep.  I am currently an old man and have had sleep problems since I was a toddler. I had night terrors at an early age and still remember the hallucinations.  I wrote about them in a previous post.  Night terrors as a kid generally predicts sleep problems and risk for psychiatric difficulty as an adult. I also inherited obstructive sleep apnea and that contributes to poor sleep quality. For most of my career, I practiced in a high stress environment and with my personality factors that also lead to significant sleep disruption in situations where there was no clear solution to the problems I was trying to treat. A good example would be catatonic patients who were not eating, drinking, or responding to treatment. I would find myself laying in bed at night and reviewing the current treatment plan and that person’s medical status – sometimes for hours. Since retiring 2 years ago that type of nocturnal stress is gone – but your life is never completely stress free.

When I do fall asleep – I generally like dreaming. I tend to dream about medical centers and anxiety provoking situations. A common dream is being in residency and realizing that I just stopped going to biochemistry class as a first-year medical student. I never took the exams or confirmed whether I got a grade or not. Instead, I find myself near the end of residency and wondering if I am going to graduate.  I am not sure if there is a black mark against my name or not. At the same time, I am engaged with many doctors – doing what we did in residency training. I wake up somewhat anxious until I realize it is just a repetitive dream. I am always amazed at the content of the dream in terms of the architecture and landscape – all manufactured from incidental memory. None of the institutions in my dreams exist in real life. The same is true of most of the people in my dreams, but occasionally there is a friend, family member, or celebrity.

I try to practice the lucid dreaming that I discovered in childhood. If I am stressed or anxious in a dream, especially to the point of bodily sensations like feeling flushed, like my heart is pounding, or shortness of breath I try to wake myself up by rehearsing what to do ahead of time.  Those bodily sensations can be associated with strenuous activity in the dream like skating or biking – but not always.  I have tried a lot of the relaxation and CBT techniques for falling asleep but did not find them very effective. I also have not used any medications for sleep.  My primary care MD gave me 3 zolpidem tablets once.  They were moderately effective but he did not prescribe any more.  I take medication that is toxic and has drug interactions so I did not try other options that might affect cardiac conduction.

What I did come up with was a technique that I call “One more dream.”  Before I get into the details – let me emphasize that this is not an instruction manual or guide for people to use this technique.  It has not been shown to be effective in clinical trials and doubt it will ever be studied. This is just a technique that I personally have found to be effective and it is not medical advice for anyone else.  And like everything on this blog I am not promoting it to make money.  The discussion is strictly educational – nothing more.

Here is an outline of the basics beyond the typical sleep hygiene measures:

1: Recall the somatic sensations just before you fall asleep:  These sensations vary widely from person to person.  In my case, I get a feeling that I am sinking and I start to lose sensation in my arms and hands – they start to feel very light. I am also aware of any stiffness in the chest and abdominal wall.  I will typically do a few breathing exercises to get rid of that stiffness.  I actively try to recall that sequence of events and the actual feeling.  I have had several instances of general anesthesia in the past 5 years and recalling that state can also be helpful. 

2:  Recreate 'sleep reverie' transition state (usually just waiting for it is enough):  Sleep reverie is the transitional state from wakefulness to sleep. There is typically a period where conscious thoughts start to run together.  If you are good at mental imagery – an image might start out with a person walking down a stairway and change in an instant to a different person engaged in a different activity.  Noticing when this occurs is typically associated with transitional images. It is also a sign that sleep is rapidly approaching.  Focusing on those instances is helpful. 

3:  The conscious goal is one more dream:  I typically try to focus on an image of something that I want to dream about but having that dream is extremely rare. These images often dissolve in the sleep reverie stage. It is also a time to rehearse endings to problematic dreams. A common theme for me is strenuous physical activity. I am overexerting myself in a dream and wake up to rapid heartbeat, palpitations, rapid breathing, and sweating. If I can recognize that in a dream – my usual rehearsed ending is to wake up and start over.   

Those are the basic steps and the mile high view. They are not completely original since there are elements of lucid dreaming and dream/imagery rehearsal – both of which have been studied, tested and used clinically (1). In clinical practice I have had good results advising people about sleep hygiene; the pharmacology of caffeine, alcohol, and addictive drugs; whether their dreams were interpretable; and how to stop unpleasant dreams or nightmares using dream rehearsal. The decision to use these techniques generally depends on the amount of autonomic arousal the person is experiencing.  For example, people with high levels of anxiety all day long who experience associated nightmares and nocturnal arousal including panic attacks, rapid heartbeat, palpitations, sweating, and ongoing sleep deprivation are much more likely to need pharmacotherapy in addition to the above measures.  Standard insomnia therapies may be useful, but more specific therapy targeting heightened adrenergic output is more likely to work, especially in the case of post traumatic nightmares.

The biology of sleep transitions remains at the theoretical stage at this point with several interesting classical and newer hypotheses (2,3).  While the hypotheses are interesting and becoming more sophisticated it is also apparent that pluralistic interventions are effective including the measures described in this post.  In other words, astute clinicians have been able to design self-help, structured, and psychotherapeutic interventions that can reduce or eliminate both primary and trauma-based nightmares and improve sleep quality and general health.  Like many other interventions in psychiatry - they work irrespective of whether a biological mechanism of action is known or not. They also do not depend on a prescribed medication or medical test. They are dependent on a skilled sleep assessment and training in these techniques.

 

George Dawson, MD, DFAPA

 

References:

1:  Yücel, D. E., van Emmerik, A. A. P., Souama, C., & Lancee, J. (2020). Comparative efficacy of imagery rehearsal therapy and prazosin in the treatment of trauma-related nightmares in adults: A meta-analysis of randomized controlled trials. Sleep Medicine Reviews, 50, https://doi.org/10.1016/j.smrv.2019.101248

2:  Saper CB, Fuller PM, Pedersen NP, Lu J, Scammell TE. Sleep state switching. Neuron. 2010 Dec 22;68(6):1023-42. doi: 10.1016/j.neuron.2010.11.032. PMID: 21172606; PMCID: PMC3026325.

3:  Osorio-Forero A, Cardis R, Vantomme G, Guillaume-Gentil A, Katsioudi G, Devenoges C, Fernandez LMJ, Lüthi A. Noradrenergic circuit control of non-REM sleep substates. Curr Biol. 2021 Nov 22;31(22):5009-5023.e7. doi: 10.1016/j.cub.2021.09.041. Epub 2021 Oct 13. PMID: 34648731.

 

Toward A Better Sedative Hypnotic Medication

(Click to enlarge the above graphic)

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.

 That brings me to the issue of quetiapine for sleep.  It is quite an emotional topic for some.  Some people will fly into a rage over the very mention of quetiapine being used off label for sleep.  As I mentioned AAPs present unique risks that other medications do not and if those risks are present they are basically cardiovascular risk factors. A significant proportion of the population being treated by psychiatrists already has cardiovascular risk factors like tobacco smoking that effectively reduces their life span by about 25 years. The addition of quetiapine of any AAP is a serious matter. 

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”.

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:

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 K_i 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

More Than 9 Questions About Sleep

I was just thinking about the PHQ-9 and it widespread use in managed care as a metric for depression.  The idea that 9 questions are all that is needed strike most psychiatrists as a gross oversimplification.  There has been plenty of debate over the years about the diagnostic criteria and waht should be included.  Kendler recently wrote an excellent paper on the fact that the diagnostic criteria as they stand in the DSM really indexes disorders rather than diagnosing them.  Some recent blog posts have looked at real patients and what is happening with them when they appear to have an elevated PHQ-9 score but are not depressed.  Past markers of psychiatric disorders like the dexamethasone suppression test had had to withstand more rigorous testing than the PHQ-9.  And lastly, the literature to support it seems to reflect the literature that justified managed care - a business concept with no basis in science or medicine.

And then I had the thought: "During an evaluation I ask more than 9 questions about sleep on the average."  By comparison the PHQ-9 has one question.  That question is:

3. Trouble falling or staying asleep, or sleeping too much?  
[Not at all] [Several Days] [More than half the days] [Nearly every day]


There are more complex sleep questionairres.  The Pittsburgh Sleep Quality Index (PSQI) and Functional Outcomes of Sleep (FOSQ, FOSQ-10) are good examples.  I thought I would tabulate my questions here.  Sleep disturbance can be a primary disorder independent of any psychiatric problem.  Sleep is also comorbid with many if not most psychiatric problems.  Most people do not recover from a priamry psychiatric disorder as long as their sleep is disturbed.  Sleep disorders can antedate the onset of mood and anxiety disorders by years and for that reason I think it is important to determine if the sleep disorder is primary rather than part of the mood or anxiety disorder.  That cannot be determined by a brief cross sectional look that considers all current symptoms as part of a mood disorder.  So during my standard evaluation I ask people the following questions about their sleep not necessarily in the following order:

When you were a kid in middle school or high school did you have trouble sleeping?
Did you have nightmares back then?
Did they occur early in the night or later in the early morning hours?
Did you sleepwalk?
Did anyone ever tell you that you had sleep terrors?
Did your sleep problems from childhood ever resolve - have you ever slept normally since then?


Do you work at night?
Do you do shift work where the work time changes?
Do you currently have sleep problems?
Do they occur when you try to fall asleep?
Tell me your experience of trying to fall asleep - what gets in the way?
Any idea how long it takes you to fall asleep?
Have you had sleepless night where you could not sleep at all?
Do you wake up off and on all night long?
Do you wake up early in the morning - like 4 or 5 AM and find that you can't fall asleep?
Is your sleep restorative - do you feel rested the next day?
Do you snore?
Have you ever had a sleep study?
Have you been diagnosed with a sleep disorder?
Do you take alcohol or any medication to help you fall asleep?
Do you take in many caffeinated beverages during the day as coffee, soda, tea, or energy drinks?

That is about 20 fairly basic questions about sleep.  It is a framework that requires elaboration.  Just the issue of sleep studies these days can lead to details about parasomnias, related surgeries, sleep disordered breathing diagnoses, restless leg syndrome, and all of the associated treatments.  For the pupose of this post that is about 18 questions or twice as many as the total on the PHQ-9. It should be apparent that severe sleep problems can lead to a score considered in the depressed range on the PHQ-9 by adding up the scores of questions 1, 3, 4, 7 and 8.  Critical distinctions need to be made between sleep problems, anxiety disorders, mood disorders, addictions, and also the excessive use of an adult attention deficit-hyperactivity disorder diagnosis.

This brief exploration should point out the problems with a screening versus a diagnostic evaluation.  If you are given a PHQ-9 or GAD-7 (for anxiety) in your primary care clinic that score alone is insufficient as a basis for a treatment plan for depression.  A person repeating the questions as confirmation does not constitute a diagnostic evaluation.  By itself it does not mean that an antidepressant prescription is indicated.

Ask that person how they know that you have depression and not a sleep disorder or something else.


George Dawson, MD, DFAPA