Friday, July 17, 2020

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, PĂ©rez-Silanes S, et al. New quinoxaline derivatives as potential MT and MT 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 Pharmacol2002;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



Monday, July 13, 2020

Airborne Transmission Denial Dies Hard ........




I started this post as I left a staff meeting today on containing the coronoavirus. We had a similar meeting 2 months ago and at that point I added that there was airborne transmission of the virus.  The only comment I got was a condescending remark about how we don't know much about airborne transmission and we need to wait and see and blah, bah, blah. It was "as if" I did not know what I was talking about or any of the surrounding controversy.  To my surprise the same people today were sold on airborne transmission. They were even interested in HVAC issues and negative pressure rooms – all of the stuff I have been studying for 20 years.  Nobody mentioned UVC or air filtration.  I decided just to keep my mouth shut. Just like I usually do when politics seems to be the priority rather than science.  But the good news was undeniable.  Airborne transmission has much greater acceptance than it did prior to the current pandemic and there are clear reasons for it.

That staff meeting is a small part of a larger landscape of what airborne transmission advocates like me have been talking about for decades or longer.  Back in the days when I was working in an outdated building that had an HVAC system that was designed to contain heat rather than provide fresh air to dilute and remove airborne pathogens – I routinely observed the effects of this approach on myself and my coworkers.  Upper respiratory infections were endemic.  If one person came into that building with a severe form of a respiratory virus – most people got it. I can recall coming down with an acute flu-like illness one morning at work and getting ill so quickly and severely that I was barely able to make it home due to the cognitive effects.  I was close to delirium.

When you are in medical facilities, the party line is always “wash your hands”. I got the respiratory infections if I washed my hands 20 times a day or a hundred times a day.  The pandemic equivalent of that advice has been “don’t touch your face”.  But it is apparently safe to eat food that has been contaminated with SARS-CoV-2 because the virus is not infectious via gastrointestinal pathways.  The expert opinion is really based on the lack of evidence that eating food or touching food packaging is associated with SARS-CoV-2 infections.  We hear about the virus being infectious through the eyes and nose. It could be rubbed into the eyes from the face or into the nose by nose picking – but how common is that?  Certainly, washing your hands and not touching your face along with physical distancing at 6 feet seem like common sense rules.  But is that going to protect you?

I have never felt like any of those measures was enough and this week a letter came out pointing out the evidence for airborne transmission of respiratory viruses in general and for SARS-CoV-2 in particular.  I was pleased to see Dr. Milton as a co-author of this statement.  I have been reading his work for 20 years on airborne viruses in buildings of different design including the viruses that have been detected both in the air and the occupants of the building. This paper is a brief commentary specific to SARS-CoV-2 with a couple of generalities about airborne viruses and it is signed by 239 scientists who support it. 
   
The commentary starts out as an appeal to the medical community to recognize the potential for airborne spread of COVID-19.  Airborne transmission is defined as the release of droplets containing viral particles during breathing, coughing, sneezing, and any type of vocalization.  There is no doubt this happens. A distribution of droplet particle sizes occurs.  The larger droplets at a typical velocity settle out of the air in shorter distances typically in about 2 meters or 6 feet. The smaller droplets can travel much longer distances.  The authors cite an example of a 5 µm droplet at an original height of 1.5 meters and expelled at a typical indoor velocity travelling for “tens of meters” before it falls to the floor. This is typical airborne transmission and it will obviously not be contained by hand washing or physical distancing.

The authors on to describe some of the well-known scenarios where COVID-19 was transmitted despite no observed direct or indirect contact among the parties where the transmission occurred by video recordings.  They go on to cite other experiments demonstrating that several viruses (influenza, Middle East Respiratory Syndrome coronavirus (MERS-CoV), and respiratory syncytial virus (RSV) can all be spread by airborne routes. Although they don’t go into a lot of technical detail in the commentary, respiratory viruses are exhaled in normal tidal breathing.  The distribution and velocity of exhaled droplets will vary based on the way they are generated.  Infective viral RNA in small (5 µm) droplets from COVID-19 has been detected.

The critical sentence from this document follows:

“Hand washing and social distancing are appropriate, but in our view, insufficient to provide protection from virus carrying respiratory microdroplets released into the air by infected people.”

The is really a landmark statement from this group of experts. In my opinion it revolutionizes the approach not only to this virus but all respiratory viruses.  They all have access to the same type of spread and many have already been shown to have permeated heating and ventilation systems.  One of the main differences is virulence of the virus.  For example, smallpox or variola virus can cause an infection from the inhalation of a single viral particle (6).  Adenovirus, a much more common respiratory virus can cause an infection by the inhalation of as little as 6 viral particles (3).  Although adenovirus is potentially a flu-like respiratory virus, the main initiative at preventing the associated morbidity and mortality occurs in the military where a vaccination is used. The SARS-CoV-2 infections dose has been estimated to be about 280 particles – but the authors of one study suggest it is in the same ballpark of influenza virus and in that paper suggest that the amount of virus leading to infection in volunteers may be twice the amount of the aerosolized virus (5).

The main implication of airborne spread is that sustained inhalation of COVID-19 in poorly ventilated spaces of just being indoors increases risk of transmission. People who are coughing, sneezing, singing or engaged in any activity that results in forceful exhalation will expel small droplets at higher rates of speed and they will remain airborne for a longer period of time and travel much greater distances than the current suggested social distancing of 6 feet. 

To reduce the airborne transmission risk they have straightforward recommendations to avoid overcrowding (every additional person in the room is generating airborne droplets), have adequate ventilation, and supplement these measure with additions like HEPA filtration, germicidal UVC light, and exhausting room air rather than recirculating it. I can recall getting into an argument at one of my Avian Influenza Task Force meetings about a fast way to change the hospital ventilation system in the event of an influx of avian influenza patients.  Recall that the hospital was designed to retain heat by recirculating room air rather than exhausting it – like modern hospital rooms.  At the time, the counterargument was that it was just too expensive to build negative airflow rooms to prevent the flu virus from leaving the room with medical staff caring for the patients.  Most hospital rooms, even the ones I worked in that were built in the 1960s, had windows to the outside.  How difficult would it be to fit these windows with exhaust fans to the exterior of the hospital? 

This consideration is important now that there are political initiatives to reopen schools and other public places.  The ventilation systems of all of these places should be looked at and that assessment incorporated into the overall decision about how safe they are to open.  Further, there should be a systematic approach to how safe buildings are in general from the perspective of transmission of respiratory viruses.  A prospective approach that looks at how buildings in temperate climates need to be designed to minimize the spread of respiratory viruses needs to be a long term goal.  

It took a virus with heightened mortality and morbidity to raise awareness that physical measures rather than any available medication may be the best way to contain respiratory viruses.  Airborne transmission of respiratory virus denial dies hard - but hopefully it is being put to rest once and for all.  That should be a continued priority for everyone and momentum we cannot afford to lose.


George Dawson, MD, DFAPA

References:

1:  Lidia Morawska, Donald K Milton, It is Time to Address Airborne Transmission of COVID-19, Clinical Infectious Diseases, , ciaa939, https://doi.org/10.1093/cid/ciaa939

2:  Erin Bromage.  The Risks - Know Them - Avoid Them.  Erin Bromage COVID-19 Musings.  May 16, 2020.  Link

3:  Yezli S, Otter JA. Minimum Infective Dose of the Major Human Respiratory and Enteric Viruses Transmitted Through Food and the Environment. Food Environ Virol. 2011;3(1):1–30. doi: 10.1007/s12560-011-9056-7. Epub 2011 Mar 16. PMCID: PMC7090536.

4:    Nicas, M., Hubbard, A. E., Jones, R. M., & Reingold, A. L. (2004). The Infectious Dose of Variola (Smallpox) Virus. Applied Biosafety, 9(3), 118–127. https://doi.org/10.1177/153567600400900302

5:  Schröder I. COVID-19: A Risk Assessment Perspective. J Chem Health Saf. 2020;acs.chas.0c00035. Published 2020 May 11. doi:10.1021/acs.chas.0c00035


Previous Airborne Transmission Posts from this Blog:

SARS-CoV-2 Is An Airborne Virus?

Viruses Are In The Air - Protection From Airborne Viruses

Hand Washing

New Twist On An Old Method To Kill The Flu Virus


Is It Time To Quarantine Air Travelers?


Supplementary:

This statement from a recent Nature article:

"But this conclusion is not popular with some experts because it goes against decades of thinking about respiratory infections. Since the 1930s, public-health researchers and officials have generally discounted the importance of aerosols — droplets less than 5 micrometres in diameter — in respiratory diseases such as influenza."

from:  Dyani Lewis.  Mounting evidence suggests coronavirus is airborne — but health advice has not caught up.  Link.



Graphics Credit:

Graphic at the top is from Reference 1 based on the following CC License.  This is an Open Access article distributed under the terms of the Creative Commons Attribution- NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/),




Monday, June 29, 2020

Should You Trust Your Physician?




As far as I can tell there are two basic considerations in whether or not you trust your physician. The first is combination of personality and cultural factors and the resulting expectations you have when you see a physician. That may have something to do with your actual experience, but also may have more to do with observations from the care of other people. As an example, you saw your father was cared for and thought it was excellent care and expect the same care for yourself. That can also backfire in the case where you believe the observed care was substandard and led you to be more skeptical of medical care administered by physicians. From a cultural standpoint, you may be from a culture that does not trust authority figures or even physicians.  These are all very complicated issues, that I will illustrate with personal examples of treatment I have received over the years.

The second approach to whether or not you trust your physician, is to adopt a very performance-based approach. That approach is the answer to the question: “What has this doctor done for me and do I like those results?” Medicine is a complex field made more complicated by subjective assessment of the patient in their experience of care and treatment. As a psychiatrist, I see people who are very satisfied with their care from physicians and surgeons and many who are dissatisfied. I see people who have had the exact same procedure – let’s say a hip replacement with identical functional results.  One of these patients will tell me, that they are doing very well and the other will describe disappointment.  The disappointed patient will often tell me they are only slightly improved than when their joint was “bone on bone”.

My own experience with physicians is mixed at best. When I was a teenager, was in a doctor’s office and developed acute facial swelling, wheezing, and my eyelids were swollen to the point I could barely see. The explanation was given to my parents at the time was it was “psychosomatic” I was not treated with anything. The next several years, the only treatment I got was to get up at night go out into the cool night air and drink caffeinated soda. Needless to say that was suboptimal. When I finally saw an allergist about six years later I was “allergic to everything” and finally started taking antihistamines. But eight years later when I was intern, I saw an allergy specialist who spent the entire interview demanding to know what I wanted to try immunotherapy. I guess it was his form of motivational interviewing.  I never went back.

In medical school, I started to get gout attacks. With the first attack I went the emergency department and spent six hours there.  I was discharged with acetaminophen and codeine – a medication that is essentially worthless for gout pain. During a follow-up appointment in the orthopedic clinic, I was told that I probably sprained my ankle in bed and they put a cast on it. Gout pain gradually resolves after about two weeks and that is what happened. But the gout saga does not end there. During residency I started to get acute wrist pain. I went to a primary care clinic where the physician learned my history and then tried to aspirate my wrist joint with a large needle. That was a skill set that he did not have, but he did end up aspirating some tissue into the syringe that was eventually identified as synovium from the joint.  At some point, I also had a left inguinal lymph node biopsy that went awry. I went back to work and started gushing blood all over my khakis. The surgeon advised me to come to his office right away and by then my shoes were full of blood. I left bloody footprints all over his carpeting.  He cut open the incision and tied off the artery in the office while two nurses held me down.

That is a sampling of my negative experience. There is actually a lot more, but despite these fiascoes I have been able to find physicians that I trust and routinely go back to see. I have been seeing the same primary care physician for the past 30 years - recommended by psychiatric colleague who worked with him.

From a cultural standpoint, I was taught to be skeptical of everyone. My father was a blue-collar worker who routinely talked about the abuses of the administrative class and how working people were taken advantage of. He was in a union and would routinely show me the house that the president of the union lived in compared to our house.  That perspective is still ingrained at some level, but it does not prove very useful when it comes to medical care. The reason is that at some point almost everybody needs medical care and that typically includes care that involves doing something that you would rather not do. That might be surgical procedure or taking medication for a long time or even getting an immunization. But the choices are often fairly dire and that is continue to be miserable or die or accept the recommended treatment. Despite my medical misadventures, I continue to accept doctor’s recommendations even when they have significant risk.

I also come at this from the perspective of interacting with thousands of patients, many of whom don’t trust doctors at all. In most extreme circumstances, I had to interact productively with people who not only did not trust doctors but were simultaneously being coerced into treatment by the probate court system. In other words they were on involuntary holds, probate court holds, or civil commitment. That was the best possible experience to conceptualize the physician trust issue. A typical exchange follows:

MD:  “Hi – I’m George Dawson and I’m the psychiatrist here. It looks like I am seeing you because you were admitted to this unit on a 72-hour hold.”

Pt: “I don’t trust psychiatrists. I just want to be discharged.”

MD: “In order to do that, I have to make an assessment of the situation and determine if you can be released or not.”

Pt: “Why should I trust you?”

MD: “I can’t think of a reason why you should. You just met me. I would suggest that we proceed with the evaluation and see how that goes. At the end of the evaluation I will let you know what my impression and recommendations are. You can decide whether or not you trust me based on what happens. If you decide to follow my recommendations you can also base your decision on whether or not those recommendations work for you. Does that seem reasonable?”

That is the basic framework that I tried to outline for people are focused on trust. The focus is on actual performance as well as subjectivity. The subjective elements are a number of factors on the patient’s side.  They include all of the conscious and unconscious factors involved in interpersonal assessments as well as any overriding psychopathology. The most important element of the patient’s conscious state is whether or not they can incorporate the information that they are receiving from the physician into their responses and adapt a different framework for the interaction. Not everybody is able to do that, but the great majority of people are to some degree.

The above example is from what is probably the most contentious situation.  I think the approach works even better in outpatient settings where people have had adverse experiences in psychiatric care like my experiences with medical care.  In some of those situations a description of the therapeutic alliance is useful. That might go something like this:

“It might be useful to discuss how these interviews work.  You and I are both focused on the problems that you identify.  We discuss them and at some point, my job is to give you the best possible medical advice on how to address them.  Your job at that point is to think about that advice and whether or not you find it useful and want to use it.  It is also possible that your problems are not medical or psychiatric in nature. I will let you know if I think so.”

That clarifies a few points.  The interview is not a unilateral “analysis”.  Many people have the psychiatric stereotype that a psychiatrist can just look at you and figure out the problem. To this day, many people that I casually meet still ask me if I am “analyzing them.”  It also points out that I am interested in what they identify as problems – not somebody else’s idea of the problem. Unless that is explicit, many people go out of their way to tell me that it was their idea to see me or go to treatment.  Most importantly – it emphasizes that this is a cooperative effort.  I have no preconceived idea about their problem or diagnosis.  My ideas develop from the discussion and there has to be agreement that I am on track.

That is my basic approach to the trust issue in interactions with patients.  There are many variations on that theme.  Although what I have written here is from the physician perspective – I can add that from the patient perspective the performance dimension is very important.  My personal internist always takes enough time to assess my problems and do an adequate evaluation.  He has made some remarkable diagnoses based on those evaluations.  That performance over time builds trust as well.  It also highlights another important aspect from the patient perspective and that is empathy towards the physician.  Is there an understanding of how the physician’s cognitive ability and emotional capacity can be affected by outside factors? Is there any allowance for even minor physician errors or lapses in etiquette – like being very late for an appointment?  People vary greatly in that capacity and often it is necessary to keep a productive relationship going.

Most medicine these days is run by corporations rather than physicians. That makes it harder to establish long term relationships with physicians. In the above narrative I hope that I outlined the advantages of that relationship as opposed to one that may be more like being asked 20 questions about a medical condition by different people every time you go into a clinic.



George Dawson, MD, DFAPA








Sunday, June 14, 2020

Depression Prevalence and Other Checklist Limits




I finished reading a paper last night about estimating the prevalence of depression using the PHQ-9 (1). The paper had 76 authors including one of the most well recognized epidemiologists in the world. It was focused on the differences in estimating depression prevalence using a structured research interview specifically the SCID (Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders versus the PHQ-9 - a nine item checklist based on the DSM criteria for major depression. If you ever need a reference paper for how to write an epidemiology paper based on a literature search this is probably a good one to have.

The authors did an extensive literature review in the end found 44 (n=9,242) studies that looked at comparisons between the PHQ-9 and the SCID.  The result was that the pooled results showed that depression prevalence estimates with the PHQ-9 (total score ≥ 10) were about 25% and for the SCID it was 12%.  Modifying the criteria for the PHQ-9 to a score of ≥ 14 and using a separate PHQ-9 diagnostic algorithm resulted in a lower prevalence estimate but a wide margin of error.  The authors conclude that structured interviews are the best approach to prevalence estimates largely because they are closer to clinician style interviews and through clarification, they can limit confounding variables. Nobody ever seems to comment on the restrictive aspects of both checklists and structured interviews.  After all,  DSM criteria that are embedded in the matrix of questions and elaborations in the SCID are basically converted to nine unidimensional questions in the PHQ-9. It should be obvious that there would be a correlation between the two when the PHQ-9 is validated against the SCID, but instead it is accepted as an academic exercise.

The first thing I thought about when I saw these numbers and read the paper was “even the SCID prevalence figures are too high”.  I base that on numbers available in a standard textbook on psychiatric epidemiology (2).  Reviewing much larger sample sizes across 25 countries yields one-year prevalence figures for depression of 2.6-10.3% (median 5.3%) lifetime prevalence figures of 2 to 16.2% (median 8.6%). In that table the variation in very large community samples ranging from 5000 to 42,000 subjects in the United States seem to depend on the research methodology more than anything and structured interviews other than the SCID were used.

The selected samples from reference 1 are detailed in table 1 and very few of them are community samples. They are relatively small outpatient samples of identified medical patients or people seeking medical services for themselves or another person. Many of the conditions have known comorbidity with depression. The authors list this as a study limitation particularly “where the presence of transdiagnostic somatic symptoms and adjustment to illness or injury may have contributed to error variance”.  They also comment on the heterogeneity of the study settings and how that might affect the data. That is certainly my concern for post stroke patients, multiple sclerosis patients, Parkinson’s disease patients, epilepsy outpatients, and other neurological conditions for depression is a common comorbidity. The implicit message from this paper is that depression prevalence estimates from clinical samples will be higher than estimates from epidemiological community surveys.

But there is a much larger lesson here than differences in depression prevalence estimates based on methodology or clinical sample. For me the heart of the matter is the difference between a psychiatric interview, a structured clinical interview, and a checklist.  I have expressed my concerns over the years that checklists are currently surrogates for psychiatric interviews and I can confirm this on a weekly basis. Most the patients I see have seen primary care physicians or nonpsychiatrists and they tell me how they are given a PHQ-9, a diagnosis based on that rating scale, and a prescription. That model of care is promoted by some organizations as “evidence-based medicine”. In some cases it is called “measurement based medicine”. The state of Minnesota for example has a project were all PHQ-9 scores are collected from any clinic treating patients with a diagnosis of major depression. This was supposed to be some kind of quality measure even though an analysis of all the cross-sectional data has never been done.

When I talk with people who have taken these checklists and asked them about depression it is common to hear the question “What do you mean by depression? I am still not sure about what that means and the difference between depression and anxiety.” I hear those questions from people who have been filling out the rating scales and getting medications prescribed to them based on those scores and yet they are uncertain about the concept of depression. How can that happen?

The obvious way is by limiting choices. If a nine-item checklist is given to a person and they are told to answer a specific question as one of 4 choices, most people will check a box.  In the case of the SCID – there is more elaboration.  People are asked about whether there was a time in the last month when they felt “depressed or down most of the day nearly every day?”. They are asked to elaborate and whether or not it affected their interest or pleasure in activities. They are asked if it lasted as long as two weeks. At that point there is a qualifier that says the interviewer is not supposed to include symptoms “that are clearly due to a physical condition, mood-incongruent delusions or hallucinations, incoherence are marked loosening of associations, or that are clearly part of the residual or prodromal phases of schizophrenia”. Additional questions about symptoms of the depressive syndrome follow.

Many clinics use electronic health record (EHR) templates that include checklists about all of the major classes of psychiatric syndromes. They are a variation on the SCID but they generally result in more spontaneity and elaboration than a checklist but not as much as the structured interview. What is lost along the way?  I would suggest – a lot.

The rationale for structured interviews is reliability or consistency in responses.  If any population is given a matrix of the same questions to differentiate different conditions – no matter how exhaustive - there will be a pattern of responses that has internal consistency. Viewed from that perspective, the PHQ-9 is just a very abbreviated and less specific version of the SCID – hence the difference in prevalence estimates.

Although prevalence estimates are often the focus of criticism (too high, too low, just right) what is typically missed is that they really have limited application to good clinical psychiatry. Psychiatrists do not do SCID interviews on patients and the reasons may not be that apparent. Psychiatric diagnoses depend on a lot more than a symptom checklist and the total time to administer a SCID (2-3 hours) is prohibitive. There is also a question of efficiency.  In practice the psychiatrist has to be able to focus on all relevant aspects of the identified problem not areas that are not considered to be a problem.  Most importantly – the psychiatric interview needs to recognize that the person in the conversation has a unique conscious state that is interpreting their emotional, cognitive, and physical experience. The psychiatrists has to understand how that is happening.

There is probably no better discussion of this crucial aspect of the interview than that provided by Nordgaard, Sass and Parnas (3). These authors use the term “a conversational, phenomenologically oriented interview, performed by am experienced and reliability-trained psychiatrist.”  as the more optimal and preferred approach.  After reading their work, I realized that it is what I have been doing for the past 35 years.  In a more recent article, this group has compared American phenomenology to a simple study of signs and symptoms and suggested their use of the term is more consciousness based:

“It refers to a faithful exploration, description, and conceptualization of the patient’s contents and structures of subjective life and modes of existence (eg, not only the content of the delusion but its mode of emergence and articulation and ways of experiencing the delusion)” (4)

They suggest this requires an interview that maximizes self-description and a knowledgeable physician with a “rich conceptual repertoire”.  Since the DSM approach is intentionally atheoretical – it speaks to the need to be trained in a variety of psychopathological theories.  Andreasen (5) has previously written about the death of phenomenology as being an unintended consequence of the DSM approach.  In my experience it is easily approached in residency training as the need for a empathy based formulation that makes sense to the patient.  In their article (3) the authors provide a table comparing what is elicited with a structured interview as opposed to a phenomenologically based conversational interview.  In the table below I provide my own example for a patient with depression. I will add that in most electronic health records these days there are templates that are essentially structured interviews requiring brief responses and very little discussion about the process or content of those responses. Those templates are further limited by the fact that all of the information needs to be entered by the psychiatrist doing the interview - a further inefficiency.

Structured Interview
Conversational Interview
She has been depressed all of her life with very few periods of neutral mood. The depression includes periods of extreme irritability.  The depression worsens from time to time.
She had had long term depression but it is clearly worsened in specific contexts. There are situations that specifically make her anxiety worse and when this happens, she “spirals down” into a depression and will often spend the entire weekend in bed. A lot of these episodes are associated with a stressful job and a specific interpersonal conflict at work.
She describes a motivational deficits and anhedonia.
During the episodes of worsening depression and isolation – she watches TV all day long. She is not motivated to exercise but occasionally will push herself to go for a jog. She was the high school state record holder in the quarter mile. Even though it is initially difficult she feels much better afterwards and the activity reminds her of the importance of exercise in her life and how she used to work out in high school.
Decreased concentration and memory problems
She has had life long concerns about her memory and at one point considered “getting tested” for ADHD. She got a degree in molecular biology and graduated summa cum laude. She is currently working in a professor's lab and thinking of applying for a PhD program. She has no problem reading and retaining information from highly technical journals and devising lab protocols or her favorite science fiction. She attends meetings where her mind wanders.
Depressing thoughts
“I am a perfectionist and am my own worst critic.” She was encouraged from an early age to get A grades in school and had a nearly catastrophic reaction when she got a B in high school.  She still remembers that teacher who told her that getting a B would be “good for her”. Her parents were always critical and she realized at some level she has internalized some of these criticisms especially when it comes to body image and weight: “I don’t think being petite and wearing the latest fashions makes me a better scientist”. Despite fairly constant self-criticism it never gets to the point where she feels worthless.  
I have some suicidal thoughts but have never made a suicide attempt or an attempt to hurt myself.
“I read a journal article somewhere that looked at the prevalence of suicidal thoughts and they are fairly common.” She describes intrusive thoughts about suicide that are obsessional in nature. “I drive across this bridge every day.  If I am having a bad day, I think about cranking the wheel at the half way point and driving off. But I know I will never do it.  I am too chicken and I have too much going for me.  I want to hang around and see what happens.”

The conversational interview is information rich and allows for more extensive pattern matching.  The PHQ-9 and even the SCID describes a very limited pattern or as Kendler (6) describes indexing of major psychiatric disorders.  That is the primary (and limited) intent of the DSM.  But Kendler points out that it is really a jumping off point for the additional study of psychopathology.  I would also point out that it ignores what is the elephant in the room for psychiatrists – human consciousness.  Consciousness in psychiatry tends to be mentioned only when it is grossly impaired rather than existing as the every day moderator of everything.

When the additional pattern matching takes place, the only real limit is the interviewer’s ability to recognize it and what it means. In the ideal world that should lead to further elaboration of the patient’s concerns, education based on the psychiatrist’s understanding of the general problem and more specifically how it affects the unique patient, and specific treatments that have worked before.  It can extend to a unique approach to the associated DSM disorder that would not have been possible with a highly structured interview.  One of the best examples I can think of are life long sleep problems that become anxiety and depressive disorders as an adult – because the development of those disorders and the sleep disorder is not covered in detail.  There are a lot of examples.

In closing this post, prevalence estimates for psychiatric disorders vary greatly.  That is the expected result of the screening methodology that includes the instrument used, the population sampled, and the prevalence of the disorder being screened in the population. Very basic screens like checklists used as a proxy for diagnoses will have the highest prevalence estimates. More comprehensive structured interviews will be somewhat lower. The gold standard for epidemiological work (structured interview) is not the gold standard for clinical work (the semi-structured phenomenologically oriented interview).  It is also the reason psychiatrists need to know psychopathology, phenomenology, and case formulations based on those disciplines.

George Dawson, MD, DFAPA



References:
  
1:  Levis B, Benedetti A, Ioannidis JPA, et al. Patient Health Questionnaire-9 scores do not accurately estimate depression prevalence: individual participant data meta-analysis. J Clin Epidemiol. 2020;122:115128.e1. doi:10.1016/j.jclinepi.2020.02.002

2:  Hasin DS, Fenton MC, Weissman MM.  Epidemiology of depression disorders. In: Tsuang MT, Tohen M, Jones PB, editors.  Textbook of Psychiatric Epidemiology, Third Edition. West Sussex: Wiley Blackwell, 2011: 289-309.

3:  Nordgaard J, Sass LA, Parnas J. The psychiatric interview: validity, structure, and subjectivity. Eur Arch Psychiatry Clin Neurosci. 2013;263(4):353364. doi:10.1007/s00406-012-0366-z

4:  Parnas J, Zanderson M. Rediscovering disordered selfhood in schizophrenia. Psychiatric Times.   Jun 08, 2020

5:  Nancy C. Andreasen, DSM and the Death of Phenomenology in America: An Example of Unintended Consequences, Schizophrenia Bulletin, Volume 33, Issue 1, January 2007, Pages 108–112, https://doi.org/10.1093/schbul/sbl054

6:  Kendler KS. DSM issues: incorporation of biological tests, avoidance of reification, and an approach to the "box canyon problem". Am J Psychiatry. 2014;171(12):12481250. doi:10.1176/appi.ajp.2014.14081018