The Era of Blockbuster Drugs In Psychiatry Is Almost Over

Four years ago, I commented on a prediction that the era of “blockbuster drugs” in psychiatry would soon be over. That designation is used for medications that generate $1 billion in sales per year. Even at the time of my original comment, most of the drugs prescribed by psychiatrists were generic drugs that were often very inexpensive. The example that I frequently refer to is the antidepressant citalopram that was available for four dollars per month.

Last week PharmaCompass, a drug industry analytic and service company came out with a list of the top 100 drugs by sales in that industry. They listed the top 30 drugs by sales and their website lists the top 500 drugs with additional metrics such as whether or not sales are increasing or decreasing and by the percentage. There were no psychiatric drugs in the top 30. Lyrica or pregabalin, a drug used primarily for neuropathic pain and fibromyalgia came in at number 16 and generated $4.6 billion in sales. Some consider it to have a tertiary indication for anxiety but I would not consider it to be a drug primarily for psychiatric applications.

Sales Position	Company / Companies	Product Name	Active Ingredient	Main Therapeutic Indication	2018 Revenue in US$ billion
1	AbbVie Inc., Eisai	Humira®	Adalimumab	Autoimmune Disorder	20.47
2	Bristol Myers Squibb, Pfizer	Eliquis	Apixaban	Cardiovascular Diseases	9.87
3	Celgene	Revlimid	Lenalidomide	Oncology	9.69
4	Bristol Myers Squibb, Ono Pharmaceuticals	Opdivo	Nivolumab	Oncology	7.57
5	Amgen, Pfizer, Takeda	Enbrel	Etanercept	Immunology	7.45
6	Merck & Co.	Keytruda	Pembrolizumab	Oncology	7.17
7	Roche	Herceptin	Trastuzumab	Oncology	7.05
8	Roche	Avastin	Bevacizumab	Oncology	6.92
9	Roche	Mabthera/ Rituxan	Rituximab	Oncology, Immunology	6.82
10	Bayer, Johnson & Johnson	Xarelto	Rivaroxaban	Cardiovascular Diseases	6.58
11	Bayer, Regeneron	Eylea	Aflibercept	Ophthalmology	6.55
12	Johnson & Johnson, Merck & Co., Mitsubishi Tanabe	Remicade	Infliximab	Autoimmune Disorders	6.44
13	AbbVie, Johnson & Johnson	Imbruvica	Ibrutinib	Oncology	6.21
14	Pfizer	Prevnar 13/ Prevenar 13	Pneumococcal 7-Valent Conjugate	Vaccine	5.80
15	Johnson & Johnson, Mitsubishi Tanabe	Stelara	Ustekinumab	Immunology, Dermatology	5.25

Medications for neurological and mental disorders had a total market share of $55.8 billion or 10.2% of the entire market. There were only three medications that would qualify as blockbuster drugs and being used by significant numbers of psychiatrists and they included Latuda (lurasidone), Chantix (varenicline), and Abilify Maintena (aripiprazole).  The blockbuster drugs listed are all concentrated in a few specialties. Several are from the same class.  For example both Eliquis and Xarelto are novel oral anticoagulants (NOACs).  The total market share of the top 15 drugs greatly surpasses any amounts every attained by psychiatric medications. That makes sense because many are treating conditions that have a high prevalence and these medications generally represent an advance in pharmacotherapy.

I posted this mostly to note the trends over time. Journalists and other commentators tend to get carried away with market snapshots. I have not really noticed any negative commentary about the fact that the current blockbuster drugs that have nothing to do with psychiatric disorders are generating much more pharmaceutical company income. I also have not heard any commentary on how there is a natural fluctuation in this market based on drug discovery and the current rules on patent exclusivity. Many of the previous psychiatric “blockbusters” are obviously rapidly losing market share now that there are generic versions. I would argue that the current data also may indicate that restrictions on current medications may be limiting their market share.

The issue of direct to consumer advertising has typically not been discussed in these opinion pieces.  I have seen Rexulti frequently in television ads.  The application is generally antidepressant augmentation - accompanied by a very fast and diluted compilation of symptoms of both tardive dyskinesia and neuroleptic malignant syndrome. How much do those ads contribute to the market growth of Rexulti? My speculation is quite a lot. It would not take much for a person taking an antidepressant and not experiencing adequate relief to call their primary care physician for the addition of Rexulti.  I have seen similar ads for Vraylar.

Looking only at market share and pharmaceutical revenue only provides a look at one cost of this market. There is a huge pharmaceutical benefit manager component that generates revenue primarily by requiring their authorization for specific medications and also packaging deals for managed-care organizations. There is definite cost what they do but they currently are allowed to force physicians to work for them for free.

I hope that this information allows people take a more skeptical look at political and journalistic pieces that use pharmaceutical sales numbers and specialty sales for one rhetorical purpose for another. I am specifically referring to the recent good old days of the psychiatric drug “blockbusters” where much of what was written was an indictment against psychiatry and those psychiatrists who either worked directly for pharmaceutical companies or received some minor perk. There was the conspiracy theory that pharmaceutical companies had influenced the DSM-5.  That is both unrealistic and it greatly exaggerates the importance of that book. The data illustrates that no amount of physician manipulation can maintain a pharmaceutical product as a “blockbuster” independent of market forces.  

Those market forces also have a significant political and regulatory component where the real conflict of interest lies.  Allow me to translate that to Congress and the FDA.

George Dawson, MD, DFAPA

Graphics Credit

The top table from PharmaCompass was posted with their permission. 


Disclaimer:

I had to identify and hand count the psychiatric drugs on the PharmaCompass web site from their graphic interface.  It is possible that I missed some or the count is off (they were not numbered).  Let me know if you detect any errors.

A Great Independent Film and Its Lessons

When I first saw the trailer for The Last Black Man in San Francisco I knew it was a movie I had to see. The trailer itself suggested great cinematography and a unique story. By the time I looked for it again at my local cinema it was gone. I subsequently learned it was critically acclaimed but did not make much at the box office. I was very pleased when I was working out two nights ago and it popped up as a streaming choice on Amazon. It turns out that this is an outstanding independent film and I will probably come back to it.

I have not reviewed a film on this blog for some time but will include the customary spoiler alert. Some people just prefer a global recommendation rather than details. At this point I am going to proceed with some details.  This film is primarily about the relationship between two young black men - Jimmie Fails and Montgomery “Mont” Allen. Over the course of the film we learn that they are best friends.  We also learn that they are both staying with Mont’s blind grandfather. The conditions are less than optimal. We see Jimmie sleeping on the floor of Mont’s room. We see all three men watching television and Mont providing a running commentary for his grandfather sometimes to Jimmie’s exasperation. We learn that Mont is an aspiring playwright and artist. We catch glimpses of his work and his grandfather is very encouraging.

In the opening scene Jimmie and Mont skateboard to a very large Victorian house in another part of San Francisco. We learn that Jimmie used to live in this house and that he said his grandfather built it in 1946. The opening scene at the house he is painting some windows but there is a couple in the house and the woman of that couple is very angry with him for not staying away from the house. Jimmy and Mont talk about maintaining various aspects of the house. At one point the couple moves out and they move in. They go so far as to get furniture from Jimmie’s aunt’s home and move that into the place. There is not a very clear plan for possession of the house. They eventually have some interactions with a realtor, a banker, and a county official. None of those interactions are productive in terms of helping them purchase or acquire rights to stay in the home. Jimmie eventually tells Mont that his plan is to stay there no matter what. We eventually learn that Jimmie’s grandfather really did not build the house and that it was constructed in the late 19^th century.

As Jimmie and Mont travel between Grandpa Allen’s home in the mansion they regularly encounter a group of young black men out of the street.  One of them was a tall young man named Kofi who Jimmie knew from the year he spent in a group home. They were both skateboarders.  Jimmie thought that Kofi was quite good and asked him if he was still skateboarding. Kofi said that he was not. The skateboarding theme was important because Jimmie appeared older than most skateboarders and as his father put it “dressed like a white boy” in a red flannel shirt and khaki pants. There was a lyrical scene when Jimmie was skating down the San Francisco hill to Jefferson Airplane - until he wiped out three quarters of the way down the hill. I took the skateboarding as a symbol of Jimmie being stuck in an earlier time and what he has to do with the skateboard in order to move on - confirms this later in the film.

Kofi was the only young man invited to the Victorian house by Jimmie and Mont. When he was there, they all seemed to enjoy themselves. That was in contrast to the confrontations that Jimmie and Mont had with the young group of men in general.  They had very different styles of interacting with these young men. Mont was nonconfrontational and seemed to take a didactic role with them in that in one scene was described as “directing”. Jimmie was more confrontational and at one point asked Mont about his style of interacting. Mont told him that by avoiding confrontation he was able to appreciate these other men for who they really were.

The dynamics between Mont, Jimmie, and this young group of men was one of the most interesting aspects of this film. Jimmie characterized this group as “talking shit”.  This is a colloquial expression for young men engaging in interactions that could be considered sarcastic or overtly mocking. In some cases physical threats are feigned and there is always some risk of bullying or actual physical confrontation. This type of behavior in young men is common and as far as I know occurs in all cultures. A common way of dealing with it is to just avoid it. Mont and Jimmie do not avoid it.  Mont continues with what I saw as an empathic but at times eccentric approach to the mocking. Jimmie tends to deal with it in a more straightforward way by making similar statements or feigning physical aggression. The risk of “talking shit” is highlighted when Jimmie and Mont learned that their friend Kofi was shot and killed by a gang in one of these confrontations.

Jimmie and Mont learned about Kofi’s death from the group of young men they encounter. Jimmie becomes very confrontational trying to learn about what actually happened and it appears that he is at risk for a physical confrontation with one of the men. Instead that man becomes very tearful, start sobbing, and embraces Jimmie in one of the more emotional scenes of the film.

Kofi’s death was the subject of a one-man play put on by Mont in the Victorian house. In the play he confronted the small audience of local people and what they really knew about Kofi. During the exercise he  elicits a number of superficial observations from the audience. He asked Jimmie for comments and he described the positive and negative aspects of his relationship with Kofi concluding “people aren’t one thing”. From there and in the same setting Mont confronts Jimmie about the fact that his grandfather did not build the house. Jimmie gets angry and leaves and all of the theatergoers file out after that.

Jimmie eventually accepts the reality that he will never be able to stay at the Victorian house that his family used to live in. He grows more uneasy staying with Mont and his grandfather.  He leaves one night, with a note behind to Mont thanking him for being his best friend.

That basic story line is set in what I would describe as a separate visual story. That story has elements of how people have been misplaced in San Francisco by the current housing crisis, how that toll has fallen unevenly and unfairly on people who are not making high incomes, and how people who show up for a job in that area might not have the same appreciation for the area as long-term residents do. There is the clear message that the plight of low income people is being ignored by responsible officials to the point that their health is endangered. At one point Jimmie asks the rhetorical question about why a millionaire is more entitled to stay in his old family home than he is.  From the visual standpoint the story is brilliantly told.

On an interpersonal level, this is a story about relationships between men. The main characters Mont and Jimmie are interesting and likable. I found myself rooting for them and hoping that nothing bad would happen to them. In the final scene Jimmie is rowing a small boat in Pacific swells by the Golden Gate Bridge.  He is not in any danger but you wonder where he is headed.

And you wish him well.

George Dawson, MD, DFAPA



Graphics Credit:

Shutterstock per their standard agreement. "Painted ladies from Alamo square park over San Francisco skyline during the day."   By Sergey Novikov.

Antidepressants Are Not Miracle Drugs - They Are Also Not Tools Of The Devil

I decided to end the year on a less intense but serious note about antidepressants. I am currently working on some posts on biological psychiatry most notably on the hypothalamus. When you see that posted it will hopefully contain some licensed graphics, numerous worthwhile references, and it will be the first post on this blog where copy-paste function will be blocked.  I have seen the results of not blocking my blog content and many people pointed out that it is just copied to another site and not referenced.  In what had to be a worst case scenario, I was at a conference where an academic used my custom graphics in his PowerPoint presentation without referencing that they were from this blog.  Hopefully those days are over.

But in the meantime a few comments about the war on antidepressants which is really a war on psychiatry. There are numerous posts on this blog refuting some of the published material but I want to speak about what happens at the clinical level without all of the academic references and articles. I decided to post this because antidepressants have been heavily politicized over the years. The initial rhetoric was that psychiatrists were prescribing them because they were being corrupted by pharmaceutical companies. The next step was to suggest that antidepressants were highly toxic medications for one reason or another. When both those criticisms were obviously not valid, the next step was to suggest that antidepressants simply don’t work at all.  In social media this takes on a tone that discourages people from treatment.  Psychiatrists are shamed for prescribing these medications and patients are shamed for taking them. Why would a rational person take a medication that did not work?

There have been slight modifications along the way. A good example would be the “chemical imbalance” theory that has been heavily criticized and attributed to psychiatry despite the fact that no psychopharmacology books contain this reference and the discovery that the term is an advertising meme from the late 20^th century. Some of the critics like the “critical psychiatry” movement came out with an actual position paper that proposed medications basically work because of side effects rather than any primary therapeutic effect. That is an incredible position to maintain and that may be why nobody pays attention to it. The critics of antidepressants and psychiatry are very vocal and if they are not complaining about psychiatric expertise or medications they are complaining about criticism they might receive. But the overall tone of their arguments illustrates that they have nothing positive to offer.  Many of these critics have the luxury of not treating people with severe psychiatric disorders.  In some cases that extends to denying that these disorders exist.

One of the critics complained about being “gaslighted” for some of criticisms. This is more than a little ironic for several reasons.  The standard positions of most antipsychiatrists is the very definition of gaslighting.  That position is to basically create a hostile environment that denies the legitimacy of psychiatry and psychiatric practice and treatments.  I have received hundreds of posts to this blog that never see the light of day. Some say (in many posts) that I am a hack who should not be treating patients. They claim I am an agent of the pharmaceutical industry (search all of the databases and you will see that I have not accepted as much as a nickel). They tell me that my research is poor and I have very little understanding of the literature. Some have suggested that they would like to see me physically assaulted.  One of them went so far as to hide the fact that he was a writer for a major anti-psychiatry blog until the last possible moment. I think he was really expecting that I was going to publish his post and name so that everyone on that website could have a good laugh at my expense. These critics seem to have a very thin skin and can’t take the slightest criticism for what are typically outrageous positions. 

I could quote all the evidence to the contrary hundred times but it would not do any good.  The dynamic is very similar to other antiscience arguments, like the arguments against vaccines.  The average person with a realistic concern about antidepressants should just be aware of the process at this point. There are a group of people who are out to discredit psychiatric care and medications that psychiatrists use strictly based on political agenda that has nothing to do with whether or not medications or psychiatry works.  The lesson of politics is that "the narrative" becomes the truth - particularly if one side "wins." Demonizing a perceived opponent is a common political strategy that may be amplified by social media.  This process focused on demonizing psychiatrists and the medications they prescribe can be observed in social media on a daily basis. 

There’s no better evidence that psychiatry works than the fact that we all go to work and see hundreds of thousands of people every day. Those people come back to see us because they are satisfied both with the relationship they have, the advice they get, and the fact that their treatment is effective. That includes treatment with antidepressants.  People don't take time out of their day, endure the problem of finding a psychiatrist who can see them and hassles with their insurance company, and follow treatment recommendations if the treatment is not effective.  

As I noted in the title - antidepressants are certainly not miracle drugs. About one person out of seven or eight that I see cannot tolerate selective serotonin reuptake inhibitors (SSRIs). About one person out of 15 cannot tolerate any antidepressant from any class. That fact alone points out one of the limitations of antidepressants. Additional patients will get more isolated side effects that create physical effects or affect their lifestyle and they have to make tough decisions especially if the medication is effective. They have to decide whether they want to keep taking it or not. But the clinical truth that you don't hear among the critics is that the majority of people can take an antidepressant and not get any side effects.  I know this because, I ask that specific question to every person I see who is taking a medication - every time I see them.

A more challenging clinical situation occurs when a patient asks me to start an antidepressant that they are certain has worked for them in the past and now they develop a symptom that may be a side effect that they did not have in the past. We need to figure out what is happening and what the best plan will be. The more common scenario is the person for whom the antidepressant does not work completely and we need to figure out how to get rid of their depression or anxiety.

All the negative talk about antidepressants is designed to take psychiatrists out of the equation. Nobody talks about the psychiatrist who is in the room with the patient actively working on and solving all of these problems. The problems that need to be solved from a medical and psychiatric standpoint can often make up a long list. Pre-existing medical conditions, 5-10 medications that are being taken for those conditions, drug interactions with any pre-existing conditions or medications, medication side effects, unstable medications, ECG abnormalities, medical causes of the psychiatric symptoms, neurological problems, significant renal or hepatic disease, and alcohol and substance use problems are all in that room and all need to be acted on by the psychiatrist and the patient in the room.  If somebody suggests that psychiatrists are doing less than that - take a look at the way psychiatrists are actually trained.  The ask yourself why you are not getting the whole story.

And even before we get to that point, there has to be some clarification of a diagnosis indicating that medication might be useful. There has to be a diagnostic formulation looking at how that diagnosis fits into that person’s life and conscious state. The prescription of a medication can’t be a formula based on a checklist. There are many times when a prescription medication is not the right answer. Don’t expect to hear that level of discrimination from somebody who tells you that antidepressants or psychiatrists are either generally bad or all bad.  When you hear that opinion - drill down and figure out what their conflict of interest is.  

In my current capacity, a significant number of people I see have suicidal ideation and many have attempted suicide or are actively contemplating suicide. Some have survived highly lethal suicide attempts. Most of them have depression and substance use disorders. I have to figure out the most likely diagnosis out of about 40 possibilities. In proceeding with treatment, my job is to help the person get well, recover from depression, and recover from suicidal thinking. That is a complex process and it is not just a question of prescribing medication. What is said and done in that process is not the same for any two people. I have to make sure the person is getting well and making necessary changes along the way to recover. There are many people along that path to confirm that the treatment is proceeding in a positive direction. This process is one of many leading to the demand for psychiatrists across the country. Psychiatrists have the clinical expertise to solve these problems and we are often consulted at the last possible moment after all of the other attempts have failed. 

With any luck it will be a better year ahead. I don’t expect the anti-psychiatry gaslighters to go away. I do want to reassure people that psychiatrists are result oriented and we are trained to work intensely with people to help them get better. If you see suggestions contrary to that fact - consider the source. If you see someone suggesting that they are being “gaslighted” by psychiatrists remember what I said about the posts I get here on this blog. And remember, antidepressants are just like any other medication. They don't work for everybody, but most people who can tolerate them notice a difference.  For some people the difference is life changing and it allows them to function the way they used to function. Like practically all medications, the decision to take antidepressants is a highly individual one and a decision that is not made lightly.  Most people making that decision are not making it based on what is on social media.

As professionals we take a safe recovery from mental disorders and substance use problems very seriously. 

Happy New Year!

George Dawson, MD, DFAPA

Graphics Credit:

Color gradient during the sunset in Antarctica. Vernadsky Station. Antarctic Peninsula 2008.

By Maksym Deliyergiyev from Shutterstock per their standard user agreement.

Supplementary:

Academic gaslighting?  Of course, it exists.  I realize that it is a vague and non-specific term A few examples follow from this blog.  Unfortunately, journal editors either don’t seem to get it or they are too desperate for content to care.

The Identity Crisis Card: https://real-psychiatry.blogspot.com/2019/11/there-is-no-identity-crisis-in.html

The Diagnostic Heterogeneity Card: https://real-psychiatry.blogspot.com/2019/09/recent-opinion-about-diagnostic.html

The Epistemic Injustice Card: https://real-psychiatry.blogspot.com/2019/07/some-of-greatest-minds-in-psychiatry.html

The Chemical Imbalance Card: https://real-psychiatry.blogspot.com/2019/05/chemical-imbalance-as-advertising-meme.html

The Critical Psychiatry Card: https://real-psychiatry.blogspot.com/2019/05/chemical-imbalance-as-advertising-meme.html

The Antipsychiatry Card: https://real-psychiatry.blogspot.com/2018/08/why-antipsychiatrists-have-it-all-wrong.html

The Antidepressants Are Toxic Card: https://real-psychiatry.blogspot.com/2018/04/sensational-antidepressant-piece-from.html and this recent review.

The Physicians Are Corrupted by Big Pharma Card:  https://real-psychiatry.blogspot.com/2017/05/wait-minute-is-psychiatry-less-unhinged.html

The Too Much Neuroscience Card: https://real-psychiatry.blogspot.com/2016/10/the-balanced-rhetoric-against.html

The Psychiatrist Shortage Card: https://real-psychiatry.blogspot.com/2016/08/a-better-analysis-of-psychiatrist.html

The Reductionism Card: https://real-psychiatry.blogspot.com/2015/11/reductionism-is-not-dirty-word.html

The Monolithic Psychiatry Card: https://real-psychiatry.blogspot.com/2015/06/the-myth-of-monolithic-psychiatry.html

The Philosophy Card - written by an expert on Foucault: https://real-psychiatry.blogspot.com/2013/02/moralizing-about-psychiatry-and-limits.html

This Supplementary section was added on 1/2/2020 at 0200.  The body of the original post is unchanged.

A Positive Story for Christmas

I ran across the story posted by Minnesota Public Radio about a psychiatrist retiring in northern Minnesota. The past 30 years or so Dr. Hardwig was the only psychiatrist in International Falls Minnesota. For people not familiar with Minnesota geography I included a map of the state at the top of this post.  It is a town of about 6400 people right on the Canadian border.  It is ranked as the 133^rd largest city in Minnesota. The closest Metro area would be Duluth with a population of about 85,000 people.  International Falls is 163 miles from Duluth and 296 miles from Minneapolis.  As noted in the article, this is a tough place to practice psychiatry. There are few resources and no easily accessible psychiatric beds.

Dr.  Hardwig practiced exclusively in this environment until his recent retirement. In the article we learn that his schedule was always full. He was always willing to fit people into his schedule based on need. He provided a valuable service to this patient’s and primary care physicians in the area. He successfully developed a way to interact with his patients in the community and maintain clear boundaries. He treated the entire spectrum of psychiatric disorders out of necessity. There were no specialists for him to refer to at least in the practical sense. When you advise people that they have to travel 100 or 200 or 300 miles to see a specialist they are willing to do it once or twice but not for the rest of their life.

Full disclosure on my part, I know Dr. Hardwig professionally. He was one of my predecessors as president of the Minnesota Psychiatric Society.  That means over the three years of that professional cycle, he commuted to the Twin Cities and developed agendas, ran meetings, met with MPS members, and conducted all of the other duties of those offices. He was a thoughtful president with a unique perspective also conducted one of our more unique scientific meetings. He also belonged to a discussion group about medicine and psychiatry in that group he talked about his ideas for recruiting psychiatrists into rural areas. That idea was one of the main points of the MPR article.  The shortage of mental health professionals in general and psychiatrists in particular was emphasized. 

This shortage is nothing new. When I started out as a psychiatrist back in the late 1980s, I was assigned to a physician shortage area in northern Wisconsin. I was the only psychiatrist in a county of about 50,000 people for a period of three years. During that time I was the medical director of a community mental health center and for one year commuted to a town 65 miles away to keep their small inpatient psychiatric unit open. They had a deal with the federal government and would lose significant funding if that unit closed down.

One of the early lessons I learned was that I was no longer practicing medicine in a large multi-specialty clinic with unlimited resources.  It is quite a shock to go from an academic psychiatry department with about 60 full-time staff and 24 residents to be the only psychiatrist in town. Professional isolation has been the term used to characterize that situation and also explain why psychiatrists don’t want to wander too far from Metropolitan areas. The atmosphere has improved to some degree with the advent of a functional Internet. While I was in that position, they were trying to get me a telepsychiatry connection through a local hotel satellite television. In the end the cost was exorbitant at about $20K/year and we never tried it.  Today telepsychiatry is routine in the same area and has been used for a decade by the local VA clinic.

The workload was fairly intense at times because our clinic handled all of the crisis calls from the county and I was backup for any nurse, case manager, or psychologist who was doing crisis intervention in the community or in some cases the county jail. There was no cross coverage for vacations or professional conferences.  I was on call 24/7 wherever I was across the country.  On any given night I could find myself seeing somebody in jail, at home, in the small general medical and surgical hospital in town, or any of several nursing homes. But even more pressing was the fact that I was a lightning rod for those people with mental illness and a propensity for violence. All these factors led me to return to a large multi-specialty group at the end of my three-year tenure.

When it comes to figuring out what it takes to be the only psychiatrist in town, treat all possible problems, and do that for decades - I don’t have the answers.  Dr. Hardwig clearly does and by all accounts he did a great job. In my postings of the MPR article in various places around the Internet, I had another psychiatrist question my use of the word “great”. I don’t really see any other way to describe it. What else can you say about the psychiatrist or any physician who practices intensely with minimal support and resources and gets the job done?

There are all kinds of reasons why physicians are critical of one another. There is the competitiveness of youth and the need to secure a position. Most physicians notice that slips away by midcareer and a more important function is teaching and mentoring rather than competing against everyone in the field. Psychiatry is at a disadvantage relative to other medical specialties. The media spin on psychiatry is decidedly negative as I noted in several recent posts. I don’t know if that just gets uncritically accepted or internalized especially by psychiatrists who are criticizing the rest of us. Even though this MPR story was positive it mixed Dr. Hardwig’s career accomplishments with the specter of psychiatrist shortages in rural America. I understand their point, but in terms of motivation focusing on this accomplishment would have potentially done more to motivate people to practice in that environment.  The accomplishments of Dr. Hardwig are certainly inspirational.

I have nothing but the best wishes for Dr. Hardwig in his retirement. Even though there are tens of thousands of psychiatrists to go to work every day and get the job done, his job was probably more demanding with no cross coverage for call or vacations. They have been trying to recruit a replacement ever since he announced he was going to retire and have no success so far. 

I hope they do succeed in finding a psychiatrist as unique as the one who just retired.

George Dawson, MD, DFAPA


References:

Alisa Roth. In International Falls, the last psychiatrist for 100 miles just retired. December 20, 2019. Link.


Graphics Credit:

User: Wikid77 (from National Atlas of the United States) [Public domain]: File URL: https://upload.wikimedia.org/wikipedia/commons/e/ed/Map_of_Minnesota_NA.jpg

Sleep and Addiction

One of the major problems that I treat in people with significant substance use disorders is insomnia of all types.  I see people who have had insomnia since childhood.  A significant number have had insomnia and nightmares since childhood.  In that case the insomnia often precedes the development of any associated psychiatric diagnoses – it is a primary problem. In many cases, it is one of the reasons that people develop a substance use problem.  Alcohol, sedative hypnotics (often benzodiazepine type drugs), opioids, and cannabis are commonly taken for sleep and typically lead to many secondary problems.  Alcohol for example, will often lead to faster sleep onset, but as tolerance develops, the person will start to make up at 2 or 3 in the morning.  With increasing tolerance, a decision about taking more drinks at that time or toughing it out until the morning will need to be made. Some people can get to the point that they ingest large enough quantities of alcohol that they sleep the entire night and wake up with elevated blood alcohol levels.  Some do not realize the problem until they are arrested driving into work the next morning for intoxicated driving.

The available medications for treating insomnia in patients with addiction are limited.  We can currently treat a significant number of patients with sleep problems but there are still many that have very difficult to treat insomnia.

Medication	Probable Sleep Mechanism of Action
Trazodone	H-1 antagonist, NE antagonist, 5-HT2 antagonist
Doxepin	H-1 antagonist, NE antagonist, Ach antagonist
Mirtazapine	H-1 antagonist, 5-HT2 antagonist
Hydroxyzine	H-1 inverse agonist, Ach antagonist
Quetiapine	H-1 antagonist, NE antagonist, Ach antagonist, 5-HT2 antagonist, DA antagonist
Ramelteon	MT-1/MT-2 agonist  MT-1> MT-2
Melatonin	MT-1/MT-2 agonist  MT-1>MT-2
Prazosin	α1- adrenergic antagonist
Gabapentin	inhibition of the alpha 2-delta subunit of voltage-gated calcium channels
Benzodiazepines (detox only)	GABAA receptor agonist
Opioids (detox, MAT)	MOR agonist

 

The general strategy of using these medications is apparent from the purported mechanisms. For example, brain histamine (H) and acetylcholine (Ach) are alerting and arousing neurotransmitter systems so that antagonists/inverse agonists would be expected to decrease arousal and facilitate sleep.  Noradrenergic (NE) systems are wake promoting so NE antagonists would be expected to decrease this function.  The compounds in the above table work the best in addictive states when a person is abstinent from intoxicants and chronic use of intoxicants and after they have been detoxed.  Benzodiazepines and opioids are in the table for that purpose.  Although I have seen detox protocols that include many of the medications listed in the table as needed for insomnia and anxiety it is unlikely that they will work until detoxification has occurred.  In many cases, the expected duration of detox is much longer than anticipated and sleep problems are a prominent reason.    

That brings me to the primary focus of this post and that is a recent paper entitled “Drugs, Sleep, and the Addicted brain.” I generally don’t get too excited about research papers these days, but after reading this brief paper by Valentino and Volkow – I was fairly excited.  In this paper the authors main goal is to demonstrate how the biological substrates that regulate sleep interact with the reward system and how they can be direct targets for substance use. 

The first system they look at is the locus ceruleus (LC)-norepinephrine (NE) system that is involved in arousal. LC-NE neurons do not fire during REM sleep.  Activation of the LC results in firing of noradrenergic neurons that activate the cortex. Corticotropin-releasing factor (CRF) leads to LC activation and heightened arousal.  Endogenous opioids lead to damped excitation and decreased arousal.  Tolerance to exogenous opioids would lead to an expected inability to dampen the LC-NE system and increased activation and arousal during opioid withdrawal.

The serotonin (5-HT) dorsal raphe nuclei (DRN) system is also a system implicated in both sleep and arousal.   5-HT neurons are active during waking and do not fire during REM sleep. 

Histaminergic (H) neurons in the tuberomammillary nucleus (TMN) have an arousal function on cortical neurons.  They are active in the awake state.

Midbrain dopaminergic neurons (DA) in the ventral tegmental are (VTA) specifically those projecting to the nucleus accumbens (NAc) increase wakefulness upon activation but activation of the other major set of DA neurons in the substantia nigra has no effect.  This is a critical circuit in substance use because this system determines the value function of stimuli in the environment including addictive compounds and affects arousal.

Cannabinoids promote sleep, sleep onset, slow wave sleep, and sleep duration.  They decrease REM sleep.  CB1 agonists and antagonists respond in the expected manner.  The effects of CB1 agonism may be mediated by adenosine which increases in response to the stimulation of this pathway.  Caffeine is an adenosine antagonist and that may be the reason is promotes wakefulness.  Endocannabinoids also inhibit orexin neurons (arousal promoting) in the lateral hypothalamus and increase the activity of melanin neurons.  These combined effects of cannabinoids on the endogenous cannabinoid system explain the expected insomnia when these compounds are stopped for any reason.

The orexin system in the lateral hypothalamus and dorsal medical hypothalamus/perifornical area is activated during wakening and silent during sleep.  It is the system that is disrupted in narcolepsy.  It is also the system that coordinates the activity of the other arousal centers in the brain including the TMN-HA, LC-NE, DRN-5-HT, VTA-DA, and cholinergic neurons in the Nucleus Basalis of Meynert (NBM-Ach).  This relationship is depicted in the following graphic from the paper and detailed in reference 3.

Orexin A and Orexin B are wake  promoting neuropeptides the general structure of which is given below.  These peptides bind to Ox1R and Ox2R G-protein coupled receptors.  Orexin A has equal binding affinity to both receptor but Orexin B preferentially binds to the Ox2R receptor.  Detailed information is available from PubChem.

Human Orexin A

The orexin system may be critical not just in arousal but also in reward.  Patients with narcolepsy have orexin deficiency and generally do not overuse opioids and are less likely to overuse stimulants even though many have been prescribed very high doses.  Opioid users have increased orexin neurons in the lateral hypothalamus.  This increase in orexin signaling may lead to profound insomnia and the associated arousal state after prolonged exposure to opioids and makes this insomnia very difficult to treat.  Orexin can directly potentiate reward in some models.  Orexin is implicated in states where a high level of motivation to acquire the target substance is required or where there are external stimuli like stress, and specific cues for drug use that lead to increased motivational states.  The authors in reference 2 refer to orexin's ability to affect the approach toward a reinforcing stimulus or active withdrawal from an aversive stimulus as motivational activation.

Suvorexant is an interesting compound in that it antagonizes Orexin A and Orexin B wake-promoting neuropeptides and prevents them from binding to Ox1R and OXxR receptors decreasing wakefulness.  It is currently FDA approved as a treatment for insomnia, but the authors propose that it is a compound of interest in that it can potentially counter the arousal and reward potentiation associated with drug seeking states.  If that is the case it could be a useful treatment for both insomnia and the primary addictive disorders.

When I look at possible treatments for insomnia in addiction, a central question is whether or not they will potentially worsen the addictive state.  That is why there are no specific benzodiazepine related sleep compounds in the table at the top of this post.  The benzodiazepines listed there are all basically used on a short term basis for detox and then tapered and discontinued.  In the case of mu-opioid receptors (MOR), medication assisted treatment with both buprenorphine and methadone are possible on an ongoing basis. The package insert for suvorexant suggests possible problems in that subjects with recreational polydrug use rated their "liking" of the drug as being similar to zolpidem 15 and 30 mg doses.  Zolpidem is a standard sedative hypnotic that can be used to treat insomnia.  It definitely has abuse potential and in some cases patients can end up taking very high doses per day until they can be detoxified.  That is not reassuring in terms of safety for persons with substance use problems but I would not take it as proof that it cannot be safely used.  According to the DEA, suvorexant is currently a Schedule IV drug or low potential for abuse or dependence. Some articles on insomnia suggest that despite what appears to be a comprehensive mechanism, the short term efficacy of suvorexant is no greater than zolpidem but at a much greater cost.

I am currently looking at the medicinal chemistry and clinical trials literature to assist me decision making on orexin receptor antagonists and just how much of withdrawal related insomnia is due to orexins. The other important question is whether it will also decrease drug seeking states and withdrawal avoidance.   

George Dawson, MD, DFAPA

References:

All full text and all excellent

1: Valentino RJ, Volkow ND. Drugs, sleep, and the addicted brain. Neuropsychopharmacology. 2020;45(1):3–5. doi:10.1038/s41386-019-0465-x

2: James MH, Mahler SV, Moorman DE, Aston-Jones G. A Decade of Orexin/Hypocretin and Addiction: Where Are We Now?. Curr Top Behav Neurosci. 2017;33:247–281. doi:10.1007/7854_2016_57

3: Peyron C, Tighe DK, van den Pol AN, et al. Neurons containing hypocretin (orexin) project to multiple neuronal systems. J Neurosci. 1998;18(23):9996–10015. doi:10.1523/JNEUROSCI.18-23-09996.1998

Graphics Credit:

The brain graphic is from reference 1 and is used here without modification per the Creative Commons Attribution 4.0 License.

Disclaimer:

This post may change significantly over the next two weeks.  I had to put it up to see what it looks like and plan to elaborate the behavioral pharmacology of orexin and the pharmacology of suvorexant.