More on Benzodiazepines (Like Xanax).

The topic of benzodiazepines will just not go away.  At the top and bottom of this post - I include a number of book covers from my library on the topic from the last 30 years.  The publication dates are 1983, 1985, and 1990.  I wrote a brief review for the Psychiatric Times and included my unedited version  on this blog from earlier this year.  My overall message was that benzodiazepines as a group are great for very specific indications.  In fact for some indication like detoxification from alcohol or sedative hypnotic drugs and catatonia they are life saving.  The majority of benzodiazepines are not prescribed for those indications.  They are prescribed primarily as add on medications for anxiety and insomnia.  Their use is limited by tolerance and addictive properties that are expected from a medication that reinforces its own use.  It is also problematic to prescribe them to any population of patients where alcohol use is prevalent and not expect significant drug interactions or abuse.

I really wanted to include a graphic from the paper listed below (1) from JAMA Psychiatry on the prescribing rates of benzodiazepines in patients being treated for depression.  I will post it if I get permission.  That graph illustrates the growth in benzodiazepine prescribing from 2001 to 2104.  During that time the fraction of patients taking a benzodiazepine in addition  to an antidepressant rose from 6% to 12.5% of the depression treated patients.  Subgroups were analyzed and psychiatry came across as a the top prescriber of benzodiazepines across all years.  Other practitioners and specialists came in under the curve prescribed by psychiatrists. 

 A recent anxiety disorder diagnosis was a strong predictor of concurrent use of benzodiazepine use with 24.1% of patients with a recent unspecified anxiety disorder diagnosis and 39.1% or patients with a panic disorder diagnosis taking both the benzodiazepine and antidepressant.  At 6 months 45.6% of the antidepressant + benzodiazepine and 48.1% of the antidepressant monotherapy were still taking an antidepressant.  After initial adjustments 12.3% of the simultaneous benzodiazepine and antidepressant users received long term benzodiazepines with 5.7% taking them for one year.  The prescribed benzodiazepines were almost all high potency including alprazolam (43.9%), lorazepam (26.3%), and clonazepam (21.8%).  About a tenth (13.5%) of the patients got a limited supply of for only 1-7 days).

The authors generally conclude that benzodiazepine prescribing seems to be consistent with current guidelines.  These suggest that a Cochrane report that concomitant benzodiazepine use with antidepressants increased the short term antidepressant response and decreased the drop out rate attributable to antidepressant side effects.  I would think that would be offset at least as much by guidelines suggesting limited use.

The overall strength of this report is that it is a study of a very large insurance database population of 684,100 new antidepressant users and 81,020 simultaneous antidepressant and benzodiazepine users. They give a breakdown of antidepressant classes (overwhelmingly SSRIs).  Only 12.7% and 16.5% (respectively) of the patients in each class were treated by psychiatrists.  Interestingly 77.4% and 80% of each class had not received any form of psychotherapy, although it is conceivable that at least some patients were being seen by therapists outside of the database.  As noted psychiatrists were more likely to prescribe combination therapy.  The authors speculate that may be due to referral patterns and psychiatrists seeing patients with more severe anxiety and depression, training patterns in psychiatry, or more familiarity with benzodiazepine pharmacology.  I think a more likely factor is chronicity and the fact that psychiatrists tend to see more patients with chronic anxiety and temperamental forms of anxiety that are not taken into account in DSM-5 nosology.

Despite the large N, there are many drawbacks to database studies like this one.  I think it is useful in terms of the basic pharmacoepidemiology of prescriptions but it doesn't say anything about symptoms severity and many of the practical issues involved with benzodiazepine prescribing (like substance used disorders) are eliminated by the study protocol.  The authors do a good job of describing the downsides (use disorders, falls/fractures, motor vehicle accidents) of benzodiazepines in their discussion.  I would have included cognitive problems and tolerance. It also does not address the optimal way to address combined anxiety and depressive disorders. My biggest concern is the current "evidence based" fad of diagnosing anxiety and depressive disorders using symptom rating scales like the PHQ-9 (Patient Health Questionnaire-9) and the GAD-7 (Generalized Anxiety Disorder 7-item).  In a primary care setting they pass for a diagnosis.  In a psychiatric setting they short circuit any analysis of the etiological factors of anxiety or depression.  Instead these disorders are conceptualized as disorders that that require a basic medical treatment and they resolve.  That is a gross oversimplification.     

But the main limitation should be evident - we do not have a specific enough diagnostic system with reliable objective markers.  In that context a large N doesn't mean as much unless we know how many subtypes there are and the associated treatment parameters.

George Dawson, MD, DFAPA

References:

1:  Bushnell GA, Stürmer T, Gaynes BN, Pate V, Miller M. Simultaneous Antidepressant and Benzodiazepine New Use and Subsequent Long-term Benzodiazepine Use in Adults With Depression, United States, 2001-2014. JAMA Psychiatry. 2017;74(7):747–755. doi:10.1001/jamapsychiatry.2017.1273

Minnesota's Abandonment Of Severely Mentally Ill - Nearly Complete

For years I have been documenting the systematic dismantling of the public mental health system in the state of Minnesota.  A chronic unanswered question is how the midwest's most liberal state has come up with such a horrible system.  The most obvious answer is that the system is being run by people who do not have a clue about the treatment of mental illnesses.  A Governor's Task Force, convened a year ago has not put a dent into the further systematic deterioration.  This 30 year race to the bottom in terms of deterioration is why I was not surprised at all by the latest piece of bad news.

The Minneapolis Star Tribune published a story three days ago that St. Joseph’s Medical Center in Brainerd Minnesota stopped accepting patients who were being treated on an involuntary basis under civil commitment.  They cite an increased length of stay and safety issues. Both of these are valid concerns with people committed for treatment of a mental illness.  The system of hospital reimbursement put in place in the 1980s encourages rationing and absurdly short length of stays in inpatient psychiatric units.  People who have undergone civil commitment generally have more difficult to stabilize mental illnesses compounded by a lack of recognition that they have a problem.  Some of them are also violent and aggressive and those behaviors are directly attributable to the mental illness.  The article refers to an incident where one of these patients threw a wooden chair at a nurse and the next day six voluntary patients requested discharge.  This is a relatively mild incident compared to what is possible in acute inpatient settings trying to care for people with the most severe forms of mental illness.  The most important aspect of treating violent and aggressive patients is having an environment of highly trained people to work with them.

The reality of the situation is reflected by the balance of both acute care and public psychiatric hospital beds.  There are 145 hospitals in the state of Minnesota and 125 have 24 hour emergency departments. Thirty two of these hospitals have psychiatric units.  These community hospitals have a total of  1,124 inpatient mental health beds statewide. Nine hundred sixty of these beds are for adults, and 164 for children and adolescents.  On the public side, there are 194 public beds for patients with severe mental illnesses who are committed.  Only committed patients can be admitted to these beds.  According to the Treatment Advocacy Center states need about 50 beds for 100,000 people.  Minnesota has 3.5 per 100,000 public beds and 22.8 per 100,000 beds in community hospitals.  Notice that in a comparison to psychiatric beds in OECD nations, the national average in the US is 22 beds per 100,000.  The United States ranks 29 out of 34 countries ranked in terms of fewest psychiatric beds.  Beds in public hospitals are not equivalent to beds in community hospitals and the newspaper report highlights the differences.  Like most states Minnesota continues to lose beds largely because of mismanagement at the level of state government and what has been an implicit initiative to shut down the state hospitals system.

The bed situation is compounded by a number of factors besides the lack of beds.  There is inadequate housing for people disabled by severe mental illness and inadequate resources to help them live independently.  The average person is expected to come in and see a psychiatrist for a discussion of medication and whether or not their acute symptoms are in remission.  Treatment for combined severe mental illness and substance use disorders is practically non-existent.  The inpatient crisis got worse when legislators passed a very poorly thought out law allowing incarcerated mentally ill patients to be transferred to remaining state hospital beds as a priority over committed patients waiting for transfer in community hospitals. This was an initiative to correct the statistic that Minnesota incarcerates 1.2 people with severe mental illness for every 1 person that it hospitalizes. 

All of the usual commentators are appear in the article - the Commissioner of Human Services and an advocate.  The reader is told that everyone is troubled by this development and wringing their hands.      

Well I'm not.  The entire sequence of events has been observable and is totally predictable.

This is a system that has been severely rationed nearly to the point of near extinction by Minnesota lawmakers and bureaucrats.  It has been interfered with by advocates and in some cases by very bad hiring decisions of people who were supposed to correct the problem.  The only thing we have to show for 30 years of hand-wringing is a a non-existent system of care that does not start to pull resources together until after a person has gone through a civil commitment hearing.  Psychiatrists have been marginalized in the process in favor of administrators who come up with one bad idea after the next.  Managed care systems seem to only recognize dangerousness as an admission criteria to inpatient psychiatric units.  The impact of that bias on commitment frequency, damage to the physician-patient alliance, and damage to the inpatient milieu is probably significant but nobody is interested in studying it.

From the article, the problem is clearly solvable.  There are an estimated 4,000 patients a year who need these services and only 194 beds available to them.  They cannot be humanely treated in community hospital acute care units.  They can also not be humanely treated in group homes designed to be surrogate state hospital beds.  They receive the least humane treatment in jail. The solution is not to blame community hospitals who cannot treat the problem.  One of the issues not mentioned in the article is that the state hospitals have been so decimated - they also cannot treat the problem.  There are probably three community hospitals in Minnesota who have adequate staffing and professional resources to address this problem.  It is conceivable that many more of the remaining 28 community hospitals with psychiatric units will adopt similar policies if they can.  The administrative measure of saying that they can't do this is really not a solution because they really can't provide the necessary care.  The state should know this from their failed initiative to provide smaller local units for committed patients.  That initiative failed for the same reason that St. Joseph's Medical Center no longer accepts committed patients.  They cannot provide adequate care for severe mental illnesses especially when aggression and violence is involved. 

I have posted the solutions in the past and they are obvious. Today I just have three:

1.  Build facilities necessary for the humane treatment of people with severe mental illnesses. Staff these facilities adequately and develop continuity of care with local facilities  when patients are ready to be discharged.  Build these facilities as state-of-the-art facilities in metropolitan areas and not rural areas.  The time is past when people were sent away to the country with mental illness.  Modern mental hospitals need easy access to advanced diagnostic and treatment equipment as well as expertise that is only concentrated in large cities.

2.  Immediately stop arbitrary transfers from county jails to state hospitals, unless the incarcerated patients have been assessed by psychiatrists who agree that a state hospital setting is the best place for them to be. 

3.  Get out of the way of the people who were trained to work there and run them - psychiatrists, psychiatric nurses, and social workers.     


George Dawson, MD, DFAPA



References:

1:  Chris Serres. Brainerd hospital stops admitting patients with severe mental illnesses, citing state bottlenecks: Brainerd decision alarms officials, mental health advocates.  StarTribune November 1, 2017.

Supplementary 1: The image used for this post is of Dexter Asylum attributed to Lawrence E. Tilley [Public domain], via Wikimedia Commons. The original image was Photoshopped with a graphic pen filter.

Another PSA On Pain, Opioids, and Addiction

It turns out that Twitter is an inadequate forum for discussing the issue.  Twitter is an ideal format for discovering if a poster knows anything at all about the problem.  A lot of people don't and they seem to just be there to argue.  I don't have a lot of time to waste on political approaches to medicine.  Political approaches to medicine typified by managed care companies, pharmaceutical benefit managers, and government guidelines that are supposed to improve care but don't are the reasons we have an expensive, fragmented and inefficient health care system.

The apparent political factions on Twitter consist of pain specialists who take the position that pain care and access to opioids is now being rationed and their pain patients are being unjustly treated.  They claim there is a faction of addiction specialists making various claims that they take offense to.  But my experience there is the past few days is that these are all basically red herring arguments.  A few of those claims include the idea that addiction specialists would consider pain patients "drug seekers", would recommend treating pain with only acetaminophen, are calling pain specialists "quacks", and of course that addiction specialists have some interest in distorting and overplaying the dangers of opioids.  In some cases the arguments have gotten to the absurd claim that the pain advocates (or more appropriately anti-addiction contingent) claims that most heroin users start using heroin directly rather than using legitimately prescribed or diverted pain medications first.

Where is the reality in all of this distortion?  The reality centers like most things in medicine in primary care settings.  The hundreds of thousands of internists and family physicians who provide the bulk of care for almost all problems in the US.  As I have posted on this blog many times, the evidence from both the CDC and CMS is that the majority of these physicians do a good job with opioids.  Only a fraction of their number prescribes a disproportionate amount of opioids.  Many of these physicians have a bias to underprescribing if anything.  That means the bulk of physician punitive legislation about mandatory course for opioid prescribing for these physicians will be just that - punitive toward most physicians who already know about prescribing these medications.  That legislation is also untested in terms of whether it will have any impact on the physicians who are overprescribers.

The other facet of the problem is overprescribing in general.  Part of the quality problem in medicine today is that the business and governmental management systems are focused on a brief physician-patient encounter where some medication gets prescribed.  That is the focus of the encounter. Patients expect that and come in the door with a medication request.  That results in predictable overprescriptions of medications from many classes.  The classes that reinforce their own use - opioids, stimulants, and benzodiazepines are more problematic than the rest.

At the extremes of this landscape are the pain specialists on one end and addiction specialists on the other.  Both have a broad spectrum of quality settings from state of the art to nonexistent.  These specialists know this and they know there is very little that can be done about it except to mind your own business and do the best job possible.  There are pain clinics that are "pill mills" where there is an understanding that a cash exchange with a prescriber will get you a script that can be filled on site for opioids.  That prescription is then sold in the parking lot for diversion.  There are other pain clinics where no attention is paid to addiction, psychiatric comorbidity, polypharmacy or the functional capacity of the patient being treated.  There are similarly low quality addiction treatment facilities where people are warehoused with no active treatment.  Where there is no therapeutic environment because nobody in the program is willing to consider that they may have an addiction.  There are programs where there is no medical supervised detoxification.  There are programs where there is no medication assisted treatment for opioids or alcohol use.  There are programs that do not address psychiatric comorbidity.  There are programs based on some sketchy ideas that have no proven relevance in treating addictions.  The houses of both pain and addiction specialists are not perfect because of these serious flaws.  And let's face it - the regulators of every state in the union are to blame for having so many low quality pain and addiction treatment facilities open for business and accepting reimbursement for shoddy services.   

For a moment - let's return to the idealistic world of the Twitter protagonist where the position seems to be "I am all knowing and do a perfect job."  The realities will  differ based on whether you are on the addiction or pain specialist end of the spectrum.  To illustrate, I am on the addiction end and 100% of the people are see have addictions or substance use problems.  On any given day the problematic substances average out to about 30% alcohol, 30% opioids, 20% mixed, 15% stimulants, and 5% cannabis.  Of the opioid users 30-50% have chronic pain problems.  In every case, I have a detailed discussion with the patient about how their substance use problem evolved and what keeps it going.  Over the years I see thousands of people with these problems and in that process come to know a lot about the associated issues.  My opinion is not based on my personal experience or politics.  My opinion is based on understanding the problems of thousands of people that I am supposed to help.  For example, when somebody tells me that the "average" heroin user in this country starts using heroin rather than prescription painkillers - I can say that is unequivocally wrong.  I have heard all of the details about how heroin use begins and it is almost always with a prescribed or diverted pain medication.  When somebody tells me that taking a person who is addicted to opioids and who has chronic pain off of opioids is cruel - I can also say that they are wrong.  I have had those same people tell me that they have never felt better and in less pain in years.   I can also say the following based  both on research, theory and clinical experience:

 1.  A significant portion of the population is predisposed to addiction - 

My estimate would be about 40%.  When a genetically predisposed person uses an intoxicant their reaction to it is markedly different from a person who lacks that predisposition. Opioid users report an energetic hypomanic felling where they have mental clarity like they have never experience before.  In some cases they will say that they felt like they had become the person they always thought that they could be.  This is a highly reinforcing state that leads to more opioid use.

2.  If the population predisposed to addiction is significant - the only limiting factor is access or availability -

This is the basic reality of the current opioid epidemic and of course very drug epidemic (methamphetamine, cocaine) that the US has seen over the past 200 years.  It is quite easy to look down from the high perch of a low availability area with low addiction rates to a high availability area with high addiction rates and conclude that "there is something wrong with those people".  The usual conclusion has been that they are morally defective.  This is how addiction services have been rationed, poorly researched, and fragmented over the years.  Even if you subscribe to a top health plan in the country - it is likely that you will have poor access to quality addiction care because of these attitudes.

3.  The burden of prescribing medications that reinforce their own use falls squarely on the prescriber - 

It is above all else an informed consent issue.  The patient needs to know that the medication they are taking is not a panacea and that there are significant risks up to and including addiction and death.  They also need to know that these medications can have cognitive side effects and affect their day-to-day functioning.  They should not be prescribed solely out of the notion that the physician feels like they need to do something for the patient.  There needs to be a pain diagnosis and treatment plan.  In the case of chronic pain the patient needs to know that there is no known medication that completely alleviates chronic pain and therefore continued dose escalation of opioids is not a solution.  The treatment plan needs to contain more elements than taking the opioid prescription.

An associated prescriber issue is polypharmacy.  Chronic pain is frequently associated with anxiety, depression, and insomnia.  That can lead to a contraindicated polypharmacy environment that includes a benzodiazepine, a z-drug, or a sedating antidepressant used with the opioid.  It can also lead to the patient taking alcohol or diverted sedatives on their own initiative with the opioid.

4.  Chronic pain patients taking opioids need thorough evaluations if possible -  

Some people in the Twitter debate seemed shocked by the idea that opioids are taken for reasons other than pain relief.  I suppose they would be even more shocked if they heard that there are people that take them who get no pain relief at all from them.  They taken them strictly because of the positive euphorigenic effects.  There are also people who take them despite the side effects for the same reason.  The first thing a physician needs to do is step back from the indication - prescription mode that most American physicians have been trained in to take a look at the entire prescribing landscape.

That means that is a person has come to idealize a medication or abusable substance they will start to use it for anything - insomnia, anxiety, depression, or "just to feel right to get through the day."  As many people tell me: "Look doc - if you can't get rid of this depression I know what I can take to feel OK for a couple of hours."  On Twitter and some other blogs readers are incensed that these behaviors exist and yet they are documented in the literature (see paragraph 6).

When I say if possible I am more aware of the fact that patients lie to physicians than non-addiction specialists.  I have had an endless number of patients tell me that they can get whatever addictive medication they want out of one physician or another.  The Mayo clinic had an addiction medicine conference three years ago and one of the presenters was a patient in recovery who basically talked about how he systematically lied to physicians to get opioids for years.  He talked about how he could identify a physician who would give him the script that he wanted and who would not.  In the case of the latter he would just move on to another clinic.

Many non-addiction specialists consider it to be poor form to suggest that patients lie.  That denies the basic reality that everybody lies.  It also denies the reality of addiction, that you are transformed into a person who is dishonest and a person that you never thought that you would become.  In the addiction field it is critical to acknowledge this to help people deal with guilt and shame so that they can recover.  The worst thing that can happen is to collude with dishonesty when the final result is the prescription of an addictive drug.  I do not consider it to be an issue that I can get this history when the physicians being approached for the medication cannot. It is all part of the illness of addiction.  On the other hand, if you are the opioid prescribing physician - the amount of information that you can get asking the direct questions about problematic use is not known until you try it.   

All things considered it is possible to treat people with chronic non-cancer pain with opioids.  I have been involved in that treatment before I switched to seeing only patients with addictions.  I consulted with some of the top pain experts in the state.  All the limits in this post need to be acknowledged and cautiously addressed.  The treatment of chronic pain is not perfect, I know that because I see a lot of the failures.  Addiction treatment is not perfect either.  The treatment needs to be highly individualized.

I wish that I could provide more clear guidance to the patients involved.  As an individual I cannot just start pointing fingers at the places (pain clinics and addiction treatment) that I think should be shut down.  I think that you need to depend a lot on your primary care physician referring you to places that he or she knows will do good work.  On either the addiction or pain end of the spectrum - there has to be more going on than the prescription of medications.

Even the most basic psychological models suggest that other cognitive, emotional, affiliative, spiritual and reconditioning changes need to occur.


George Dawson, MD, DFAPA 

  








   

Updated Review of Systems (ROS) for Medical Psychiatrists

The review of systems for psychiatry has changed significantly over the years.  Those changes were due to billing and coding decisions rather than clinical utility.  If you have been practicing long enough you have witnessed the transformation from a document very similar to what primary care physicians use, to one that is more focused on the sleep and appetite disturbances associated with psychiatric disorders. That results in a distinctly different ROS in psychiatry than the rest of medicine.  That puts medically based psychiatrists like myself at a disadvantage because the electronic health record (EHR) templates may not include the physical symptoms that I am most interested in and that requires more documentation. 

These changes are not unique to psychiatry.  Patients find themselves filling out checklists in many clinics that are essentially a surrogate ROS.  Something that your physician used to ask you in person and ask you to elaborate on is now a checklist.  In the modern EHR, the ROS is often just a series of checkboxes.  No elaboration required thank you.  The form that you fill out in the waiting area is incorporated into the physician's note often without reviewing it with the patient.  In some systems employing scribes or persons to do the documentation the scribe will type or dictate this form into the record. There is one additional point where the physician might read any ROS incorporated this way and that is during the read of the final note for signing.  That review is usually cursory because of time constraints - I doubt it is read with any regularity.  There is not enough time to read documentation 2 or 3 times as it is complied, transcribed, and entered into the EHR.

Another EHR strategy that is used from time to time is a statement: "A complete 10-point review of systems was done and it was negative."  Use of that statement depends on the billing, coding, and compliance staff and whether they think it meets the subjective standards of the day to demonstrate to somebody that the work was done. In my experience, unless you are interviewing a very healthy 20 or 30 year old it is unlikely that the ROS is completely negative.

The expanded ROS is more specific to medicine and it assumes that the physician is asking clarificatory questions.  I have found over the years that a very basic structured exercise like the ROS produces very different results depending on asking all of the questions, asking clarificatory questions, and pursuing obvious leads to other sets of questions depending on the patient response. Treating the ROS like it is a static series of yes or no questions is likely to produce the minimum amount of diagnostic information.

As an example consider the following example:

The ROS is being conducted on a 75 year old man.  He is being seen for insomnia.  In taking the medical history he says he was diagnosed with congestive heart failure 2 years earlier. He has impaired physical performance due to CHF and can only walk 100 feet and slowly climb a flight of stairs with great effort. On the ROS he endorses needing to prop himself up to breathe and occasionally wakes up suddenly at night due to shortness of breath.  Those symptoms and additional physical exam findings suggest that CHF is the problem rather than insomnia and the treatment needs to change accordingly. 

A more common example:

The ROS is being conducted on a 50 year old man.  He denies any cardiac or pulmonary symptoms and is only taking an 81 mg aspirin in addition to two different antidepressants. He has a 30 year history of smoking a pack a day of cigarettes.  The interviewer asks: "Have you ever had stress test?"  The patient states he does not know what that is. "You walk on a treadmill and they keep increasing the grade until you have to stop".  The patient replies that he took the test and the Cardiologist came in and sprayed something into his mouth. "Do you think that was nitroglycerin spray?" The patient states that it was and he had an immediate angiography and stent placement. 

Both examples illustrate that the ROS is dynamic and not static.  Filling it out in the waiting room may seem to be efficient, but the amount of information obtained in that setting is likely to be low relative to real medical problems that exist.  The probability of increased information from a more dynamic ROS increases with the age of the patient due to accumulated medical problems with age.

In addition to the list of symptoms in the ROS, additional heuristics at the level of pathological mechanisms can be considered to hone in on a specific syndrome.  The following table illustrates two of them.  For example, the General category in the ROS generally implies some kind of infectious, metabolic or endocrine condition - but it is not enough to make an actual diagnosis without further delineation. ROS categories are supposed to roughly correlate with body systems rather than pathological mechanisms, but many of the symptoms do not have a definable body system.

VINDICATE	VITAMIN D
V – Vascular I – Inflammatory N – Neoplastic D – Degenerative / Deficiency I – Idiopathic, Intoxication C – Congenital A – Autoimmune / Allergic T – Traumatic E –  Endocrine	V – Vascular I – Inflammatory T – Trauma A –  Autoimmune M –  Metabolic I – Iatrogenic N –  Neoplasm D -  Degenerative

If I think the patient has a flu-like illness I ask about specific symptoms of flu-like illness. In addition to fatigue, weight change, fever, chills I might ask about - malaise, cough, rhinorrhea, nasal, congestion headache, sore throat, myalgias, chills, and sneezing.  Positives on several of these symptoms greatly increases the likelihood of a diagnosis of a flu-like illness.  Asking those questions occurs when an infectious etiology is suspected.

The typical review of systems that I used for years is printed below with red highlights for additional points that I ask if there are any markers in the initial history that suggests that they might be positive.  For example, if I am seeing a 50 year old with a long history of stimulant use, on three different antihypertensives and an anti-arrhythmic medication I will generally ask all of the cardiopulmonary symptoms and the additional questions about cardiac testing imaging and diagnoses.  For example: "You mentioned that you have never had a heart attack or a stroke, but has any doctor every told  you that you had cardiomyopathy or a thickened wall of the heart? Do you remember where all of that testing occurred?"

Review of Systems

General:  fatigue, weight change, fever, chills, night sweats

Endocrine: hot or cold intolerance, thyroid problems, hx of neck irradiation

HEENT: decreased visual acuity, hearing loss, tinnitus, vertigo, epistaxis, hoarseness or voice change, sinus/nasal infection or discharge, ear pain, history of ear infections, decreased auditory acuity

Pulmonary: dyspnea, cough, sputum production, chest pain or tightness, hemoptysis, asthma, bronchitis, emphysema, hx pneumonia, hx TB, hx positive/negative PPD, smoking hx

polysomnography, CPAP, APAP, BiPAP, nightmares, night terrors, parasomnia

Cardiovascular: chest pain, palpitations, tachycardia, syncope, edema, orthopnea, paroxysmal nocturnal dyspnea, claudication, phlebitis, hypertension, hx rheumatic heart disease, family hx heart disease

stress test, echocardiogram, angiography, stent placement, congestive heart failure, cardiac ablation, cardiac event monitoring, tilt table testing

Gastrointestinal:  nausea, vomiting, hematemesis, melena, dysphagia, indigestion, heartburn, abdominal pain, abdominal swelling, jaundice, hx hepatitis, hematochezia, diarrhea, constipation, hernia, hemorrhoids, peptic ulcer disease, gallbladder disease, pancreatitis, GI surgery

esophagogastroduodenoscopy, colonscopy, hepatic ultrasound, pancreatitis

Genitourinary: urinary frequency, urgency, dysuria, nocturia, hematuria, hx kidney stones, flank pain, hx STD, genital lesions, testicular mass or pain, sexual dysfunction

Hx acute renal failure

Gynecological: menarche, menopause, last menstrual period, description of menstrual periods, pelvic pain, vaginal discharge or bleeding, sexual dysfunction, breast mass, breast discharge, last breast exam, last mammogram

pregnancy history, hx pre-eclampsia or eclampsia

Skin: mole, other lesion, pruritus, rash, bruises, contusions, lacerations, burns, hx skin cancer

Hematopoietic: excessive bleeding, hx anemia, family history of disorder, lymphadenopathy

Neurological: headaches, migraines, ataxia, incoordination, vertigo, gait problems, falls, loss of consciousness, seizures, head injury, skull fracture, focal weakness, focal sensory change, hx stroke, micropsia, macropsia, metamorphopsia, chronic pain

Brain imaging, EEGs, coma, encephalitis, meningitis, chronic fatigue syndrome, movement disorders

Musculoskeletal:  joint pain, joint stiffness, joint swelling, muscle cramps, muscle pain, muscle wasting, hx fractures

Gout, Lyme Disease, fibromyalgia, rheumatic diseases, treatment by rheumatologist

Allergic/Immunologic: hay fever, rhinitis, seasonal symptoms

Allergy testing, specific allergens, immunotherapy


These are techniques that I have found useful over the years.  In psychiatry, the ROS is useful because I frequently have gotten past the medical history section and inquired about all major surgical and medical diagnoses from the past and the result is surprisingly thin.  More specific prompting about the diagnoses and which physicians the patient has seen in the past can produce much more information in an interview setting.  For psychiatric purposes, the ROS is also included in follow up visits and it seems necessary.  I find it useful for documenting intercurrent illnesses and medication side effects.  

Each class of psychiatric medications has their own relevant ROS that can be recalled with practice.  I might try to type those out at some point in time - but not tonight.  My main point here is that the ROS does have a function above and beyond the psychiatric history for psychiatrists.  People tend to view it as a difference necessary for one billing code or another.

I see it as an opportunity to figure out what is really going on medically with my patient and possibly diagnose another illness. It is also necessary to know that the patient does not have an underlying medical condition or treatment for that condition that contraindicates or necessitates closer monitoring of the proposed psychiatric treatment.

George Dawson, MD, DFAPA


ROS Files:  You can download the ROS files used for this post at the following links as Word documents.  Any suggestions for further modification appreciated:

ROS modified 

ROS standard

Additional Fact: 

A poster on Twitter [Alasdair Forrest @alasdairforrest] let me know that the ROS in the UK is called "systemic enquiry".

Sex Scandals - Human Sexual Consciousness and Prevention

Over the past three weeks the country has been rocked by another entertainment business sex scandal.  An endless series of actresses describing very similar inappropriate behaviors and in some cases sexual assault.  The allegations alone at this point have led to major disruptions in family life, businesses, and professional recognition and honors.  Women have been encouraged to come forward and report these incidents and there is a movement to spark a sea change in the culture that lead to the problem of the sexual exploitation of women in the entertainment industry.   In some cases men have come forward. There are also claims that the specifics of child sexual exploitation in Hollywood will soon become public.   This seems to be a familiar scenario that unfolds from time to time, but never before at this scale.  What are the implications?

Looking at the epidemiology of sexual harassment leads to a wide range of statistics.  The first reliable medical reference that I could find was in the American Journal of Psychiatry from 1994. That article was a review of existing literature showing that sexual harassment was commonplace with estimates varying from 42-73% of women and 15-22% of men in occupational and medical educational settings and that a small percentage of the people affected (1-7%) file formal complaints.  The Equal Employment Opportunity Commission (EEOC) is the federal agency that monitors and enforces civil rights in the work place and one of those rights is not to be sexually harassed.  The agency has very little useful information on their web site in terms of epidemiology, primarily looking at enforcement data. Since this represents a minority of incidents and there is overlap from year to year depending on when the claim is settled it has limited utility in determining the scope of the problem.  As far as I can tell there are no definitive studies done with similar definitions across a representative population, but all of the subgroup studies indicate it is an ongoing significant problem despite legislation and the EEOC.

Inappropriate sexual behavior has been a significant focus of every educational and employment situation that I have been in over the course of my career.  The approaches have varied widely from stating rules and implying what was unacceptable right up to prohibitions of behaviors and the fact that violations could lead to reprimands or immediate termination.  The unacceptable behaviors included a wide range of unwanted approaches or statements, suggestive humor, inappropriate touching, and included dating subordinate employees.  There were comprehensive approaches that explained the rationale for all of these rules.  In other cases there were not.  In psychiatry, the boundaries have become even more clear in terms of dating former patients and supervisees.  It is no longer considered appropriate for a psychiatrist to ever date or have a sexual relationship with a former patient. In some places where I have worked with other disciplines - I noticed that there is a time frame where such behavior is allowed for non-psychiatrists.  As far as I can tell - there are no uniform approaches that seem to apply to all employees and all disciplines.

Apart from employment expectations when working in health care environment, sexual trauma is overrepresented in people  being treated in psychiatric settings.  There are high rates of depression, post traumatic stress disorder, suicide attempts, and suicide.  The World Health Organization has several resources on the available statistics for violence toward children and adults and sexual maltreatment and violence.  They classify sexual harassment as a form of sexual violence against women.  Their definition of sexual violence is:

 "any sexual act, attempt to obtain a sexual act, unwanted sexual comments or advances, or acts to traffic, or otherwise directed, against a person’s sexuality using coercion, by any person regardless of their relationship to the victim, in any setting, including but not limited to home and work." 

The available estimates are high.  In the US, 14.8% of women  over the age of 17 report that they have been raped and an additional 2.8% have been subjected to attempted rape. The WHO report documents other forms of sexual assault but had no clear data on sexual harassment.

The WHO report is interesting because it has some suggested strategies for prevention.  They begin by discussing secondary prevention for both the victims and perpetrators of sexual violence.  An educational and developmental model was discussed that includes discussion of a sexual aggression and setting boundaries for appropriate sexual relationships.  Improved health care interventions for victims of sexual violence is another WHO priority ranging from forensic evaluations to the prevention of sexually transmitted diseases.  Legal reform is also suggested as necessary particularly in the areas of legal definitions of sex crimes and the court processes that are used for these cases.  Child marriage is a variation of sexual abuse that continues to exist world wide. In the US, like elsewhere the practice is culturally based (2) and even though there are generally minimum ages for marriage in some states the courts can grant exceptions.  These exceptions allowed children between the ages of 10 and 15 to get married in the US.  The WHO report has a few paragraphs on primary prevention of stopping sexual violence before it occurs.  Most of that is directed at educational programs that target changing cultural and individual attitudes about sexual behavior.

I found a recent paper on a specific subculture (anthropological fieldwork) (3) that was studied by anthropologists. This paper looked at the issue of sexual harassment in the context the expectations of that subculture.  The authors found that when there were clear rules in the workplace and an expectation that they would be enforced - the field experience was more productive and there were far fewer reports of harassing behaviors.  The authors included discriminatory behavior along with harassment and assault.     

I included some of the additional information on sexual violence to show that is only slightly more studied than sexual harassment.  From the descriptions of recent victims, there is a clear association between sexual harassment and sexual violence.   It is apparent to me that the scientific study of problematic human sexual behavior at the levels of epidemiology and causation is primitive to non-existent.   Society seems to depend on a legal model including civil and criminal penalties as potential corrective factors - but there is no evidence that has had much impact.  Society might also be a bit too self congratulatory on attitudes about human sexual behavior. Tolerance for nudity and pornography has not translated into less victimization.  Neither has widespread exposure to detailed information on the mechanics of sexual behavior.

The brain has been left out of the discussion, specifically human sexual consciousness and why there are people who can routinely negotiate this most sensitive aspect of interpersonal relationships, while others leave a number of traumatized victims in their wake.  Retrospective analysis and armchair psychoanalysis is always easy after the fact.  I have seen many of these men referred to as sociopaths, psychopaths, or narcissists.  The perpetrators themselves often claim "sex addiction" as a problem and go to a rehabilitation facility to treat the problem.  Social etiologies are also part of these analyses, especially the idea that most perpetrators are likely victims of sexual abuse.  All of these diagnoses seem to be a function of the crisis situation rather than any useful diagnosis that results in treatment and life change.  The diagnoses also seem to be based on a very simplified model of how the mind/brain work.  The models typically included cognitive, behavioral, moral and social elements that do not produce a viable theory to produce much treatment or prevention.  The models also do not explain individual variation, but generally look at class variation (men versus women).  More biological based models of sexual differences (4) look at imaging studies, limited cognitive tests, and functional imaging and differences are typically minimal.

A consciousness based approach may be more useful to look at real differences between men and women.  The focus of these studies would be to look at the conscious states associated with sexual behavior and what actually happens in the optimal and sub-optimal or abusive states.  Any  study of these conscious states typically begins with phenomenology and in addition to epidemiology - it is lacking in this area.  The largest literature continues to be psychodynamic and psychoanalytical that has produced non-falsifiable theories based case reports and experience with individual cases.  That same literature is also limited by the theories and interpretations of the authors.  A phenomenology of sexual consciousness needs to take a look at the current theories of consciousness and how they might apply to very specific situations.  In a previous post I quoted Tononi and Koch speculating about the complex that occurs when they see a particular actress in a movie.  They focus a lot on the neural correlates associated with the visual representation but also the neurons that are associated with higher order concepts.  What are the specific complexes generated when people meet?  We currently do not know what they are.  There seems to be a broad idea that every person has an internalized moral code or set of rules that comes into play, but is that a realistic way to view the process or any associated problems.  Consciousness researchers seem more focused on ideas about machine intelligence and possible machine consciousness these days than the issue of sexual consciousness.

For now, there does appear to be a societal approach to minimize sexual harassment and abuse, but it is limited by self report.  It depends on transparency and enforcement that is spotty at best. The strong wave of advocacy that we have seen originating in the entertainment industry is a potential positive force - but we have seen these waves in the past lose momentum.  Like many readers of this post, I hope that does not happen.  In the meantime, a focus on sexual consciousness may lead to important ideas about how to address inappropriate sexual behavior and it will lead to a more complete science of human sexual biology.     

 George Dawson, MD, DFAPA


References:

1: Charney DA, Russell RC. An overview of sexual harassment. Am J Psychiatry. 1994 Jan;151(1):10-7. Review. PubMed PMID: 8267106.

2:  Diane Cole.  Children Get Married In The US, Too: 15 Girls   http://www.npr.org/sections/goatsandsoda/2015/10/28/452540839/children-get-married-in-the-u-s-too-15girls

3:  Nelson, R. G., Rutherford, J. N., Hinde, K. and Clancy, K. B. H. (2017), Signaling Safety: Characterizing Fieldwork Experiences and Their Implications for Career Trajectories. American Anthropologist. doi:10.1111/aman.12929

4: Mueller SC, De Cuypere G, T'Sjoen G. Transgender Research in the 21st Century:A Selective Critical Review From a Neurocognitive Perspective. Am J Psychiatry. 2017 Oct 20:appiajp201717060626. doi: 10.1176/appi.ajp.2017.17060626. [Epub ahead of print] PubMed PMID: 29050504.

5: Centers for Disease Control and Prevention.  A Guide to Taking A Sexual History. Link.

I included this document to illustrate where the focus is on sexual behaviors - in this case detecting sexually transmitted diseases.

Blade Runner 2049

In keeping with the previous two posts - I did get out to see Blade Runner 2049 last Saturday.  It was clearly a first rate science fiction film and I guess some viewers not used to the genre might also call it a thriller.  Visually I thought it was less stunning that the first due to the lack of street level scenes and the hectic activity on the street.  It has critical acclaim but because of the high cost is being described by some critics as a "box office bomb".  In this film replicants (bioengineered androids) have become Blade Runners.  In some reviews of the film they are referred to as bioengineered humans and that is not a trivial difference since the main plot theme is whether or not the androids can reproduce.  The focus is on K (Ryan Gosling) who is the main protagonist.   We seem him interacting with and dispatching another replicant in the initial scene.  That replicant asks for mercy on the basis that they "are the same kind" and that there is a higher calling based on the miracle that he has witnessed.  When K returns to the station (LAPD) he undergoes a rapid debriefing protocol, test questions with monitoring of various anthropometric and physiological parameters.  The meaning of the test questions is not clear but the implication is that it determines if he has stayed at his baseline or his status had been perturbed in some way.   The test is also being administered for a very different reason than the Voight-Kampff protocol since the test subject is a known replicant.

There are three generations of replicants in the film starting with K - a Nexus 9 series, to the Nexus 8 replicant he retires in the original scene, the the Nexus 7 series that dates back to Rachael in the original Blade Runner film.  Over the course of that time frame the replicant population has become less subservient and more interested in equality or autonomy.  There is a rebellious faction.  We learn later in the film based on a series of events that the common "miracle" that the replicant population refers to is the birth of a child by Rachael in the original film.  In that film in the final scene she was leaving with Deckard (Harrison Ford).  There were implications that Rachael was a specially modified replicant and in retrospect the question is whether she was modified to reproduce.   

The competing forces in the film were threefold.  First, the LAPD is invoked as the police force determined to suppress any replicant rebellion.  K is a detective for the LAPD and after discovering Rachael's remains buried at the site where he encounters the initial replicant and there is evidence that she gave birth to a child..  Second, Tyrell corporation has been replaced by the potentially more evil Wallace Corporation header by Niander Wallace.  Wallace is very explicit about the need for replicant reproduction since he does not believe that manufacturing capacity can ever meet the need for replicants in service of his corporation and its off world needs.  And finally there is the role of K as a free agent in all of this.  Does he do the bidding of his boss at LAPD or not?  His boss emphasizes the importance of killing any story that replicants have reproduced - she sees it as a game changer for civilization as they know it.  She assigns him to find and kill the child.  He is later assigned to kill Deckard for the same reason.

I will leave the plot specifics to the various reviews and descriptions already out there and concentrate on the main issues that have to do with consciousness in the film.  At one point K is asked about childhood memories and recalls being bullied by a group of boys who wanted a small hand carved horse that he was carrying.  We see him escaping the boys and burying the toy in a pile of ashes in the bottom of an old furnace.  Later he consults with an expert to determine if the memory is real or not.  She confirms that it is a real memory and that leads him to believe he may be the child of Deckard and Rachael.  I asked myself at that point if K's interest in the memory was even possible if he was a replicant.  By definition in Tononi Koch theory, this experience requires consciousness and even perfectly engineered system mimicking the human brain could not generate the human experience associated with the memory much less the integrated emotions associated with this scene.  When K finally finds Deckard he is in a state of emotional turmoil related to information that Deckard provides him about his origins.  In a shootout Deckard is captured by Wallace Corp and is in the process of being tortured to find out information about the location of his and Rachael's child.  He is both rescued by K and united with his child by K.  In both Blade Runner movies Deckard is rescued in the end by a replicant.

My summary may not match up well with other reviews about specifics.  I did not view the protocol being given to K as the Voight-Kampff protocol, since it did not seem like it was an updated version.  Keeping Tononi Koch theory in mind it would be totally unnecessary even if he was really a highly sophisticated bioengineered replicant.  It would only be necessary to place a transcranial magnetic stimulation (TMS) coil close to his brain and observe the high density electroencephalogram (EEG) pattern.  If consciousness exists the theory predicts a pattern of widespread activation and deactivation.  It should also be possible to observe the characteristic sleep EEG pattern of transitioning from consciousness to unconscious dreamless sleep and back.  Of course these androids would need to be flawlessly engineered to protect circuitry from magnetic and electrical fields that occur with these measurements. 

In summary, I thought that Blade Runner 2049 was an excellent film just based on the plot and artistry.  I can always see the distinction between real science and science fiction.  If Tononi Koch theory is accurate, it is hard to imagine that a replicant would not be obvious to conscious humans.  I guess we will need to either wait until that day comes or until the theory has more widespread acceptance and proof.  The other parallel aspect of this film is bioengineered human reproduction.  It is difficult to see how that could ever be done, especially through human sexual contact with machines.  Sexual contact with bioengineered androids is a more frequent science fiction theme these days than in the past.  It is probably easier to see how that might happen from the human side.

There is currently not enough information about human sexual consciousness to imagine how it could be built or programmed into an android.     


George Dawson, MD, DFAPA               

Tononi Koch Test for Machine Consciousness

In follow up to my previous post and before I saw Blade Runner 2049, I wanted to post a more modern take on the Turing Test based on a coherent theory of consciousness  by Tononi and Koch - both experts in the neuroscience of consciousness.  Their theory is the Integrated information Theory (IIT) of consciousness.  I have included the reference (1) and a graphic from their public access paper on the theory and there are also several very useful videos available to listen to the verbal descriptions of the theory.  I have been following consciousness research for at least the past 20 years including the two main listservs on this topic until they shut them down.  When a topic is so specialized, barring any breakthroughs the arguments become repetitive and a lot of time is spent bringing novices up to speed.  The videos fill a useful gap that these listservs previously addressed although I must admit  that I am always biased toward the written rather than the spoken word because it is a much more efficient information transfer for me.  The videos listed at the bottom of this page also serve another useful purpose.  The viewer is able to see how researchers in this area define consciousness and describe their theories.  I think that it is possible to notice that some of the definitions and descriptions are so vague as to have limited utility.

That is one of the reasons that I like the approach by Koch and Tonini.  I will also also say from the outset that I am not sure whether they view the theory as a joint venture or not.  As an example of what I mean looking at this specific search on consciousness finds that Tononi has been working in this area for at least 20 years.  A similar search on Koch goes back even 8 years earlier.  I don't know either of the authors but based on reading this paper it seems like a joint effort and that seems to come across in  the available videos of their presentations. (see addendum).

In the paper, that authors outline phenomenological definitions that are more exacting than any that I have seen in the past from other authors.  They are also neuroscience based and that makes a difference to me.  In various venues people often faintly praise but then lament psychiatry's emphasis on biology.  That is obviously not true or at least without reason and it also illustrates the lack of research that people do when it comes to critiquing psychiatry.  Psychiatrists have actively researched practically all forms of social, psychological, and biological etiologies of mental illness since the specialty was founded.  Any cursory review of a general psychiatric text illustrates that point.  So if a psychiatrist is focused on brain biology, it is certainly not without reason.  I previously posted a breakfast that I had with a mentor and after a long career as a psychiatrist he summed it up the way a lot of psychiatrists do: "It is all about the biology."  Critics take that to mean some kind of medical intervention.  They are certainly studied, but every other non-medical intervention has been studied as well.  It is common to read about non-medical interventions (psychotherapy, meditation, etc) altering the brain in some way.  In psychiatry that has been known within the field for at least 70 years.

There are two levels to study the work of Tononi and Koch.  The first is at the purely descriptive level.  That is the level that you will find in the first reference.  The second level is at the level of neuroscience and mathematical theory.  The authors have produced this work as well and reference it in this paper, but for the purpose of this post I am going to stay at the descriptive level and possibly post a more technical article on the advanced theory at a later date.  I will add that there are several competing theories of consciousness that I am not going to mention here.  I have studied several of them and think that they have less to offer than the Integrated information Theory (IIT) of consciousness.  I am admittedly a reductionist seeking to close the explanatory gap between brain biology and how conscious states are generated.  In some of the videos available online where there are panel discussions it is clear that the proponents of the other theories think that their own theories are correct and IIT is wrong. I have been down the rabbit hole with a few of those theories and don't want to take time to criticize them.  Feel free to look them up and form your own opinion.  For now I will focus on IIT.   

If you have never heard of Tononi, Koch, or IIT the first task is to read the paper.  I found it to be very clear in terms of definitions, postulates, and a clearly stated theory.  They point out that every experience will have an associate neural correlate of consciousness (NCC). There is currently an explanatory gap at the level of how conscious experiences are actually produced by the NCC.  They discuss the axioms necessary for a coherent phenomenology of consciousness.  From there they move on to the postulates.  Eventually they discuss how a conceptual structure that is maximally irreducible conceptual structure occurs in the brain.  These states are also known as quale.

They give a couple of examples about how conscious states occur within their theory.  They provide and example of how to calculate the quality and consciousness given a particular state containing elements (Figure 4).  They provide a clear example of the physical substrate of experience (complex), and a set of maximally irreducible cause-effect repertoires (concept), and a maximally irreducible "cause -effect structure in cause-effect space made of concepts..." or conceptual structure (quale)(p. 12).  The quantity of experience or consciousness is specified as Φ^max.  The quality of experience is the form or shape of the conceptual structure. Distinct shapes occur with different experiences.

A more accessible example is discussed on page 9 and that is seeing Jennifer Aniston in a movie.  In that case, the complexes at the neuronal level affects the probability of past and future states. Consistent with neuroanatomy many specialized neurons are firing or not firing in the visual system that are associated with Jennifer Aniston as an invariant concept.  Other neurons are associated with other invariant concepts that allow for a fuller description in terms of appearance, age, etc.  All of the elements of the complex are intrinsic information and do not depend on visual inputs for example if dreaming or imagining the actress.

The authors also briefly review some of the experimental evidence that is consistent with the theory. They find that the theory is predictive in number of experimental paradigms. Transcranial magnetic stimulation (TMS) can be applied to to conscious individuals and unconscious (dreamless sleep, general anesthesia) individuals. In the conscious state there is a widespread pattern of activation and deactivation noted with high density EEG.  In the unconscious state cortical response is local or global and stereotypical - integration and information are lost.  A metric called the perturbation complexity index (PCI) a measure of the EEG compressibility from TMS stimulation can be used consciousness and it decreases in states that lack it.   

Tonini has been very explicit about the issue of machine consciousness - it doesn't exist no matter how sophisticated the machine is.  Any machine recognizing inputs that the human nervous system would recognize and producing identical outputs, even if that machine duplicates the structure and function of the human brain - is not conscious.  Tononi uses the consciousness science term zombie to characterize such machines.  By definition a zombie system is one that lacks consciousness and they are described as being subsystems in humans (2) when they are active outside the sphere of conscious recognition.

That brings us back to the ability to detect machines from humans.  If a machine is a perfect human zombie in terms of its input and output, we would not expect an empathy or Turing test to throw it off.   IIT theory acknowledges that what appears to be human input and output can be perfectly simulated.  The original Blade Runner protocol seems more than an empathy test. Specific questions about past memories illustrate an attempt determine if there is continuity between any current and past experiences, even though in the case of Rachael - the memories are false and implanted.

That being said IIT states there there is no Turing test for consciousness.  By now it does seem that fairly basic programs (like self learning neural nets) can replicate a narrowly defined human skill. In that case many people speculate that there is an intelligence or even human consciousness behind it.  On the other hand the perturbation complexity index (PCI) seems like a potentially useful test based on current results.



George Dawson, MD, DFAPA


References:

1: Tononi G, Koch C. Consciousness: here, there and everywhere?  Philos Trans R Soc Lond B Biol Sci. 2015 May 19;370(1668). pii: 20140167. doi: 10.1098/rstb.2014.0167. Review. PubMed PMID: 25823865; PubMed Central PMCID: PMC4387509.

2:  Koch C, Crick F. The zombie within. Nature. 2001 Jun 21;411(6840):893. PubMed
PMID: 11418835.

Addendum:

I read Christof Koch's book Consciousness - Confessions of a Romantic Reductionist a couple of months after this post.  In it he credits Tononi for Integrated Information Theory:

..."The theory of integrated information, developed by the neuroscientist and psychiatrist Giulio Tononi, starts with two basic axioms and proceeds to account for the phenomenal in the world." (p. 6)