Drug Overdoses As A Proxy For Drug Epidemics

Figure 1 - Mortality rates from unintentional drug overdoses.

(A and B) Mortality rates for (A) individual drugs and (B) all drugs. Detailed data for individual drugs are only available from 1999 to 2016, although additional data for all drugs are available since 1979 (this area is grayed out). The exponential equation and fit are shown for all drugs. (Synth Opioids OTM: synthetic opioids other than methadone. This category includes fentanyl and its analogs.) from reference 1 with permission.

A recurrent topic on this blog is drug overdoses due to street drugs and the epidemiology of these overdoses.  As an addiction psychiatrist it is obvious that access to drugs and alcohol is a critical feature of epidemics and the broad exposure has resulted in increased accidental overdoses. The clearest example I can think of is the spread of heroin overdoses to rural America.  That phenomenon did not exist 20 years ago.  The implicit aspect of the access argument is that other commonly held reasons for addiction and overdose deaths like poverty, race, culture, etc are really not reasons that people get addicted to drugs and alcohol.  That happens because they have a biological predisposition and they have access. There is a lot of resistance to this basic idea because it runs counter to the idea of broad legalization of cannabis and other drugs like psychedelics. It runs counter to the idea that the war on drugs is the real problem here and the situation would improve without it.  It also runs counter to the alternate theories about substance use that some people see are identifying remediable problems like poverty and disparity.  I see those theories as being equally stigmatizing and inaccurate.

For all of these reason I was very interested in the recent paper in Science (1) that looks at accidental drug overdoses as a chronic problem rather than a discrete series of events.  The authors analyzed a total of 599,255 deaths from 1979 through 2016 from the National Vital Statistics System, specifically the Mortality Multiple Cause Micro-data Files.  Their main finding is illustrated in Figure 1 above and that is the aggregate overdose mortality rate increases exponentially for a period of 38 years (panel B).  The individual drugs are broken out in panel A. Only accidental deaths due to drugs were included and that determination adds some element of uncertainty to the numbers.

This is probably the best place to comment on the methodology of this research and further visualizations of the data.  Inspection of the individual drug shows that there are a total of 7 drugs.  Common drugs of concern in overdose situations like benzodiazepines and z-drugs are not mentioned specifically but there is a category of unspecified drugs and unspecified options.  The supplementary material lists accidental poisoning due to antiepileptic, sedative-hypnotic, antiparkinsonism and psychotropic drugs - not elsewhere classified, hallucinogens - not elsewhere classified, other drugs acting on the autonomic nervous system, and unspecified drugs, medicaments and biological substances.  By that description benzodiazepines, z-drugs, and other neurological and psychiatric medications are probably in that category. Poisoning by solvents or intentional use was not included. Intentional drug poisoning - both suicide and homicide was not included.  The coding of the cause of death changed substantially in 1999 providing more detail and allowing for the separation of synthetic and semi-synthetic opioids after that time. Mortality rates were calculated by drug type, age, sex, and urbanicity.

A few points from the initial graphs. Mortality curves have generally increased for all of the drugs of interest since 2010 except methadone and the unspecific drugs. By the authors definition the range of the unspecified drugs is so broad that it may conceal clear trends within subcategories like benzodiazepines and z-drugs - both important in polydrug overdoses.  The authors suggest that the variability in some of these lines like the dip in the prescription opioid line after 2010 may have been related to attempts to reduce the number of prescriptions, laws making mandatory checking for prescriptions for controlled substances prior to prescribing, and the production of a long acting and less abusable form of oxycodone in 2010.  It seems as likely that that a lot of prescription opioid users switched to heroin at that point reflected by the rapid increase in heroin death rates from 2010 to the end of the study period.  There is a time lag to 2013 and at that point the fentanyl death rates begin an even steeper curve to the end of the study period.  There is no associated decrement in the heroin or prescription opioid curve at that point suggesting that the fentanyl rates reflects a different problem from the baseline opioid death rates. Those problems could include the fact that fentanyl is much more toxic, it could be an adulterant, it could be sold as heroin by diluting it, and it could be sought out as a way to pursue a high when tolerance has developed to the original opioid being used. The authors points out that increased access to fentanyl was documented by increased seizures by law enforcement. The decrease in methadone deaths may have been due to its removal from pain formularies and  CDC initiative on discouraging use for pain medication due to excessive toxicity.

In panel B, the authors shade the area up to 1998 to show when the opioid epidemic begins.  They make the point "of particular interest is the observation that the first half of this long smooth exponential growth curve predates the opioid epidemic."  While that may be true, it is obvious graphically that the 1979-1998 curve could also be extended without the inflection point in 1998 without the superimposed opioid epidemic and significantly higher mortality rates.

The authors also examined what they referred to as drug specific subepidemics, building on their assumptions that the exponential mortality curve that they describe is due to subepidemics. Their methods of analysis included heat mapping and geospatial hotpot analysis.  I elected to license the latter image and include it below.

Figure 2 - Geospatial hotspot analysis by drug and period.

The Gi* statistics are standardized using pooled statistics across all drugs and periods. The various shades of red and blue indicate pooled standard deviations above and below the pooled mean, respectively, as shown in the legend. The small black circles indicate major cities with populations greater than 300,000 people. None of the regions were less than 2 pooled standard deviations below the pooled average. (Synth Opioids OTM: synthetic opioids other than methadone. This category includes fentanyl and its analogs.) From reference 1 with permission.

For the above geospatial hotspot analysis. the authors looked at 8 drug categories, during 4 times frames and all of the time frames are from the opioid epidemic. The only drug that showed a peak intensity and spatial distribution followed by a decline was methadone. All of the prescription and nonprescription opioids show a progressive increase during this time frame.  That patterns are also remarkable for a spread from metro areas to non-metro areas. There are some interesting geographic observations including a relatively cold spot of overdose mortality in the north central states.

Heatmap analysis (not shown) showed a bimodal distribution of mortality in 20-40 yr olds and 40 to 60 yr olds.  Heroin, synthetics, white race, male gender, and urban counties were over represented in the younger group. The older group deaths were predominately white women in rural counties using prescription opioids.  Prescription drug mortality rates four times higher in younger men than women were attributable largely to synthetic opioids.

The authors main point in the paper is that the combination of epidemics came together to compose the exponential curve after the inflection point and that there is no clear way to figure out how that happened. They emphasize the importance of understanding these forces and cite a number of possibilities including supply side components of more efficient manufacturing of drugs, better supply chains, high purities and lower prices.  These are all well known factors in why people stop using prescription opioids and fentanyl from legal sources.  They discuss sociological factors like fragmentation of communities, despair and a lack of purpose. They discuss public health interventions like community surveillance for patterns of drug use and availability of addiction treatment for secondary and tertiary prevention.

As I read the article, I thought about my model of addiction and that is biological vulnerability + access leads to addiction.  Certainly there are people who will say that the sociological concerns described by these authors can lead to the biological vulnerability, but the protective factors in some of those communities are generally ignored. The authors seem to have at least some of the data here to show that socioeconomic status and race do not determine drug epidemics. Availability determines drug epidemics and there is no better example than some of the data they present here. In addition to race, urbanization is also an example of vulnerability + access with the spread of overdose mortality out into the country side. There is an additional dimension of data here that could be used to look at these mortality rates and that is US Census data provided tract-level measures of poverty, education, crowding, and race/ethnicity. In other words how does the mortality correlate with these factors. A recent study of alcohol retail density showed a high correlation with these factors.  In other words, urban minority populations face a higher level of retail alcohol outlet density and exposure than white populations in urban or rural zip codes. The only difference from the study in reference 2 is that there are no clear measures of opioid exposure. 

This is an important study with a unique approach to the problem of progressive drug epidemics.  Mortality rate from overdoses is not the same as measuring the total drug exposure and resulting addiction but there is no clear way to determine that.  I would also not consider the heroin and fentanyl mortality rates to be independent of the original increase due to prescription opioids. My rationale is that there are very few people that start using either compound. Once an addiction to opioids starts there are progressively larger numbers of people each year competing for the pool of illicit opioids. They are looking for less expensive alternatives. Many are not risk averse and are consciously looking for more potent opioids. Although there is no data to support the progression from prescription opioids to fentanyl and heroin - clinical experience suggests it is the likely explanation and it could account for the mortality curve in Figure 1 as a single rather than multiple epidemics. 

These authors have come up with a unique contribution to the literature and I encourage anyone interested in the epidemiology of drug epidemics to read the full text of this paper.

George Dawson, MD, DFAPA 



References:

1:  Jalal H, Buchanich JM, Roberts MS, Balmert LC, Zhang K, Burke DS. Changing dynamics of the drug overdose epidemic in the United States from 1979 through 2016. Science. 2018 Sep 21;361(6408). pii: eaau1184. doi: 10.1126/science.aau1184. PubMed PMID: 30237320.

2: Berke EM, Tanski SE, Demidenko E, Alford-Teaster J, Shi X, Sargent JD. Alcohol retail density and demographic predictors of health disparities: a geographic analysis. Am J Public Health. 2010 Oct;100(10):1967-71. doi: 10.2105/AJPH.2009.170464. Epub 2010 Aug 19. PubMed PMID: 20724696.

Permission:

Both Figure 1 and Figure 2 above are used with permission from the American Academy for the Advancement of Science (AAAS) the copyright holders.  The figures are both from reference 1 above used with permission per the following license number  4441420359702  obtained on October 3, 2018.  The AAAS also requires the following notice based on this content:

"Readers may view, browse, and/or download material for temporary copying purposes only, provided these uses are for noncommercial personal purposes. Except as provided by law, this material may not be further reproduced, distributed, transmitted, modified, adapted, performed, displayed, published, or sold in whole or in part, without prior written permission from the publisher."

Components of Patient Outcome

It is a good idea to go back and take a look at some basic components that predict patient outcome in medical (including surgical) treatment. There is a  skewed representation of practically all medical information that is portrayed in the press.  A big part of that misrepresentation comes back to missing what the real components are that determine the outcome.  I have listed a few of what I consider to be the major components in the above diagram and will take a look at each one in order.

Technical expertise of the physician is obvious in surgical and other invasive procedures.  Henry Marsh covered it in a book on his career as a neurosurgeon (1).  He discussed the process of surgery but also the unpredictable results.  An operation may have seemed flawless but the patient ends up with a postoperative complication that had to be due to the surgery and dies or is permanently disabled.  I have discussed the issue with neurosurgeons myself and directly observed them in action.  There are clear differences in skill level and operative outcomes that appear to be based strictly on manual dexterity and coordination. There are differences based on the number of procedures that are done.  Expertise is easy to conceptualize at a manual level.

Psychiatrists on the other had usually balk when I refer to the technical expertise required in the field.  The clearest example in training is learning about inpatient psychiatry before proceeding to outpatient clinics.  Most psychiatric trainees just don't know enough as first year residents to proceed to an outpatient clinic and start to treat anyone who walks through the door.  The inpatient setting provides the training necessary to address emergencies first.  Outpatient skills can be built on that foundation. An associated issue is how much you need to know. If you are immersed in medical settings like hospitals, you probably need to know about a broad range of medical and surgical conditions and how they can lead to or complicate treatment of psychiatric disorders. That knowledge base includes a broad range of basic sciences and the updates relevant for the field. Expertise in psychiatry also encompases the interpersonal dimension. Psychiatrists should be the medical specialists that have the highest level of competency in the interpersonal dimension and how their personal feelings toward patients can complicate care.  That requires a significant level of training and expertise.

Biological variability is poorly understood by nonphysicians.  The best examples are allergic reactions to medications and severe idiosyncratic reactions like liver failure or kidney failure in response to a medication.  But they can also be more common on a population wide basis and mediated though a number of mechanisms.  The variability has to do with both the way the medication is absorbed and metabolized and also specific effects that occur at the tissue level.  In some cases this leads to clinical trials where the results do not seem that impressive (antidepressants, radiofrequency ablation for atrial fibrillation) but where there is a clear consensus that the intervention works.

 Every procedure in medicine whether it is a prescription, a surgical procedure or a medical device is characterized by a study.  The quality of those studies varies in terms of design and statistical analysis.  The usual goals of early studies is to gain FDA approval for release into the market in the US and elsewhere.  In the process of the safety and efficacy studies, quire a lot is learned about the drug characteristics applied over a larger population.  That data is applied toward describing that population based effect to the physicians who will eventually be prescribing the medical or procedure.  In some cases there are considerable political cross currents that can affect the straightforward statistical data as in the case of coronary artery bypass grafting or the use of beta blockers for hypertension or preventatively post acute MI.  There is currently an active debate about prostate screening and the burdens and harm done by screening, but at the same time there are clinical trials that show prostate cancer survival is improved by radical prostatectomy (RP) - but that there is no difference between standard RP versus robotic surgery.  It is  doubtful that the statistical facts of the procedure will ever be far from the expertise domain.

The final critical outcome parameter is the patient's ability to consent. It is not an easy task to hear about current medications or interventions with imperfect results and decide what the best course of action is.  Apart from the cognitive analysis, there is an emotional component of having a significant illness.  There is also the requisite ability to tolerate risk. Practically no medical interventions are risk free but some have much higher risks that others. The risk ranges from death or disability to an allergic reaction or long list of possible side effects.  The risk of not taking the medication or having the procedure done can also be significant including death.         

One of the best examples in the literature about the importance of the patient related component of these outcome variables was Kurt Gödel.  He was a renowned mathematician and logician who suffered from severe medical problems including gastric ulcers, prostatic hypertrophy with severe lower urinary tract obstruction who either postponed or refused treatment to the point where he was near death or in severe distress. He had a severe urinary tract obstruction and refused surgery to correct the obstruction. He elected to remain catheterized for a period of 4 years until the time of his death.  He eventually died of starvation in a hospital refusing to eat because he believed his food had been poisoned and at the time of his death weighed 65 pounds (he was 5'6" in height). Gödel was one of the geniuses of the 20th century who experienced problems that consistently and adversely affected his health.  Shortly before his own death and Gödel's death his friend economist Oskar Morgenstern made this observation in his diary (from reference 2; p 251) after a phone call from Gödel:

"It is hard to describe what such a conversation means for me; here is one of the most brilliant men of our century, greatly attached to me ..... [who] is clearly mentally disturbed, suffering from some kind of paranoia, expecting help from me, and I am unable to extend it to him. Even when I was mobile and tried to help him I was unable to accomplish anything. [Now,] by clinging to me - and he has nobody else, that is quite clear - he adds to the burden I am carrying." - July 10, 1977.

Morgenstern died 16 days later of metastatic prostate cancer.

 The main takeaway message from this brief commentary of variables affecting patient outcome is that it is a complicated process. There needs to be open communication about the uncertainty at every step of the way. In the informed consent discussion (that should always occur) there should be enough information exchanged so that the patient/decision maker has a clear idea of the risk involved.

Even then, the most intelligent decision makers can fail.


George Dawson, MD, DFAPA



References:

1:  Henry Marsh.  Do No Harm. Thomas Dunne Books, St. Martin's Press; 2014.

2:  John W. Dawson.  Logical Dilemmas: The Life and Work of Kurt Gödel. Natick, MA: AK Peters, LTD; 1997: 229-253.





     

Anti-ECT Rhetoric ........

There is probably no clearer example of the pernicious effect of rhetoric in psychiatry than what has happened with electroconvulsive therapy or ECT.  ECT has a demonstrated therapeutic and life saving effect for decades and yet it is a flashpoint for antipsychiatry groups.  I had the experience of being attacked for pointing this out and the people attacking me posted references from a book that was published in 1980 and it was debunked at the time of publication in a book report in the New England Journal of Medicine.  Ignoring what the facts are - often for decades is one of the rhetorical techniques. Interestingly that technique was pointed out in the book report.

There is no doubt that ECT is a very safe and effective treatment. The onset of action is also much faster than can be expected from medications of psychotherapy. But the most important aspect of the ECT recommendation is way it is recommended by clinical psychiatrists.  It is not recommended for everyone just because it is highly effective.  Clinical psychiatrists recommend ECT for treatment resistant depression. By definition, that means various treatment modalities have been tried and found to be ineffective.   That may have included many antidepressant trials. It is often forgotten these days that psychiatrists are seeing patients who have been treated for decades with antidepressants.  I often see people who have been taking the same antidepressant with dose modifications for 10-15 years or people who have been taking 5-9 different antidepressants over the same period of time.  Those antidepressants have been prescribed by various non-psychiatrists.  The majority of these patients have also seen psychotherapists and list the acronyms (CBT, DBT, IPT, ACT, REBT, etc) and specifics about the therapy. They are also clear that they were not helped by psychotherapy.

The process of being stuck in that situation by itself can lead to increasing hopelessness associated with the thought: "Am I always going to be depressed? Is there anything that can be done to get rid of this depression. Would it be better for myself and anyone else if I was just dead rather than hanging on like this?" In the case of more dangerous forms of depression, delusional thinking presents a greater level of danger in the form of suicide attempts and completions.  One of the ironies of depression is that the public perceives it as a minor condition that is easily treated.  That ignores the fact that most people that die from suicide are depressed.  Severe depression is a lethal condition and not a minor one. Ignoring severe depression and not treating it is an option only by denying that it exists.

A second group of people who need ECT as a life saving treatment are people with catatonia.  Catatonia is a potentially lethal condition that develops in association with other severe mental conditions - especially mood disorders.  Malignant or delirious catatonia had an extremely high mortality rate (80%) prior to use of ECT.  Death from catatonia typically occurred from severe food and water refusal, agitation leading to congestive heart failure, injuries from severe agitation, and in some cases autonomic dysregulation often seen as elevated body temperature with no evidence of infection.  This group of patients is hospitalized and cannot function outside of a hospital setting. Even inside a hospital they need very intensive monitoring to protect them from injury.  The fastest way to treat these patients, keep them safe, and help them to get out of the hospital is ECT.  In fact, it may be the only consistently effective therapy.   

People with severe medical problems who cannot tolerate antidepressant or antipsychotic medical constitute another group who can benefit immensely from ECT.  In many cases these patients are disabled by depression and do not appear to be recovering form their associated medical illness.  They may be in a coronary care unit and taking in inadequate amounts of food and fluids due to depression.  At the same time they may not be able to take medications due to an acute cardiac condition.   They can generally be safely treated with ECT.

A final important group of people are those with experience with ECT.  They typically have a form of disabling depression, know that most of the usual medications either do not work or cause unacceptable side effects.  They are also typically very functional people and know that they need to get back to work as soon as possible.  They request elective ECT for treatment.

Why should anyone want to deny ECT to people in the above groups when it is safe and effective?  Here is some of the rhetoric evident in any Internet discussion. 


1.  I don't like it and will never accept it!

You don't have to.  First it is only indicated for a limited number of severe conditions like treatment resistant depression, depression, catatonia, treatment refractory mania, psychosis, and high suicide risk. If you don't have any of those conditions no psychiatrist is going to recommend it to you.  But further - even if you have the conditions a psychiatrist may not recommend it because it is not available in the area.  Political rhetoric may have driven it out.  Other less effective treatments like ketamine infusions and transcranial magnetic stimulation (rTMS) may be recommended instead.

The second issue is informed consent.  You can decide you don't want it. Story over at that point.  I have no interest in talking anyone into it.  My job is to provide the latest information and the patient decides and consents or does not consent. 

2.  ECT causes brain damage!

Irrelevant based on the informed consent issue outlined above unless you are trying to make a political argument.  But more striking is the body of evidence that has accumulated that there is no evidence at all that ECT alters brain anatomy or leads to neuropathological changes. Denial or lack of scholarship are the most likely explanations of this problem.  Given the ease with which medical information can be accessed these days and the fact that many people making these arguments use antiquated and disproved data while ignoring the contradictory positive data - denial or intentional distortion of the data are the only obvious motives.

3.  There are important political and ethical considerations!  

Are there really?  Not when you look at the severity of the problem. Considering psychiatric illness and disease on par with other physical illnesses is difficult if you have never seen what happens on an acute care psychiatric setting where the most serious problems in psychiatry are treated.  In the current American healthcare system these patients are often committed and in some cases transferred to state hospitals if they do not get well.  In some cases, states have found it easier to close hospitals so that these extremely ill people are sent back to their families, to jail, or to the streets.  I routinely see patients who have had a severe psychiatric illness and were ill and unstable for decades.  In many cases they are chronically ill and never regain stability because of neglect or inability to treat them. All of those years of suffering and in many cases death could have been avoided with proper treatment early in the course. In many cases the proper treatment was ECT.

How does that compare with the rest of medicine? It does not. People with life threatening and/or disabling conditions are allowed access to high risk treatment options. A few examples can illustrate this point.  Cancer is a good example.  Chemotherapy agents are high risk medications that can lead to serious and in some cases lethal side effects. Giving informed consent for treatment with chemotherapy requires agreeing to accept the risk of congestive heart failure and many other serious and potential lethal side effects from those agents. The explosion of immunotherapy agents for autoimmune disorders provides similar risk.  Even more importantly, every patient consenting to the treatment are considered to be competent consentors.  In other words they are  considered able to understand the information, make rational decisions about it, and provide consent on that rational basis.  Patients consenting to ECT may not be competent cosentors based on vulnerability laws in states.  Consent is not considered to be competent necessarily based on status (on an inpatient psychiatric unit or outpatient clinic) or by specific statutes about diagnoses or recent behavior.  Those same rules do not apply to people giving consent for high risk medical or surgical treatments.  Keep in mind that ECT is portrayed as a high risk procedure - but in reality it is not.

4.  What about involuntary treatment with ECT?   

Some states have statutes that allow courts to decide on whether or not people who are civilly committed and have high risk psychiatric illness.  That is typically based on a hearing with opposing attorneys and a judge.  Unique state statutes provide the standards that must be met in those hearings.  The court typically hires examiners (psychologists, psychiatrists) to testify about diagnosis and recommendations.  Since ECT is a medical procedure psychiatrists may be required to examine the patient and testify about the recommendation.  These hearing may also be used because the patient is not competent to consent, but clinical competency is not a formal legal decision until it has been made by a court.  In these cases the state has an interest in preventing death and disability of its citizens. 

I have thought a long time about getting rid of involuntary treatment with ECT but how would that work?  The psychiatrist would be in a position that would be difficult to defend from a clinical standpoint.  Anyone with a severe disorder not responding to standard treatment needs to hear about ECT as an option.  Their treating psychiatrist needs to make sure that happens and that the discussion is documented as well as the patient's response. If involuntary treatment was not an option for severely ill people who were unable to consent, they would basically be maintained in a chronically disabled, high risk, or worsening course of illness. I don't think that is a decision that a psychiatrist can make because it is essentially one with a dubious basis.  At that level court intervention makes sense.

5.  What can be done to address ECT side effects if I get them?

First, like all medical procedures make sure the ECT is provided by an expert, working with an anesthesiologist who is used to providing general anesthesia for ECT.  Second, that expert needs to assess the results and side effects of those treatments on a treatment to treatment basis.  Modifications in techniques and side effect prevention need to occur on a regular basis if side effects are there.  In the case of voluntary ECT and significant side effects, stopping the treatment at any time is an option for the patient. In the case of involuntary treatment or substituted consent by a court involved family members or the patient can advocate for the same discontinuation.  The attending psychiatrist can also initiate discontinuing the treatment at any time based on side effects.

The perplexing issue is the number of people who write about numerous ECT side effects and that they have had a course of many treatments.  I ask myself, how does that happen?  Have they been told that they will get used to side effects?  Were the side effects ignored?  What happened?  Why didn't they just decide to stop? In those cases, the first step should always be to discuss the issues with the attending psychiatrist and psychiatrist performing the ECT.  If that is not effective, every state in the United States has multiple forums for investigation.  In the state of Minnesota, there is an Ombudsman for Mental Health and the Board of Medical Practice. Both of these agencies will exhaustively investigate any complaint brought to their attention. People are encouraged to complain about physicians and a national watchdog agency monitors how many complaints are made in each state and holds states with low complaint rates in a negative light.

More problematic is the political approach to ECT and how it has affected policy and has the potential to decrease the availability of this modality for very ill patients.  A recent editorial review pointed out how the process in the UK was factored into NICE guidelines that were restrictive and that those guidelines may adversely affect ECT practice in the US (1).  The restrictive nature of the NICE guidelines was apparently based in part on a flawed study suggesting more dissatisfaction and memory loss than expected.  A re-analysis of that data (3) describes the nature of those flaws that include in part:

"Two other studies selected individuals from user/advocacy groups generally biased against ECT and were probably overlapping. The significance of memory problems was not mentioned in any of the studies."

It is interesting that it took 9 years to reassess the original data and come to that conclusion and in the meantime it apparently was enough to alter ECT policy in the UK.

No other medical specialty allows political biases to affect practice standards, especially when it compromises the care of severely and potentially fatally ill patients. 

There is no reason why psychiatry should either.
 

George Dawson, MD, DFAPA 


 References:

1: McDonald WM, Weiner RD, Fochtmann LJ, McCall WV. The FDA and ECT. J ECT. 2016 Jun;32(2):75-7. doi: 10.1097/YCT.0000000000000326. PubMed PMID: 27191123

2: Rose D, Fleischmann P, Wykes T, Leese M, Bindman J. Patients' perspectives on electroconvulsive therapy: systematic review. BMJ. 2003 Jun 21;326(7403):1363. Review. PubMed PMID: 12816822.

3: Bergsholm P. Patients' perspectives on electroconvulsive therapy: a reevaluation of the review by Rose et al on memory loss after electroconvulsive therapy. J ECT. 2012 Mar;28(1):27-30. doi: 10.1097/YCT.0b013e31822d796c. Review. PubMed PMID: 22343578.

4:  FDA (Proposed Rule for reclassifying ECT devices):  Neurological Devices; Reclassification of Electroconvulsive Therapy Devices Intended for Use in Treating Severe Major Depressive Episode in Patients 18 Years of Age and Older Who Are Treatment Resistant or Require a Rapid Response; Effective Date of Requirement for Premarket Approval for Electroconvulsive Therapy for Certain Specified Intended Uses AGENCY: Food and Drug Administration, HHS. ACTION: Proposed order.

 https://www.gpo.gov/fdsys/pkg/FR-2015-12-29/pdf/2015-32592.pdf

5:  Electroconvulsive Therapy (ECT) Devices for Class II Intended Uses Draft Guidance for Industry, Clinicians and Food and Drug Administration Staff.  

https://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM478942.pdf

To All Of The Opioid Epidemic Deniers........

I encountered an absolutely stunning piece the other day about how there really was no opioid epidemic.  The author's various arguments all centered on the basic idea that law enforcement and other special interest groups spread the lie about opioid use being epidemic so that they could increase law enforcement measures and make it more difficult for chronic pain patients to get access to opioids.  There are a lot of these conspiracy theories going around. There are active posters on Twitter who continue to beat the drum that this is a heroin or fentanyl problem and not a problem with prescription opioids. The same group will suggest that the problem is now benzodiazepine prescriptions - maybe even gabapentinoids! They make the false claim that "anti-opioid zealots" want to stop opioids for chronic non-cancer pain, even if it means that some of those pain patients will commit suicide. They continue to post debunked information about how a trivial number of pain patients become addicted to opioids if they are properly prescribed.

Time for a lesson about the opioid epidemic and how it evolved from the land of 10,000 lakes - my home state of Minnesota.  The graphics I am posting here are all from the Minnesota Department of Health and the Minnesota Department of Human Services.  In some cases the opioid involved overdose mortality is broken down into specific categories and in other cases it is just an aggregate number.  The first graphics I am going to post is on the epidemiology of admissions for substance use treatment from two time intervals for comparison.

These maps are county by county density plots of the rate of admissions from a particular county comparing 2007 to 2017.  There are certainly limitations using administrative data but on the other hand it is the only data available and I would not be surprised if there was not some reporting obligation by licensed treatment programs to the state.  The most significant limitation on admissions data is that services in the US are rationed and there are never enough openings or finances to treat the people who need it.  Treatment programs also open and close. There is the question about whether all admissions are captured.

Given those limitations it is clear that the rate of admissions form Minnesota counties of residents being being treated for heroin use, methamphetamine use and intravenous drug use (IVDU) have all increased significantly from 2007 to 2017. In fact, the total number of IVDU admitted in 2017 was about the same for both heroin (N=5148) and methamphetamine (4843) users.  By comparison, in 2007 the number for IVDU were about 20% of the current numbers with heroin admissions at 1008 and methamphetamine admissions at 798.  In a separate report speedballing or the injection of methamphetamine and heroin is discussed but there are no numbers given on people who are using both.

The first lesson from admissions data is that the total number of residents using this compounds per county and the rate of use per county are both increasing. The geography of the spread is also of interest.  Minnesota has 54 counties and only 7 are considered metropolitan or urban counties.  The rest are considered rural.  Large blocks of these rural counties have increasing numbers of residents being treated for heroin, methamphetamine, and IVDU.  To me that is an epidemic.

 Additional data looking at the epidemic in Minnesota comes from reference 2.  It is interesting because it is a direct comparison of deaths occurring in rural versus metro or urban counties.  It also looks at the types of drugs involved in the overdoses.

As can be seen in the above graphs, opioid and heroin overdoses both increased over the 16 years of the study period. In the Metro sample, the baseline rate of opioid overdose deaths was 43 Metro and 11 Greater Minnesota in 2000 and by 2016 this had increase to 256 and 138 respectively.  In the case of heroin overdose deaths the baseline rate was 1 Metro and 1 Greater Minnesota in 2000 and by 2016 the increases were to 110 and 40 respectively.  The rate of increase in opioid and heroin deaths in Greater Minnesota may have been impacted by the greater rate of increase in stimulant use and associated deaths.  This may imply greater availability of stimulants across a wider population area than opioids - but overdose deaths is an obvious problems for all of the compounds listed on these graphs.  According to my arithmetic that is a 9 fold increase in the death rate due to opioid and heroin overdoses over 16 years.

The final consideration is how is it that so many people started using heroin and fentanyl?  Many of the epidemic deniers seem to be suggesting that it just happened that way.  It was totally unrelated to opioid prescriptions.  If a clinician like me tells them that I have talked to hundreds of opioid users and I have heard initial use of heroin from exactly one person - they suggest that I don't know what I am talking about.  That is where this compelling graphic about opioid prescriptions comes in showing about an 8-fold increase in opioid prescriptions in the USA over about the last two decades. It would place opioid overdose deaths as about the 13th leading causes of death in the state.  Once an addiction starts, the economics of drug use is that most people can get heroin for considerably less than they can buy prescription opioids on the street.  That and the general characteristics of addiction lead to higher risk use of intravenous heroin and a greater potential for overdose.

Even though every data set has it's limitations, the alternate hypotheses by the epidemic deniers need to be considered as alternate explanations.  Conspiracy theories about people scheming to prevent the treatment of chronic pain and the "war on drugs" don't make any sense. If either explanation were true it would have to explain the explosion in opioid prescriptions in the 21st century and everything that unfolded since.

It does not.

The only reasonable public policy must stop these overdoses and explode the associated myth that excessive opioid prescribing is necessary for the treatment of chronic non-cancer pain.



George Dawson, MD, DFAPA


References:

1:  DAANES SUD Detox and Admission Trends CY1995-CY2017.  Minnesota Department of Human Services, 2018.

2:  Drug Overdose Deaths among Minnesota Residents 2000-2016.  Minnesota Department of Health Injury and Violence Prevention Section, 2018. Link


Graphics:

All graphics are from public documents from the Minnesota Department of Health and Minnesota Department of Human Services.

Happy Labor Day 2018!

I have posted Labor Day greetings here since 2013 and did not want to miss this year. The previous posts highlight the problems of being a physician in the USA including being treated like production workers, mismanagement by managed care and their backer in the US government, the electronic health record as a physician burden, maintenance of certification and burnout.  There was continued concern over the past year about burnout and physician suicide. Like my last posts there was very little positive to report. Physicians are still laboring under a ridiculous productivity system that reimburses them a trivial amount with the expectation of physicians who can form their own independent groups and escape the burden of management by health care corporations.  Healthcare corporations in turn seem quite content to hire non physicians to replace the doctors who have left.  The question is:  "Have there been any bright spots?"

On the whole the answer is "No." In one of my previous posts I pointed out the number of young colleagues in Minnesota who were going into private practice and I considered that to be a plus.  Let's take a look at the scorecard:


1.  Physician productivity - physicians directly employed by healthcare companies or those who accept private insurance are still working under a rationed system that expects excessive productivity to make up for both insufficient reimbursement and the fact that physicians have to waste at least half of their time as clerical workers or working to legitimize and insurance or pharmaceutical benefit managers rationing decision.  I am seeing more paperwork rather than less and that is a hot topic on Physician Twitter.  In addition to prior authorizations and denial of care, these companies are now sending out notifications about prescriptions and prescription patterns.  They frequently get the prescribing physician wrong and they issue warning for medication  that are antiquated like: "Doctor did you know that your patient is on two medications form the same class?" Or "Doctor - did you know that your patient did not refill their antidepressant at the expected time?"  The vast majority of these warnings are irrelevant - but they want a return fax upon receipt but warn that all personal health identifiers must be shredded.  A new way to harass physicians with irrelevant faxes and mailings.

2.  EHR -  there have been no breakthroughs in the EHR.  It is still a repetitive stress disorder clickfest that produces unreadable documents.  The major EHR companies continue to have monopoly power and the ability to charge outrageous licensing fees for some of the poorest quality software ever written.  They have no incentives to change anything. At least members of Congress are no longer talking about how the enhanced productivity from this software will result in cancellation of medical inflation.  None of that has happened.  The only potential bright spot is that some regulators are talking about bringing some high tech companies into the area because the existing companies have done as poor a job at interoperability as they have about everything else. 

3.  Pharmaceutical benefit managers -  every physicians nightmare has stayed about as bad as ever with the exception of the forms I mentioned that seem to be a very crude attempt at saying they are engaged in pharmacovigilance.  Of course they are not because quality is a distant memory when you are monitoring a medication that the physician may not have wanted in the first place.  It may be a medication that the PBM got the patient to take because they denied the physician's first choice or erected a steep enough copay that the patient could not afford the physician's first choice.

4.  Managed care/Health Insurance companies - they continue to run the healthcare system in the USA as proxies for the irrational ideas from Congress.  The most irrational of these ideas is that a systems that has led to a 3,000% increase in administrators in the past 30 years can shortchange patients and physicians enough to in some cases turn a profit for shareholders.  The coexisting political myths that this is about "market choice" or "single payer/socialized medicine versus capitalism" don't help anyone but apparently reassure Congress that these proxies are doing what they want them to do. 

5.  Maintenance of certification - The American Board of Medical Specialties and the respective specialty boards continue to have a stranglehold on physicians with this arbitrary expensive and time consuming recertification process.  In combination with the work expectations and inefficiencies, MOC is a significant contributor to burnout and there has been no gain in patient treatment or outcomes related to this process.  Life long learning has been the mainstay of physician education rather than arbitrary exams that seem suitable for prep school rather then working professionals.  There have been some decided bright spots in this area.  The National Board of Physicians and Surgeons (NBPAS) has more visibility as an organization that supports the longstanding tradition of life long medical education as the standard for recertification.  It is gaining support in some states and some physicians in states where it is not formally supported have learned that they can get NBPAS certification and use it nonetheless.  Make no mistake about it - this is a hot political issue and there are many organizations with a clear interest in using MOC to sink physician autonomy once and for all.  To me this is reminiscent of when a manged care company took over a hospital I worded at and the physician department heads were either fired or replaced by administrators. Every politician and bureaucrat out there knows that the best way to squelch physician dissent is to work them to the point they have no time to do anything else. MOC burns bright as the last tool they need to make this happen.

6.  Burnout - number 1 - 5 above directly lead to physician burnout.  The only bright spot in this category is rhetorical.  Articles suggesting that self-management or a yoga deficiency are less likely to be advanced as causes of burnout.  Physicians are not longer accepting this propaganda and I was an early proponent rejecting those arguments.  The only meaningful way to improve on the burnout situation is by improving the work environment.  Now that we have rating scales for burnout, there is a real danger that we will see groups rated from year to year and any random fluctuation on a hardly used scale will be taken as a sign of improvement.  If there have been no concrete improvments in 1-5 above - be assured that burnout is unchanged.

The other bright spots here are the Cardiologists who have stepped up with both NBPAS and the Practicing Physicians of America initiative to go after the organizations behind this MOC movement from an antitrust and fraud perspective.  I never thought Cardiologists were that politically active but these initiatives have clearly changed my mind.  The incongruency in this process is that physicians everywhere belong to professional organizations often more than one.  Physicians in the trenches everywhere support traditional life long medical education and not the MOC appraoch and yet none of our expensive professional organizations will make that stand or for that matter take a stand on any of the above matters.  This is a classic example of what happens when a few special interests get in positions of power in professional organizations. 

That is the summary for this year. I am really hoping that the NBPAS and PPA can make differences and make the lives of physicians everywhere somewhat easier.  I did not touch on the subject of physician suicide.  It is a topic that requires a more detailed discussion and improving the work environment for physicians is likely to have an impact.

Every week I talk with doctors in very stressful circumstances who are trying to solve difficult problems.  None of them should have to work in the present work environment for physicians. 


George Dawson, MD, DFAPA






   

The Importance of Electrocardiography In Psychiatric Practice....

The US Preventive Services Task Force came out with general recommendations for resting and exercise electrocardiography a few days ago in JAMA Cardiology.  I posted the above comments on Twitter to emphasize the importance of the ECG in psychiatric practice.  I was also pleased to hear the word I frequently hear when patients, families, and other staff question the need for electrocardiography and my refusal to start of continue certain medications without seeing that ECG. That word is that the ECG is an expensive test and why do we want to incur the additional expense?  It is not an expensive test and the information it yields for the money spent is high.  The actual guidelines are available free online and if you are a psychiatrist or any other practicing physician I encourage you to read them.

The interesting aspect of this publication is that the accompanying editorial by Joseph S. Alpert, MD is more informative that the USPSTF document.  The conclusion of the USPSTF document is that screening asymptomatic individuals with resting or exercise electrocardiography does not provide useful information for predicting or preventing events due to cardiovascular disease. Dr. Alpert points out that this is a straw man argument and provides a very handy list of 15 clinical indications for resting or exercise electrocardiogram (ECG) recording.

Over the past 30 years I have ordered hundreds of ECGs and in reviewing that list, I found 6 of the common indications.  Admittedly some of these tests were in suboptimal conditions.  I am thinking primarily of the patient on a psychiatric unit with chest pain. In settings where I have practiced, several factors led to situations where I was getting the ECG and doing the early work before the consultant arrived.  In some rare cases, the troponins were being collected while the patient was still on the psychiatric unit.  In those cases the indication was to rule out acute ischemia pending additional biomarkers. 

If you examine patients, I found it was a common occurrence to makes diagnoses of arrhythmias - that were previously unknown to the patient - most commonly atrial fibrillation.  In some cases, ventricular arrhythmias and rhythms due to conduction disturbance are also noted.  An ECG is a very inexpensive test to determine what is happening. It is also a good way to get consultants interested in the problem.

The advent of concern about the QTc interval in psychopharmacology was probably the biggest driver for psychiatrists to order ECGs.  According to Dr. Alpert this is a legitimate indication for ordering the ECG and the bulk of ECGs I have ordered have been focused on matters of cardiac conduction.  The majority of those orders are based on the characteristics of the medication.  The FDA has made this problem a lot harder than I think it needs to be.  It would be useful to have a screening test for rapidly identifying patients who might be at higher risk for this abnormality but that would probably not take into account anatomical abnormalities that can affect the problem.  There is a certain amount of mystery in this area - when I see medications like haloperidol flagged for QTc prolongation and I have consulted on ICU patients taking haloperidol on telemetry and never seen a case - it tells me that some of this screening and concern may not be that well founded.

I also use the ECG (in addition to the cardiac review of systems) in cases of polypharmacy when the patient is taking multiple QTc prolonging medications.  That may involve a baseline ECG and repeat ECGs over the course of treatment.  On the front end of the evaluation, I often show the patient a drug interaction profile with all of the QTc prolongation flags, discuss the plan with them, and advise them to attend to cardiac symptoms suggestive of rhythm problems.  Even though the USPSTF is usually against screening I have picked up many problems with screening ECGs including QTCs of greater that 510 msec and complete heart block.  I think the problem with characterizing ECGs as screening seem to imply that the patient is asymptomatic and has no cardiac risk factors.  Adding a Bayesian term for the patients psychiatrists see would generally taken them out of that low risk category.  That fact and the low cost of the ECG make this an ideal test for the above problems. 

When I consider the ECG issue and the fact that I have ordered more and more of these tests over the years - I also think back to the 1980s and 1990s when it was not uncommon to see a QTc of 500 msec on a person taking thioridazine.  The Cardiology consultants would ask the high risk threshold question: "Does he really need the medication?"  Any affirmative answer usually resulted in leaving the medication in place.

As psychiatry has evolved, I think that psychiatrists are now in a place where they are (or can be) much more proactive about cardiac conduction problems - both in the initial pharmacological approach and in reacting to ECG abnormalities. The only consistent problem I see is the availability of ECG machines and technicians if the clinic is isolated from medical resources.  It may be impossible to get ECGs when you need them for the above purposes.

If you are a resident or an experienced psychiatrist, I think it will pay to get a copy of Dr. Alpert's editorial and take a look at the list.  I think it is also useful to remember there is screening and there is screening.  While you are at it - consider Cardiology Twitter and follow the Cardiologists there who post ECG tracings, how to read them, and what the clinical findings and treatment was. It is an outstanding learning resource in this skill.

Carefully consider all of the cardiac risk factors affecting the patients that you treat and I am sure you will agree with me - the threshold for obtaining ECGs in patients with severe psychiatric disorders should be low. 



George Dawson, MD, DFAPA


Reference:

1: Alpert JS. Does Resting or Exercise Electrocardiography Assist Clinicians in Preventing Cardiovascular Events in Asymptomatic Adults?. JAMA Cardiol. 2018;3(8):678–679. doi:10.1001/jamacardio.2018.1800.

Why The Antipsychiatrists Have It All Wrong

Twitter is an odd place to read about antipsychiatry.  There are apparently some academics in the UK who are keeping it alive and well. I sent this Tweet about the continued mischaracterization of psychiatry by various antipsychiatry factions. Those factions certainly are varied ranging from cults to academics - but they all seem to have an agenda that they are promoting. I certainly don't hope to correct their various rants and obvious conflicts of interest - only to set the record straight from this psychiatrist's perspective.

In a previous post, I pointed out how some of the more famous antipsychiatrists characterize psychiatry as monolithic and fail to appreciate both the diversity in the field and the complexity of the field.  Examples of those errors abound and I included them in previous posts about the monolithic mischaracterization and another rhetorical attack on the DSM-5.

It comes down to power and that argument is a gross distortion of reality. Before I proceed, let me say that I am talking about the time frame that encompasses my training and clinical practice. At this time that is the last 32 years post residency. During that time I have lived and breathed psychiatry and know what really happens in the field.  I came in to this field with my eyes wide open since I had a family member with severe bipolar disorder who was treated for years by primary care physicians with benzodiazepines and antidepressants so that by the time she was able to see psychiatrists - she could be partially stabilized but continued to have significant comorbidity. That family member was my mother.  As her son, I experienced first hand the lack of concern and care by any responsible entity in the community.  When she was extremely agitated and ill to the point that the police were being called repeatedly, I know what it is like when you are a kid and an angry cop says to you: "Do you want us to lock her up like a chicken in a chicken coop?" The cop of course knew nothing about severe mental illness and just wanted to leave and not have to deal with my mother's illness and her 5 young kids (my father was deceased).  In addition to my mother's illness, I witnessed first hand the toll that psychiatric illness had on the neighborhood as I walked to school every day. My point here is that I am not the only kid who had these problems.  In fact, I am certain the general view that psychiatric illnesses and addictions are diseases begins with this experience.

As a clinical psychiatrist with a solid medical orientation, my method has always been one that tries to engage the patient in a detailed analysis and solution to their problem.  Like many physicians, as a resident there is always an emphasis on what you are doing to solve the person's problem, but it was fairly evident that medical interventions themselves were risky and that higher risk interventions should be reserved for high risk conditions. It was also obvious that medical treatment depended on informed consent.  In other words provide the information to the patient and they either consent or don't consent to treatment.  It is really no different than seeing any other physician.

Since antipsychiatrists are a diverse group, they advance diverse rhetoric to advance their agendas.  That typically includes making money or seeking to elevate their status over psychiatry.  I will focus on a single common agenda and that is power.  The last time I actually studied power it was in a physics class.  It certainly never came up in medical school.  Studying psychiatry was an identical process to studying medicine and surgery.  Recognize the problems, diagnose, and treat them.

Somewhere along the line I realized that people were using rhetoric based on Foucault and whatever Szasz adapted from that to suggest that psychiatry had a hidden agenda.  It is so well hidden that it is unknown to psychiatrists.  It is more or less of a conspiracy theory that psychiatry wants to medicalize the treatment of all human behaviors and treat those behaviors as an illness.  Of course along the way, psychiatrists will enrich themselves and inflict untold suffering on the people they misdiagnose and treat.  Take a look at this argument that the DSM-5 was supposed to be a manual about how to live as an example. Their supporting arguments range from the non-existence of all mental illness to the fact that there are no tests that prove there is such a thing as mental illness.  The underlying antipsychiatry theories are predominately from the 1960s and 1970s and they have been classified by philosophers (1).  There has been little change since then - just a long series of repetitive recycled arguments.  The rhetoric can range from the recycled arguments of Szasz to overt threats.  One uniform feature of antipsychiatrists is that they believe they are above any sort of criticism.

The table below contains some of the common rhetoric used by antipsychiatrists. It is not exhaustive, but it is a good example of the rhetoric I referred to in my Tweet.

Here is why their power arguments and all of the associated rhetoric are irrelevant. The reality is that psychiatrists represent only 5% of mental health providers in the US.  Primary care physicians and now nurse practitioners and physician assistants prescribe far more medications than psychiatrists do and they have for some time.  Even though psychiatrists are a little slow in picking up on it – health plans are replacing physicians with non-physician prescribers and that is also true of psychiatry.  In fact, in most cases if you are trying to see a psychiatrist about medications you will end up seeing a nurse practitioner. Does that sound like an all-powerful profession?

The second point that the detractors seem oblivious to is that physicians in general have not run the field of medicine for the past 35 years. Nobody cares what a psychiatrist or for that matter any physician has to say.  Businessmen and politicians determine who patients see, for how long, and what those physicians are paid.  The only exception is specialty groups (Radiology, Orthopedics, Neurology, Urology, Ophthalmology) that can avoid employment relationships with healthcare organizations.  Does that sound like an all powerful profession? Strange that the antipsychiatrists with guild issues don't get that since they are under the same constraints from these monopolies.  

More to the point – if you see any physician in the USA and you don’t like what you are hearing – you are free to walk away and see somebody else.  It is not a question of being a victim of medical or psychiatric treatment.  In fact, psychiatric treatment is just as straightforward as I have portrayed it.  Come in, sit down and we will talk about your problems. My job is to give you the best possible scientifically based advice.  Your job is to decide whether to take it or not.  There is no medical treatment known that does not involve some risk.  Accepting treatment involves risk. If you accept that risk and are injured that does not mean that you were intentionally victimized by that physician or the profession.  In fact, only antipsychiatrists seem to routinely use that argument. 

Consider an example very familiar to me. Let’s say you are diagnosed with a hormone secreting pituitary adenoma.  The neurosurgeon you are seeing recommends removal but also says there is a chance that the carotid artery may be cut and the result would be catastrophic and irreparable.  Your choices are an experimental procedure with an uncertain outcome that may lead to surgery or radiation therapy (gamma knife) or doing nothing and trying to manage symptoms that will lead to your eventual death by congestive heart failure.  The risks are clear and significant, but the majority of people who I have met who have had this conversation decided on surgery. Antipsychiatrists will say it is not the equivalent to a suicidal person deciding to take an antidepressant.  I would say the risk of no treatment is equivalent, but the actual risk of psychiatric treatment is much less.  I have not seen a catastrophic, irreversible event from taking antidepressants as prescribed.  As far as the power dynamic – there is no comparision.  Being unconscious under general anesthesia for hours while an ENT surgeon and a neurosurgeon drill through your sphenoid bone into your pituitary fossa doesn’t compare to consciously talking to a psychiatrist for an hour, picking up a prescription, and then deciding on a day to day basis to keep taking an antidepressant pill.  There is really no comparison at all.

The point of this example is not that patient injuries do not occur during patient care. The point is that they do occur but that is the risk people generally have to take to get well.  The notion that psychiatrists are somehow more likely to cause these injuries and that the entire profession should be blamed as a significant cause of injuries compared with other specialists is a dubious argument at best.   

Antipsychiatry rhetoric has really not changed much over the years.  There is just a question of how much distortion, overt paranoia, or conflict of interest it contains.  In the 50 years that the antipsychiatrists have been hard at work, they have had more than ample time to come up with an alternate way to help people with severe mental illness.  To my knowledge they have not come up with a single treatment for mental illness. Of course that is no problem if you don't believe mental illness exists or that there is any way to diagnose or treat it.

That would also mean that the antipsychiatrists would have to do something positive instead of just blaming psychiatrists.  I am not holding my breath for that day to come.

George Dawson, MD, DFAPA




References:


1:  Fulford KWM, Thornton T, Graham G.  Oxford Textbook of Philosophy and Psychiatry.  Oxford University Press, Oxford, 2006: 17.



Graphic Credit:

Samei Huda contributed 3 points on the graphic.