Wednesday, 22.03.2017

Jose de Leon: Training Psychiatrists to Think like Pharmacologists

Jose de Leon’s reply to Malcom Lader’s comment


     Dr. Lader has 370 articles in PubMed (as of 7/5/16) and is a senior psychopharmacologist from the Institute of Psychiatry, in my view, the leading European psychiatric research center. So I am very grateful that he is willing to comment on my course, a burdensome task since it currently has 30 lectures and is expected to have a total of 32 in the final 2015-16 version.  I need to apologize to him since he is an expert on benzodiazepines (141 articles on them in PubMed) and it would have been easier for him to review a presentation on benzodiazepines, but I have no presentation on “Pharmacokinetics of Benzodiazepines” or on “Pharmacodynamics of Benzodiazepines”. They are planned for the 2017 version, assuming that I can update my course.  


     Dr. Lader raises multiple issues.  I plan to specifically address the most important ones, as follows:  1) INHN placement, 2) comparison with psychopharmacology courses from psychopharmacology organizations (such as CINP, ECNP, or ACNP), 3) peer review, 4) potential benefit for young psychiatrists, 5) excessive technical focus on pharmacokinetics, 6) fundamental premise is wrong, 7) wrong emphasis on case histories, and 8) facilitation of my career.


1. INHN placement. I have to acknowledge that I am extremely grateful to Tom Ban for the offer to place my presentations with INHN, but as Dr. Lader explains, I was not sure that a web page focused on the history of psychopharmacology was the best place for them. However, talking to Carlos Mora removed any doubt that I had. Dr. Mora’s work is teaching psychiatric residents in Argentina, a country without the high level of resources found in the USA and European countries.  In Dr. Mora’s view, INHN should play a major role in helping educate psychopharmacology psychiatrists all over the world, particularly in those countries with fewer resources. I completely agree with Dr. Mora’s approach and I have tried to ask people from different countries to translate my psychopharmacology course into their language so psychiatrists can read them in their own language. Translating 32 lectures with approximately 150 slides per presentation means translating more than 4,800 slides, not an easy task. I know that some of my lectures have been translated into Chinese. If anybody who reads these words is interested in translating my course to other languages, please contact me. I only ask that the presentations be translated such that they can be useful to clinicians and be available without cost on the Internet.


2. Comparison with psychopharmacology courses from psychopharmacology organizations (such as CINP, ECNP or ACNP). I apologize, but I am not familiar with these courses. As far as I understand, the number of psychiatry residents worldwide who have repeated access to ACNP, ECNP or CINP meetings is very small. In summary, my psychopharmacology course was designed to be free and available on any computer in the world that can handle a pdf file. I was not trying to compete with those courses organized by psychopharmacology organizations.


3. Peer review. Specific slides may not have gone through peer review, but I am convinced that probably 90% of the information described in the slides has gone through peer review. Let me provide a couple of examples regarding: a) theoretical lectures and b) clinical cases.

a)      Theoretical lectures. Seven of the 9 theoretical lectures on drug classes are based on 7 review articles that were peer-reviewed in journals (de Leon 2015a;b; de Leon et al., 2012; Italiano et al., 2014; Spina et al., 2014;2016a;b).          

b)      Clinical cases. There are 18 cases. One (Lecture 25 on the INHN web site) was published in a peer-reviewed journal by other authors. My comments are not peer-reviewed. Of my 17 cases, 15 have been published in peer-reviewed journals and the other 2 are being written for publication.


4. Potential benefits for young psychiatrists and residents. Most of the science on pharmacokinetics and on the cytochrome P450 (CYP) has been developed in the last 20 years, so I have seen very few of my contemporary psychiatrists, in their 50s and 60s, who can remember the various CYPs unless they make a systematic, consistent and prolonged effort to learn them. My job as a consultant in a state in the middle of the US means that mainly I supervise and teach practicing clinicians, while rarely teaching medical students. My experience is that most practicing clinicians appear unwilling to study the new CYP knowledge that was not available when they went through medical school. After many years, in the 2010s the medical schools finally updated their pharmacology curriculum to include CYP science. My hope is that young 21st century psychiatrists and psychiatry residents may be more open to these advances but, honestly, I am not too optimistic. On the other hand, I can testify that in my university pharmacy students and pharmacists are much more sophisticated in pharmacological mechanisms than my psychiatry residents or practicing clinicians. Therefore, if young pharmacists can master CYP science, there is hope that medical schools can also improve pharmacological teaching if they decide to do so. I am pretty sure that drug-drug interactions and pharmacokinetics are important since I review the deaths at public psychiatric facilities and at some community programs, and some of the preventable deaths are explained by drug-drug interactions. 


5. Excessive technical focus on pharmacokinetics.  I agree 100% with Dr. Lader that if you compare my presentation with the average psychopharmacology textbook in psychiatry, my work appears to have an excessive emphasis on pharmacokinetic science. The reason is that since 1996, when the Food and Drug Administration (FDA) started to “force” pharmaceutical companies to deal with drug metabolism in order to avoid the multiple deaths caused by drug-drug interactions with terfenadine (Flockhart, 1996), psychiatry has abdicated pharmacokinetic science to the pharmaceutical companies. In my opinion, this has been catastrophic because most pharmaceutical companies have engaged in a systematic effort to “cover up” the clinical relevance of drug-drug interactions of inhibitors (many antidepressants) and inducers (many antiepileptic drugs). My presentations contend that the best way of dealing with drug-drug interactions is to acknowledge their existence and provide recommendations on how to deal with them, such as the use of what I call “correction factors” and/or the measurement of blood levels. Therefore, I agree that my presentations are what statisticians call “outliers” when compared with typical psychopharmacology courses. However, as described in my lithium pharmacokinetic lecture (de Leon, 2016), that was not true in the 1980s, when lithium and tricyclic antidepressant (TCA) use was frequent and psychiatric researchers were heavily invested in pharmacokinetic research. At that time, practicing psychiatrists routinely used blood levels in their day-to-day practice. Moreover, the earlier revolutionary and major classic milestone pharmacokinetic articles that make possible personalized psychopharmacology were not written by the pharmaceutical companies but by pharmacologists such as Sam Gershon and his senior collaborators on lithium in 1955 (Trautner et al., 1955), or by Sjöqvist and his collaborators for the TCAs, in 1967 (Hammer and Sjöqvist, 1967). In summary, I have the extremely naïve and backward idea that 21st century research psychiatrists and practicing psychiatrists need to be like their 1980s colleagues and master pharmacokinetics and use pharmacokinetic knowledge to personalize the dosing of psychiatric drugs.


6. Fundamental premise is wrong. Dr. Lader states, “I do question the fundamental premise that psychiatrists should be instructed to think like psychopharmacologists.” I apologize, because it appears that I have given the impression in my presentations to Dr. Lader that I think that psychiatrists ONLY need to think as pharmacologists. However, I agree 100% with Dr. Lader’s statement, “In other words, we should train psychiatrists to think and behave like experts in the disciplines by supplementing their psychiatric expertise with knowledge from related cognate topics including neuropsychology, neurology, epidemiology, pharmacology and so on. In summary, they should think like a pharmacologist, neuropsychologist, and etc., but act like a multidisciplinary psychiatrist.”  Only recently have I started to write about my views of training psychiatrists to diagnose patients (please see Table 5 from de Leon, 2015c).  To be more precise, I believe that medical (and psychiatric thinking) is a combination of what I call narrative, mechanistic and mathematical thinking. Hopefully, in one year I will have some articles in PubMed explaining what I mean by that. Moreover, I hope that in 5 years, I have another set of PowerPoints focusing on integrating these types of thinking to teach psychiatric residents about psychiatric diagnoses. 


7. Wrong emphasis on case histories. Dr. Lader states, “But I do urge caution concerning the incorporation of case histories. The selection of illustrative examples is a selective process and can distort the emphasis. However, the ones I read seemed unexceptionable.” I am afraid that this is the only statement Dr. Lader has made which I think is wrong.  My experience is that young people in this era have become progressively disinterested in books and are getting “addicted” to visual tools such as PowerPoint, which present simplistic views of complex issues. It has become increasingly difficult to convince my psychiatry residents to read one of my “long and boring” review articles; it is becoming harder to convince them to review my “boring” theoretical lectures on PowerPoint, although they like my lectures on PowerPoint on cases because they are not as “boring”. In the 21st century, being “boring” appears to guarantee being ignored.


8. Facilitation of my career. I am extremely grateful for Dr. Lader’s extremely kind wish that “I hope it facilitates his career.” For some time, I was not sure that placing my course here at INHN was the best choice. Lately, I had been thinking that ResearchGate ( would have provided much more exposure to scientific researchers all over the world but, on the other hand, what I would wish is greater exposure to young medical students and psychiatric trainees all over the world, not to research scientists. Then one day, I received an e-mail from one of the top psychopharmacologists of my generation, who trained with Dr. Gershon. He praised my PowerPoint lectures and encouraged me to write books like the ones that Stephen Stahl writes. I made the huge mistake of mentioning that to my wife and showing her Dr. Stahl’s web page with his multiple books. It was the definitive proof for her that her husband was absolutely incompetent as a marketer. I had to repeat to her that her husband, unfortunately, values current success less than what will happen in 50 years when he is dead. Using that criterion, placing his psychopharmacology course on a web page associated with names like Tom Ban, Sam Gershon or Barry Blackwell is the best guarantee that something will remain of his work. As a matter of fact, if in the 1980s when my wife was dating me, a young psychiatry resident in Spain, she had told me that in 30 years I would be somewhat connected to any of these 3 names, I would have responded that it was absolutely impossible. At that time, they looked like unreachable heroes to me. In that sense, my career cannot be in a better place; my name is on a web page promoted by psychiatrists such as Ban, Blackwell and Gershon. Thank you, Dr. Lader, for giving me this opportunity to write these thoughts.             



de Leon J. The effects of antiepileptic inducers in neuropsychopharmacology, a neglected issue. Part I: A summary of the current state for clinicians. Revista de Psiquiatria y Salud Mental 2015a; 8:97-115.


de Leon J. The effects of antiepileptic inducers in neuropsychopharmacology, a neglected issue. Part II: Pharmacological issues and further understanding. Revista de Psiquiatria y Salud Mental 2015b;  8:167-88.



de Leon J. Is psychiatry only neurology? Or only abnormal psychology? Déjà vu  after 100 years. Acta Neuropsychiatrica 2015c; 27: 69-81.


de Leon J. 29. Pharmacokinetics of lithium. PowerPoint presentation. Inhn.Courses.Jose de Leon: Training  psychiatrists to think  like pharmacologists.  April 24, 2016.

de Leon J,  Santoro V, D'Arrigo C,  Spina E. Interactions between antiepileptics and second-generation antipsychotics.  Expert Opinion on Drug Metabolism and Toxicology 2012; 8: 2-24.


Flockhart DA. Drug interactions, cardiac toxicity, and terfenadine: from bench to clinic? Journal of Clinical Psychopharmacology 1996; 16: 101-3.


Hammer W, Sjöqvist F. Plasma levels of monomethylated tricyclic antidepressants during treatment with imipramine-like compounds. Life Sciences 1967; 6 :1895-903.


Italiano D, Spina E, de Leon J. Pharmacokinetic and pharmacodynamic interactions between antiepileptics and antidepressants.  Expert Opinion on Drug Metabolism and Toxicology 2014;  10: 1457-89.


Spina E, de Leon J. Clinically relevant interactions between newer antidepressants and second-generation antipsychotics.  Expert Opinion on Drug Metabolism and Toxicology 2014; 10:721-46.


Spina E, Hiemke C, de Leon J. Assessing drug-drug interactions through theraputic drug monitoring when administreing oral second-generation antipsychotics.  Expert Opinion on Drug Metabolism and Toxicology 2016a; 12:407-22.


Spina E, Pisani F, de Leon J. Clinically significant pharmacokinetic drug interactions of antiepileptics drugs with new antidepressants and new antipsychotics. Pharmacological Research  2016b; 106: 72-86.


Trautner EM, Morris R, Noack CH, Gershon S. The excretion and retention of ingested lithium a

nd its effect on the ionic balance of man. Medical Journal of Australia 1955; 42:280-91.



Jose de Leon

September 8,2016