Comment by Aitor Castillo

Aitor Castillo's comment on Barry Blackwell: Anxiety Enigma

In order to be able to comment on Blackwell´s essay “The Anxiety Enigma”, it is necessary to review and try to understand his biography and his multiple interests and duties as physician, psychiatrist, family doctor, industry physician, philosopher, professor, clinician and researcher.

It is interesting that the author starts his paper remembering the biography and scientific contributions of Hans Selye and Frank Berger. Interesting enough, Selye, Berger and Blackwell himself migrated from Europe to America. I wonder what kind of anxiety deeply pushed these three men to leave behind them their roots and look for new destinies.

I would say that not only anxiety is an enigma but the whole field of psychiatry is an enigma. We still do not know for sure the etiology of the psychiatric disorders and most of treatments are based on trial and error and I agree with Blackwell’s concept that the number of psychotherapeutic drugs has proliferated with little genuine progress in the last decades.

If we accept that anxiety is a kind of warning sign for danger recognition through our existence, in order to adapt and to survive and, taking into account that our contemporary world is full of daily stress and challenges, the question is why only a minority of the population develops anxiety and depression in a clinically significant way (1). Blackwell recognizes that brain imaging, neuroscience and genetics “have yet to solve” the riddle. [However, he does not realize that these disciplines are solving much of the enigma right now.]--unclear For example, there is a huge amount of data about neuroplasticity, stress, allostasis and allostatic overload in relationship with some medical and psychiatric diseases (2, 3).

Recent evidence is elucidating the mechanisms that underlie how adversity gets under the skin. Some epigenetic regulation of the glucocorticoid receptor gene explains which early postnatal experience influences adult response to stress (4, 5, 6). Similarly, new data are showing the molecular pathways that mediates resilience to stress and the putative therapeutic targets (7, 8).

I am somewhat disappointed with Blackwell using old-fashioned terms like “major tranquilizer”, “minor tranquilizer” and “sedative”. This terminology means nothing to me and represents a sort of confusion that do a disservice to modern psychopharmacology.

I cannot understand why Blackwell does not mention the work of Roche Laboratories chemists Leo Sternbach and Earl Reeder who developed the first benzodiazepine chlordiazepoxide in the mid-1950s (9).

In the same direction, talking about anxiety disorders, I regret the author forgets to refer to drugs like buspirone, pregabaline and etifoxine that represent some advances not only in the treatment of anxiety but on the understanding of its pathophysiology as well.

Although Blackwell’s assertion that his opinions are not a repudiation of contributory biochemical factors in (anxiety) etiology or treatment, as a matter of fact, I do perceive some sort of prejudice against biological psychiatry and biological treatments when he writes, “only philosophical or psychological understandings and interventions provide long lasting or permanent relief that ends the need for medication”.

In 1993 an international survey to develop a representative body of expert judgment and opinion on the clinical use of benzodiazepines was published (10). A selected group of 73 psychiatric experts on the pharmacotherapy of the anxiety and depressive disorders was appointed around the world. The completion rate was 90%. The main conclusions were: 1) qualitative differences in abuse liability among the benzodiazepines are minimal; 2) physical dependence at therapeutic doses is not a major clinical problem; 3) when physical dependence occurs, it can be readily managed clinically by the treating physician; and 4) the relative abuse liability of the benzodiazepines as a class is low.

After all, I certainly thank Blackwell for his contribution to the study of anxiety and the development of therapeutic strategies. He appears to me as a clever, honest and compassionate man. His autobiographical anecdotes are a reflection of his transparency and acute power of observation. The dream he relates in the last section of his essay reveals his own anxiety regarding his approach and the mixed feelings he evokes through his controversial point of view.




1.American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders. Fifth Edition. DSM-5. American Psychiatric Publishing, Washington DC, 2013

2.Olie J, Costa e Silva J, Macher J: Neuroplasticity. A new approach to the pathophysiology of depression. Science Press, London, 2004

3.Hellhammer D, Hellhammer J (Eds): Stress. The Brain-Body Connection. Karger, Basel, 2008

4.Hyman S: How Adversity Gets Under the Skin. Nat Neurosci 2009; 12: 241-243

5.McGowan P, Sasaki A, D’Alessio A, et al: Epigenetic Regulation of the Glucocorticoid Receptor in Human Brain Associates with Childhood Abuse. Nat Neurosci 2009; 12: 342-348

6.Murgatroyd C, Patchev A, Wu Y, et al: Dynamic DNA Methylation Programs Persistent Adverse Effects of Early-Life Stress. Nat Neurosci 2009; 12: 1559-1566

7.Vialou V, Robinson A, LaPlant Q, et al: ΔFosB in Brain Reward Circuits Mediates Resilience to Stress and Antidepressant Responses. Nat Neurosci 2010; 13: 745-752

8.Dias C, Feng J, Sun H, et al: β-catenin Mediates Stress Resilience Through Dicer1/microRNA Regulation. Nature 2014; 516: 51-55     

9.Ballenger J: Benzodiazepines. In, Essentials of Clinical Psychopharmacology. Schatzberg A, Nemeroff C (Eds). American Psychiatric Publishing, Washington DC, 2001

10.Balter M, Ban T, Uhlenhuth E: International Study of Expert Judgment on Therapeutic Use of Benzodiazepines and Other Psychotherapeutic Medications: I. Current Concerns.  Human Psychopharmacology 1993; 8: 253-261


Aitor Castillo

September 3, 2015