John H. Krystal, MD

John H. Krystal, MD, discusses the new FDA approval of BioXcel Therapeutics' dexmedetomidine (Igalmi™) sublingual film for the acute treatment of agitation associated with schizophrenia or bipolar I or II disorder in adults. To read more abou this approval, see "

New Approval for Treatment of Agitation Associated with Schizophrenia or Bipolar I or II Disorder.

is the Robert L. McNeil, Jr. professor of translational research; professor of psychiatry, neuroscience, and of psychology; and codirector at the Yale Center for Clinical Investigation. He also serves as chair and chief of psychiatry at Yale-New Haven Hospital. He is also the director of the NIAAA Center for the Translational Neuroscience of Alcoholism, and director of the clinical neuroscience division at the VA National Center for PTSD.

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How is this new drug going to help in the treatment of agitation in patients with schizophrenia or bipolar disorder? 

Treating Agitation: A New FDA Approval 

[Editor's Note: American College of Neuropsychopharmacology (ACNP) president Dr John Krystal recently produced a strong rebuttal to anti-psychiatry charges made by a prominent physician and former editor of 

Here, with permission, is Dr Krystal's recently published piece (see 

In a widely read 2-part article  published in the New York Review of Books   ("

   used the platform of books review to criticize the field of psychiatry   for issues that have long been recognized within our field and are thus   targeted by current research (

see, for example, my ACNP President's   Letter

): psychiatric diagnoses are based on symptoms rather than   pathophysiology, our treatments are insufficiently effective, newer   medications have provided limited (if any) benefit over older   medications, the pharmaceutical industry has had inappropriate   relationships with individuals and organizations within our profession,   there are problems in access to psychosocial treatments for psychiatric   disorders, psychiatrists prescribe medications to treat symptoms rather   than correcting known biological abnormalities, our understanding of the   neurobiology of psychiatric symptoms is limited, and there are not   objective biomarkers to guide diagnosis or to match individual patients   with particular drugs. Vigorous responses to Dr Angell's articles were   offered, albeit largely rejected by her, making the points that clinical   data provide empirical support for the validity of symptom-based   diagnoses, psychiatry is hardly unique in prescribing medications based   on symptoms rather than pathophysiology, and while psychiatric   pharmacotherapies have limitations, they are not very different in   relative efficacy from current treatments for many chronic medical   disorders.

"Exchange," New York Review of Books August 18, 2011

What   was strikingly missing in the responses to Angell's article was a   response to her direct and implied criticism not only of the underlying   science of psychiatry, but of the reality of the distress and disability   of psychiatric patients. These are critical issues because (1) the   ability of psychiatry to effectively treat its patients now and in the   future depends on the quality and integrity of its science, and (2)   the doubt cast on the seriousness of the distress and impairments of   patients seeking psychiatric treatments feeds into the residual   ignorance and stigma that continue to be so harmful to patients. As   president of the ACNP, I thought it was important to respond to her   criticisms.  Psychiatry is engaged in a challenging battle to understand   the most complex aspects of human biology and behavior and to reduce   the burden arising from psychiatric disorders. It is rather shocking   for a former editor of a leading medical journal to fail to recognize   the challenges of brain science, the progress that has been made, and   the enormous and well-documented remaining unmet medical need.

  By   demeaning the real-world challenges faced by psychiatrists and their   patients, selectively ignoring scientific progress that challenges her   assertions, and presenting tendentious and highly selected information   about the status of psychiatric neuroscience, Angell misuses her   standing as a former editor of 

 and   the pulpit of the New York Review of Books to further stigmatize the   field of psychiatry and patients with mental disorders.

1. Angell mistakenly implies that psychiatry could abandon its   diagnostic system without harming patients.

 She begins the first part of   her essay with, "Americans are in the midst of a raging epidemic of   mental illness . . . are we simply expanding the criteria for mental illness   so that nearly everyone has one?" She does not consider the possibility   that reduction in stigmatization of people carrying psychiatric   diagnoses and improved treatment may explain changing patterns of   treatment seeking. While she does not draw conclusions, the review is   replete with innuendo. She suggests, for example, that the   medicalization of psychiatry and its development of empirical diagnostic   criteria emerged from inappropriate relationships of psychiatry and the   pharmaceutical industry that served the industry's purpose of   increasing the prescription of drugs. It is beyond the scope of this   commentary to evaluate this hypothesis. It is noteworthy, however, that   the disorder that has had the greatest increase in apparent prevalence   in the US in the past decade is autism (see 

). Whether there is a real increase in prevalence is a matter of   contention, but factors contributing to increased case recognition were   destigmatization and the emergence of effective, if highly laborious,   behavioral interventions that improve language and social skills. 

Angell   seems to assume that it is a mystery to the field that the DSM system   is flawed. Indeed it is widely recognized that this is a provisional   diagnostic system pending progress in better understanding uniquely   human disorders of our most complex organ. That said, the processes of   review and revision of the DSM system involve extensive reliance on   epidemiology, family studies, twin and increasingly other genetic   studies, that can usefully inform a descriptive diagnostic system. It   is easy to criticize a descriptive system, but given the current early   state of brain science, it is not very easy to suggest a better   approach. Abandoning the DSM system at present would undercut diagnosis,   treatment, and communication with patients and families. In my opinion,   it is a mistake to suggest, even through innuendo, that society could   afford for psychiatry to abandon DSM before science is at an advanced   enough stage to deliver a superior alternative.

2. Angell uses a   biased argument in the attempt to label antidepressants as both   ineffective and harmful, without consideration of the impact of these   assertions on patients who currently benefit from these medications or   who might need these medications in the future.

 It is widely known that   antidepressant medications are variably effective in people with   depression. The studies by Turner et al

   raise important questions about who benefits from antidepressant   treatment and to what degree they benefit. But these studies also have   limitations, critiqued elsewhere

). Other studies provide evidence of antidepressant efficacy   in the majority of patients,

 even those patients with relatively   mild depression.

 non-responders to   antidepressant medication improved less than patients treated with   placebo, suggesting that ongoing monitoring of treatment response may be   a critical step for improving outcomes and limiting negative effects of   treatment. Additional signals of antidepressant effectiveness also   emerge from health services research. For example, one randomized   clinical trial suggests that antidepressant treatment is more cost-effective than either an evidence-based psychotherapy or placebo.

 The cost-effectiveness of antidepressant treatment, generally embedded   within psychosocial treatment,

 is further supported by evidence   that optimal antidepressant treatment is more costly but more cost-effective than antidepressant treatment marred by suboptimal dosing,   non-adherence to prescribed medication, or medication discontinuation.

 Also, although the newer antidepressant medications offer   little if any evidence of enhanced efficacy over older medications,   improved medication adherence with the new medications may make them   more cost-effective.

 Clinicians face enormous challenges in   weighing the risks and benefits of pharmacotherapy with each patient,   educating patients about these risks and benefits, and monitoring these   risks and benefits on an ongoing basis during treatment. Faced with a   conflicting literature and the responsibility to mobilize all available   resources in the effort to alleviate suffering, physicians do not have   the luxury of abandoning current antidepressants while waiting for more   effective alternatives. As with DSM, in my opinion it is a mistake, even   through innuendo, to suggest that this might be possible. To quote Dr   Peter Kramer on this issue, "It is dangerous for the press to hammer   away at the theme that antidepressants are placebos. They're not. To   give the impression that they are is to cause needless suffering" (See: 

Similarly, Angell writes about   medication effects on the brain in a pejorative and misleading manner:   "After several weeks on psychoactive drugs, the brain's compensatory   efforts begin to fail, and side effects emerge that reflect the   mechanism of action of the drugs. For example, the SSRIs may cause   episodes of mania, because of the excess of serotonin. Antipsychotics   cause side effects that resemble Parkinson's disease, because of the   depletion of dopamine (which is also depleted in Parkinson's disease)"   (See: 

). She fails to be clear that antidepressant medications do not cause   bipolar disorder and it is not at all clear that antidepressants have a   causal effect in most "switches" in mood among bipolar patients.   Moreover, parkinsonian side effects of antipsychotic medications are   avoidable in most patients, even when treated with older antipsychotic   medications.

3. Angell employs information selectively   and inappropriately to attack the lack of credibility of psychiatric   diagnoses and psychiatric treatments.

 Dr Angell highlights widely   acknowledged limitations in our symptom-based diagnostic system, but she   fails to celebrate the substantial efforts led by Dr Thomas Insel and   NIMH to advance psychiatry toward pathophysiology-based diagnoses, the   Research Domain Criteria.

 She cites neuroimaging evidence to   support her hypothesis that psychiatric medications are harmful to the   brain. However, she does not cite evidence that antidepressants and   lithium protect against or reverse the ill effect of stress

 in animal studies. She quotes Dr   Steven Hyman as saying that long-term treatment with psychoactive   substances produce "substantial and long-lasting alterations in neural   function . . . the brain . . . begins to function in a manner 'qualitatively as well   as quantitatively different from the normal state'" (See: 

).   But she fails to note that this partial quotation, taken out of context,   omits the critical aspect of Dr Hyman's message. In a personal   communication to me, Dr Hyman noted that the long-lasting alterations   of which he frequently speaks, ie, brain plasticity, explain the slow   onset of therapeutic effects, as well as some late emerging effects as   tardive dyskinesia. Slowly developing therapeutic effects may not only   reduce symptoms, but also produce neuroprotective and neurotrophic   effects on brain structure

 effects on   brain circuit function in patients. Angell also criticizes the   increase in pharmacotherapy relative to psychotherapies, ie, Dr   Eisenberg's "shift from brainlessness to mindlessness." However,   Eisenberg first made his comments in the context of his Eli Lilly   Lecture to the Royal College of Psychiatrists in 1996, over 15 years   ago. Angell ignores the widespread acceptance that medication and   psychotherapeutic treatments do not work at cross-purposes.

   Rather, antidepressant psychotherapies, pharmacotherapies, and brain   stimulation treatments have converging effects on brain circuit function

 and generally work more effectively in combination, something   that is recognized in most modern treatment guidelines.

Angell   condemns psychiatric neuroscience for espousing a theory that it never   fully accepted and certainly abandoned more than 2 decades ago. The   monoamine hypotheses of depression were introduced in the 1960s and   1970s in the context of the first biological studies in patients,   conducted largely by founding members of the ACNP.  It was doubted   almost from its origin, based on the temporal dissociation between the   rise in monoamine levels produced by antidepressants and the emergence   of their therapeutic effects.  It was fully abandoned by the 1990s,   when it was evident that depression had a complex biology that went   beyond global monoamine deficits.

 She does not refer to the past   30 years of research on the neurobiology of depression that introduced   fundamentally new mechanistic hypotheses.

 While it is fair   to criticize simplistic phrases like "low serotonin" and "chemical   imbalance" used in advertising or by some physician communications to   patients, all fields of medicine strive to find ways of communicating   complex biology to lay audiences. The "chemical imbalance" locution is   not one that I endorse, but it hardly reflects the state of psychiatric   neuroscience.

4. Angell presents without seriously questioning   the hypothesis that neurobiological findings in psychiatry reflect toxic   effects of psychopharmacologic treatment rather than the underlying   neurobiology of psychiatric disorders.

 Dr Angell fails to acknowledge   that there are now replicable genetic risk variants for a growing list   of psychiatric disorders, including autism

 in close step with progress on other heterogeneous, genetically   complex disorders such as type 2 diabetes mellitus. Dr Angell also   failed to comment on the growing links between these genetics advances,   neuropathological findings in post-mortem brain tissue, and   pathophysiologic hypotheses.

 She ignores a generation of   neuroimaging and neuropsychological research that indicate that brain   structural and functional alterations in schizophrenia

 precede exposure to pharmacotherapeutic drugs. She   also fails to cite research that shows that healthy never-medicated   family members of people with psychiatric diagnoses often exhibit traits   that are similar to, but less severe than, their ill relatives.

 Similarly, she did not acknowledge growing evidence that risk   genotypes for psychiatric disorders also contribute to neuroimaging and   clinical phenotypes associated with these psychiatric disorders.

  In addition, she criticizes psychiatry for its lack of   understanding of the neurobiology of psychiatric symptoms, but she   ignores progress toward explanatory cognitive neuroscience models of   psychiatric symptoms, including hallucinations,

5. Perhaps most seriously, Angell seems to belittle the plight of people   suffering with psychiatric disorders.  

According to the World Health   Organization, neuropsychiatric disorders are the largest cause of   disability (DALYs) in the world and depression, a major focus of Dr   Angell's essay, is the leading cause of disability.

 Yet she   denigrates the diagnostic system that enables depressed people to obtain   care, she denies the efficacy and safety of the most common treatment   for major depressive disorder, and she repudiates the notion that   psychiatry research has the capacity to identify brain mechanisms   underlying depression that could lead to new treatments. Dr Angell   never gets beyond her criticisms to assert a positive agenda that might   help to alleviate the suffering of patients.  Depression is under-funded   by NIH relative to its burden of disease.

 As a result, she might   have called for more research to better understand the neurobiology of   depression and to improve treatment.  Also, she notes, correctly, that   there are important barriers to access to psychotherapies.  But, she   fails to call for better funding for these treatments by third party   payers.  She stigmatizes psychiatry, but fails to address the   consequences of stigma for psychiatrists and patients, including   discouraging medical students from entering psychiatry (

) or dissuading suffering people from seeking needed treatment.

  The absence of a positive agenda in Angell's essay was   unfortunate. After all, what value is there in critiquing psychiatry,   if not to call for actions that address the needs of psychiatric   patients and society? Angell's article was an example of bad   journalism. It is shocking that it was written by a former editor of 

 a journal renowned for impartiality   and rigor.

Angell has written an article filled with   half-truths that would seem to call for society to abandon psychiatric   diagnoses, antidepressant medications, and psychiatric neuroscience.   Angell shows utter disregard for the negative impact of each of these   actions on individuals with psychiatric disorders and society.  She   provides no alternatives to the status quo or a constructive agenda that   might ultimately speed the alleviation of human suffering.  Instead,   she attacks the one clear path to better diagnoses and more effective   pharmacotherapies, translational neuroscience. By stigmatizing a field   progressing toward a scientific foundation and by disparaging treatments   that show signs of efficacy, Dr Angell's facile criticism of   psychiatry could do harm. Perhaps, in this case, doing harm in the name   of ethics is, to borrow a phrase from Angell, a form of illusion.

Dr Krystal's financial disclosure can be viewed here [pdf]

 for the full list of references [pdf]. 

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Anti-psychiatry proponents forget it is widely recognized that the DSM is a provisional diagnostic system pending progress in better understanding uniquely human disorders of our most complex organ.

John H. Krystal, MD

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