1 Boring Old Man

Usually, when we think of circuits, we think about a roughly circular path that ends in the same place it started, then repeats – like an electrical circuit or Escher’s fantastic circuit. But when people are talking about neural circuits, they seem to be using the term more like it’s used in the phrase, circuit boards, those peculiar green thingees that populate the gizmos that make our lives work.

In fact, when experts diagram their neural circuits, the figures even look a bit like those boards with their discrete elements [chips and the like] connected with rows of rigid copper conductors scurrying from element to element. But as tempting as it is, making analogies between computer hardware [or, for that matter, other electric circuitry] and the brain doesn’t hold much further than this.

Basal Ganglia Circuits as Targets for Neuromodulation in Parkinson Disease.

by DeLong MR and Wichmann T

JAMA Neurology. 2015 72[11]:1354-1360.

IMPORTANCE: The revival of stereotactic surgery for Parkinson disease [PD] in the 1990s, with pallidotomy and then with high-frequency deep brain stimulation [DBS], has led to a renaissance in functional surgery for movement and other neuropsychiatric disorders.

OBJECTIVE: To examine the scientific foundations and rationale for the use of ablation and DBS for treatment of neurologic and psychiatric diseases, using PD as the primary example.

EVIDENCE REVIEW: A summary of the large body of relevant literature is presented on anatomy, physiology, pathophysiology, and functional surgery for PD and other basal ganglia disorders.

FINDINGS: The signs and symptoms of movement disorders appear to result largely from signature abnormalities in one of several parallel and largely segregated basal ganglia thalamocortical circuits [ie, the motor circuit]. The available evidence suggests that the varied movement disorders resulting from dysfunction of this circuit result from propagated disruption of downstream network activity in the thalamus, cortex, and brainstem. Ablation and DBS act to free downstream networks to function more normally. The basal ganglia thalamocortical circuit may play a key role in the expression of disordered movement, and the basal ganglia-brainstem projections may play roles in akinesia and disturbances of gait. Efforts are under way to target circuit dysfunction in brain areas outside of the traditionally implicated basal ganglia thalamocortical system, in particular, the pedunculopontine nucleus, to address gait disorders that respond poorly to levodopa and conventional DBS targets.

CONCLUSIONS AND RELEVANCE: Deep brain stimulation is now the treatment of choice for many patients with advanced PD and other movement disorders. The success of DBS and other forms of neuromodulation for neuropsychiatric disorders is the result of the ability to modulate circuit activity in discrete functional domains within the basal ganglia circuitry with highly focused interventions, which spare uninvolved areas that are often disrupted with drugs.

^{[adapted from the paper]}

When I was in medical school, we all learned about some neural circuits – the ones that were known then: like the motor system [how the cortex send messages to the muscles] or the visual system [how the sensors in the eye connect to the visual cortex at the back of the brain]. Those two actually are like wiring diagrams and important for localizing brain lesions [tumors, strokes]. But the only thing I remember knowing about the Movement Disorders like Parkinson;s Disease is that they involved the extrapyramidal [postural] system which had something to do with the mysterious basal ganglia structures deep in the brain.

But now, the basal ganglia thalamocortical circuits are better characterized [above]. The boxes are brain structures/regions and the arrows are the ways in which they act on each other to make the system work. These circuits are spatially distant from the voluntary motor system, so they can be manipulated without loss of function. In this same article, there’s a figure that shows the abnormalities in Parkinson’s Disease, followed by another that shows where the symptoms arise and where treatments act. Now they know enough to successfully treat medication resistant disabling symptoms with surgical lesions or deep brain modulation, putting this basic science to direct clinical use.

So we have a primitive understanding of this particular neural circuit – something like a highway map. It tells how to get from place to place, but not much about what happens in the places the roads connect. There are undoubtedly a myriad of such functional neural circuits with similar nodes, pathways, and feedback loops in our brains just doing their various jobs whether we yet know about them or not. And it’s sure easy to see why neuroscientists of various ilks are so eager to know a lot more about them – and ultimately how to safely tweak them when they sputter and cause dis·ease.

Brain circuitry model for mental illness will transform management, NIH mental health director says

British Medical Journal

1 September 2011

… The seismic shift had been driven by what he [Tom Insel] described as three “revolutionary changes” in thinking, the first of which was that mental illness was increasingly being recognised as a disorder of brain circuitry, rather than as a chemical imbalance, thanks to neuroimaging techniques and the discovery of some key biomarkers…

[see also Director’s Blog: Mental Illness Defined as Disruption in Neural Circuits, Insel Outlines the Psychiatry of the Future Treating Disorders of Neural Circuitry]

Even in his exuberance, I kind of wish Dr. Insel had said "some mental illness might even turn out to be disorders of brain circuitry." But whatever he said isn’t the point. This post is my attempt at an introduction to exploring what I started in weary…, the Decade of “Jumping the Gun“…., and this comment.

• a Protocol defines how the study is to be conducted and analyzed
• the protocol is submitted to the Institutional Review Board [IRB]
• on approval of the protocol, the trial is Registered on clinicaltrials.gov
• the Trial is conducted, double blinded
• the Results are Analyzed per the protocol, then submitted/published

The citalopram CIT-MD-18 pediatric depression trial: Deconstruction of medical ghostwriting, data mischaracterisation and academic malfeasance

by Jon Jureidini, Jay ^{Amsterdam, and Leemon McHenry}

International Journal of Risk & Safety in Medicine. 2016 28[1]:33-43.

A Randomized, Placebo-Controlled Trial of Citalopram for the Treatment of Major Depression in Children and Adolescents

by Karen Dineen Wagner, Adelaide S. Robb, Robert L. Findling, Jianqing Jin, Marcelo M. Gutierrez, and William E. Heydorn

American Journal of Psychiatry. 2004 161:1079-1083.

[full text online]

• Who designed, analyzed, and wrote the article?
  ^{Reviewing subpoenaed internal emails, it was clear that the protocol was written by under the direction of the sponsor’s Associate Medical Director, analyzed by the Forest Laboratory’s staff, and the first draft was written by a contracted ghost-writer, so it was first seen by the listed academic authors in its second draft. The later denial that the academic authors didn’t know it was ghost written was directly contradicted by the subpoenaed emails. Simply put, the academic authors were merely figure·heads for this industry produced article. This finding is well referenced in Jureidini et al.}
• How was the data analyzed and reported?
  Primary Outcome Parameter:
  ^{Change from baseline to week 8 on the Children’s Depression Rating Scale-Revised [CDRS-R] total score}
  ^{The Protocol specified that “Any patient for whom the blind has been broken will immediately be discontinued from the study and no further efficacy evaluations will be performed" There were nine such cases. Jureidini et al didn’t have the raw data, but they did have the Clinical Study Report. In fact, several versions. On 09/12/2001 – these cases were removed, acknowledged in a footnote. the p-value was 0.052. In a later version, these subjects were added back in, the footnote disappeared, and the p value was 0.038. It’s the second version that made it into the paper. Again, this finding is fully referenced in Jureidini et al. There were other irregularities, among them, a reported effect size of 2.9 [an outrageous number]. When confronted, it was revised to 0.32 without explanation of the error.}
  Secondary Outcome Parameters:
  ^{Clinical Global Impression [severity and improvement subscales], Kiddie Schedule for Affective Disorders and Schizophrenia [depression module], and Children’s Global Assessment Scale.}
  

  While they reported the CGI-S and CGI-I scales [not significant], they failed to report the other two. Instead, they reported  the CDRS responders [as significant] – an outcome parameter that wasn’t even mentioned in the a priori Protocol.

  Adverse Events:
  ^{By reporting the quantitative numbers, they were able to avoid mentioning agitation and a case of hypomania.}
  

^{"… every trial is written up differently. Why is that?"}

This negative study was used to support an FDA Approval for Citalopram [Celexa®] in adolescents, even though by that time, Dr. Karen Dineen Wagner, the first author, had been cited by the US Senate for unreported industry income. When the American Journal of Psychiatry discovered that this article was ghost written, they published a strong note [see the jewel in the crown…], but did not retract the study. The case against Forest Laboratories that brought all of these documents to light ultimately settled [see September 15, 2010: Drug Maker Forest Pleads Guilty: Will Pay More Than $313 Million to Resolve Criminal Charges and False Claims Act Allegations]. And unscathed, Dr. Karen Dineen Wagner is the President Elect of the American Academy of Child and Adolescent Psychiatry, the recipient of lifetime achievement awards for research in Mood Disorders in Children, and she was recently promoted to Chairman of the Department of Psychiatry at UTMB.

• 
• 2002: Fluoxetine for Acute Treatment of Depression in Children and Adolescents: A Placebo-Controlled, Randomized Clinical Trial. "Fluoxetine was superior to placebo in the acute phase treatment of major depressive disorder in child and adolescent outpatients with severe, persistent depression."
  by Emslie GJ, Heiligenstein JH, Wagner KD, Hoog SL, Ernest DE, Brown E, Nilsson M, and Jacobson JG
• 
• 

The citalopram CIT-MD-18 pediatric depression trial: Deconstruction of medical ghostwriting, data mischaracterisation and academic malfeasance

by Jureidini, Jon, Amsterdam, Jay, McHenry, Leemon

International Journal of Risk & Safety in Medicine. 2016 28[1]:33-43.

OBJECTIVE:Deconstruction of a ghostwritten report of a randomized, double-blind, placebo-controlled efficacy and safety trial of citalopram in depressed children and adolescents conducted in the United States.

METHODS:Approximately 750 documents from the Celexa and Lexapro Marketing and Sales Practices Litigation: Master Docket 09-MD-2067-[NMG] were deconstructed.

CONCLUSION:Deconstruction of court documents revealed that protocol-specified outcome measures showed no statistically significant difference between citalopram and placebo. However, the published article concluded that citalopram was safe and significantly more efficacious than placebo for children and adolescents, with possible adverse effects on patient safety.

Background for Reference:

• 2001: Efficacy of Paroxetine in the Treatment of Adolescent Major Depression: A Randomized, Controlled Trial. "Paroxetine is generally well tolerated and effective for major depression in adolescents."
  by Keller MB, Ryan ND, Strober M, Klein RG, Kutcher SP, Birmaher B, Hagino OR, Koplewicz H, Carlson GA, Clarke GN, Emslie GJ, Feinberg D, Geller B, Kusumakar V, Papatheodorou G, Sack WH, Sweeney M, Wagner KD, Weller EB, Winters NC, Oakes R, and McCafferty JP
• 2002: Fluoxetine for Acute Treatment of Depression in Children and Adolescents: A Placebo-Controlled, Randomized Clinical Trial. "Fluoxetine was superior to placebo in the acute phase treatment of major depressive disorder in child and adolescent outpatients with severe, persistent depression."
  by Emslie GJ, Heiligenstein JH, Wagner KD, Hoog SL, Ernest DE, Brown E, Nilsson M, and Jacobson JG
• 2003: Efficacy of sertraline in the treatment of children and adolescents with major depressive disorder: two randomized controlled trials. "…sertraline is an effective and well-tolerated short-term treatment for children and adolescents with MDD."
  by Wagner KD, Ambrosini P, Rynn M, Wohlberg C, Yang R, Greenbaum MS, Childress A, Donnelly C, Deas D; and the Sertraline Pediatric Depression Study Group
• 2004: A randomized, placebo-controlled trial of citalopram for the treatment of major depression in children and adolescents. "…treatment with citalopram reduced depressive symptoms to a significantly greater extent than placebo treatment and was well tolerated."
  by Wagner KD, Robb AS, Findling RL, Jin J, Gutierrez MM, and Heydorn WE

• 2006: ACNP Task Force Report on SSRIs and Suicidal Behavior in Youth.
  by Mann JJ, Emslie G, Baldessarini RJ, Beardslee W, Fawcett JA, Goodwin FK, Leon AC, Meltzer HY, Ryan ND, Shaffer D, and Wagner KD

A Forest laboratory official in a letter of April 17, 2009, acknowledged that: "Forest retained a medical communications company to assist with preparation of the manuscript, a practice we understand to be common among pharmaceutical companies. Following discussion with the article’s named authors, the medical communications company created an initial draft of the manuscript. Over the course of time, however, from the initial draft to the final publication, the manuscript went through multiple iterations with the input of the named authors, as well as others who reviewed and commented on the manuscript; throughout this process, the medical communications company continued to provide copy editing, formatting, referencing and other editorial support. The manuscript was then submitted to AJP by Dr. Wagner, who, along with the other named authors, maintained control over the final content of the manuscript."

A Randomized, Placebo-Controlled Trial of Citalopram for the Treatment of Major Depression in Children and Adolescents

by Karen Dineen Wagner, Adelaide S. Robb, Robert L. Findling, Jianqing Jin, Marcelo M. Gutierrez, and William E. Heydorn

American Journal of Psychiatry. 2004 161:1079-1083.

[full text online]

Objective: Open-label trials with the selective serotonin reuptake inhibitor citalopram suggest that this agent is effective and safe for the treatment of depressive symptoms in children and adolescents. The current study investigated the efficacy and safety of citalopram compared with placebo in the treatment of pediatric pa- tients with major depression.

Method: An 8-week, randomized, double- blind, placebo-controlled study compared the safety and efficacy of citalopram with placebo in the treatment of children [ages 7–11] and adolescents [ages 12–17] with major depressive disorder. Diagnosis was established with the Schedule for Affective Disorders and Schizophrenia for School- Age Children—Present and Lifetime Version. Patients [N=174] were treated initially with placebo or 20 mg/day of citalopram, with an option to increase the dose to 40 mg/day at week 4 if clinically indicated. The primary outcome measure was score on the Children’s Depression Rating Scale— Revised; the response criterion was defined as a score of ≤ 28.

Results: The overall mean citalopram dose was approximately 24 mg/day. Mean Children’s Depression Rating Scale—Revised scores decreased significantly more from baseline in the citalopram treatment group than in the placebo treatment group, beginning at week 1 and continuing at every observation point to the end of the study [effect size=2.9]. The difference in response rate at week 8 between placebo [24%] and citalopram [36%] also was statistically significant. Citalopram treatment was well tolerated. Rates of discontinua- tion due to adverse events were comparable in the placebo and citalopram groups [5.9% versus 5.6%, respectively]. Rhinitis, nausea, and abdominal pain were the only adverse events to occur with a frequency exceeding 10% in either treatment group.

Conclusions: In this population of children and adolescents, treatment with citalopram reduced depressive symptoms to a significantly greater extent than placebo treatment and was well tolerated.

Editors’ Note

by Robert Freedman and Michael D. Roy

American Journal of Psychiatry. 2009 166[8]:942-943.

The article "A Randomized, Placebo-Controlled Trial of Cilalopram for the Treatment of Major Depression in Children and Adolescents," published in the June 2004 issue of The American Journal of Psychiatry [vol. 161, pp 1079-1083] is alleged by the United States Department of Justice in an ongoing suit to have been written and submitted to the Journal by a commercial medical writer on behalf of Forest Laboratories, Inc.

We requested responses from Drs. Karen Dineen Wagner, Adelaide S. Robb, and Robert L Findling [authors in their role as investigators in the clinical trial at their respective universities], Dr. William E. Heydom [the senior Forest laboratories study director], and Forest laboratories. Drs. Wagner, Robb, and Findling reported that they had received an initial draft from Dr. Heydom to which they contributed through several drafts, This paper was submitted as a Brief Report, which the Journal’s editors requested be resubmitted as a full-length Article. Drs. Wagner, Robb, and Findling report that they contributed with Dr. Heydorn to the resubmission and that they were not aware that Dr. Heydorn was working with a commercial writer. Dr. Heydorn did not respond to our request for comment.

A Forest laboratory official in a letter of April 17, 2009, acknowledged that: "Forest retained a medical communications company to assist with preparation of the manuscript, a practice we understand to be common among pharmaceutical companies. Following discussion with the article’s named authors, the medical communications company created an initial draft of the manuscript. Over the course of time, however, from the initial draft to the final publication, the manuscript went through multiple iterations with the input of the named authors, as well as others who reviewed and commented on the manuscript; throughout this process, the medical communications company continued to provide copy editing, formatting, referencing and other editorial support. Hie manuscript was then submitted to AJP by Dr. Wagner, who, along with the other named authors, maintained control over the final content of the manuscript."

We are satisfied that the named contributors of this article satisfy the criteria for authorship as set forth in the "Uniform Requirements for Manuscripts Submitted to Biomedical Journals" from the International Committee of Medical Journal Editors. However, the Journal’s Instructions to the Authors in 2004 and our policy today do not allow contributions by unnamed writers to the preparation of a paper. Thus, the editorial contributions of Prescott Medical Communications Group should have been acknowledged in the published article as required at the time the article was published.

Furthermore, Forest Laboratories failed to disclose to the Journal that it was aware of data from a study by Lundbeck that showed increased suicidality in children and adolescents who were treated with citalopram. Authors and sponsors are expected to disclose the existence of all data that affects the interpretation of their study. This note will appear in Medline and other databases as a Comment on the paper.

The official complaint [United States and Christopher R. Gobble v. Forest Laboratories Inc. and Forest Pharmaceuticals Inc. Civil Action No. 03-10395-NMG] is posted at …

It may seem peculiar, but it makes sense to me. As a young guy in medicine, I was pulled in two directions – research into things we don’t yet know, and the application of things we do know. The former was where my mind naturally headed, but the latter was what gave me a sense of purpose. While it’s only in retrospect, it makes perfect sense to me that I would’ve ended up being a psychoanalytically oriented psychotherapist [n=1 research with a practical application] where every case is something new. Similarly, my retirement fun has been re·search·ing the post-DSM-III psychiatric research where I’ve stayed on the practical side – psychopharmacology, clinical trials, diagnosis. I’ve shied away from the neuro·anatomy, neuro·physiology, neuro·science side of things, I think because I’m not convinced we know enough yet for there to be a practical side to the equation.

The whole of the past decade in psychiatry might be called the Decade of Jumping the Gun.

The fact is that we simply don’t have good enough neuroscience tools yet to allow us to answer the clinically important questions. We just don’t. We might get there eventually but at the moment we are not there.

Given which, any attempt to ‘translate’ our primitive neuroscience into clinical practice will be an effort to jump the gun.

by Neuroskeptic…  

Blood-oxygen-level dependent contrast imaging, or BOLD-contrast imaging, is a method used in functional magnetic resonance imaging [fMRI] to observe different areas of the brain or other organs, which are found to be active at any given time. Its proof of concept was provided by Seiji Ogawa and colleagues in 1990, following an experiment which demonstrated that an in vivo change of blood oxygenation could be detected with MRI. Other notable pioneers of BOLD fMRI include Kenneth Kwong and colleagues, who first used the technique in human participants in 1992.

Neurons do not have internal reserves of energy in the form of sugar and oxygen, so their firing causes a need for more energy to be brought in quickly. Through a process called the hemodynamic response, blood releases oxygen to them at a greater rate than to inactive neurons. This causes a change of the relative levels of oxyhemoglobin and deoxyhemoglobin [oxygenated or deoxygenated blood] that can be detected on the basis of their differential magnetic susceptibility.

In 1990, three papers published by Seiji Ogawa and colleagues showed that hemoglobin has different magnetic properties in its oxygenated and deoxygenated forms, both of which could be detected using MRI. This leads to magnetic signal variation which can be detected using an MRI scanner. Given many repetitions of a thought, action or experience, statistical methods can be used to determine the areas of the brain which reliably have more of this difference as a result, and therefore which areas of the brain are active during that thought, action or experience…

from Wikipedia… 

The fMRI [1992] and the mapping of the human genome [2000] had the bio-medical psychiatrists  peeing in their pants  filled with excitement at the turn of the century. And it was pretty exciting. Tom Insel became the Director of the NIMH and announced psychiatry was to become clinical neuroscience. The DSM-5 Task Force tooled up to add biomedical findings to their coming diagnostic manual. A new century and a new psychiatry based on solid brain science was just around the corner. They had already jumped the gun some in the Decade of the Brain [the 1990s], but this time, they forgot the adages, "look before you leap" "don’t count your chickens before they hatch", and dove into the deep end, and ended up with a long chain of disappointments fueling disillusionment and skepticism. So now we’re presented with a big NIMH Study, this time about neural circuits [see weary…].

Already we are seeing multiple approaches to identifying abnormal functional activity in the brain, from functional MRI to in vivo neurochemistry and studies of brain receptors. One approach uses functional imaging to identify differences in regional activity. For instance, evidence from several different approaches implicates circuitry involving ventral, medial prefrontal cortex [Area 25] with major depressive disorder… Individuals with the short allele of the serotonin transporter gene have reduced expression of the transporter and appear to be at a higher risk for developing depression following stressful life events. Recently, this short allele has been shown to be associated with reduced gray matter volume of Area 25 and uncoupling of an anterior cingulate-amygdala circuit necessary for extinction of negative affect, providing a model for linking genetic risk and environmental stress to a specific neural circuit implicated in depression. One might imagine that studies of this circuit could be used to predict response to treatment, just as imaging in cardiology or oncology can be used to predict treatment response.

from Psychiatry as a Neuroscience Discipline…   

But what I would’ve preferred from these articles would have been something solid and well referenced about the neural circuits themselves. Perhaps such things are widely talked about and known in neuroscience circles, but they’re not in the general population of practitioners, psychiatrists, or others who aren’t specifically immersed in the world of neuroimaging. The articles are so busy addressing possible translations that they give short shrift to  the basics – basics that most readers [like me] don’t know much about. Since this study is essentially a data gathering exercise with the behavior of the neural circuits on the front burner, I ought to know more about that than I do after reading these papers repeatedly.

Five years ago, I ran across an Australian company called Brain Resources. It appeared to be primarily a Brain Training enterprise, but they were into a lot of other things too. They were financing iSPOT, a clinical trial of personalized medicine trying to predict antidepressant drug choice based on Genetic and/or other testing. And they were amassing a Database of subjects testing all things neuro [testing, genetics, imaging, etc]. There were two principals: Evian Gordon, a Brain Training guru type, and Leanne Williams, second in command, in charge of the database which was to be made publicly available. They had put together an amazing conference in the US about personalized medicine, attended by KOLs from far and wide [roster][video] called the Mayflower Initiative. And there were a number of KOLs involved in their iSPOT trial. To be honest, I didn’t know what to make of it. The personalized medicine meme swept through psychiatry. Besides Brain Resources’ iSPOT, there was EMBARC, a similar trial funded by the NIMH with Madhukar Trivedi as P.I. Nemeroff gave talks about it. Insel blogged about it. Papers were published along the way.

Meanwhile, right around the same time, Tom Insel’s NIMH introduced its Research Domain Criteria [RDoC] [Genes and Circuitry, Not Just Clinical Observation, to Guide Classification for Research January 2010]. Born from the frustration of the poor specificity of psychoactive drugs for clinical diagnosis, the RDoC proposed to search for other parameters that might define syndromes that more accurately map to drug response. But while personalized medicine and the RDoC may sound like different things, operationally, they’re the same – broad surveys of objective parameters [genomic, imaging, clinimetrics, etc] analyzed looking for clusters or correlations not apparent in the traditional clinical categories [using big data statistical techniques].

Precision psychiatry: a neural circuit taxonomy for depression and anxiety

by Leanne M Williams

Lancet Psychiatry. 2016, Published Online April 14, 2016

Although there have been tremendous advances in the understanding of human dysfunctions in the brain circuitry for self-reflection, emotion, and cognitive control, a brain-based taxonomy for mental disease is still lacking. As a result, these advances have not been translated into actionable clinical tools, and the language of brain circuits has not been incorporated into training programmes. To address this gap, I present this synthesis of published work, with a focus on functional imaging of circuit dysfunctions across the spectrum of mood and anxiety disorders. This synthesis provides the foundation for a taxonomy of putative types of dysfunction, which cuts across traditional diagnostic boundaries for depression and anxiety and includes instead distinct types of neural circuit dysfunction that together refl ect the heterogeneity of depression and anxiety. This taxonomy is suited to specifying symptoms in terms of underlying neural dysfunction at the individual level and is intended as the foundation for building mechanistic research and ultimately guiding clinical practice.

How neuroscience could determine your mental health treatment

Brain waves

By Tracie White

Stanford Medicine, Winter 2016

… a fluff-piece in the Stanford Medicine Magazine about Dr. Leanne Williams…

Developing a clinical translational neuroscience taxonomy for anxiety and mood disorder: protocol for the baseline-follow up Research domain criteria Anxiety and Depression [“RAD”] project

by Leanne M. Williams, Andrea N. Goldstein-Piekarski, Nowreen Chowdhry, Katherine A. Grisanzio, Nancy A. Haug, Zoe Samara, Amit Etkin, Ruth O’Hara, Alan F. Schatzberg, Trisha Suppes, and Jerome Yesavage

BMC Psychiatry. DOI: 10.1186/s12888-016-0771-3. Published: 15 March 2016

[full text online]

Background: Understanding how brain circuit dysfunctions relate to specific symptoms offers promise for developing a brain-based taxonomy for classifying psychopathology, identifying targets for mechanistic studies and ultimately for guiding treatment choice. The goal of the Research Domain Criteria [RDoC] initiative of the National Institute of Mental Health is to accelerate the development of such neurobiological models of mental disorder independent of traditional diagnostic criteria. In our RDoC Anxiety and Depression [“RAD”] project we focus trans-diagnostically on the spectrum of depression and anxiety psychopathology. Our aims are [a] to use brain imaging to define cohesive dimensions defined by dysfunction of circuits involved in reactivity to and regulation of negatively valenced emotional stimulation and in cognitive control, [b] to assess the relationships between these dimension and specific symptoms, behavioral performance and the real world capacity to function socially and at work and [c] to assess the stability of brain-symptom-behavior-function relationships over time.

Methods and design: Here we present the protocol for the “RAD” project, one of the first RDoC studies to use brain circuit functioning to define new dimensions of psychopathology. The RAD project follows baseline-follow up design. In line with RDoC principles we use a strategy for recruiting all clients who “walk through the door” of a large community mental health clinic as well as the surrounding community. The clinic attends to a broad spectrum of anxiety and mood-related symptoms. Participants are unmedicated and studied at baseline using a standardized battery of functional brain imaging, structural brain imaging and behavioral probes that assay constructs of threat reactivity, threat regulation and cognitive control. The battery also includes self-report measures of anxiety and mood symptoms, and social and occupational functioning. After baseline assessments, therapists in the clinic apply treatment planning as usual. Follow-up assessments are undertaken at 3 months, to establish the reliability of brain–based subgroups over time and to assess whether these subgroups predict real–world functional capacity over time. First enrollment was August 2013, and is ongoing.

Discussion: This project is designed to advance knowledge toward a neural circuit taxonomy for mental disorder. Data will be shared via the RDoC database for dissemination to the scientific community. The clinical translational neuroscience goals of the project are to develop brain-behavior profile reports for each individual participant and to refine these reports with therapist feedback. Reporting of results is expected from December 2016 onward.

Trial registration: ClinicalTrials.gov Identifier: NCT02220309.

Brain circuitry model for mental illness will transform management, NIH mental health director says

British Medical Journal

by Caroline White

1 September 2011

The field of mental health is on the cusp of a revolution, which is set to transform the diagnosis and treatment of mental illness and reverse the lack of major progress made in curbing associated ill health and death over the past 100 years, the director of the US National Institute of Mental Health, has claimed. “We are at an extraordinary moment when the entire scientific foundation for mental health is shifting, with the 20th century discipline of psychiatry becoming the 21st century discipline of clinical neuroscience,” Thomas Insel said before a meeting on the challenges facing mental health research at the Royal Society in London on 31 August…

The seismic shift had been driven by what he described as three “revolutionary changes” in thinking, the first of which was that mental illness was increasingly being recognised as a disorder of brain circuitry, rather than as a chemical imbalance, thanks to neuroimaging techniques and the discovery of some key biomarkers. Secondly, mental ill health was now recognised as a developmental disorder for which early intervention was vital, said Professor Insel, highlighting US research showing that 50% of study participants had reported the onset of mental health problems by the age of 14, and 75% by the age of 24. “We are still stuck with getting to the problem very late. The future will be about understanding the trajectory of illness so that we can identify the first signs before it develops into psychosis,” he said…

[see also Director’s Blog: Mental Illness Defined as Disruption in Neural Circuits, Insel Outlines the Psychiatry of the Future Treating Disorders of Neural Circuitry]

^{One late night on-call, I was interviewing a man brought to the hospital because he was contemplating suicide. I no longer recall the specifics, but I do remember what occurred to me while I was talking to him. I realized that when I saw a suicidal patient, I got anxious and didn’t think quite right. I became focused on things like "is he really going to do it?" "does he have a plan?" With suicidal patients, the stakes were suddenly raised by the threatened action, and I started worrying that I was going to do the wrong thing, "blow it." Without really knowing it was happening, I was abandoning the patient as a suffering person and becoming focused on risk management and suicide prevention. Not that there’s anything wrong with that – in fact it’s the right thing to do [evaluating risk], but not the only thing. It certainly didn’t mean that I should forget that I was talking to someone in a lot of pain and confusion – a unique person, not a category. And if ever there were a group of people who deserve our fullest individual attention, they’re among this group…}

My sister, an academic, wrote a paper long ago analyzing Shakespeare’s Hamlet using double-bind theory. I think I would’ve thought it brilliant even if we didn’t share a name and a history. She showed how Hamlet’s soliloquy on suicide applied to all of the characters, each of whom was in a double bind, and how madness and suicide were tempting solutions to the impossible situations each of them faced. I can’t count the number of suicidal patients I’ve seen where parsing the double binds they were experiencing was the key to finding their way out of a suicidal dilemma. I owe both Shakespeare and my kid sister for that insight.

Another great writer who made a major contribution was William Styron, the author of Sophie’s Choice, another variation on the theme of double binds, impossible situations. It’s a must-read book and a must-see movie if you are someone who sees suicidal patients. One will never find two better teachers than William Styron and Meryl Streep. And Styron gave us something else. His Darkness Visible is a first hand account of the pain of Melancholia that makes the why of the suicidal risk in the afflicted patients unforgettable. Another must-read.

And speaking of the great writers, Virginia Woolf and her Mrs. Dallaway are in close contention with the next paragraph’s featured author as the best piece of fiction ever written. The book is, in part, about her character, Septimus, a man with a War Neurosis who kills himself to avoid being committed. Some 16 years after writing the book, Woolf herself committed suicide as an episode of her periodic psychotic illness was coming on – likely for the same reason. I have three books on my shelf, each explaining her illness convincingly, each with a different diagnosis [Schizophrenia, Bipolar Disorder, and PTSD]. I can’t summarize her themes – but they’re all there.

William Faulkner is the other contender for the greatest piece of fiction ever written [personal opinion]. It’s two books: Absolom, Absolom and The Sound and the Fury. The books explore the interplay of culture, history, myth, and personal biography as they lead his character Quentin to suicide. I expect that my own history as a Southerner has something to do with my reverence for these two books. But even with that COI declaration, their complex messages have frequently come to mind with suicidal patients and opened up fruitful avenues for exploration.

While countless academics and graduate students have had their way with Émile Durkheim’s 1897  Treatise, Suicide, his insights have weathered the century. His study compared suicides among Catholics and Protestants using a scientific method. "Overall, Durkheim treated suicide as a social fact, explaining variations in its rate on a macro level, considering society-scale phenomena such as lack of connections between people [group attachment] and lack of regulations of behavior, rather than individuals’ feelings and motivations." Wikipedia. It’s a piece of Sociology important to consider at the individual level with suicidal patients..

We all likely know about Karl Abraham’s and Sigmund Freud’s thoughts about the relationship of anger to depression and suicide. But Karl Meninger‘s 1938 contributions in Man Against Himself are what actually come to mind with every suicidal person I’ve ever seen. Paraphrased, suicidal people want to die [escape], to be dead [relief], and to kill [rage] – and I try to find the personal version of each one of them in every interview. This is a timeless book that isn’t often mentioned these days, but it should be. I had to occasion to reread it a few years ago along with a student, and it was as fresh and useful as it was the first time I read it.

Albert Camus’ Myth of Sisyphus is a classic on many fronts. While the philosophical point is that Hamlet’s existential dilemma has to be resolved to truly live authentically, to choose to live, I found it helpful with any number of patients. Concretely, I had cases who had a lethal cache of medications as a beloved possession, a talisman, a way of holding out, a way of not fully stepping into life until life proved itself. And there were a significant number who kept their cache secret until they decided to throw them away and step into life after all. That’s a whole psychotherapy topic of its own, but for the moment, suffice it to say that Camus is definitely a required read.

Dr. Insel’s selection as Director of the NIMH in 2002 was a surprise choice. After losing his position in the NIMH Intramural program, he came to Atlanta to head the Yerkes Primate Center. After one term, he was not reappointed [the scuttle-but – too controlling] and then became Director of a Translational Center, a research consortium of the area Universities put together by Emory Chairman, Charlie Nemeroff. It was a time when Dr. Nemeroff was known as boss-of-bosses with influence felt far and wide, and locally we assumed that Nemeroff had a lot to do with Dr. Insel’s surprise appointment at the NIMH. Years later, after Dr. Nemeroff’s fall from grace, Dr. Insel presumably returned the favor by helping Nemeroff secure another Chairmanship in Miami.

1. Clinical Neuroscience: That was a surprise – his becoming a champion for making a dramatic change in a clinical specialty. He wasn’t a clinician himself, and for the NIMH to set the direction for a medical specialty [and even try to change how that specialty approaches diagnosis] is unprecedented. But that’s what happened [fulfilling the scuttle-but – too controlling]. Admittedly, it was a time when biological psychiatry and psychopharmacology were in their ascendency, but Dr. Insel catapulted brain science to an almost exclusive centrality. His enthusiasm for neuroscience breakthroughs was in every talk, every blog post, almost every call for proposals. By natural selection, the NIMH iterated towards becoming the National Institute of Brain Science – at least that’s how it looked to me. And while he often talked about public health statistics, the growing menace of depression, and the need for more treatments, the research was heavily weighted towards basic neuroscience – brain circuitry…
2. Blaming: In the summer of 2011, it became apparent that the pharmaceutical industry was fleeing CNS drug development like rats from a sinking ship. After twenty-five years of variations on a couple of simple themes, they ran out of molecules, and were under siege for overplaying their hands in almost every dimension. Dr. Insel changed. He seemed disgruntled, angry, blaming. He talked of our current treatments as inadequate and seemed to be trying to gear up the NIMH to do something about that through a series of policy changes: RDoC, short trials, accessing industry’s discarded molecules. He was becoming even more controlling than before. It was as if he’d suddenly noticed that the NIMH was out of the loop with treatment research and he was frantically trying to catch up.
   I expect that I’m not the only person who saw those Suicide Statistics as an indictment of our mental health systems and the NIMH directions. And while we’ll probably never know the story, I would expect that those numbers along with other disheartening indicators probably had something to do with Dr. Insel’s surprise exit as Director of the NIMH. I suspect it was a suggested exit. It’s apparent in the things he’s said since announcing his retirement that he’s in the blaming mode:
   •Why did you leave the National Institute of Mental Health to work for Google?
   I have to confess that after giving heart and soul to mental-health problems over the last 13 years working in government, I have not seen any improvement for either morbidity or mortality for serious mental illness – so I’m ready to try a different approach. If it means using the tools available in the private sector, let’s go for it.
   • Are you saying Google is a better place to do mental-health research than the NIMH?
   I wouldn’t quite put it that way, but I don’t think complicated problems like early detection of psychosis or finding ways to get more people with depression into optimal care are ever going to be solved solely by government or the private sector, or through philanthropy. Five years ago, the NIMH launched a big project to transform diagnosis. But did we have the analytical firepower to do that? No. If anybody has it, companies like IBM, Apple or Google do – those kinds of high-powered tech engines…
   Who is he mad at? He was in charge, the leader, yet it sounds like he’s mad at somebody for letting him down. He sounds bitter. And I find that hard to hear, because from my perspective, he grabbed the wheel, set the course. He’s the one that let us down. And while we haven’t heard about it directly, it specifically sounds to me like they had the idea that they could use some kind of big data technology [analytic firepower] and extract a basis for their RDoC – but somehow it just didn’t work out _{[speculation alert – see below]}.
3. Reflection: However, in a few of his more recent comments, he’s also beginning to do some self-reflecting:
   • What could you have done differently to change that trajectory?
   We need better science. Just as we need that in cancer and heart disease and diabetes, we need to do that for mental illness. So we have to keep raising the bar, investing in science, getting the very best science done. When I first came into the job in 2002, one of the very first talks I gave I talked about the excitement of the science, and at that point, I was talking mostly about epigenetics [the study of how environments affect genes], which was just becoming a reality. And it seemed to me to be transformative and so exciting. It was such an innovation. And [then] someone in the audience said, “Excuse me, but our house is on fire, and you’re talking to me about the chemistry of the paint.” I never forgot that. And I think we have to be very honest with ourselves. That indeed the chemistry of the paint is important and very interesting and it will probably make sure it’s a better and safer house in 10 to 20 years. But we have to do something with the house that’s on fire as well. I worry that we didn’t do well enough on that score.
   • What would you have liked to have done at NIMH that you were not able to do?
   When I look at what I would say is my biggest failure, it’s that I don’t think that the investment we made with the money that we were given had an impact on the suicide rate, on the morbidity of any major mental illness. There are lots of explanations for why the rapid progress in science didn’t translate to much better outcomes for people with serious mental illness. I hear all that, but what keeps me up at night is knowing that the suicide rate is now higher than the mortality rate from breast cancer — I just find that extraordinary. That there are almost three times the number of suicides as homicides in this country — the homicide rate has come down by 50 percent and the suicide rate is trending up. That is, to me, unacceptable…
   The chemistry of paint story is poignant, but I have trouble believing Dr. Insel never forgot it. It seems to me that he ignored its essence throughout his tenure, even fought back against its lesson. So I’m cataloging that vignette under recent reflections accompanied by "the return of the repressed" or lamentations over the "road not taken."

Not long after Insel arrived, he announced his plan to rebrand Psychiatry as a Clinical Neuroscience Discipline. Illustrated with this slide:

Look at the Ordinate Axis [Y]. It’s Technology, specific new technologies. The APA was making the same bet in planning for their DSM-V [A Research Agenda for the DSM-5]. They [NIMH, APA, APF] jointly spent a ton of money on a long series of Symposia aiming to make the neuroscience/biological jump they’d been hoping for since the beginning [1980 – DSM-III]. As it became apparent they were going nowhere, the NIMH [AKA Insel] came up with the idea of revamping psychiatric diagnosis – Research Domain Criteria [RDoC] – to revamp diagnosis along other than clinical lines. Nobody seems to know quite what it is, but it’s often mentioned as the coming thing. It’s actually not that hard to figure out. The plan is to assemble a great huge database of subjects and then use big data techniques to find correlations and clusters – then construct the RDoC based on the results. It has 100,000 subjects right now. It’s there to nose around in already, but you’ve got to be vetted to gain access.

But that’s all we know. Based on Insel’s comment above, "Five years ago, the NIMH launched a big project to transform diagnosis. But did we have the analytical firepower to do that? No. If anybody has it, companies like IBM, Apple or Google do – those kinds of high-powered tech engines…", I’m thinking the RDoC is not working out. They haven’t said that yet, but I’m willing to wager good money that’s where all this bitterness is coming from. They bet the ship on Genomics, Neuroimaging, Proteinomics, etc the first time around and it didn’t come through. Then they turned to the power of data search engines to find their bio-diagnoses for them. And one by one, the technologies they worshiped didn’t come through for them.

So Dr. Insel et al blame the technologies [or the version of those technologies they can access] for their inability to find what they’re sure must be there. But I wonder if they’ve considered the simpler possibility? that it’s not there to find in the first place, at least not there in anything close to the magnitude they  expected   predicted  wished for…

All Aboard! As the ripples from the recently released suicide figures spread across the water, the usual suspects are being lined up to take the blame: not enough antidepressants, too many antidepressants, biomedical psychiatry, the American Psychiatric Association, the FDA’s Black Box Warning, Tom Insel’s NIMH, Managed Care, the Pharmaceutical Industry, Hospital Corporations, things like 911 or the Iraq War, the great recession, Republicans, Democrats, the NRA. And the non-psychiatric community who have been reimbursed to take over ongoing mental health care [along with their guilds] earned their right to be added to the list: Psychologists, Social Workers, LPCs, etc. Nobody gets off the hook here. There’s room on this train for every one of us. All Aboard!

Trends in Prescription Drug Use Among Adults in the United States From 1999-2012

by Kantor ED, Rehm CD, Haas JS, Chan AT, and Giovannucci EL

JAMA. 2015 314[17]:1818-1831.

hat tip to Justin Karter…

Increase in Suicide in the United States, 1999–2014

National Center for Health Statistics

Centers for Disease Control and Prevention

by Sally C. Curtin, Margaret Warner, and Holly Hedegaard

NCHS Data Brief No. 241, April 2016

"Now, the other thing that we were anticipating with some dread was the aftermath of the black box on antidepressants," says Oquendo, referring to a warning label that in 2004 the Food and Drug Administration required for commonly prescribed antidepressants. The label says that in people under age 26, the medications can actually increase the risk of suicidal thoughts and actions. Research has suggested that the warning scared doctors away from prescribing antidepressants to people of all ages. "And some of the increment in suicide deaths in the younger populations is potentially linked to an understandable reluctance by physicians who see these youngsters to prescribe antidepressants, even when they’re aware that the individual is suffering from depression," says Oquendo. Research has shown that the benefits of prescribing antidepressants to mentally ill children tend to outweigh the risk of suicidal tendencies…

When I read population statistics like the suicide figures in the last post [what’s missing…], I don’t exactly know what to do with them, what to take away that might help in my own work. Ned Shorter points us to one thing – the dramatic increases in suicides in teenaged girls [Teen Suicide: Parents Guard Your Daughters], likening it to the well known historical waves of peer suggestability in this demographic. I would only add that it elevates the newer teen identity "emo" to something bigger and more ominous than a fad. It’s an area often discounted as attention seeking, but it apparently needs more of our attention.

My own take was that the overall increased suicide rates says something about our mental health system, or perhaps I should say the dysfunctional state of our mental health system. I would think that independent of any of the other factors that may or may not be operative. We haven’t risen to the challenge. How many articles have you read lately about emergency psychiatric services? or systems? or programs? or suicidality? – not just in Psychiatric journals? but in Psychology? or Social Work? And whatever the term Managed Care means, those forces have jumped on the concept of Evidence Based Medicine and used it to restrict or deny services that are actually vital to any functional mental health system, public or private. In many [most?] cases, suicidality is subjective, deeply rooted in the unique circumstances and narrative of the individual. As such, the only valid control would be the individual him·or·her·self. Likewise, the only thing the mental health system can do about suicide rates has to do with the patients it actually sees and engages. So we can make services easily accessed and effective. And to be effective they must include what we know, not just what we can prove with objective Evidence Based Medicine. And we’re just not doing any of it.

NIH’s mental health chief on why he’s leaving for Google: Technology may hold key to better diagnosis

Washington Post

By Lena H. Sun and Amy Ellis Nutt

October 8, 2015

What could you have done differently to change that trajectory?

Insel: We need better science. Just as we need that in cancer and heart disease and diabetes, we need to do that for mental illness. So we have to keep raising the bar, investing in science, getting the very best science done. When I first came into the job in 2002, one of the very first talks I gave I talked about the excitement of the science, and at that point, I was talking mostly about epigenetics [the study of how environments affect genes], which was just becoming a reality. And it seemed to me to be transformative and so exciting. It was such an innovation. And [then] someone in the audience said, “Excuse me, but our house is on fire, and you’re talking to me about the chemistry of the paint.” I never forgot that. And I think we have to be very honest with ourselves. That indeed the chemistry of the paint is important and very interesting and it will probably make sure it’s a better and safer house in 10 to 20 years. But we have to do something with the house that’s on fire as well. I worry that we didn’t do well enough on that score.

What would you have liked to have done at NIMH that you were not able to do?

Insel: When I look at what I would say is my biggest failure, it’s that I don’t think that the investment we made with the money that we were given had an impact on the suicide rate, on the morbidity of any major mental illness. There are lots of explanations for why the rapid progress in science didn’t translate to much better outcomes for people with serious mental illness. I hear all that, but what keeps me up at night is knowing that the suicide rate is now higher than the mortality rate from breast cancer — I just find that extraordinary. That there are almost three times the number of suicides as homicides in this country — the homicide rate has come down by 50 percent and the suicide rate is trending up. That is, to me, unacceptable…

Tom Insel wears a monocle that always sees the same thing – a future age of understanding of the neurobiological core of mental illness revealed through a series of new technologies responsive to biological interventions, and has relentlessly driven the NIMH towards that goal. He’s even spearheading the development of a new classification of mental phenomena based on the findings from these technologies – Research Domain Criteria [RDoC]. In a January blog post, he wrote of challenges to his monocular view:

Balancing Immediate Needs with Future Innovation
NIMH Director’s Blog
By Thomas Insel
January 26, 2012

NIMH, like all Institutes at NIH, has an advisory council that meets three times each year. The National Advisory Mental Health Council (NAMHC) is a distinguished group of scientists, advocates, clinicians, and policy experts. Each of our meetings includes a closed session to review individual grants considered for funding and a session open to the public that engages this diverse group in discussions about the larger issues that guide NIMH funding.

At last week’s session, we heard a recurrent tension around one such larger issue. Some members of Council bear witness to the poor quality of care, the unmet medical need, and the diminishing investments by states on behalf of people with mental disorders. They reasonably ask, “How are we ensuring that the science that NIMH has produced is implemented where the need is greatest?” They also question on the pay-off of genetics research. After all, two decades after the gene for Huntington’s disease was identified, we still have no effective treatments, and Huntington’s disease is genetically far simpler than schizophrenia or bipolar disorder. In contrast to so many neurological diseases, we have effective treatments for schizophrenia and bipolar disorder. NIMH should be investing to ensure these are available.

The opposing argument runs something like this. There has been no major innovation in therapeutics for most mental disorders since 1960. Current treatments are not good enough for too many. Rather than investing scarce dollars for incremental improvements or increased dissemination of mediocre interventions, we need invest in the fundamental science of brain and behavior so that we can understand how to develop better treatments.

While I may have oversimplified the two sides of this debate, the divide is substantial. Some advisors want more funds in services research; other advisors want more funds in basic neuroscience. Some are thinking of the immediate needs; others are focused on the paradigm shifts that may be revealed by another decade of research. And with the NIMH budget stretched, tough choices must be made…

His answer was clear – monotonously clear:

Sixty years ago, the nation faced a similar short-term vs. long-term debate about polio. The needs were growing and the causes were unknown. Some wanted funds invested only in better services, including improved iron lungs. Others argued for investing in a vaccine with a long-term goal of eradication. As David Oshinsky explains in his outstanding retelling of this debate, the government went with the services approach, leaving advocates and families to raise funds for vaccine development. Let us hope we don’t short-change our grandchildren, sixty years from today, by failing to invest in the long-term promise of more effective diagnostics and therapeutics for mental disorders.

Tom Insel has created a National Institute of Clinical Neuroscience with a particular leaning towards psychopharmacological interventions. The focus is on the future discoveries that he feels are bound to come from his efforts. If there’s a model, it’s something like the Manhattan Project or DARPA, the great examples of research teams that created the Atomic Bomb, the Space Program, and the Internet – programs whose success needed a monocle to reach their goal, programs where they really did know where they were going and a lot about how to get there. What the National Institute of Mental Health is supposed to be is a funding agency that makes it possible for creative scientists with good ideas to explore them. That’s not what it is. It’s an agency with a one track mind, and that track is not perpetuated by huge successes. It’s sustained by the monocular view of Dr. Tom Insel and like-minded colleagues who have collectively been pointing us in the same direction for close to a generation without too much to show for it. I don’t personally feel so breathless, more in the range of tired and stuck. I find myself thinking we could use a pair of new glasses with two lenses looking at mental health research with less conviction that it has only one preordained direction and limited dimensions [AKA a rut]…

So his lamentations in that interview are too little too late – infuriatingly late. He leaves us with his bizarre attempt to replace clinical diagnosis with whatever the RDoC is, a mental health system that has forgotten what it’s even for, and evidence all around of what has been ignored [as in those suicide statistics].

U.S. Suicide Rate Surges to a 30-Year High

New York Times

By SABRINA TAVERISE

APRIL 22, 2016

Suicide in the United States has surged to the highest levels in nearly 30 years, a federal data analysis has found, with increases in every age group except older adults. The rise was particularly steep for women. It was also substantial among middle-aged Americans, sending a signal of deep anguish from a group whose suicide rates had been stable or falling since the 1950s.

The suicide rate for middle-aged women, ages 45 to 64, jumped by 63 percent over the period of the study, while it rose by 43 percent for men in that age range, the sharpest increase for males of any age. The overall suicide rate rose by 24 percent from 1999 to 2014, according to the National Center for Health Statistics, which released the study on Friday.

The increases were so widespread that they lifted the nation’s suicide rate to 13 per 100,000 people, the highest since 1986. The rate rose by 2 percent a year starting in 2006, double the annual rise in the earlier period of the study. In all, 42,773 people died from suicide in 2014, compared with 29,199 in 1999…

But you know what? A lot of those are psychosocial explanations [throwing in MDD was facetious anyway]. I’m not a bit surprised that the suicide rate has crept up in almost every domain during that time period. I’d say that it’s because it represents an era when we’ve turned our backs on the patients we’re charged to take care of. If a patient shows up in a psychiatris’ts office suicidal – they’re going to get medications. If a patient shows up in a psychologist’s or social worker’s office suicidal – they’re going to be referred for medications. If they go to or are taken to an ER, they’re going to get medication. And my point is not anti-medication here. They may indeed need medication. It’s that medication is all they’re going to get. The same is true if they get admitted somewhere. It will be to a stabilization unit which they’ll leave in several days on medications [a lot of medications] and that will be that.