1 Boring Old Man

^{Occam’s razor, also known as Ockham’s razor, and sometimes expressed in Latin as lex parsimoniae [the law of parsimony, economy or succinctness], is a principle that generally recommends selecting from among competing hypotheses the one that makes the fewest new assumptions. The strict translation is "Plurality is not to be posited without necessity."}

But I did decide that chasing this down would be worth the effort. It might take a while because this has obviously worked its way into government guidelines. So I’m going to table it for a time when I run out of other things to look into. In the meanwhile, I’m going to see how it worked its way into my clinic.

Rethinking recommendations for screening for depression in primary care

by Brett D. Thombs, PhD, James C. Coyne, PhD, Pim Cuijpers, PhD, Peter de Jonge, PhD, Simon Gilbody, DPhil, John P. A. Ioannidis, MD DSc, Blair T. Johnson, PhD, Scott B. Patten, MD PhD, Erick H. Turner, MD, and Roy C. Ziegelstein, MD

Canadian Medical Association Journal. 2012 184[4]:413-418.

[full text online]

…

Conclusion:
The prevalence of depression and the availability of easy-to-use screening instruments make it tempting to endorse widespread screening for the disease. However, screening in primary care is a resource-intensive endeavour, does not yet show evidence of benefit and would have unintended negative effects for some patients. Evidence from one simulation study using Canadian national data found that the overall burden of depression could be reduced by providing more consistent treatment to reduce symptoms and prevent relapse among people with recurrent disorders, but not by increasing treatment through screening.

We hope that a rigorous review of current evidence will encourage the developers of future guidelines, including members of the Canadian Task Force on Preventive Health Care, to carefully consider their stance on screening for depression. We also hope that, consistent with the 2010 guidelines of the National Institute for Health and Clinical Excellence, such developers will conclude that evidence from well-conducted, randomized, controlled trials of the benefit of screening, in excess of its likely harms and costs, is needed before it can be recommended in primary care settings. Specifically, the benefits and harms of screening should be tested in a trial in which all patients identified as having depression should have access to the same integrated care for their condition, regardless of whether they are identified through screening in the intervention group or via physician recognition and referral in a control group. It is possible that such a trial would find that screening benefits patients to a degree that would justify the cost and the harms associated with the process. Until then, however, given the lack of evidence of benefit from screening and the concerns that we have described, it is not reasonable to simply assume that depression screening is good policy.

Key points

• Screening for depression in primary care is recommended in the United States and Canada under certain conditions, but not in the United Kingdom.
• No trials have found that patients who undergo screening have better outcomes than patients who do not when the same treatments are available to both groups.
• Existing rates of treatment, high rates of false-positive results, small treatment effects and the poor quality of routine care may explain the lack of effect seen with screening.
• Developers of future guidelines should require evidence of benefit from randomized controlled trials of screening, in excess of harms and costs, before recommending screening.

Recommendations on screening for depression in adults

Canadian Task Force on Preventive Health Care

Canadian Medical Association Journal. 2013 185[9]:775-782.

[full text online]

…

Conclusion:
Our recommendations highlight the lack of evidence about the benefits and harms of routinely screening for depression in adults. In the absence of a demonstrated benefit of screening, and in consideration of the potential harms, we recommend not routinely screening for depression in primary care settings, either in adults at average risk or in those with characteristics that may increase their risk of depression. However, clinicians should be alert to the possibility of depression, especially in patients with characteristics that may increase their risk of depression, and should look for it when there are clinical clues, such as insomnia, low mood, anhedonia and suicidal thoughts.

Summary of recommendations for clinicians and policy-makers:
Recommendations on screening for depression in primary care settings are provided for people 18 years of age or older who present at a primary care setting with no apparent symptoms of depression. These recommendations do not apply to people with known depression, with a history of depression or who are receiving treatment for depression.

• For adults at average risk of depression, we recommend not routinely screening for depression. [Weak recommendation; very-low-quality evidence]
• For adults in subgroups of the population who may be at increased risk of depression, we recommend not routinely screening for depression. [Weak recommendation; very-low-quality evidence]

Why screening for depression in primary care is impractical

by Roger C. Bland CM MB ChB, David L. Streiner PhD

Canadian Medical Association Journal. 2013 185[9]:753-754.

[full text online]

…

Key points

• There is little evidence of sufficient quality to guide practitioners about what type of screening, if any, to use to detect depression in adults in primary care settings.
• The number of false-positive screens with current assessment tools is too high, and the follow-up required to rule them out too time-consuming, to justify routine screening for depression in primary care practices.
• If false-positive screens are not ruled out. patients are at increased risk of receiving the wrong diagnosis and inappropriate treatment.

^{Summary for Canada, US, UK
table from the Canadian Task Force on Preventive Health Care 2013}

Screening is not recommended. In the US, it says don’t screen unless you are in a system that can offer full services to evaluate, treat, and follow-up the results.

Decision Memo for Screening for Depression in Adults [CAG-00425N]

Centers for Medicare & Medicaid Services [CMS]

Final Decision

October 14, 2011

[full text on-line]

The Centers for Medicare & Medicaid Services [CMS] has determined that the evidence is adequate to conclude that screening for depression in adults, which is recommended with a grade of B by the U.S. Preventive Services Task Force [USPSTF], is reasonable and necessary for the prevention or early detection of illness or disability and is appropriate for individuals entitled to benefits under Part A or enrolled under Part B.

Therefore CMS will cover annual screening for depression for Medicare beneficiaries in primary care settings that have staff-assisted depression care supports in place to assure accurate diagnosis, effective treatment and follow-up. For the purposes of this decision memorandum:

• A primary care setting is defined as one in which there is provision of integrated, accessible health care services by clinicians who are accountable for addressing a large majority of personal health care needs, developing a sustained partnership with patients, and practicing in the context of family and community. Emergency departments, inpatient hospital settings, ambulatory surgical centers, independent diagnostic testing facilities, skilled nursing facilities, inpatient rehabilitation facilities and hospice are not considered primary care settings under this definition.
• At a minimum level, staff-assisted depression care supports consist of clinical staff [e.g., nurse, physician assistant] in the primary care setting who can advise physician of screening results and who can facilitate and coordinate referrals to mental health treatment.

I’m old enough to have health problems of my own so I have a physician seeing after me [as they say around here], and I work some in a rural clinic myself.  Except for still being awed by how many overmedicated patients show up, I rarely think about the things I write about here when I’m either patient or doctor. I just see after my patients [and appreciate being seen after]. But last week, I had my yearly wellness visit on Monday and then worked myself on Tuesday, and I found myself reflecting on the role of patient and doctor [from the inside]. When I got to my appointment, the receptionist said, "This is a wellness visit so I need for you to fill out some forms. Use the marker for the one on top, and the pen for the second one."

So I sat down in the waiting room to do my forms. I’m the guy who actually hears the background Musak® in stores and so I was painfully aware of the television in the waiting room with an endless stream of ads for medical products with a few health tips thrown in here and there. The magazines were in the same genre, things like prostate health and the like with sponsored ads [I longed for the days of old People magazines and aging US News & World Reports]. The machine graded form [marker] was a Review of Systems – fairly standard. But then there was a mental health questionnaire, something new, apparently trying to find out if the scourge of mental illness and suicidality could be detected in this local waiting room. I was so tempted to answer with a bunch of misery just to see if anyone read it, but I was good and accurately attested to my stellar mental health. At the end of a helpful doctor visit, he apologetically said, "Sorry – We have to do this" and did some kind of memory test to look for my dementia and reviewed my "shots."

The next day at work, after my clinic our new medical director came around to show me the new form the patients had to fill out on each visit. It was the PHQ-9. I discovered it a few years back [see PHQ-9®™…]. It’s a mental health questionnaire created by Robert Spitzer [funded by Pfizer]. Four years ago, I wrote "This article came out 12 years ago, and the PHQ-9 obviously hasn’t caught on, since this is the first I’ve heard of it…" [so much for my predictive powers]. I asked him why we were doing it [having just seen a way overly full clinic and hardly in the looking-for-work mood]. He said [sheepishly], "Sorry – We have to do this" [we’re starting to see Medicaid and the ACA-insured, and with that comes a lot of "have to do this" kind of things].

As I was driving to my daughter’s for Thanksgiving [8 hours and two States north], I found myself thinking about those forms. I’m the only psychiatrist in my county or the several counties north to the state line that’s not inside of a tv set [a few telepsychiatrists at a few mental health clinics here and there]. So I wondered who was going to deal with the yield from these forms. In our clinic, if they’re seen by our clinic doctors, they’ll just send them to me [groan]. But what does my internist do with the ones from his office? My guess is that he’s expected to follow-up and maybe prescribe something [double-groan]. My wife was napping, and this stayed on my mind for a while.

Brain expert: Why I jumped ship to Google

… 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.

"Major depression is now recognized as a highly prevalent, chronic, recurrent, and disabling biological disorder with high rates of morbidity and mortality. Indeed, major depression, which is projected to be the second leading cause of disability worldwide by the year 2020, is associated with high rates of mortality secondary to suicide and to the now well-established increased risk of death due to comorbid medical disorders, such as myocardial infarction and stroke…"

VNS Therapy in Treatment-Resistant Depression [2006]

Screening and case finding instruments for depression

Cochrane Reviews

By Gilbody S, House A, and Sheldon T

19 October 2005

The use of depression screening or case finding instruments has little or no impact on the recognition, management or outcome of depression in primary care or the general hospital.

Authors’ conclusions: There is substantial evidence that routinely administered case finding/screening questionnaires for depression have minimal impact on the detection, management or outcome of depression by clinicians. Practice guidelines and recommendations to adopt this strategy, in isolation, in order to improve the quality of healthcare should be resisted. The longer term benefits and costs of routine screening/case finding for depression have not been evaluated. A two stage procedure for screening/case finding may be effective, but this needs to be evaluated in a large scale cluster randomised trial, with a prospective economic evaluation.

Background: Screening or case finding instruments have been advocated as a simple, quick and inexpensive method to improve detection and management of depression in non-specialist settings, such as primary care and the general hospital. However, screening/case finding is just one of a number of strategies that have been advocated to improve the quality of care for depression. The adoption of this seemingly simple and effective strategy should be underpinned by evidence of clinical and cost effectiveness.

Objectives: To determine the clinical and cost effectiveness of screening and case finding instruments in: [1] improving the recognition of depression; [2] improving the management of depression, and [3] improving the outcome of depression.

Search strategy: The researchers undertook electronic searches of The Cochrane Library [Issue 4, 2004]; The Cochrane Depression, Anxiety and Neurosis Group’s Register [2004]; EMBASE [1980-2004]; MEDLINE [1966-2004]; CINAHL [to 2004] and PsycLIT [1974-2004]. References of all identified studies were searched for further trials, and the researchers contacted authors of trials.

Selection criteria: Randomised controlled trials of the administration of case finding/screening instruments for depression and the feedback of the results of these instruments to clinicians, compared with no clinician feedback. Trials had to be conducted in non-mental health settings, such as primary care or the general hospital. Studies that used screening strategies in addition to enhanced care, such as case management and structured follow up, were specifically excluded.

Data collection and analysis: Citations and, where possible, abstracts were independently inspected by researchers, papers ordered, re-inspected and quality assessed. Data were also independently extracted. Data relating to: [1] the recognition of depression; [2] the management of depression and [3] the outcome of depression over time were sought. For dichotomous data the Relative Risk [RR], 95% confidence interval [CI] were calculated on an intention-to-treat basis. For continuous data, weighted and standardised mean difference were calculated. A series of a priori sensitivity analyses relating to the method of administration of questionnaires and population under study were used to examine plausible causes of heterogeneity.

Main results: Twelve studies [including 5693 patients] met our inclusion criteria. Synthesis of these data gave the following results:

1. the recognition of depression: according to case note entries of depression, screening/case finding instruments had borderline impact on the overall recognition of depression by clinicians [relative risk 1.38; 95% confidence interval 1.04 to 1.83]. However, substantial heterogeneity was found for this outcome. Screening and feedback, irrespective of baseline score of depression has no impact on the detection of depression [relative risk 1.00; 95% confidence interval 0.89 to 1.13]. In contrast, three small positive studies using a two stage selective procedure, whereby patients were screened and only patients scoring above a certain threshold were entered into the trial, did suggest that this approach might be effective [relative risk 2.66; 95% confidence interval 1.78 to 3.96]. Separate pooling according to this variable reduced the overall level of heterogeneity. Publication bias was also found for this outcome.
2. the management of depression: according to case note entries for active interventions and prescription data, a selected subsample of all studies reported this outcome and found that there was there was an overall trend to showing a borderline higher intervention rate amongst those who received feedback of screening/case finding instruments [relative risk 1.35; 95% confidence interval 0.98 to 1.85], although substantial heterogeneity between studies existed for this outcome. This result was dependant upon the presence of one highly positive study.
3. the outcome of depression: few studies reported the impact of case finding/screening instruments on the actual outcome of depression, and no statistical pooling was possible. However, three out of four studies reported no clinical effect [p<0.05] at either six months or twelve months.

No studies examined the cost effectiveness of screening/case finding as a strategy.

A cold rainy day here in the Georgia Mountains – home from a long Thanksgiving holiday trip. I was sort of buzzing by the web sites I missed last week, and I couldn’t help but notice that the topic of drug costs was far and away the dominant topic. It was already on my mind. If you’re a doctor, you get used to medical questions, but on this trip, it was all about the cost of medications, from both young and old. I’ve tried not to get caught up in that issue here – the odd comment about Martin Shkreli or Solvaldi, but otherwise I haven’t seen much reason to join the chorus. Decrying price gouging doesn’t need much more of a voice – there are plenty around already.

But thumbing through the blogs and news today, I kind of changed my mind. Here are three recent blurbs from Ed Silverman’s Pharmalot – companies who were clearly way over the line with their pricing. As an aside, they share something else kind of encouraging. In each case, somebody’s fighting back!…

Express Scripts to cover low-cost alternative to $750 Turing drug

Pharmalot

By Ed Silverman

December 1, 2015

Martin Shkreli faces a new hurdle selling his decades-old anti-infective pill for $750. Express Scripts, the nation’s largest pharmacy benefits manager, will cover a new compounded version that costs just $1 a tablet. Moreover, two leading physicians’ groups quickly endorsed the move, suggesting that Shkreli’s Turing Pharmaceuticals will encounter substantial — and unexpected — competition.

“This will solve a big point of pain in health care costs,” said Dr. Steve Miller, the chief medical officer at Express Scripts. The decision comes amid ongoing controversy over Daraprim, which Turing last summer bought from another company and then boosted the price from $13.55 a pill to $750, a 5,000 percent increase. The price hike triggered a new round of scrutiny of pharmaceutical costs and transformed Shkreli — who used social media to deride his critics — into a poster boy for greed and outsized drug pricing…

Gilead pricing for Sovaldi hepatitis C drug slammed by senators

Pharmalot

By Ed Silverman

December 1, 2015

Gilead Sciences placed profits before patients in pricing its groundbreaking Sovaldi hepatitis C treatment, according to the results of an 18-month US Senate investigation. The drug maker was aware more patients could have been treated if Sovaldi were priced for less than $1,000 a pill, or $84,000 for a full course of treatment. Instead, it refused to lower the price or offer meaningful discounts in order to maximize and outmaneuver competition, the investigation found. And Gilead did the same thing with its Harvoni follow-up treatment.

“The company knew its prices would put treatment out of reach for millions of Americans,” said Senator Ron Wyden, a Democrat from Oregon who, along with Iowa Republican Senator Chuck Grassley, discussed their probe at a media briefing. “If Gilead’s approach is the future of how blockbuster drugs are launched in America, it’s going to cost billions and billions of dollars to treat just a fraction of patients in America”…

Valeant’s unsavory ways a lesson for us all

Pharmalot

By Ed Silverman

November 1, 2015

Valeant CEO J. Michael Pearson is not your typical drug executive. Pearson built his company into a moneymaking machine by acquiring other drug makers and products, not by investing in research and development. The approach contradicted longstanding industry doctrine, but it won high praise from investors. For years, the Canadian drug company’s stock went nowhere but up.

Not anymore. A slew of questions about its business practices has turned Valeant from a Wall Street darling into a Main Street poster child for questionable behavior. Federal prosecutors have issued subpoenas. Lawmakers are conducting investigations. Pharmacy benefit managers stopped doing business with a company that was important to Valeant’s operations…

We’ve traditionally given new drugs a period of legal monopoly in return for private enterprise becoming the development arm of medicine. But the pharmaceutical and medical support industries have increasingly come to represent the dark side of capitalism. The three companies mentioned above developed nothing. They got hold of their products and are only looking to reap a big profit. There’s not much else to say. And when I step back and think about it, this issue of the financial bottom line is the ultimate culprit in everything I find myself complaining about in modern medicine – the conflicts of interest, the jury-rigged clinical trials, the distortions of scientific evidence, the corrupted key opinion leaders, the outrageous pricing of drugs, etc.

APA Receives Federal Grant to Train Psychiatrists in Integrated Care

PSYCHIATRICNEWS

by Mark Moran

October 29, 2015

This major milestone is in recognition of APA’s commitment to integrated care. The training that psychiatrists receive will enable them to expand their psychiatric expertise to larger populations of primary care patients.APA is one of just 39 health care organizations selected by the Centers for Medicare and Medicaid Services [CMS] to participate in the Transforming Clinical Practice Initiative, a grant program in which APA will receive $2.9 million over four years to train 3,500 psychiatrists in the clinical and leadership skills needed to support primary care practices that are implementing integrated behavioral health programs.

APA will train psychiatrists in collaboration with the AIMS [Advancing Innovative Mental Health Solutions] Center at the University of Washington and will offer both online learning modules and in-person training at APA meetings. Ultimately, it is expected that psychiatrists will be able to join ongoing learning communities designed to continuously share information and advice about how to implement the skills of integrated care into their practices and to transform clinical practice.

“We hope to leverage APA’s district branches to create local learning communities dedicated to changing clinical practice,” said Anna Ratzliff, M.D., Ph.D., associate director for education at the AIMS Center and director of the University of Washington Integrated Care Training Program.

The award is a milestone for APA, a high-profile recognition of APA’s commitment to integrated care and to the goals of its so-called “Triple Aim”: improving the individual experience of care, improving the health of populations, and reducing the per capita costs of care for populations. Of the 39 health care organizations, there are 29 health care networks, and just 10 “Support and Alignment Networks” [SAN], of which APA is one…

^{[click image for description]}

She was in her early thirties, obviously "dressed up" to go to the doctor and clearly apprehensive about the visit. She lead with symptoms, "anxiety and depression" for the last several months. Her friend had noticed and suggested she come to the clinic and get on some medications. She was a stay-at-home mom with children 9 and 3. Her husband had a good job and their financial situation was stable. Her symptom list jibed with DSM-5 MDD. Exploration for some reason she might be depressed, something wrong in her life, was negative.

She’d been married ten years. They were making it financially, owned their own house, and each had a car. Her kids were easy. Her husband was a "good provider," working as a plumber. He was from a city several hours away, a college town where they’d met. Like many in our rural area, he worked out of town, and was gone two or three nights a week. Most of his out of town work was in his home town. So when he was gone, he stayed at his mother’s.

When I asked what it was like for him to be gone that much, the apprehensiveness returned. It wasn’t too much longer before she said, "Lately, he leaves in his plumber’s clothes, but he’s been taking a change of good clothes with him. Why doesn’t he just take pajamas?"  So I asked "What got you to worrying about that ‘several months ago’?" Without hesitation, she responded. "One night, I called to find out when he’d be home. He didn’t answer. I called over and over. Finally, he answered. He was on the road coming home. He said he must’ve turned off his phone by accident. He never does that"

Whenever I read about Collaborative Care, cases like this pour into my mind. This young woman was from a week ago, the last time I worked in the clinic. I feel kind of funny mentioning anecdotes and add some disguises to insure privacy. While it feels like bragging to present cases like this, I just don’t know how else to talk about what bothers me about Collaborative Care. When I look at that firewall between me and the patient in that diagram [twice removed], I feel defeated. It’s obviously put there to insure that I’ll stick only to medication management. And it’s a sure bet that’s what she’d be treated with if someone didn’t go poking around to find out what’s wrong. I don’t know how to poke through proxies – the care manager and the primary care physician. But I’m sure she isn’t likely to need any of my medication management expertise.

^{this is the way the world ends  
this is the way the world ends  
this is the way the world ends  
not with a bang but a whimper
                    T.S.Eliot 1922}

Dr. Tom Insel to Step Down as NIMH Director

… A national search for a new NIMH Director will be launched, but in the meanwhile Dr. Collins has issued an official statement appointing Dr. Bruce Cuthbert as Acting Director. Bruce has held a number of leadership positions at NIMH, including leading our RDoC initiative as well as the NIMH Division of Adult Translational Research. He is an internationally recognized researcher. I greatly appreciate his willingness to lead the Institute during this transition period. I know with Bruce at the helm and the leadership team in place at NIMH, I leave the Institute in strong, capable hands.

The post  millennial honeymoon didn’t last as long as many hoped. We know about the negative stuff – the drugs’ exaggerated efficacy, the sometimes dire side effects, the exposed corruption of the academic-pharmaceutical alliances, and the accompanying rampant conflict of interest problems among key opinion leaders in high places. It seemed as if the once venerated position of department chairman had become a stepping stone to political and financial gain. And while these revelations of tarnished power became increasingly apparent, there was a much bigger problem in the background. The research was flat as a pancake – producing little to none of the kind of neuroscience breakthroughs assumed to be just around the corner. And the drugs which were selling like hotcakes were little more than clones of two basic themes – SSRIs and Atypical Antipsychotics.

So by the end of the first decade of our new century, the DSM-5 Task Force had to abandon its grand plan for a neuroscience-based DSM and fell into a much-ado-about-nothing mode. And speaking of abandonment, the pharmaceutical industry was pulling out of CNS drug research and development altogether for lack of results – and busied itself dealing with the multiple civil and criminal suits coming their way. Insel’s NIMH apparently concluded that its lackluster results were due to a faulty clinical diagnostic system. Abandoning the DSM-5, they embarked on creating one of their own – the RDoC [Research Domain Criteria] – envisioned as a dimensional system based on… neurobiology? or something like that. [see Dr. Carroll’s Clinical science and biomarkers: against RDoC and Dr. Insel’s parting comments in Brain expert: Why I jumped ship to Google].

Federal Agencies Partner to Promote Coordinated Services for Patients with First Episode Psychosis

Coordinated specialty care may become more readily available

NIMH • Science Update

October 29, 2015

NIMH is the world’s leader in mental health research, yet it’s rare for that research to have an immediate impact on clinical practice. However, the NIMH-funded RAISE initiative is an exception. On October 16, 2015, the Centers for Medicare & Medicaid Services posted an informational bulletin to State Medicaid Directors about covering treatment for first episode psychosis. The bulletin represents a joint effort by several agencies: NIMH, CMS’ Center for Medicaid and Children’s Health Insurance Program, and the Substance Abuse and Mental Health Services Administration. A key feature of this bulletin is CMS’ support for coordinated specialty care [CSC], the evidence-based treatment approach tested in the Recovery After an Initial Schizophrenia Episode [RAISE] initiative.

The bulletin says that the two RAISE studies, as well as the Specialized Treatment in Early Psychosis [STEP] study from Yale University, “demonstrate convincingly [1] the feasibility of first episode psychosis specialty care programs in U.S. community mental health settings, [2] that young people with psychosis and their family members accept these services, and [3] that CSC results in better clinical and functional outcomes than typical treatment.”

The rest of the bulletin goes on to explain how states can use the federal Medicaid program to pay for evidence-based first episode psychosis services, such as those tested in RAISE…

Not that it matters so much anymore, but I don’t buy the narratives of the hour. By any parameter, both the NIMH’s Clinical Neuroscience and the APA’s Biomedical DSM-5 have been colossal failures. So my guess is that Dr. Insel was no longer able to bring off the argument he advanced in Balancing Immediate Needs with Future Innovation back in 2012:

Finally, we have an unprecedented opportunity for progress, real progress, in understanding mental disorders. The answers are likely to be more difficult and more complex than cancer or many single gene disorders, but the tools are now becoming available. High throughput sequencing for DNA and RNA, whole genome epigenomics, high resolution imaging of the human brain, connectomics—all of these tools are giving us a first opportunity to understand mental disorders at many levels beyond the reported symptoms or the observed signs. What the EKG did for cardiology, the bacterial culture did for infectious disease, and molecular biology did for oncology, neuroscience should provide for the study of mental disorders.

Some think the technology is just not yet up to the task. Others think that locating mental illness in the brain was off the mark from the start. And there are infinite gradations in-between. But there’s not much argument with the fact that we haven’t gotten anywhere. Whether Insel’s exodus was fueled by his own frustration or the frustration of others with his results is likely something we’ll never know. Parenthetically, I don’t see RAISE as a product of Insel’s NIMH. They jumped on available ARA funds and it became a future policy before it was even completed. That RAISE program could use some liberal tweaking, but I  gather  hope it’s more template than injunction. Whatever the case, increasing funding and attention directed towards the first episode of psychosis has to be a good idea.

Getting treatment for depression is critical

special to the Miami Herald

by Dr. Charles Nemeroff

November 23, 2015

Depression is a commonly used and terribly misunderstood term. When mental health professionals refer to depression, they are referring to a syndrome – a constellation of symptoms that persists every day for two weeks or longer. Patients may feel blue, hopeless and "down in the dumps." They also may complain of fatigue, sleep disturbances, changes in appetite and decreased concentration. Think about the saddest you’ve ever felt and feeling like that every day for no obvious reason – this is a good description of major depression.

In the past two decades, we have learned much about the causes of depression. We now know from brain imaging studies that depression, like Parkinson’s disease and stroke, is a brain disease. In addition, depression can run in families.

Depression can be effectively treated by antidepressant medications — such as Prozac, Effexor, Zoloft, Lexapro and others — and/or certain forms of psychotherapy [cognitive-behavior therapy and others]. Patients who fail to respond to one antidepressant often respond to another. Those who do not respond to antidepressants or psychotherapy treatments can receive other approved and effective treatments, including repetitive transcranial magnetic stimulation [rTMS] or electroconvulsive therapy [ECT].

The good news is that the vast majority of patients can be effectively treated; the bad news is that many patients remain underdiagnosed and untreated or are reluctant to seek treatment from mental health professionals. When it comes to mental health, patients should always seek out mental health experts – just as they would for any illness.

While the category Major Depressive Disorder is probably a heterogeneous collection rather than a discrete syndrome, there’s one thing for sure – we don’t now know that Major Depressive Disorder or any subset of that collection is a brain disease by neuroimaging. It’s hardly possible that Dr. Nemeroff doesn’t know that, meaning that his mis·statement is not a mistake. It’s a conscious exaggeration at best, but more likely simply a calculated lie – something he wants to be true to fit an agenda. It’s hardly his first.

We know at least one part of why? [why he does it]. He has made a series of such deliberate mis·statements since he appeared on the stage in the early 1990s, and the motive has usually been financial reward for himself personally and for the companies he advises, though sometimes it’s to argue for some pet theory [see business as usual…]. The why? I don’t know is why the academic psychiatric community, or the Miami Herald puts up with such antics. Yet he’s the chairman of a psychiatry department, holder of an NIMH Grant, gets invited here and there to give talks with  conclusions  speculations like this …

… is  the senior author on review articles in the American Journal of Psychiatry [infomercials…], has no problem getting published [averaging well over an article a month for over 30 years] …

… is a co-editor of a major text in psychopharmacology, speaks in multiple C.M.E. courses, etc. Whenever there’s something new, he’s right there to talk about it [personalized medicine, Ketamine, various electro-stimulation devices, lithium patches, etc.]. So he seems bulletproof, untouched by his track record of betting on a series of failed enterprises, chasing edgy hypotheses that don’t pan out, or the public exposures for agenda-driven exaggerations, mis·statements, and lies like in this little blurb in the Miami paper.

While it may seem that with all the attention being focused on Data Transparency for Clinical Trials and things like the AMA voting to oppose Direct-to-Consumer advertising, we are iterating towards a time when the battle against the corruption of medical practice by commercial interests is making some real progress. But it seems to me like there’s always the rumbling of distant thunder. As physicians, we should be attuned to such early warnings. After all, there’s an important medical principle involved – Preventive Medicine. While talking about such things can begin to sound like early psychosis, the alternatives are too well known to ignore. Particularly dangerous are things that look innocent, maybe even like progressive reform to solve some contemporary problem, but later turn out to have been the proverbial wolf in sheep’s clothing.

In psychiatry, we have a number of examples, but the one that jumps off the page is the Texas Medical Algorithm Project [TMAP]. When the Atypical Antipsychotics were first introduced, we couldn’t have been more primed and ready. They were effective alternatives to our older drugs but with a markely reduced incidence of neurologic side effects. The experts agreed and said so in widely publicized guidelines. Since the majority of antipsychotics are prescribed in public systems, it only made sense to insure that the less fortunate treated in these public systems have access to this medical breakthrough – implemented in Texas through the TMAP Guidelines which prescribed ‘try the Atypical Antipsychotics first.’ It was such a good idea that the Texas Mental Health officials became evangelical, ultimately spreading the gospel to about a third of our states [with a bit of financial help from the manufacturers]. When it was all said and done, the Texas Medicaid program was all but bankrupt; it became clear that the Atypicals were neither more effective nor better tolerated than the older drugs; and they had some toxic side effects all their own.

And now? Well there’s the Trans-Pacific Partnership that many worry will bring many rewards to the pharmaceutical industry including even longer periods of patent exclusivity. I’ll have to admit that my understanding of this trade agreement remains embryonal even after several attempts to understand it. Some of the problem is their secrecy, but I fully admit absolutely no expertise in the area. But there’s another one that, though my understanding of the basics is equally poor, I think the rat I smell is very real.  It’s a bill in Congress called the 21st Century Cures Act that has passed the House already [see The F.D.A.’s Medical Device Problem, 21st Century Cures Act: A huge step backward for FDA standards, and Will the 21st Century Cures Bill Lower Standards for Some Drug Approvals?]. The sheep’s clothing is that getting drugs approved is a long, slow process. And patients, particularly patients with desperate or terminal illnesses understandably don’t want to wait. But the very large wolf is that the proposed solution is "fast-tracking" drugs and devices, without the preapproval Clinical Trials, relying on antedotes and other indirect evidence. That opens Pandora’s Box allowing dangerous drugs on the market, particularly the kind of drugs used to treat dire illnesses.

The Clinical Discovery of Imipramine

by Walter A. Brown, M.D. and Maria Rosdolsky, M.D.

American Journal of Psychiatry. 2015 172[5]:426-429.

The major classes of psychotropic drugs were introduced in an extraordinary decade of discovery between the late 1940s and late 1950s. In the present climate of pessimism about the absence of new drug development, it may be instructive to look back at the research methods used during that era. The study that identified the first antidepressant is a case in point. It was conducted by Roland Kuhn, a Swiss psychiatrist working in a remote psychiatric hospital. Kuhn, like the other pioneering researchers of his day, was given access to new drug entities, and the method he used to discover their clinical effects was open-minded, exploratory, comprehensive, clinical observation…

By today’s clinical research standards, Kuhn’s method of unfettered, exploratory, clinical observation was substandard, haphazard, even messy. Yet it produced a major breakthrough—the discovery that a drug can alleviate depression—that has had a lasting impact on the treatment of depression and on the development of antidepressant drugs. Kuhn’s experience might usefully inform our strategies of drug development.

^{[The graphic is my rendition of Kuhn’s guestimate about response rates]}

Über die Behandlung depressiver Zustände mit einem Iminodibenzylderival [G22355]

by Kuhn Roland

Schweiz Med Wochenschr 1957 87:1135–1140.

Symptoms of depressive mood that are obvious when observing the patient’s appearance often improve significantly under treatment with G22355. The facial expression loses rigidity, modulation and expression abilities return. The patients become livelier, the depressive whispering becomes louder, patients become more communicative, and moaning and whining can no longer be heard. If the patient was discontented, querulous or irritated, he changes into a friendly, content and amenable person. Hypochondriac and neurasthenic complaints are no longer dominant or disappear completely. Patients who had great difficulties in getting up in the morning, get out of bed early with their own initiative, at the same time as other patients. They initiate relationships with other people, start conversations, participate in the daily life of the clinic, write letters, and are again interested in their family matters. They start working spontaneously, get their work done, and the slowness in their life is replaced by a normal vitality. With these improvements, the patients become popular in the ward. Their mood and behavior appear to be balanced. Several times, family members were fascinated and told the physician that the patient had not been in such a good condition for a long time.

Most of the time, the patients notice the change, report it, are, of course, very joyous about it and talk about a miraculous cure. The feelings of heaviness, tiredness, weakness, depression, inner tension, rigidity and restlessness subside. The patients feel free again, inhibition of thoughts and activities disappears, thoughts and activities return. A sad, depressed, desperate and fearful mood turns into a neutral unburdened or somewhat cheerful mood with the feeling of healing and increasing strength. Feelings of guilt, delusions of impoverishment or culpability simply disappear or lose their affective importance, move into a distance, and the patient becomes indifferent and unconcerned with respect to these feelings. It happened that a pronounced suicidal intent of a patient suddenly disappeared! If sleep was disturbed by depressive symptoms, it normalizes quickly without sleep-inducing medications, even in cases who did not respond to common hypnotic agents. Nightmares, sometimes occurring in depressive people, with blood, dead bodies, terrible accidents, and gruesome atrocities, frequently accompanied by terrible fear, no longer occur under the treatment. Morning moodiness and other daytime fluctuations of the depressive state are no longer observed. If the patient had no appetite, his appetite returns. Sometimes, constipation due to depression improves.

A CONTROLLED TRIAL OF IMIPRAMINE IN TREATMENT OF DEPRESSIVE STATES

BY J. R. B. BALL AND L. G. KILOH

British Medical Journal. 1959 2:5199:1052-1055.

[full text on-line]

All the cases included in the trial were out-patients, and anyone showing gross retardation or extreme agitation and those in whom the risk of suicide was considerable were automatically excluded, as they were admitted for in-patient treatment. Nevertheless, a number of the patients included were quite severely depressed…

The results of treatment were assessed as symptom free, greatly improved, somewhat improved, no change, or worse. For the purpose of assessing the value of the drug as a significant therapeutic agent, the first two of these categories have been combined as a good or worth-while result and the other three as a poor result. Patients showing a good result were able to return to their normal activities without undue effort…

Of 55 cases of endogenous depression treated, 27 received imipramine and 28 the placebo. On imipramine 20 responded well, while 7 did badly. On the placebo, 6 did well and 22 badly. This is a highly significant difference, and, with Yates’s correction applied, P<0.01. Of the 42 cases of reactive depression 22 received imipramine and 20 the placebo. Of those given imipramine 13 were improved and 9 were not; while of the 20 controls 4 improved and 16 showed a poor result. This, too, is a significant result [P<0.02]. When improvement occurred it was nearly always evident by the end of the third week,  sometimes as early as the fourth or fifth day. The mean was 9 to 10 days…

Flash forward: A few years later, I was in a psychiatry residency, spending my first year on inpatient units, and I had the second version of my thought, "So this is what depression [really] is." It wasn’t a reported symptom or a way of saying "my life’s a mess". It was something you could see, even feel, as soon as the patient walked into the room. And the distinction made above between Endogenous and Neurotic Depression wasn’t severity – both were severe. I don’t think I had ever seen that kind of palpable depression before my psychiatric residency program except in the occasional patient on Reserpine. But in those days, I understood what my friend had been trying to tell me back on the base a few years earlier.

NIMH Director Tom Insel labeled the time of this speech four years ago as "an extraordinary moment," but I recall it in a different way. The DSM Task Force had just admitted that its push for a neuroscience based DSM-5 was being abandoned [for lack of confirmation]. And it had just become crystal clear that PHARMA was making a massive exodus from CNS R&D [no discoveries, no leads]. The KOL set was at DEFCON 4 and having multiple meetings hoping to get PHARMA to recant. I guess Dr. Insel and I saw it as different kinds of extraordinary moments.

I have no idea what he was referring to with "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." I still don’t know. I assumed at the time that he was rallying the disheartened troops with hope for the future. I specifically recall the quote because it was the first time I heard the term "chemical imbalance" from a psychiatrist, and it was absolutely the first time I ever heard "a disorder of brain circuitry" from anyone – ever.

I now see that summer of 2011 as marking a change in Dr. Insel. Before that he seemed to be an inspired neuroscience cheerleader filled with a boyish exuberance.  Since that summer, he’s talked a lot about how inadequate the current drugs are; lamented the intransigence of the mental illness statistics; come up with scheme after scheme to jump-start drug development; broken away from the APA’s DSM diagnoses; declared his nebulous RDoC to be a prerequisite for NIMH Grant money. It seems like he began to talk as if we know nothing, like we’re starting over from scratch.

Insel Outlines the Psychiatry of the Future Treating Disorders of Neural Circuitry

PsychiatricNews Update

by Tom Insel

May 3, 2014

The diagnosis and treatment of mental illness is haunted by four “inconvenient truths.” That’s what NIMH Director Thomas Insel, M.D., told APA members today in his annual meeting lecture “From Psychiatry to Clinical Neuroscience.” Those inconvenient truths are these:

1. We have failed to “bend the curve” in the prevalence and the cost of mental illness
2. More people are getting more treatment, but outcomes are not getting better. So, more of today’s treatments may not be sufficient to bend the curve.
3. We don’t know enough to ensure prevention, recovery, or cure for too many people with serious mental illness.
4. We need to transform diagnostics and therapeutics if we are going to make significant progress.

Insel outlined some of the problems that have hindered efforts to bend the curve. These include the fact that diagnosis is limited to observable symptoms, and detection is almost invariably late; etiology of most mental illness is unknown; and prevention is not well developed for most disorders. Treatment is trial and error, and there are no cures and no vaccines.

Moreover, what is known as the mental health “system” is a poorly integrated maze of nonspecific pathways of care, with some people entering through the emergency department, criminal justice system, the primary care system, or nonprofessional services. Diagnosis and treatment vary from provider to provider and from patient to patient.

Knowledge of the brain, despite enormous advances in recent years, is still in its infancy, Insel pointed out. “The brain is a world consisting of a number of unexplored continents and great stretches of unknown territory,” he said. But Insel also described a promising future in which mental illness is re-envisioned as a disorder of brain circuitry that will be greatly advanced by the president obama’s brain initiative, announced in April 2013.

Research is revealing how chemical imbalances can lead to circuit dysfunction, and in turn to behavioral symptoms, and Insel said the connections that are emerging can be used in the development of diagnostic tests for brain disorders that are today diagnosed late through observation of symptoms. “We can now study the mind with the tools of neuroscience,” he said. For instance, he presented evidence that is revealing ADHD to be a disorder of delayed cortical maturation. He also presented evidence of schizophrenia as neurodevelopmental disorder with distinct risk and prodromal stages that allow for early intervention.

Finally, he described the NIMH Research Domain Criteria [RDoC] project, which he said will work in tandem with DSM. “DSM/ICD will continue to be the basis of clinical care,” he said. “RDoC is a framework for research in which NIMH will support researchers to deconstruct current diagnostic categories or identify dimensions that extend across categories. RDoC will develop through an information commons that integrates data from many sources, transforming the way we diagnose mental disorders in the future.”

Brain expert: Why I jumped ship to Google

Silicon Valley offers a fresh way to tackle conditions such as schizophrenia says US mental-health expert Thomas Insel

The New Scientist

By Sally Adee

Nov 4, 2015

… 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.

… 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…

Were I to speculate about what went wrong, I’d list a number of things. Everything about his NIMH’s effort was based in technology and ideology rather than precise clinical medicine and high standards in scientific reporting. Insel was right when he figured out that the DSM was a big problem – no basis for research. But the problem wasn’t clinical diagnosis, it was that system itself. Instead of limiting the domain by careful case selection, almost every study went for a home run. He would’ve done well to go back to basics. He was too controlling about what the applicants did instead of setting high standards for how they did it and how it was reported. Instead of locating and developing solid scientists, he supported the usual suspects. There is likely a segment of mental illness where his Clinical Neuroscience is an appropriate model, but he drank the koolade and  saw it as everything. So instead of home runs, he ended up giving us a fist full of rain checks. But my Monday morning quarterbacking isn’t the point. The point is that Tom Insel wanted to officiate a paradigm shift, and he seems bitter and somewhat blaming about the results. That’s just not what was in his cards. Instead, he was around for a recession.