1 Boring Old Man

The first blog I encountered when I realized how much corruption there was in the medical literature was Health Care Renewal. It wasn’t about the psychiatric medications, but it was  about the problem I was stirred up about at the time. I found others, but most of them had some underlying agenda of their own. Health Care Renewall didn’t seem to have that problem. I went back and read the inaugural post and that cinched it – Roy Poses was talking about what I needed to read about. His referenced paper is available full text on-line, as right today as the day he wrote it [it’s telling which journal ended up publishing it]:

Since then, I’ve read his blog religiously. I don’t mention it often because the only thing to say is "yes!" He has a recurrent theme that it took me a while to fully comprehend – anechoic. It means what it says. When yet another example of corrupted medicine appears, it may be a big story [briefly], but then it goes away [quickly] – it doesn’t echo. It gets lost in the wind. A prime example is Jureidini, Amsterdam, and McHenry’s recent paper:

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.

[full text on-line]

Using subpoenaed verbatim internal documents, they demonstrate an example of a pharmaceutical company actively distorting an analysis. It should be a nidus for a collective call to arms, but it’s not even much yet read.

Transparency International Reports on Massive Corruption in the Pharmaceutical Sector – Media Hardly Notices

Health Care Renewal

by Roy Poses

June 08, 2016

Corruption in the Pharmaceutical Sector

Transparency International UK

June 2016

[full text on-line]

Executive Summary

The launch of the Sustainable Development Goals in September 2015 signals a more comprehensive global development agenda. This plan specifies that all governments must fight corruption. For the health sector, this will mean integrating good governance into policy making and implementation to reduce the risk of corruption.

Within the health sector, pharmaceuticals stands out as sub-sector that is particularly prone to corruption. There are abundant examples globally that display how corruption in the pharmaceutical sector endangers positive health outcomes. Whether it is a pharmaceutical company bribing a doctor for prescribing its medicines irrespective of a health need or a government employee facilitating the infiltration of substandard medicines into the distribution system, public resources can be wasted and patient health put at risk.

For policy makers to implement successful anti-corruption measures there is a need to identify and understand corruption vulnerabilities in the pharmaceutical sector. To support this task this paper identifies key policy and structural issues in selected activities of the pharmaceutical value chain, along with relevant anti-corruption policies. This analysis showed that anti-corruption policies are needed throughout the pharmaceutical value chain to increase transparency around key decision points and strengthen the accountability of actors.

Four overarching challenges derived from structural issues and anti-corruption policies across the selected activities of the value chain have been identified. These are:

• A lack of objective data and understanding of corruption inhibited by environmental context, the complexity of issues in the sector and policy makers not viewing corruption as an issue.
• A weak legislative and regulatory framework because of poor investment, a lack of oversight and national regulatory frameworks that are often decentralised and reliant on self-regulation for key decision-point.
• The potential for undue influence from companies due to a high degree of autonomy over key decision points and unparalleled resources, on policy and regulation so profit maximisation goes beyond ethical norms and negatively impacts health outcomes and public health objectives.
• A lack of leadership committed to anti-corruption efforts from all actors. National leaders often only implement reforms after a crisis, with their inaction regularly hindering other actors.

Similarly, three key action areas to mitigate corruption vulnerabilities in the pharmaceutical sector are examined. These include establishing leadership committed to addressing corruption, adopting technology throughout the value chain and ensuring accountability through increased monitoring, enforcement and sanctions. These overarching challenges and action areas are neither novel nor resource-intensive, stressing the lack of effective action in the past; as well as the difficulty of dealing with corruption in a sector that is extremely complex, has a high level of government intervention and often has regulatory systems in place that are inadequate to properly govern the value chain. Only by overcoming these challenges and focusing on these action areas will the global health community be better able to meet the health Sustainable Development Goals.

^{One feature of living here at the edge of the galaxy is frequent power outage – regular with storms, but sometimes they just happen. So I’ve got an XL battery backup for my computer. But every year or so, the big batteries go kerfunkle and need replacing. The replacements were on the floor next to my chair awaiting installation when the power went poof! this morning while I was in the middle of writing something that evaporated into cyber-wherever. Sitting on the porch watching the sun come up [and waiting for the power to return], I realized that the power outage was fortuitous. It actually addressed the topic I was writing about – a value-added power outage…}

Several of the responses to Cipriani et al’s new meta-analysis of medication in adolescent depression [see antidepressants in kids? a new meta-analysis…] raised the question, "So what is the treatment if it’s not antidepressants?" In the companion comment in the BMJ [Antidepressants fail, but no cause for therapeutic gloom], Jureidini suggests "watchful waiting." And in the The Pharmaceutical Journal article, Bazire points out that CBT might be gone with the wind as well, and seems concerned that we have nothing to offer.

I’m old enough the have done my psychiatric residency BD and BP [before the DSM-III and before Prozac®]. My 6 month 3rd year elective was spent on an adolescent milieu treatment unit. I saw late adolescents in practice, and after retiring, I volunteered in a child and adolescent clinic for four or five years. They had a great group of clinicians, and we did [my version of] collaborative care. I’d see the patients they were either confused about or they thought might need medications, then we’d staff the cases and come up with a treatment plan [only sometimes including medication]. I actually left that clinic because there was an abrupt turnover in staff, and the new crop of clinicians were a different and less talented breed who pressed for medications.

But my point is that there is plenty that needs considering when dealing with troubled depressed adolescent BD and BP. And antidepressants were never the first-line response for me back then or up here. For that matter, the diagnostic formulations pre-DSM-III rarely included a diagnosis of Major Depressive Disorder, even when the kid was depressed. A blog is hardly the place to launch into a discussion of all the forces operating in adolescence or adolescents – things like character formation, identity, dependence vs independence, relating to peers and society, moral development, acting out, sexuality, substance abuse, etc – or all the things that can go awry. But, for me, formulating an approach to a troubled, off-track teen is a much bigger deal that focusing only on how they feel and symptomatic relief.

These days, the primary focus is on evidence-based short-term treatments, case-finding [screening], and cost containment. Those are very important things to consider, but that doesn’t mean that we don’t need to figure out what’s going on with the kid. This is one place where the omnibus category, Major Depressive Disorder, really lets us down. Even back in the day, I could see that the unit I worked on was effective, but way over-kill, often disruptive to the family [and kid], stigmatizing, and expensive to a fault. And I was impressed that in my more recent experience, we could do a good job with far less. Sometimes, just the evaluation process got a confused family back on course, and that’s all that was required.

Back to my main point. Perhaps, right-sizing the use of medication in adolescents is not a power-outage after all – it’s a wake-up call. Adolescence is teeming with shoals, but it’s also a time of life with great promise and possibilities. What could possibly be more cost effective than getting back to focusing broadly in our evaluations and intervening wisely? Pretending that some symptomatic medication is more effective than it is may make some Managed Care actuary feel better, and some PHARMA executive happier, but those are obviously just fantasies that don’t take the long term costs of missed opportunities for change into account.

^{Note: The main article [Cipriani et al] is available full text on line at the time I’m writing this, but I can’t tell for how long. If pediatric depression is of any interest to you, I would recommend saving it to your computer/desktop as that access might disappear.}

Andrea Cipriani is an Oxford-based psychiatrist and author of numerous Systematic Reviews and Meta-analyses of psychiatric medications – many published by the Cochrane Collaboration. In short, he’s the real deal. I had an opportunity to see an advanced copy of this paper and my thought after reading it that this should be the  new gold standard for this much discussed topic. The accompanying comment by Jon Jureidini is quite good, though I can’t locate a full text source on-line.

This has been such a conflicted issue from the earliest of days. Prozac® [fluoxetine] was approved for adolescent depression, then later Celexa®/Lexapro® were approved around the same time that the FDA appended the Black Box warning in 2004. No other SSRI/SNRI drugs have been approved for kids since then. This is a highly contentious issue ["this" being Are the drugs safe in kids? Are the drugs even effective in kids? Do they cause suicidality in some kids? suicides? homicides?].

Comparative efficacy and tolerability of antidepressants for major depressive disorder in children and adolescents: a network meta-analysis

by Andrea Cipriani, Xinyu Zhou, Cinzia Del Giovane, Sarah E Hetrick, Bin Qin, Craig Whittington, David Coghill, Yuqing Zhang, Philip Hazell, Stefan Leucht, Pim Cuijpers, Juncai Pu, David Cohen, Arun V Ravindran, Yiyun Liu, Kurt D Michael, Lining Yang, Lanxiang Liu, and Peng Xie

Lancet. Published online June 8, 2016

[full text on-line]

[audio interview]

Background: Major depressive disorder is one of the most common mental disorders in children and adolescents. However , whether to use pharmacological interventions in this population and which drug should be preferred are still matters of controversy. Consequently, we aimed to compare and rank antidepressants and placebo for major depressive disorder in young people.

Methods: We did a network meta-analysis to identify both direct and indirect evidence from relevant trials. We searched PubMed, the Cochrane Library, Web of Science, Embase, CINAHL, PsycINFO, LiLACS, regulatory agencies’ websites, and international registers for published and unpublished, double-blind randomised controlled trials up to May 31, 2015, for the acute treatment of major depressive disorder in children and adolescents. We included trials of amitriptyline, citalopram, clomipramine, desipramine, duloxetine, escitalopram, fluoxetine, imipramine, mirtazapine, nefazodone, nortriptyline, paroxetine, sertraline, and venlafaxine. Trials recruiting participants with treatment-resistant depression, treatment duration of less than 4 weeks, or an overall sample size of less than ten patients were excluded. We extracted the relevant information from the published reports with a predefi ned data extraction sheet, and assessed the risk of bias with the Cochrane risk of bias tool. The primary outcomes were efficacy [change in depressive symptoms] and tolerability [discontinuations due to adverse events]. We did pair-wise meta-analyses using the random-effects model and then did a random-effects network meta-analysis within a Bayesian framework. We assessed the quality of evidence contributing to each network estimate using the GRADE framework. This study is registered with PROSPERO, number CRD42015016023.

Findings: We deemed 34 trials eligible, including 5260 participants and 14 antidepressant treatments. The quality of evidence was rated as very low in most comparisons. For efficacy, only fluoxetine was statistically significantly more effective than placebo [standardised mean difference –0·51, 95% credible interval [CrI] –0·99 to –0·03]. In terms of tolerability, fluoxetine was also better than duloxetine [odds ratio [OR] 0·31, 95% CrI 0·13 to 0·95] and imipramine [0·23, 0·04 to 0·78]. Patients given imipramine, venlafaxine, and duloxetine had more discontinuations due to adverse events than did those given placebo [5·49, 1·96 to 20·86; 3·19, 1·01 to 18·70; and 2·80, 1·20 to 9·42, respectively]. In terms of heterogeneity, the global I² values were 33·21% for efficacy and 0% for tolerability.

Interpretation: When considering the risk–benefit profile of antidepressants in the acute treatment of major depressive disorder, these drugs do not seem to offer a clear advantage for children and adolescents. Fluoxetine is probably the best option to consider when a pharmacological treatment is indicated.

Antidepressants fail, but no cause for therapeutic gloom

by Jon Jureidini

Lancet. Published online June 8, 2016

Most antidepressants are ineffective in children and teenagers, study shows

by Susan Mayor

British Medical Journal. Published 09 June 2016

Most antidepressants ineffective for children and teens

The Pharmaceutical Journal

By Debbie Andalo

9 JUN 2016

Most antidepressants prescribed for children and adolescents with major and acute depressive disorders are ineffective, according to research published in The Lancet. Following a meta-analysis of data from 34 trials including 5,260 patients, researchers concluded that only fluoxetine was more effective than placebo in relieving symptoms in these young patients.

“Antidepressants in the acute treatment of major depressive disorder… do not seem to offer a clear advantage for children and adolescents,” say the researchers, led by Andrea Cipriani, department of psychiatry, University of Oxford, and Xinyu Zhou, department of neurology and psychiatry, the First Affiliated Hospital of Chongqing Medical University, China. “Fluoxetine is probably the best option to consider when a pharmacological treatment is indicated,” they conclude…

But the researchers warn that the quality of the evidence was “very low” and poor study design makes it difficult to give a true and confident picture about the effectiveness and potential harm of these drugs for children and young people.“We cannot rule out the possibility that some unpublished studies are still missing or that published reports might overestimate the efficacy of treatments,” they say…

In an accompanying comment piece, Jon Jureidini, from the Critical and Ethical Mental Health research group at the Robinson Research Institute at the University of Adelaide, Australia, says the findings reinforce the need for independent researchers to be given access to individual patient level data in order to inform their research… Jureidini adds that the effect of misreporting is that antidepressants, possibly including fluoxetine, are likely to be more dangerous and less effective treatments than has been previously recognised. “There is little reason to think that any antidepressant is better than nothing for young people,” Jureidini concludes.

Katherine Delargy, deputy chief pharmacist at Barnet, Enfield and Haringey mental health NHS Trust, described the meta-analysis results as “important” but asks for more research to be carried out…

Steve Bazire, former chief pharmacist at Norfolk and Waveney Mental Healthcare Partnership NHS Trust, questions some of the reviewers’ conclusions: “The paper doesn’t necessarily show that antidepressants don’t work, just that we can’t prove or disprove it yet as the evidence was classed as very low quality.” He also queries the researchers’ suggestion that the first choice for adolescent depression should be “evidence-based psychotherapy”…

Bazire points out that previous research that directly compared drugs with cognitive behavioural therapy (CBT) showed that drug therapy is more effective. “So if antidepressants don’t work, neither does CBT,” he says. However, he acknowledges the dangers of antidepressant use and says they must be used with caution, starting with low doses and slowly increasing the dose to avoid any akathisia or heightened anxiety. “Patients must also be monitored for akathisia linked with suicide,” he adds.

• Practice Parameter on the Use of Psychotropic Medication in Children and Adolescents [2009 AACAP]
• Depression in Children and Adolescents – Webinar with Dr. Karen Dineen Wagner [2013]
• Recommendations about the Use of Psychotropic Medications for Children and Adolescents Involved in Child-Serving Systems – [2015 AACAP]

The Medicaid Health Home State Plan Option, authorized under the Affordable Care Act [Section 2703], allows states to design health homes to provide comprehensive care coordination for Medicaid beneficiaries with chronic conditions. States will receive enhanced federal funding during the first eight quarters of implementation to support the roll out of this new integrated model of care.

^{[participating states so far]}

…"only around 40 percent of Americans with a diagnosable mental illness received any specific mental health treatment in the prior year, and only around one-third of those – therefore, approximately one in seven overall – received treatment that could be characterized as minimally adequate based on practice guidelines."

"… and many of these patients do not receive these medications in sufficient doses or for a sufficient duration; while others continue to use medications even if they are not effective for them, rather than having their treatment adjusted, due to lack of regular monitoring and clinical inertia. As a result, as few as 20 percent of patients started on antidepressant medications in usual primary care show substantial clinical improvements. Many patients referred to psychotherapy receive an insufficient number of visits and/or ineffective forms of psychotherapy, so that treatment response for this type of treatment is also as low as 20 percent under usual care. Finally, poor quality of medical care in patients with mental illness may explain a significant portion of their excess mortality."

The Collaborative Care Model: An Approach for Integrating Physical and Mental Health Care in Medicaid Health Homes

By Jürgen Unützer, Henry Harbin, Michael Schoenbaum, and Benjamin Druss.

EXECUTIVE SUMMARY

• Depression and other common mental disorders are common, disabling, and associated with high health care costs and substantial losses in productivity. Yet only about 25 percent of patients with these disorders receive effective care.
• Only 20 percent of adult patients with mental health disorders are seen by mental health specialists and many prefer and receive treatment in primary care settines.
• Individuals with serious and persistent mental illnesses are more likely to be seen by specialty mental health providers, but they have limited access to effective medical care and high mortality rates.underscoring the need for better connections across primary care and mental health.
• The collaborative care model is an evidence-based approach for integrating physical and behavioral health services that can be implemented within a primary care-based Medicaid health home model, among other settings.
• Collaborative care includes:
  1. care coordination and care management;
  2. regular/proactive monitoring and treatment to target using validated clinical rating scales; and
  3. regular, systematic psychiatric caseload reviews and consultation for patients who do not show clinical improvement.
• More than 70 randomized controlled trials have shown collaborative care for common mental disorders such as depression to be more effective and cost-effective than usual care, across diverse practice settings and patient populations. Collaborative care programs have been implemented by large health care organizations and health plans in both commercially insured and low income/safety-net populations.Traditional fee-for-service reimbursement programs have been a barrier to widespread implementation of collaborative care, but new* reimbursement models using capitated, case-rate payments, or pay-for-performance mechanisms may provide opportunities to expand its use.
• Implementation of evidence-based collaborative care in Medicaid – and in integrated care programs for individuals dually eligible for Medicare and Medicaid- could substantially improve medical and mental health outcomes and functionins. as well as reduce health care costs.

This brief was developed for the Centers for Medicare & Medicaid Services by the Center for Health Care Strategies and Mathematica Policy Research. For more information or technical assistance in developing health homes, visit http://www.medicaid.gov.

Job Description: Psychiatric Consultant

JOB SUMMARY

The consulting psychiatrist is responsible for supporting behavioral health care provided in primary care settings by a team comprised of primary care and behavioral health providers.

DUTIES AND RESPONSIBILITIES

1. Provide regularly scheduled [usually weekly] caseload consultation to behavioral health care managers [CMs]. These consultations are typically conducted by telephone and focus primarily on patients who are new to treatment or who are not improving as expected.
2. Provide occasional telephonic consultation to primary care providers [PCPs] as needed, focusing on patients in the CMs caseload.
3. Work with assigned CMs to track and oversee their patient panels and clinical outcomes using an electronic registry or other type of system capable of tracking clinical processes and patient outcomes.
4. Suggest treatment plan changes, including medication recommendations for patients who are not improving as expected.
5. Discuss patients who need referral for additional specialty mental health care [e.g., to a community mental health center] and advise on treatment plans until patients are engaged in such care.
6. Use a population-focused registry to document recommendations for treatment and/or referrals within 24 hours of consulting with a CM so that they can be easily shared with PCPs and other treating providers.
7. Clearly communicate to CMs and PCPs the limitations of the consultation and treatment recommendations if you did not evaluate the client in person. Include the following disclaimer statement acknowledging these limitations in all consult notes:
   The above treatment considerations and suggestions are based on consultation with the patient’s care manager and a review of information available in registry. I have not personally examined the patient. All recommendations should be implemented with consideration of the patient’s relevant prior history and current clinical status. Please feel free to call me with any questions about the care of this patient.
8. Maintain professional cell phone and Email accounts for contact during usual business hours.
9. Respond to telephone calls from primary care providers and CMs within one business day. Respond to urgent telephone calls within one hour, if available.
10. Check professional Email account daily. Respond to Email questions/consultations within two business days, sooner if urgent.
11. Coordinate with other consulting psychiatrists for vacation coverage.
12. When possible, visit each participating clinic at least once when initiating a new consulting relationship and then at least once per year to meet clinic providers and discuss ongoing collaboration.

OPTIONAL ACTIVITIES

1. Direct evaluation of patients
   Direct evaluation of patients, focusing on clients with diagnostic or therapeutic challenges who are identified in discussion with the patient’s CM and/or PCP. Such consultation may be provided in person or via telemedicine .
2. Training
   This may involve development and delivery of in-service training for primary care-based providers and staff regarding current understanding of best practices for the recognition and treatment of behavioral health conditions in primary care.

Job Description: Care Manager

JOB SUMMARY

The care manager functions as a core member of a collaborative care team that involves the patient’s primary care provider, a consulting psychiatrist and, when available, other mental health providers in the primary care clinic. The care manager is responsible for coordinating and supporting mental health care provided in the primary care clinic. He/she is also responsible for coordinating referrals to clinically indicated services outside the primary care clinic [e.g., social services, mental health specialty care, substance abuse treatment]. The care manager may provide evidence ? based treatments or work with other mental health providers when such treatment is indicated.

"Care management staff, such as a nurse, clinical social worker, or psychologist, who is based in primary care and trained to provide evidence-based care coordination, brief behavioral interventions, and to support the treatments such as medications initiated by the PCP. In some implementations of collaborative care, this staff also provides evidence-based, brief/structured psychotherapy, such as cognitive behavioral therapy."

DUTIES AND RESPONSIBILITIES

1. Support and closely coordinate mental health care with the patient’s primary care provider and, when appropriate, other treating mental health providers.
2. Screen and assess patients for common mental health and substance abuse disorders.
3. Provide patient education about common mental health and substance abuse disorders and available treatment options.
4. Monitor patients [in person or by telephone] for changes in clinical symptoms and treatment side effects or complications.
5. Support psychotropic medication management prescribed by PCPs, focusing on treatment adherence, side effects and other complications, and effectiveness of treatment.
6. Provide brief interventions using evidence-based techniques such as behavioral activation, problem-solving treatment, motivational interviewing, or other treatments appropriate for primary care settings.
7. Provide or facilitate in-clinic or outside referrals to evidence?based psychosocial treatments [e.g, CBT, IPT] as clinically indicated.
8. Participate in regularly scheduled [usually weekly] caseload consultation with the consulting team psychiatrist and communicate resulting treatment recommendations to the patient’s PCP. These consultations will primarily focus on patients who are new to treatment or who are not improving as expected.
9. Facilitate patient engagement and follow-up in care.
10. Track patient follow-up and clinical outcomes using a registry. Document in person and telephone encounters in the registry and use the system to identify and reengage patients who may be lost to follow ? up.
11. Document patient progress and treatment recommendations in the registry so that they can be easily shared with PCPs, the consulting psychiatrist, and other treating providers.
12. Facilitate treatment plan changes for patients who are not improving as expected in consultation with the PCP and the team psychiatrist. These may include changes in medications or psychosocial treatments or appropriate referrals for additional services.
13. Facilitate referrals for clinically indicated services outside the primary care clinic [e.g., social services such as housing assistance, vocational rehabilitation, mental health specialty care, substance abuse treatment].
14. Complete relapse prevention plan with patients who are in remission.

Childhood trauma predicts antidepressant response in adults with major depression: data from the randomized international study to predict optimized treatment for depression

by L M Williams, C Debattista, A-M Duchemin, A F Schatzberg and C B Nemeroff

Translational Psychiatry. (2016) 6, e799. Published online 3 May 2016

[full text on-line]

Discussion
Overall, the higher rate of trauma observed in the present MDD sample is in line with registry and observational studies.Thus, childhood trauma and especially abuse may contribute to the development of depression observed in routine practice in multiple outpatient settings spanning primary and specialist care settings. Our findings suggest that abuse in particular, and not overall exposure to traumatic events, predicts a lower rate of acute response and remission after antidepressant therapy. Sexual, physical and emotional abuse compared with other types of trauma psuch as death of a parent/sibling, personal life-threatening illness/injury, or disaster], may have a specific impact on the neurobiological mechanisms of non-response to treatment. Neuroimaging studies suggest that there may be a differential effect of childhood sexual abuse on the subsequent functioning of emotional brain circuits in adulthood depression. Childhood abuse has also been associated with a greater sensitivity to stress, cognitive impairment, alterations in brain morphometry and immune and metabolic abnormalities that may impact the course of depression and capacity to respond to antidepressants. It is also possible that abuse may recur and that it is the recurrence of the trauma that produces poor treatment outcomes.

In addition to the type of stressor, our results suggest that there is a critical period [4 to 7 years] in which childhood trauma occurs and has the most significant impact on subsequent poor response to antidepressants in adulthood. There is a rapidly growing body of work to suggest that gene polymorphisms and epigenetic modifications interact with childhood trauma to exert their effect on risk for depression, and that this effect is greatest at critical neurodevelopmental periods. This evidence is consistent with the view that the extent of brain plasticity varies during development, such that trauma occurring during critical neurodevelopmental periods may alter brain morphometry, circuit function, endocrine regulation, immune function and subsequent physiologic reactions to stress in an enduring way.

Abuse occurring at age 4 to 7 years was associated with significantly poorer outcomes following the treatment with sertraline compared with the other selective serotonin-reuptake inhibitor escitalopram and the SNRI venlafaxine-XR. The participants who were abused at this age showed significantly less improvement in both clinician and self-rated symptoms following 8 weeks treatment with sertraline. Sertraline, in contrast to other serotonin-reuptake antidepressants, has an additional relatively specific effect on inhibiting dopamine. There is some evidence that subgroups of patients are also characterized by dopamine circuit dysfunction and number of traumatic events has been associated with higher ventral striatal dopamine response to amphetamine. Although speculative, these lines of evidence suggest that a possible dopamine-related mechanism might contribute to our specific observation of especially poor outcomes following sertraline in those exposed to early abuse.

Clinical translational significance
Here, we provide evidence from a well-powered study that outpatients with MDD have a fourfold higher incidence of childhood abuse than their healthy peers, and a twofold higher incidence of early exposure to other traumatic events. The greater the exposure to trauma, the less likely these depressed patients were to remit following antidepressant response. Thus, the translational significance of these findings is that in routine clinical management of depression it may be important to screen for childhood trauma to identify those patients that may not benefit from standard first-line antidepressants and may require additional therapy to more directly address the impact of trauma.

This is one of my slides from the late 70s/early 80s showing a few lines of development plotted by age. The pictures are typical self portraits from various ages [some from my daughter] paralleling the formation of the self representation. The bottom line shows attachment/separation schema [Mahler] and the stages of cognitive development [Piaget].

The four year old sees himself "out of his eyes" with the arms and legs coming out of the head [Mr. Potato-head]. It’s not until around age seven that the child will see herself as we see her, a whole person. In-between, Mr. Potato-head gets some hair, and has some "felt" body parts [here, a heart or genitals]. It’s a vulnerable work-in-progress period, and abuse can disrupt multiple vital developmental processes. Logical constructs aren’t available in the preoperational cognitive set so the child has no tools to understand abuse. It can and does have a profound impact on the developing self image, the templates for relating to others, and the general experience and understanding of the world. Whether these unfolding developmental sequences and the toll of abuse are the result of or cause actual changes in the brain itself or take place in a psychological domain is as unknown now as it was forty years ago. But the particular vulnerabilities of the preschool child and the enduring consequences remain a paramount concern whether hardware or software. And by the way, their finding highlights the inadequacy of the Major Depressive Disorder categorical diagnosis.

Experimental Antidepressant Moves Closer to US Approval

Medscape

by Deborah Brauser

May 20, 2013

The experimental antidepressant Vortioxetine is safe and effective for treating major depressive disorder [MDD], findings from several new phase 3 randomized controlled trials [RCTs] suggest. Three studies of a total of 1545 US patients with MDD showed that those who received 20 mg of Vortioxetine had significantly decreased symptom scores on the Montgomery–Asberg Depression Rating Scale [MADRS] after 8 weeks of treatment compared with those who received matching placebo. However, there was no difference in symptom scores between the 10-mg and the 15-mg dose compared with placebo.

Interestingly, a fourth study conducted in Europe and South Africa with 608 patients showed that both the 15-mg and 20-mg doses of Vortioxetine were associated with significantly lower MADRS scores than placebo. "We wanted to address the correct dose, and across the studies, the 20-mg had the most consistent findings over placebo," principal investigator Madhukar Trivedi, MD, professor of psychiatry at University of Texas Southwestern Medical Center in Dallas, told Medscape Medical News. Dr. Trivedi noted that "it’s very hard to figure out why" the 15-mg dose did well in the European study but not in the US studies, "but this often happens in antidepressant trials"…

Planners want KOLs to appear to have done much or all of the important work behind an article, presumably because many readers would be less inclined to give credence to an article that had only pharmaceutical company authors…

Sergio Sismondo

in Corporate Disguises in Medical Science: Dodging the Interest Repertoire

Since then, I’ve just assumed that being a KOL is a profession in and of itself. In this case, the professionals would be Michael Thase, Madhukar Trivedi, and the group that signed on to the review [Schatzberg, A.F., Blier, P., Culpepper, L., Jain, R., Papakostas, G.I., and Thase, M.E. 2014. An Overview of Vortioxetine. Journal of Clinical Psychiatry. 75[12]:1411–1418.]. Today, I decided to look over the 13 RCT articles, the review article, and the meta-analysis funded by the sponsors, Takeda and Lundbeck. Recalling the figures from Cosgrove et al‘s paper, I repeated their compilation of the authors’ COI declarations with the review and meta-analysis included. The 15 articles had 60 by-line author cites spread among 31 authors. 13 of the authors were employees, making up 36 cites. Of the remaining 18 authors, only one didn’t have a financial COI with at least one of the sponsors, so 23/24 of the non-Employee cites had a COI. All 15 articles were ghost-written. And then I read them and looked over Thase and Trivedi’s presentations at the Institute of Medicine and at the FDA hearing.

you can’t learn it from books,
you can’t learn it without books.
…………………….zen saying…

As an internist and later as a psychiatrist, I read about drugs, but I really learned about them from teachers, colleagues, and patients. When I came back to that part of psychiatry after retiring, I encountered something new – the people I now call KOLs. They were a class of experts, academics who published drug studies and wrote endlessly about them. I figured out that their recommendations came from the data from clinical trials, not from their experience. I knew enough of them personally to know that they didn’t see that many patients, certainly not to follow them long term. So it was a new class for me, not one I’d encountered in my wanderings through medicine and I was wary of their advice. Since I also found the text-books unhelpful and out-of-date the day they came out, I started reading the Clinical Trial reports myself – and that’s what got me here today.

One of the early papers I read was Barriers to implementation of a computerized decision support system for depression: an observational report on lessons learned in "real world" clinical settings. The author, a Madhukar Trivedi, had a computer program with an algorithm for using the antidepressants. He was trying to study his program, but what he found was that if he didn’t look over the clinicians’ shoulders, they didn’t use it. So the paper was a sort of amateurish speculation about what psychic conflicts they might have that kept them from using his program [and scuttling his study]. Then I got to the end and read his Conflict of Interest declaration, and it was his psychodynamics I started thinking about! I wouldn’t have used his computer program either. Here’s what I had to say back then [evidence-based medicine I…]. Madhukar Trivedi, it turns out, is a KOL extraordinaire.

A Comparison of Nefazodone, the Cognitive Behavioral-Analysis System of Psychotherapy, and Their Combination for the Treatment of Chronic Depression

by Martin B. Keller, James P. McCullough, Daniel N. Klein, Bruce Arnow, David L. Dunner, Alan J. Gelenberg, John C. Markowitz, Charles B. Nemeroff, James M. Russell, Michael E. Thase, Madhukar H. Trivedi, Janice A. Blalock, Frances E. Borian, Darlene N. Jody, Charles DeBattista, Lorrin M. Koran, Alan F. Schatzberg, Jan Fawcett, Robert M.A. Hirschfeld, Gabor Keitner, Ivan Miller, James H. Kocsis, Susan G. Kornstein, Rachel Manber, Philip T. Ninan, Barbara Rothbaum, A. John Rush, Dina Vivian, and John Zajecka.

New England Journal of Medicine. 2000 342:1462-1470.

[full text on-line]

Background: Patients with chronic forms of major depression are difficult to treat, and the relative efficacy of medications and psychotherapy is uncertain.

Methods: We randomly assigned 681 adults with a chronic nonpsychotic major depressive disorder to 12 weeks of outpatient treatment with nefazodone [maximal dose, 600 mg per day], the cognitive behavioral-analysis system of psychotherapy [16 to 20 sessions], or both. At base line, all patients had scores of at least 20 on the 24-item Hamilton Rating Scale for Depression (indicating clinically significant depression). Remission was defined as a score of 8 or less at weeks 10 and 12. For patients who did not have remission, a satisfactory response was defined as a reduction in the score by at least 50 percent from base line and a score of 15 or less. Raters were unaware of the patients’ treatment assignments.…

Dr. Thase was on the faculty of the Western Psychiatric Institute in Pittsburgh from 1984 to 2007 when he moved to the Perlman School of Medicine in Philadelphia as Chief of the Division of Mood and Anxiety Disorders Treatment & Research Program. He writes broadly about the diagnosis and treatment of these disorders and so most of us think of him not in any specific role as an expert professional, but rather as a Professional Expert – a KOL who is everywhere. He still may not have caught up with Charlie Nemeroff in total publications, but he’s closing in fast [he got off to a late start].

Invited to a pharmaceutical industry conference on relationships with key opinion leaders was Dr. Michael Thase, a representative KOL. Thase, who was introduced as having authored over 500 publications and being “one of the brightest stars in neuroscience,” was a smiling and confident speaker, comfortable giving his narrative to this audience of mostly pharmaceutical company managers

Thase gave his disclosures in a practiced move. As he explained, In the past decade, I have been a consultant to the manufacturer of every compound that has been developed for the treatment of depression or the treatment of bipolar disorder, and some number of other compounds that haven’t made it through the multi phases stages of development.

Normally, he said, he presents this as two slides. He added a list of six pharmaceutical companies that had paid him to give talks in the previous 3 years, and another four that have recently funded research projects. He does not believe, he opined, that academics are very often dishonest, but he does recognize that “who you spend time with, where you make money, and so on,” can influence what you believe to be true. Dr. Thase is the quintessential KOL, a nationally recognized expert who is personable and a good public speaker. As one insider defines them, KOLs are well-known specialists who “can influence other physicians”…

A particular area of interest of mine is the increasingly acrimonious [and often sanctimonious] furor about the relationship between academic medicine and the pharmaceutical industry. Let me be up-front about my position: I am a libertarian by nature and firm believer in personal accountability, free markets, and limited regulatory interference. Unlike the editors of some of medicines more prestigious journals, however, I do not plan to write editorials broadly condemning a pseudomonolithic pharmaceutical industry while the publisher’s business office collects money for advertisements or academic supplements. Let me also be clear about this little economic fact: the Bulletin is a product of the publisher’s business, and it must at least break even to stay afloat. This means that it is essential to maintain honest, yet mutually beneficial relationships with the industry. Moreover, as "Big Pharma* is responsible for the development and introduction of virtually all new psychotropic medications, it seems an act of epic foolishness to try to impose some sort of hands-off relationship between our editorial board and the pharmaceutical industry…

^{hat tip to even more librarians…}   

^{hat tip to the librarians…}   

Boss of Bosses: Charles B. Nemeroff, MD, PhD

by James La Rossa Jr. and Genevieve Romano

TEN: The Economics of Neuroscience. 2000 2[9]:8.

Charlie Nemeroff is sitting quietly at the speaker’s table, ignoring the bustle going on around him. His face betrays nothing — neither boredom* nor interest, or apprehension. Only the blinking of his eyes distinguish him from a statue. When he hears his name he rises very slowly, and begins to move to the lectern with deliberate strides, gathering speed as he goes, brightening now. He breaks into a grin and begins speaking the minute he approaches the microphone and, before the hush of the room takes hold, he has won the crowd with a disarming and deliberate manner that cuts simply to the heart of the most complex issues in neuropsychiatry.

Charles B. Nemeroff, MD, PhD, chairman of the Department of Psychiatry and Behavioral Sciences at Emory University School of Medicine in Atlanta, finds himself addressing a room of crowded colleagues hundreds of times each year. Even in the ultra-competitive world of medicine and academia, Nemeroff is admittedly the most coveted academic speaker in psychiatry in the United States. His prolific authorship [he has published 600 research reports and reviews] along with a sheer enormity of research grants, awards, and scientific board appointments, has afforded him unprecedented celebrity within the psychiatric community. Nemeroff’s academic and intellectual largess translates to a small and influential group of close friends, including fellow department chairmen Alan Schatzberg [Stanford], Marty Keller [Brown], Dwight Evans [U-Penn], Bob Hirschfeld [U. of Texas, Galveston] and NIMH heavyweight Dennis Charney, all of whom spend a great deal of professional and personal time together. Psychiatry is a highly charged topic these days, and these six thought leaders walk a fine line between controversy and political correctness, often made possible by their strong allegiances both to topics and to one another.

The ethics surrounding the implementation of placebo-control trials is one of psychiatry’s most super-charged political issues, as is addressed in more detail in this issue of TEN. "From a scientific point of view, the best data on efficacy of any treatment is best derived from placebo-controlled trials," Nemeroff says. But with diseases like cancer and stroke, placebo trials become unethical. Thus, "the FDA in most cases has allowed for comparison between novel treatments for devastating disorders with traditional already-approved treatments." If a novel agent proves efficacious against en existing agent, it gets approved. But "that has not been the case in psychiatry. And we have to raise questions about the use of placebo in conditions like mania, where patients are terribly ill. [In these cases] one wonders why it isn’t sufficient to have evaluation based on ‘just-as-good-as’ or ‘better-than’ currently available treatments and better side effect profile."

Nemeroff is among the most coveted advisors to the pharmaceutical industry. Predictably, rumors about his alliances, or lack thereof, abound. It is safe to say that his views are expressed in a forceful manner — he is a passionate person — and he fully expects to lead the corporate strategy of those he advises. Those who do not heed his advice are often recipients of his wrath. Consequently, Nemeroff is often in favor with the most successful drug makers, since those firms are doing the lion’s share of research, which he often directs.

Privately, Nemeroff is circumspect about the role between private and public funding. Working with industry can "he a win-win. There is a shared vision but also separate mission – The university mission is a troika: research, teaching, clinical service; whereas the pharmaceutical industry [mission is to] discover new drugs and to market them effectively. Sometimes those goals are simpatico and sometimes they’re not." As an example of a situation where industry funding works to the benefit of the scientific community, Nemeroff recounts a new teaching council that he started recently with a grant from Janssen called The Young Faculty Development Program, where young professors get the opportunity to learn about clinical issues and academic life. And he talks also about the differences he sees between today’s young clinicians and those of his generation, "in the past, there was a clear schism between psychoanalytically oriented psychiatrists and so-called biological psychiatrists. Today, this mind-brain dualism seems silly … Patients of course have both minds and brains." The fact of the matter is that psychosocial factors … can certainly affect how the brain functions and we also know that the brain itself changes. The nature/nurture controversy is really no controversy, as we’ve improved our understanding of the brain."

The Bronx-NY-born Nemeroff is most content being both a researcher and a physician. As an example, he recounts a part of the very day of this phone interview. "[Earlier today] I saw four patients, one on emergency consult; at the same time, I was dealing with a number of issues related to an NIMH grant of the psychobiology of early trauma. What can be better than being a teacher and a researcher and a physician?"

By the turn of the century when this piece was written, Charlie Nemeroff was at at the top of the heap and the top of his game – the quintessential KOL. This article mentions some of the other major KOLs of the time, a core group of his friends and fellow chairmen. So as the new drugs flowed from industry at a steady rate, there was plenty to talk about, and the promise of future breakthroughs was always fertile ground for their stream of presentations and review articles. But that’s just the very public part. There were the advisory positions [left below] and those paid pharma speaker engagements to small groups all over the country [right below] generating personal income.

While this article was not written as an exposé, it offered a candid look behind the scenes at how Dr. Nemeroff and his colleagues occupied a formidable power-base in psychiatry in 2000, and hinted at how the boundary between academia and industry was disappearing. In the same year, responding to an article in the NEJM where Nemeroff and three other authors came from the group mentioned above [of the 29], editor Marcia Angell wrote an editorial, Is Academic Medicine for Sale? [after looking at the voluminous COI declarations]. Perhaps she could’ve even substituted bought and sold for for Sale, at least in the psychiatric literature on RCTs.

We all know how this story finally came to something of a close, though Nemeroff’s reign didn’t exactly end because of his industry connections – it was personal greed. In 2002, he published a review article recommending three different treatments all of which he had a personal financial stake in without disclosing that interest – easily seen by watchdogs Bernard Carroll and Bob Rubin. In spite of being publicly exposed and censured by Emory, in 2006 he did it again with a review of a treatment he and his coauthors all had financial interests in, again with no COI declarations [and in a journal he edited to boot], again seen by Drs. Carroll and Rubin. He was forced to step down as editor of the prestigious journal, Neuropsychopharmacology, and was put on a tight rein by Emory. But in 2008, when he was investigated by Senator Grassley for unreported pharma income, he lost his chairmanship [as did two of his cohorts on Senator Grassley’s list, Drs. Schatzberg and Keller].

I recognize when I get on a topic and beat it in the  ground, I’m living up to my 1BORINGoldman moniker. And right now, I’m doing that with Vortioxetine [Brintellix® AKA Trintellix®]. But I’ve got my reasons [actually two of them]. But neither reason is to prove to you that this latecomer is a particularly weak addition to an already weak class of drugs – the SSRI/SNRI antidepressants. You already know that.

One reason is in my own history as an eight year amateur Clinical Trial vetter. When I first started looking into these psychopharmacology trials, in spite of having had more than the usual amount of statistical training and experience, the clinical trial motif was new territory – and there was much to learn. But early on, like many of you, I could see that the industry funded trials were regularly distorted. And then there was the absurdity that the data itself was hidden [proprietary property of the sponsor]. And in those few instances where one could nail down the misreporting [because of subpoenaed internal documents or court-ordered data release] by the time those facts were available, they were old drugs either off-patent or nearly so. The profits were already in the bank and the drugs were established and in use. So I resolved to take a look at new drugs that came along, and if the reports looked shaky, perseverate on what was wrong – hoping to join a chorus that might finally move us away from such things in our academic journals. Vortioxetine is both new and shaky, ergo, one of my reasons to stick to it like glue.

But the second reason is that the more I read these clinical trial articles, the more aware I become of how much work goes into putting the commercial spin into every graph, table, sentence, calculation, statistical test, omission, etc. I’ve already mentioned a few in smoke and mirrors…, but there are others everywhere. In one of the the main data tables, I mentioned things like how it was sorted and which units were shown graphically.

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But then notice the absence of a p-value column, for example. And they show the aggregate results for all studies [Meta-analysis], but then they break out the aggregate for the non-US studies [Meta-analysis (non-US)]. How come? Remember that they make a big deal out of there being a dose response effect and there it is in the non-US data. But why not also break out the US studies? Well because they don’t show a dose response effect – and, for that matter, they don’t show much of any effect at all! a significant omission:

These studies involve thousands of subjects – the kind of numbers required to detect the kinds of small differences they’re reporting. The way they get these big numbers is to use a lot of sites. With the US studies, we know the cities where they were gathered. With the non-US studies, we only know the countries, not the number of sites in each. But even at that, there are many, many sites, in diverse places, each with its own staff and raters. That’s a lot of room for a lot of variability, invisible to the reader [go ahead, click on the image to see what I mean by many, many and diverse].

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I used to just pass over these presentation quirks because I couldn’t prove they were deliberate, what with this being the age of evidence based medicine and all. But they’re so universal, I give them more valence now. But the most damning finding in the industry funded trials and their reports is something that’s hard to quantify, but plain as the nose on your face. It’s the narrative itself, and this is a fine example. It’s a sales pitch, that sings that old song: accentuate the positive, eliminate the negative, latch on to the affirmative, and don’t mess with mister in-between. Just read the discussion. You can’t miss it.