the other side of the story…

Posted on Wednesday 8 April 2015

This presentation by Anthony Morrison is from the BPS DCP Conference, 2012 – after the publication of the Exploratory Study below, but before the publication of the Pilot Study results [see a pilot…, slim pickings…, and above the din…]
Mickey @ 10:01 AM

above the din……

Posted on Tuesday 7 April 2015

Back in ancient history when CBT first came along, we used to joke that if you needed a publication for tenure, you could always do a study with four groups: Placebo, CBT, Antidepressant, CBT+Antidepressant. It seemed like that was the most repeated study in history and they always seemed to come out the same. CBT and Antidepressant always came out as effective, but the combo Rx was the most effective. Back then, I think most of us incorporated some aspect of CBT. For me, it was identifying and commenting on maladaptive thinking, though I was never trained in or did CBT proper. Over the years, I’ve worked with lots of therapists, and most define themselves as having a CBT orientation these days, but in practice, most of us actually do the same things. My fantasy is that all those studies defined CBT as "evidence-based therapy," and that’s a claimable moniker in a modern world, certifiable EBM. These clinical trials, however, are CBT of the formal kind. I thought this one was a creative idea – treat the Worry in delusional patients and see if it helps with secondary symptoms [delusions]:
An explanatory randomised controlled trial testing the effects of targeting worry in patients with persistent persecutory delusions: the Worry Intervention Trial [WIT].
Editors: Freeman D, Dunn G, Startup H, and Kingdon D
Lancet. 2015 2[4]:305-313.
NCBI Bookshelf: Queen’s Printer and Controller of HMSO 2015.

BACKGROUND: Persecutory delusions are a key experience in psychosis, at the severe end of a paranoia continuum in the population. Treatments require significant improvement. Our approach is to translate recent advances in understanding delusions into efficacious treatment. In our research we have found to be an important factor in the occurrence of persecutory delusions. Worry brings implausible ideas to mind, keeps them there and makes the experience distressing. Reducing worry should lead to reductions in persecutory delusions.
OBJECTIVE: The objective was to test the clinical efficacy of a brief cognitive–behavioural intervention for worry for patients with persistent persecutory delusions and determine how the treatment might reduce delusions. Embedded within the trial were theoretical studies to improve the understanding of worry in psychosis…
MAIN OUTCOME MEASURES: The main outcomes measures were of worry [Penn State Worry Questionnaire; PSWQ] and persecutory delusions [Psychotic Symptom Rating Scales; PSYRATS]. Secondary outcome measures were paranoia, overall psychiatric symptoms, psychological well-being, rumination and a patient-chosen outcome.
RESULTS: In total, 95% of the patients provided primary outcome follow-up data. For the primary outcomes, in an intention-to-treat analysis, when compared with treatment as usual, the therapy led to highly significant reductions in both worry [PSWQ: 6.35, 95% confidence interval [CI] 3.30 to 9.40; p < 0.001] and the persecutory delusions [PSYRATS: 2.08, 95% CI 0.64 to 3.51; p  = 0.005]. The intervention also led to significant improvements in all of the secondary outcomes. All gains were maintained. A planned mediation analysis indicated that change in worry explained 66% of the change in the delusions. We also found that patients without intervention report a passive relationship with worry, feeling unable to do anything about it; worry brings on depersonalisation experiences; and the patient group has very low levels of psychological well-being.
CONCLUSIONS: This was the first large randomised controlled trial specifically focused on the treatment of persecutory delusions. Long-standing delusions were significantly reduced by a brief CBT intervention targeted at worry. The intervention also improved well-being and overall levels of psychiatric problems. An evaluation of the intervention in routine clinical setting is now indicated. We envisage developing the intervention booklets for online and app delivery so that the intervention, with health professional support, has the possibility for greater self-management.
The graph shows the result of a six week course of their focused CBT on Worry as measured by the PSWQ instrument, and the improvement was matched by a similar fall in the PSYRATSdelusion Score. While the effects weren’t massive, they were significant [shown with full 95% Confidence Interval].

But that’s not why the study is here. I was reading the Lancet COMMENT that accompanied it, and I ran across this [note the careful wording – safe and acceptable]:
Daniel Freeman and colleagues report the results from thei r trial that investigated the clinical effects of an intervention targeting worry in patients with non-affective psychosis. The authors accurately write in their Introduction that treatments for psychotic conditions, such as schizophrenia, need substantial improvement. The first-line treatment of schizophrenia—ie, antipsychotics—can suppress delusions and hallucinations, but patients still suffer from other symptoms such as negative symptoms, and often report adverse side-effects from the medication [eg, apathy, neurological side-effects, serious weight gain, and sexual dysfunction]. The percentage of non-compliance with medication in patients with schizophrenia is as high as 40–50%, and 74% of patients discontinue their medication within 18 months. Furthermore, Wunderink and colleagues report that dose reduction or discontinuation of antipsychotics during the early stages of remitted first-episode psychosis is associated with superior long-term [7 years] recovery rates [40·4%] compared with the rates achieved with antipsychotic maintenance treatment [17·6%]. Additionally, Morrison and colleagues reported that cognitive therapy significantly reduced psychiatric symptoms and seems to be a safe and acceptable alternative for people with schizophrenia and related disorders who have chosen not to take antipsychotic medication. In consideration of low patient compliance with antipsychotics, evidence for improved long-term functional recovery with dose reduction or discontinuation of antipsychotic medication,  and the promising results from trials of psychological treatments, intervention options for patients with a psychotic disorder are clearly needed that are effective, have fewer side-effects, and are more acceptable to some patients than antipsychotics.
11.1.1 Effectiveness of cognitive behaviour therapy There is a consistent evidence base suggesting that many people find CBTp helpful. Other forms of therapy can also be helpful, but so far it is CBTp that has been most intensively researched. There have now been several meta-analyses [studies using a statistical technique that allows findings from various trials to be averaged out] looking at its effectiveness. Although they each yield slightly different estimates, there is general consensus that on average, people gain around as much benefit from CBT as they do from taking psychiatric medication

The National Institute for Health and Care Excellence [NICE] considers the evidence strong enough to recommend that everyone with a diagnosis of schizophrenia should be offered CBT. NICE recommends that people should be offered at least 16 one-to-one sessions over a minimum of six months. However, this is far from being the case everywhere: indeed the Schizophrenia Commission found that only one in ten people who could benefit from it have access to good CBTp. We view this with grave concern – indeed, it has been described as scandalous

11.10 Conclusions There is now overwhelming evidence that psychological approaches can be very helpful for people who experience psychosis. However, there remains a wide variation in what is available in different places. Even the most successful approaches, such as early intervention and family work, are often not available, and nine out of ten of those who could benefit have no access to CBT. There is a pressing need for all services to come up to the standard of the best and to offer people genuine choices. Perhaps most importantly, we need a culture change in services such that the psychological understanding described in this report informs every conversation and every decision…
And this from Noel Hunter’s Report on the ISPS 2015 meeting:
There was the phenomenal work of Anthony Morrison, who is the first researcher to empirically show that psychotherapy can be effective with individuals diagnosed with schizophrenia, even when they choose to not take psychotropics. Although many know this intuitively, the scientific community is not really interested in intuition; for him to show this repeatedly through empirical data is profound.
I expect that where I’m headed with all of this is obvious. I spent more than a few days with Cognitive therapy for people with a schizophrenia spectrum diagnosis not taking antipsychotic medication: an exploratory trial and Understanding Psychosis and Schizophrenia and I didn’t find Morrison et al deserving of those accolades – nor did others [see a pilot…, slim pickings…, and the comments]. Here’s the graph again:
I’ve given only a few examples, but there are plenty of others strewn about – enough for me to think that this is a campaign extraordinaire. After all the campaigns of PHARMA, Managed Care, the Psychiatric KOLs, the misreported RCTs of the psychiatric drugs, and the DSM-5 debacle, it’s hardly surprising. But, two wrongs don’t make a right. Right now, the important agenda is Data Transparency – not more Irrational Exuberance. And these CBT results in psychosis are being way over-sold. When in a period like this one where the dominant paradigm has reached [or perhaps exceeded] its limits and explanatory powers [paradigm exhaustion], lot’s of things can happen – not necessarily good things. Looking back on the time this kind of foment was in the wind – the 1980 Psychiatry revolution – it’s hard not to notice that things can go badly and the seeds of the next major catastrophes can be planted everywhere. This is again such a time. No one who is alert and paying attention could miss that fact. It’s all around us. So we don’t need to step off on a new path with exaggeration and rhetoric like we did 35 years ago. What we need is a time of reflection, a voice of restraint, and I’m not sure I can yet hear either above the din…
Mickey @ 3:41 PM

the price of admission…

Posted on Monday 6 April 2015

A few weeks ago, I was commenting on an article in JAMA:Psychiatry by three Residency Training Directors [yellow brick roads…] who were advocating a curriculum for psychiatry residents in neuroscience [The Future of Psychiatry as Clinical Neuroscience: Why Not Now?]. The gist of the article had to do with preparing future psychiatrists for the expected breakthroughs coming in neuroscience. Going so far as to say…

The overarching goal is that residents will incorporate a modern neuroscience perspective as a core component of every formulation and treatment plan and bring the bench to the bedside.
…which I thought sounded like something the USSR of old might have come up with back in the days before the walls fell down. I recalled a graphic I came up with four years ago about Tom Insel’s campaign for clinical neuroscience. I made it from an old Red Army poster from the days of the Russian Revolution, so I guess that I’ve thought of that analogy before. The constant hype about Neuroscience has been like the seven decades of Russian Communism, hope was always in the future [a future that ever came]. Note also the allusion to the Translational Medicine metaphor – another NIMH favorite [moving research findings rapidly from "the bench to the bedside"]. Best I can tell, we’ve established a network of Translational Centers all decked out for service, but there’s been nothing of note to translate.

I suggested that a neuroscience track ought to aim at arming the residents with the tools to evaluate emerging technologies:
Rather than being "ready to embrace new findings as they emerge", tomorrow’s psychiatrist needs to know how to critically evaluate new findings as they emerge.
Psycritic has a new post up on this topic that takes a somewhat different tack than mine [Psychiatry as a Clinical Neuroscience, Why Not?] – a deeper look on the place of neuroscience in psychiatry in general though equally cautious. He mentions this example…
I remember being taught as a resident about Broadmann Area 25 being critical in the pathogenesis of depression, based on exciting initial deep brain stimulation results from Dr. Helen Mayberg. This was almost treated as an established fact, despite the very preliminary nature of the research. Well, what happened when they tried to do a larger clinical trial? Neurocritic reported that the trial was halted before its planned endpoint in December 2013, and last month it was revealed that the medical device company conducting the trial [St. Jude] stopped it due to perceived study futility.
…and that’s what bothers me about the constant focus on the brain studies – as if they are the harbingers of something just around around the corner. Tentative signals get treated as "known facts," and it feels as if there’s a real pressure to put them into action [like for example the injunction to "incorporate a modern neuroscience perspective as a core component of every formulation and treatment plan"]. I can’t imagine how one might do that. It is, in fact, the very point that our critics legitimately hammer on – psychiatry forcing everything into an biomedical framework where much of it doesn’t fit. Psycritic goes on to reflect on his college Neuroscience Professor who gave the students a broad view of brain function:
"All of the neurons together in one brain form more connections with each other than there are stars and planets in the galaxy." The professor ended his lecture by giving us some practical tips based on his knowledge of neuroscience. Time and repetition, he told us, is what will help us succeed in the class, because that is how neuronal circuits are programmed and how processes in the brain ranging from retrieving facts from memory to riding a bicycle become automatic. I use the same advice almost daily with my patients when I emphasize to them the importance of practicing new behaviors or ways of dealing with difficult thoughts and emotions. Similarly, based on my reading of research on the effects of sleep, exercise, and social interactions on the brain, I share with my patients the importance of getting enough of each.
… as opposed to the narrow view:
… the narrow view tends to emphasize things like genetics, neurotransmitters, biomarkers, and circuits.
[Being an old man, I still have permission to call that broad view "the mind" if I want to]. I’ll leave it for Psycritic to relate his Professor’s story about Hemingway’s shortest story – one worth way more than the price of admission…

Also: I would recommend reading Philosophy Professor Anderson Brown’s blog on the "Mereological Fallacy"…
Mickey @ 4:00 PM

slim pickings…

Posted on Saturday 4 April 2015

When I wrote the last post [a pilot…], I was aware that there had been letters in the Lancet about the Morrison et al article, that I couldn’t access. They’re by statistically much more sophisticated critics than I, but have similar reservations and more. But I wanted to mention the opening to the authors’ reply to the critics:
Authors’ reply
Our trial was not designed to change clinical practice. It was a preliminary trial, which needs to be followed up by a larger, pragmatic multicentre study. It is important not to over·interpret our data, and we explicitly advised against discontinuation of medication. We claimed the trial showed that cognitive therapy was safe and acceptable, not safe and effective
And that’s true – that is exactly what they said at the end of the abstract…
INTERPRETATION: Cognitive therapy significantly reduced psychiatric symptoms and seems to be a safe and acceptable alternative for people with schizophrenia spectrum disorders who have chosen not to take antipsychotic drugs.
…but I didn’t notice that subtle bit of wording the first time around [did you?]. There are some really fine comments to my last post – all worth taking a look at and adding lots of things I hadn’t really thought of. I’m not going to summarize them, but rather suggest you take a look. There’s also an excellent collection of articles on the topic at the Mental Elf – CBTp. I went back and took a look at the prequel, Morrison et al’s exploratory trial prior to this pilot trial:
by A. P. Morrison, P. Hutton, M. Wardle, H. Spencer, S. Barratt A. Brabban, P. Callcott, T. Christodoulides, R. Dudley, P. French, V. Lumley, S. J. Tai and D. Turkington
Psychological Medicine. 2012 42[05]:1049-1056.

Background Although antipsychotic medication is the first line of treatment for schizophrenia, many service users choose to refuse or discontinue their pharmacological treatment. Cognitive therapy (CT) has been shown to be effective when delivered in combination with antipsychotic medication, but has yet to be formally evaluated in its absence. This study evaluates CT for people with psychotic disorders who have not been taking antipsychotic medication for at least 6 months.
Method Twenty participants with schizophrenia spectrum disorders received CT in an open trial. Our primary outcome was psychiatric symptoms measured using the Positive and Negative Syndromes Scale [PANSS], which was administered at baseline, 9 months [end of treatment] and 15 months [follow-up]. Secondary outcomes were dimensions of hallucinations and delusions, self-rated recovery and social functioning.
Results T tests and Wilcoxon’s signed ranks tests revealed significant beneficial effects on all primary and secondary outcomes at end of treatment and follow-up, with the exception of self-rated recovery at end of treatment. Cohen’s d effect sizes were moderate to large [for PANSS total, d=0.85, 95% CI 0.32–1.35 at end of treatment; d=1.26, 95% CI 0.66–1.84 at follow-up]. A response rate analysis found that 35% and 50% of participants achieved at least a 50% reduction in PANSS total scores by end of therapy and follow-up respectively. No patients deteriorated significantly.
Conclusions This study provides preliminary evidence that CT is an acceptable and effective treatment for people with psychosis who choose not to take antipsychotic medication. An adequately powered randomized controlled trial is warranted.
Again, I had trouble reproducing their analyses [and again, access to the raw dataset would’ve been useful to figure out why]. Notice the wording:
Conclusions This study provides preliminary evidence that CT is an acceptable and effective treatment for people with psychosis who choose not to take antipsychotic medication. An adequately powered randomized controlled trial is warranted.
Here is the Primary Outcome variable [PANSStotal] for the two studies [with 95% CI]:
It looks a lot like any number of the Clinical Drug Trials I’ve vetted before. Slim pickings [slim to none]…
Mickey @ 3:32 PM

a pilot…

Posted on Thursday 2 April 2015

Living in the UK in the1970s practicing in an a US Air Force Hospital near one of the UK’s primo Hospitals [Addenbrooks, in Cambridge] was interesting. Suffice it to say that our systems and expectations are very different. I never quite ‘got it‘ – except to say ‘very different‘ and ‘interesting.’ I think I understand the term, ‘service users‘ in the papers I’m about to discuss. It means, ‘people who rely on the National Health Service‘ for their health care – according to Wikipedia, that’s 92%. If I understand correctly, NICE [National Institute for Health and Clinical Excellence] sets treatment guidelines one of which is to offer CBT [16 sessions] to service users with Schizophrenia, but it’s not really available through the NHS. That adds a commercial element to the issues brought up by the BPS report [or I could’ve misread the whole thing].

Three years ago, there was a hot and heavy debate about including the Attenuated Psychosis Syndrome in the DSM-5. There were two major groups working on trying to identify ‘prepsychotic states’ and preventing ‘overt psychosis’ – Patrick McGorry in Australia and Anthony Morrison in Manchester UK:
At the time, I felt this was a worthy endeavor, but like most worried that it would open a door to even more over·medication. As it turned out, this move died out primarily because the initial excitement about identifying "prepsychotic" patients just didn’t pan out. But I recall thinking that Dr. Morrison was giving it a yeoman’s try with CBT and CBT+Medications.

Flash Forward: A few weeks ago, the ISPS [THE INTERNATIONAL SOCIETY FOR PSYCHOLOGICAL AND SOCIAL APPROACHES TO PSYCHOSIS] held a Conference in New York. It was the site where the British Psychological Society launched the report [Understanding Psychosis and Schizophrenia] we’ve read so much about. Here are a couple of overviews from Mad In America – What I Learned at ISPS 2015 and Towards a New Understanding of Psychosis – ISPS 2015. From the latter:
There was the phenomenal work of Anthony Morrison, who is the first researcher to empirically show that psychotherapy can be effective with individuals diagnosed with schizophrenia, even when they choose to not take psychotropics. Although many know this intuitively, the scientific community is not really interested in intuition; for him to show this repeatedly through empirical data is profound.
Recognizing the name, I thought I’d take a look:
by Morrison AP, Turkington D, Pyle M, Spencer H, Brabban A, Dunn G, Christodoulides T, Dudley R, Chapman N, Callcott P, Grace T, Lumley V, Drage L, Tully S, Irving K, Cummings A, Byrne R, Davies LM, and Hutton P.
Lancet. 383[9926]:1395–1403

BACKGROUND: Antipsychotic drugs are usually the first line of treatment for schizophrenia; however, many patients refuse or discontinue their pharmacological treatment. We aimed to establish whether cognitive therapy was effective in reducing psychiatric symptoms in people with schizophrenia spectrum disorders who had chosen not to take antipsychotic drugs.
METHODS: We did a single-blind randomised controlled trial at two UK centres between Feb 15, 2010, and May 30, 2013. Participants aged 16-65 years with schizophrenia spectrum disorders, who had chosen not to take antipsychotic drugs for psychosis, were randomly assigned [1:1], by a computerised system with permuted block sizes of four or six, to receive cognitive therapy plus treatment as usual, or treatment as usual alone. Randomisation was stratified by study site. Outcome assessors were masked to group allocation. Our primary outcome was total score on the positive and negative syndrome scale [PANSS], which we assessed at baseline, and at months 3, 6, 9, 12, 15, and 18. Analysis was by intention to treat, with an ANCOVA model adjusted for site, age, sex, and baseline symptoms. This study is registered as an International Standard Randomised Controlled Trial, number 29607432.
FINDINGS: 74 individuals were randomly assigned to receive either cognitive therapy plus treatment as usual [n=37], or treatment as usual alone [n=37]. Mean PANSS total scores were consistently lower in the cognitive therapy group than in the treatment as usual group, with an estimated between-group effect size of -6.52 [95% CI -10.79 to -2.25; p=0.003]. We recorded eight serious adverse events: two in patients in the cognitive therapy group [one attempted overdose and one patient presenting risk to others, both after therapy], and six in those in the treatment as usual group [two deaths, both of which were deemed unrelated to trial participation or mental health; three compulsory admissions to hospital for treatment under the mental health act; and one attempted overdose].
INTERPRETATION: Cognitive therapy significantly reduced psychiatric symptoms and seems to be a safe and acceptable alternative for people with schizophrenia spectrum disorders who have chosen not to take antipsychotic drugs. Evidence-based treatments should be available to these individuals. A larger, definitive trial is needed.
Throughout the article, Morrison et al caution that this is a Pilot study that needs to be confirmed with a full definitive study. And that’s to their credit, since there are a number of methodological problems along the way. The primary outcome variable was the PANSS total score [PANSS positive + PANSS negative]. There were two groups of 37 subjects each: CT – treated with weekly Cognitive Behavior Therapy and TAU – treatment as usual. I’ve summarized their results here [I don’t have their raw data, so my results are on the observed cases without the adjustments to deal with missing values]. The statistical tests are mine:
The rows labeled "POSSIBLE" require some explanation [and here’s a graphic that may or may not help]:
The CBT Treatment was in the first 9 months, however:
Participants allocated to cognitive therapy received a mean of 13.3 sessions [SD 7.57; range 2–26], with each session lasting roughly 1 h [these figures do not include the four booster sessions that were available]. Adherence to cognitive therapy was reasonably good, with no patients not attending any sessions, and 30 [82%] having at least six or more sessions.
The subjects weren’t all in the study for a year and a half. Here’s the explanation [see the graphic above]:
… 74 individuals were randomised to the cognitive therapy plus treatment as usual group [n=37], or the treatment as usual alone group [n=37]. We stopped before the target of 80 individuals in accordance with our recruitment timeline, on the basis of restricted resources, to ensure that we had the possibility to obtain 9 month data for all participants. Baseline characteristics were similar between groups.
That means that 68% were in the study for all 18 months, 81% were in the study for at least 15 months, 92% for at least 12 months, and 100% for at least 9 months. Looking back at the table, two of the significant differences are at 15 and 18 months as the cohort is dwindling. Now another graph:
On the left, the dropouts appear similar, but it’s the number remaining ÷ the number POSSIBLE, and it goes up[?] Then on the right, it’s the change in scores from BASELINE for the two groups, and it makes no sense at all to me. The differences between the TAU group and the CT group are because the TAU scores went up[?] I have no clue what that means. Why would the untreated group get worse after the treated group was through with treatment? Since the change is coincident with the premature cutoff of the study, I thought it might have something to do with that, but again I can’t figure how. They reported their results in a very different way in their Table 3, a single effect estimate that I didn’t understand:
It’s there for the looking for the stats-types among you. They also queried a categorical variable, responders [a fall in PANSS total > 50%]:
By examination of the proportion of participants achieving good clinical outcomes in each disorder [defined by use of an improvement of >50% in adjusted PANSS total scores], we noted that, at 9 months, seven [32%] of 22 participants in the cognitive therapy group, and three [13%] of 23 from the treatment as usual group had achieved good clinical outcomes. At 18 months seven [41%] of 17 receiving cognitive therapy and three [18%] of 17 receiving treatment as usual had achieved good clinical outcomes.
By my calculation: 9 months [p=0.30 Fishers 2 tail NNT=5.3] and 18 months [p=0.31 Fishers 2 tail NNT=4.3]. So while I can see that the CT scores are lower that the TAU scores, I can’t find much in the way of statistical confirmation that there’s a difference using the only tools I have without the actual data.  And so I’m going to have to go with his caution that this is a Pilot Project rather that the conclusion in the abstract: "Cognitive therapy significantly reduced psychiatric symptoms and seems to be a safe and acceptable alternative for people with schizophrenia spectrum disorders who have chosen not to take antipsychotic drugs." And speaking of antipsychotic drugs – there were some after all:
With regards to use of antipsychotic drugs throughout the lifetime of the trial, ten [4%] of 37 participants in the cognitive therapy group were prescribed antipsychotics after randomisation [eight during the treatment window and two during the follow-up phase] as were ten [4%] of 37 in the treatment as usual group [nine during the treatment window and one during the follow-up phase].
I apologize for the rough tools I’ve used here. But that’s the whole point of the AllTrials campaign. We can’t really know what we’re seeing in a published paper on a Clinical Trial without some access to the raw data prior to manipulation. Both the British Psychological Society and NICE have signed the AllTrials petition, and I would hope that when there is a definitive version of this study, Morrison et al will publish their full data as a data supplement so that all of us can see what they see.

So in-so-far as I’m able to vet this study, I would see it as a pilot project showing a signal that deserves repeating, but I can’t confirm the opening quote above, the article’s conclusion, or the commentary on the article. Here’s the thing of it, my bias is on the side of confirmation. I support psychotherapeutic intervention in Schizophrenia. I’m not sure I would’ve picked CBT, but I’m not an CBT-er, and from what I can read, Morrison et al have adapted the technique to be used in this condition.

On the other hand, we’ve just been through a period where the Clinical Trial literature has been problematic to a fault, and many of the results have molded to the wishes of the sponsors rather than the data itself. The fight for Data Transparency has been long and hard, and is anything but over. And if we are to apply the standard of outside replication of analyses to the industry sponsored drug trials, we need to apply it to all trials, including a study like this. I’ve come the personal conclusion that a published article is only a proxy for the actual data [proxies…][see also Study Report, Study Reality, and the Gap Between].
hat tip to 1boringyoungman 
Mickey @ 11:15 AM

a clinical impression…

Posted on Monday 30 March 2015

David Healy has up a post about the Pilot Suicide/Murder last week [Winging it: Antidepressants and Plane Crashes]. There’s also one on his Rxisk site by Julie Wood [Pilots and Antidepressants]. Meanwhile, the Psych Listserves and Twitter feeds have been abuzz with speculations that this was an SSRI [or other Psych Med] reaction. David, who has done more than anyone to bring these reactions to our attention, does a yeoman’s job of laying out how this is likely to play out. So I’ll stay out of his way on that score, deferring to his expertise, but I do want to briefly comment on a statement he makes along the way:
There are likely to be a number of features to the current debate.
    First an impression will be created that we know more about these drugs than we in fact do.
We know almost nothing about what antidepressants actually do – we still don’t know what they do to serotonin. Rather than being effective like an antibiotic, these drugs have effects – as alcohol does. Their primary effect is to emotionally numb. Patients on them walk a tightrope as to whether this emotional effect is going to be beneficial or disastrous.
I’ve never actually read those bolded parts said that way – their primary effect is to emotionally numb – but that’s exactly what I have also concluded on my own that the SSRIs do – emotionally numb. It’s just confirming to read it in print. And I sure agree that We know almost nothing about what antidepressants actually do
Mickey @ 6:17 PM

clinician trumps ideology…

Posted on Monday 30 March 2015

Sometimes, frustration and impossibility are necessary components of learning. Try looking around on the Internet for something that captures the essence of the difference between legal and ethical, between the Rule[s] of Law and a Code of Ethics. There’s plenty to find, sure enough, but something about the last thing I found isn’t quite it, so I return to the search. As in the phrase, the letter of the Law, Laws cover a minimal definable and enforceable standard of behavior derived from Ethics, which are more felt than written, more the difference between wrong and not right. So it’s little wonder that the Case of Dan Markingson is finally being decided by a faculty senate, a panel from an accrediting agency, and a legislative body, instead of in a Court of Law. Equally telling, it has become a cause célèbre through the efforts of an academic department of bioethics.

It’s hard to imagine reading the details of Dan’s story without seeing how not right it was from day one to its tragic ending. In the narratives of most other problematic Clinical Trials, the misrepresented efficacy or de-emphasized patient harms are experience distant from the trial itself, showing up as impersonal statistics from later users of the drug. In this case, it was the conduct of the trial itself that did the damage, not just some mathematical trick in the analysis or sleight of hand in the presentation of the study’s outcome. This case is also unique in that the role of the particular academic institution involved is central to the publicity – the Department of Psychiatry, the Institutional Review Board, the Clinical Research Center, and the Administration at the University of Minnesota. And this story is populated – Charles Schultz, Stephen Olson, Eric Kaler, Dan Markingson, Mary Weiss, Carl Elliot, Leigh Turner, Mike Howard – actual people make the story more real. And of course, the fact that Dan killed himself in an altered state [making sense…] some six months after he was placed in this Clinical Trial is an indelible marker of its not rightness – un·ethical.

There’s something else unique about this case. The usual suspects aren’t incorporating it into the constant bickering about bio·medicine or ideology. One of the problems with those arguments is that without a real case they’re carried on in the abstract, so the waring parties can [and often do] have different patient populations in mind and talk at cross purposes. I wish I knew more about Dan’s clinical course, because what I think I know is confusing:

  • When his mother visited him in California June 2003, he was floridly delusional, yet was still able to convince the police that he was fine [see The Deadly Corruption of Clinical Trials].
  • His September emails were again quite delusional, as was his presentation in Minnesota in November. But again, after 12 days on Risperdal®, he seemed to have cleared [see Study Visits p. 5], passing of his former symptoms as "lack of sleep." yet, whistleblower Nikki Gjere said that he was "too sick to be in the study" at that time [a paradigm…., INVESTIGATORS: Nurse questions integrity of U of M drug researchers].
  • Notes from various sources and Dan’s journal suggest that for the last several months of his life, he was getting worse [making sense…]. From the journal:
      Mar 23, 2004: "world walking, you were at a farm house and we’re getting presents from dogs who had presents fastened in plastic bags to their snouts… in the gloaming and breening, you were thinking of naming it gloaming and greening or gloam-green. That was someone brings a snowslide in summer or midsummer. It has been left behind…" [Olson 2007 p. 467].
    But from what I can find, it certainly appears that Dan was very ill either on-and-off or throughout the study.
Again, the information is sketchy, but it suggests to me that he needed either a different drug, a higher dose, or both because he was obviously not responding to the study meds [if he was even taking them]. My point here is that when discussing an actual case, the ideological wars melt and people from multiple sides of a debate can usually agree. "Clinican trumps Ideology." And in Dan’s case, we all seem to be of one mind about his care no matter our different perspectives or degrees. That may be simply a wish on my part, but I hope I’m right. Then today, someone sent me an article about how inconvenient it is to have the Clinical Trial program shut down at the University of Minnesota [Researchers chafe at halt of psychiatric trials]. If I’m right about Dan’s clinical state, no one was looking at him closely in that Clinical Trial program, and shutting it down was absolutely the right decision – even if it was eleven years late. Rather than "chafing" that it was suspended, a better topic might be, under what circumstances should it ever be allowed to be reopened…
Mickey @ 2:11 PM

the exposome…

Posted on Saturday 28 March 2015


NIMH
by Tom Insel
03/26/2015

… This update of our Strategic Plan is a commitment to take a fresh look at our horizons so that we can refine priorities and energize our path of discovery.

We know that some scientists reject the concept of “directed science,” believing that science rarely follows a plan. True, important discoveries often result from serendipity or side roads rather than a premeditated, carefully articulated strategy. On the other hand…

While the tools of genomics and neuroscience now permit rapid progress, equivalent tools and paradigms to study environmental influences are just being developed. Over this next 5-year period, we can expect this new approach to environmental factors, sometimes called the exposome, to yield more scientific traction in understanding the mechanisms by which environmental factors alter brain and behavior, from prenatal development through the process of aging…

Strategic Plan Strategic Objective 3
Director’s Message Strategic Objective 4
Introduction Highlights
Strategic Objective 1 Appendix
Strategic Objective 2 References
Strategic Research Priorities
After a number of years of reading someone’s writing, you sort of pick up on their rhetorical style. For example, when Tom Insel is discussing something he’s been criticized for [like being a control freak], he always puts the criticism first ["important discoveries often result from serendipity"], then says something like "On the other hand…" and carries on along the path he favored in the first place, ignoring the criticism altogether. In this case, it means continuing to be a control freak. And watch out for his neologisms – things like genomics, protenomics, connectome,  – or buzz phrases – personalized medicine, translational medicine, neural circuits, etc. This new one [the exposome] is particularly creative [not to be confused with the envirome or the the interactome]. At first, I thought that the exposome looked promising [are we finally going to recognize that there are factors outside the genetic endowment that effect the mental state?]. But, alas, these are terms generated after the Genome Project that have to do with speculations about how the outside world might shape biology. I was looking for something more like having nutty parents or life-changing events. Oh well… And don’t let the brevity of my quotes and links up there fool you. They connect to a labyrinthine Strategic Plan [insert and grandiose]. There’s really not going to be much room left for that serendipity he was mentioning. For example [in Objective 1: Strategy 1.1]:
To unravel the mechanisms that lead to mental illnesses and target novel treatments to those mechanisms, more comprehensive descriptions of the molecules, cells, and circuits associated with typical and atypical behavior are necessary. What classes of neurons and glia are involved in a given aspect of mental function? Which brain regions contribute to a single thought or action, and how are these regions interconnected? These questions will be answered by defining the cellular components of circuits, including their molecular properties and anatomical connections. New tools and techniques that span biological scales—from single-cell analysis, to macro-electrode arrays, to systems-level brain imaging — are needed to address these questions.
I think the thing that bothers me the most, besides the impossibility of serendipity in Insel’s NIMH, is that his grand plan is monomaniacal and based on hypotheses cum speculations that have yet to be anchored in the reality of solid science. I’ve spent my days with the simple idea of a Hardware/Software dichotomy for mental illness [Hardware «Melancholia, Manic Depressive Illness, Autism; maybe Schizophrenia, etc» and Software «most everything else»]. So a lot of this stuff Insel dreams of has felt like he’s trying to reprogram a computer with a screw·driver and a soldering iron. I’ve focused more on the programming languages.

Pushing that simple analogy, many critics would go further and say that it’s all software [as in the BPS Report Understanding Psychosis and Schizophrenia] or Schizophrenia: a critical psychiatry perspective] taking the psycho·social·perspective to extremes, saying that mainstream psychiatry is totally at sea in its hardware bio·perspective. But as much as I enjoy reading about the neuroscience, my take on Insel’s NIMH 2015 Strategic Plan is that it’s wildly speculative, making fantasmagoric extrapolations that move way, way beyond the frontiers of anything we know [but then again, I felt something similar in the other direction about the those psycho·social articles].

Back to Insel, I first started thinking about his rhetorical On the other hand… trick back when I read this blog of his a few years ago:
NIMH: Director’s Blog
by Thomas Insel
January 26, 2012

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

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

The opposing argument runs something like this. There has been no major innovation in therapeutics for most mental disorders since 1960. Current treatments are not good enough for too many. Rather than investing scarce dollars for incremental improvements or increased dissemination of mediocre interventions, we need invest in the fundamental science of brain and behavior so that we can understand how to develop better treatments…
And in that blog, at the end, he pulled out the polio miracle to bolster his case.
Sixty years ago, the nation faced a similar short-term vs. long-term debate about polio. The needs were growing and the causes were unknown. Some wanted funds invested only in better services, including improved iron lungs. Others argued for investing in a vaccine with a long-term goal of eradication. As David Oshinsky explains in his outstanding retelling of this debate, the government went with the services approach, leaving advocates and families to raise funds for vaccine development. Let us hope we don’t short-change our grandchildren, sixty years from today, by failing to invest in the long-term promise of more effective diagnostics and therapeutics for mental disorders.
I’m convinced that so long as it’s Insel’s show, the only alternatives are to send him on a prolonged [permanent] sabbatical or rename the NIMH the National Institute of Neuroscience. I mean that without tongue in cheek. He’s so far into his on-the-other-hand-land basic neuroscience that there’s little hope that he will ever take a balanced look at Mental Health. Even when they fund a study like RAISE-ETP in First Episode Schizophrenic patients, the psychosocial component is heavily weighted towards being a chemical imbalance and take your meds manual. And as for his ability to predict the future, how about this 2005 effort from his psychiatry as clinical neuroscience days?

And I think I would insist that his successor, if we ever get one, be required to spend at least a half-day a week seeing patients in a local mental health clinic – something Dr. Insel has never done since his residency training.
Mickey @ 6:50 AM

jettison schizophrenia? no thanks…

Posted on Friday 27 March 2015

Picking up where I left off in jettison schizophrenia?…, I’m talking about my objections to getting rid of the diagnostic category called Schizophrenia for the last century. First, some case examples:
  1. Recently, I mentioned the first case assigned to me as a psychiatry resident, a woman I called Gloria [back to the drawing board…] who was hospitalized awaiting a transfer to a long term facility as a NGRI [Not Guilty by Reason of Insanity] case after drowning her son during a psychotic episode. I came to my residency after a tour of duty in an overseas Air Force hospital where I was an Internist. When I decided to change specialties, while still there, I read everything I could get my hands on about psychiatry. There was a copy of Eugen Bleuler’s 1911 Dementia Praecox or the Group of Schizophrenias in the hospital library, and I read it from cover to cover. Why it was in the small library of our small hospital in rural England is unknown to me. But I was taken with his description of the premorbid personality of patients who went on to develop Schizophrenic illnesses, and what he called the Primary Symptoms [the four As: loosened Association of thought, inappropriate Affect, global Ambivalence, and Autism – private logic]. I also read the Psychiatry Textbook of the day, Friedman and Kaplan, that had a detailed discussion of the "psychotic break" in the Schizophrenic patient. In back to the drawing board…, I mentioned a conversation with Gloria’s mother, but that was only one of several. Her mother came at every visiting time, and would often catch me and talk about her daughter. It seemed to help her tell the story, and I was more than happy to listen. She described her daughter exactly as Bleuler and the text I had read – schizoid features in her persona, periodic temper outbursts, a long period of seeming confusion prior to "the break." I was amazed at the concordance of her description and Bleuler’s century-old writings.
  2. A few years ago, I described a case I saw not long after finishing my residency [see 1. from n equals one, 2. from n equals one, etc]. She was hospitalized after she had been stopped from jumping from the 14th floor of the atrium in a downtown hotel. I was the fourth psychiatrist to see her and none of us quite knew what was going on. From my previous post:
    She was confused. My friend was confused. So was I. She didn’t seem depressed and had no explanation for her behavior. At the time I saw her, she was completely focused on getting out of the hospital because she didn’t want to be a financial burden on her parents. It was over thirty years ago, but I recall  the interview clearly. She was coherent with no signs of psychosis. She was ill-suited and untrained for her job, but mainly felt she’d failed her parents who had been instrumental in getting it through a friend at the bank. She had no explanation for her behavior. What I mainly recall from the interview was that she tried very hard to answer every question I asked her, but looked at me oddly, as if to say, "Why are you asking that?" I saw her several times, still feeling somewhat lost. By this time, the pressure to leave the hospital had escalated and they set up a plan. She would go home to her parents house, take a leave from her job, and see both my friend and I as an outpatient. Once home, she refused both options, or to take any medicine, or to see anyone else. She told her parents that she would see me in the future, when she’d "sorted things out."
    I had a hunch that this was the prodrome to a schizophrenic break based on her history, presentation [and reading Bleuler]. She had already been tried on an antipsychotic with no effect. I saw her parents as something as an advisor while she lived at home, obviously uncomfortable but steadfast in her resolve to sort things out by herself. Then one day, she asked to see me, appearing in my waiting room that afternoon in a psychotic state and was admitted for the first of several hospitalizations. I followed her at varying intervals until I retired some  twenty plus years later.
  3. In the recent weeks, we’ve finally seen the case of Dan Markingson being definitively dealt with [from Minnesota: Dan Markingson revealed…, ethics…, making sense…]. In making sense…, I was discussing the last several moths of his life. He was apparently not overtly psychotic. There’s no mention of hallucinations or the bizarre delusions that had been apparent in the earlier period of his illness. But he was not doing well at all. There are indicators from most of the venues where he was seen and his own journal that he was decompensating without the psychotic symptoms he’d had on admission – instead he had the "Primary Symptoms" as described by Bleuler.
So when Moncrieff and Middleton say [see jettison schizophrenia?…]…
    Schizophrenia is a label that implies the presence of a biological disease, but no specific bodily disorder has been demonstrated, and the language of ‘illness’ and ‘disease’ is ill-suited to the complexities of mental health problems. «Neither does the concept of schizophrenia delineate a group of people with similar patterns of behaviour and outcome trajectories»
… I wonder if they’ve seen the same kind of patients I’ve seen over the course of my career. I share their outrage with those in this generation of psychiatrists who have made such a mess of things by allying themselves with the pharmaceutical industry, or who have steadfastly stuck with the silly notion that all mental illness has some biological basis, or who think that the solution to mental illness will come in a pill bottle or a long acting injection. But I can’t imagine seriously suggesting that Schizophrenia is on a continuum with normality as we heard about in the BPS Report [Understanding Psychosis and Schizophrenia], or not even really a distinct syndrome as suggested here – merely psychosis or madness. We know a whole lot about Schizophrenia, and a lot about being Schizophrenic, and a lot about the difficulties that can come as a consequence. Rather than jettison the diagnosis, we would be better placed to jettison the mistakes of the past that may have lead to a generic and simplistic approach to this prevalent and sometimes devastating illness.

In case 2. above, if I hadn’t suspected that this patient was in the throes of an incipient Schizophrenic break, I wouldn’t have been able to work with her parents to put here in an environment that could catch her the minute she fell through the ice instead of making another forray to a 14th floor balcony and plunging to her death. I wish we knew how to short circuit the breakdown, but we don’t [at least I don’t]. In case 3., if Dan Markingson’s caretakers had been more knowledgeable about this illness and more attentive to Dan in those latter months, they might have recognized that he was decompensating in front of their very eyes, even in the absence of the psychosis and delusions that he’d shown them earlier. If they had, they would’ve removed him from the study and gotten him the treatment he clearly needed [which in this case would’ve likely involved more and/or different medication, for one thing]. And Gloria and her mother [1.] will be haunted for all times by what she did in the midst of a psychotic decompensation. If only she’d been seen by someone who knew what was happening. That’s what her mother wanted to talk to me about in those evening chats, "Why didn’t I know what I was seeing?" Throwing out the baby with the bathwater just isn’t the right way to go about things.
Mickey @ 7:00 PM

jettison schizophrenia?…

Posted on Thursday 26 March 2015


Current Opinion – Review
by Joanna Moncrieff and Hugh Middleton
2015

Purpose of review The term ‘schizophrenia’ has been hotly contested over recent years. The current review explores the meanings of the term, whether it is valid and helpful and how alternative conceptions of severe mental disturbance would shape clinical practice.
Recent findings Schizophrenia is a label that implies the presence of a biological disease, but no specific bodily disorder has been demonstrated, and the language of ‘illness’ and ‘disease’ is ill-suited to the complexities of mental health problems. Neither does the concept of schizophrenia delineate a group of people with similar patterns of behaviour and outcome trajectories. This is not to deny that some people show disordered speech and behaviour and associated mental suffering, but more generic terms, such as ‘psychosis’ or just ‘madness’, would be preferable because they are less strongly associated with the disease model, and enable the uniqueness of each individual’s situation to be recognized.
Summary The disease model implicit in current conceptions of schizophrenia obscures the underlying functions of the mental health system: the care and containment of people who behave in distressing and disturbing ways. A new social framework is required that makes mental health services transparent, fair and open to democratic scrutiny.
It would be foolish to argue with Drs. Moncrieff’s and Middleton’s point that diagnostic labels can and have been used to imply a biologic causes, particularly when the Director of our National Institute of Mental Health proposes we look at Psychiatry as a Clinical Neuroscience Discipline, or when commentary like this …
    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…
    by Sally Laden for Nemeroff et al
… abounds in the contemporary psychiatric literature and dialog. The bio-psychiatry that Moncrieff and Middleton are arguing against is actually quite a leap from Dr. Spitzer’s introduction to the DSM-III in 1980:
    For most of the DSM-III disorders, however, the etiology is unknown. A variety of theories have been advanced, buttressed  by evidence – not always convincing – to explain how these disorders came about. The approach taken in DSM-III is atheoretical with regard to etiology or pathophysiological process except for those disorders for which this is well established and therefore included in the definition of the disorder. Undoubtedly, with time, some of the disorders of unknown etiology will be found to have specific biological etiologies, others to have specific psychological causes, and still others to result mainly from a particular interplay of psychological, social, and biological factors…
    Robert Spitzer, in the DSM-III, p 6.
It’s now well known that one agenda of that DSM-III effort was to remove the influence of psychoanalysis from American psychiatry, an effort that was largely successful. And it’s also clear that the biological agenda of the neoKraepelinians was a powerful force in shaping the form of that revision. In fact, one of the enduring flaws in the DSM-III system – the lumping of the Major Depressive syndromes with the much more common reactive depressions – was driven by the zeal to remove depressive neurosis from the diagnostic system [see a mistake…]. The net result was to shut down productive research on those major syndromes [by dilution] and to open the door [by inclusion] to industry and their minions [like Dr. Nemeroff and ghost·writer Sally Laden above] for a decades·long antidepressant marketing spree. We were not led from «atheoretical with regard to etiology» to «a highly prevalent, chronic, recurrent, and disabling biological disorder» by scientific discovery – it was by rhetoric, extrapolation, and the persistent vilification of defeated enemies.
    «Schizophrenia is a label that implies the presence of a biological disease, but no specific bodily disorder has been demonstrated, and the language of ‘illness’ and ‘disease’ is ill-suited to the complexities of mental health problems»
Again, I’m not arguing with their assertion that diagnostic labels in psychiatry have come to imply the presence of a biologic disease in many circles. That bothers me as much as it seems to bother them. But it doesn’t take an Etymologist to see that the "language of ‘illness’ and ‘disease’" doesn’t come from biological causation. Both ‘ill-ness’ and ‘dis-ease’ describe how a patient feels, not what is causing the discomfort. They are symptom words. And that’s no minor point – one that describes Medicine from the dawn of time. In fact, the word diagnosis itself [Greek diagnôsis, discernment, from diagignôskein, to distinguish : dia-, apart] has nothing to do with cause. It literally means to know apart.

I came to psychiatry from a career in Internal Medicine [formerly known as Diagnosticians]. And my first encounter [in my life] with the phrase medical model of disease or the idea that a diagnosis implied biological causation came from a fellow first year psychiatry resident [whose copy of Szasz’s The Myth of Mental Illness was always within arms reach – see Szasz by proxy…]. The idea that disease was certified by objective biosignatures was foreign to me. So I read Szasz’s books and I think I gained some things by pondering the questions he raised, but his were forced arguments to me. Diagnosis didn’t lead to cause for me in either career – it lead to action, to treatment. If I were a surgeon at the Battle of Gettysburg and you were brought to me with a gunshot wound to the leg, I sawed your leg off. It wasn’t because I knew anything about infection. During our Civil War, Louis Pasteur was still studying wine-making [it was well after Appomattox when he came up with his germ theory of disease]. I sawed off your leg because I knew you’d die if I didn’t.

And as a Rheumatologist in that former life, there were only a few lab tests that helped at times, but the main guideposts for treatment and prognosis came from careful clinical diagnosis. So although like Moncrieff and Middleton, I can see that psychiatric diagnosis has been jury-rigged to imply biological causality by too many people in high places, I see that as a perversion of the meaning of medical diagnosis – something that needs to be fixed and clarified.

And agreeing with the problem they describe doesn’t lead me to necessarily agree with their solution. If they were talking about the DSM-III-IV-5 category Major Depressive Disorder, I’d jump on the train in a blue second. But I’m balking at following along with Schizophrenia. One reason for my hesitation is that their reason to jettison the diagnosis relies heavily on their aversion to the implications of the diagnosis – implications imputed there without solid scientific back-up, as perversions of the traditional meanings and uses of medical diagnosis. It’s a reaction against something. I felt the same way about the BPS Report [Understanding Psychosis and Schizophrenia] which was also driven by a reaction against that same something [see <to be continued>…, back to the drawing board…]. That’s what Dr. Spitzer’s DSM-III did, reacted so strongly against something that the result was the creation of some big problems [this one included] that we still deal with some thirty-five years later. Likewise, Moncrieff and Middleton clearly have some «alternative conceptions of severe mental disturbance» that remain as speculative as those of their biologically inclined counterparts.

But neither of those things get at my main objection to their recommendation to jettison the diagnosis of Schizophrenia. I still find that diagnosis clinically useful, much more useful than «‘psychosis’ or just ‘madness’» would be. I’ll try to flesh out why I say that in the next post…
Mickey @ 6:00 PM