A Follow Up Note on Qnexa and Obesity

First, in response to a few questions that folllowed my Qnexa post (also the associated post on my Psychology Today blog).

On Feb 22 the FDA Advisory Committee voted to recommend approval - which usually signals that approval will be granted; but the final decision is to be made mid April. In other words, as of now, Qnexa does not have FDA approval for obesity.

But these questions about approval stirred my curiosity about the level of buzz Qnexa has generated.

How can one gauge that?

Well here is what I did.

I decided to use a reputable medical meta-search engine and compare the number of hits for Qnexa with the number of hits for some other new medication for a different indication.

I've chosen Trip Database as my meta-search engine. Trip Database not only provides a very solid search tool but also presents the search results in a format that makes it easy to differentiate between the different types of  retrieved data (eg, original research, guidelines, textbooks or news). I then compared the search results for "Qnexa and obesity" with the search results for "asenapine and schizophrenia".

Why choose asenapine? Asenapine is neuroleptic that got FDA approval for the treatment of schizophrenia back in 2009. As such it's still a relatively new medication (for a fair comparison with the very new Qnexa) and at the same time it's been around for long enough to generate some news (or so you'd think).

Why choose schizophrenia? As, similar to obesity, it represents another major public health issue. In case you don't know the most recent global burden of disease data form the World Health Organization place schizophrenia at #9 on the top 20 causes of disability word-wide. For comparision sake I should also mention that obesity, while a major health issue in the US, doesn't even make it on the same world wide top 20 list.

What are the results?

In a couple of my prior posts I used the "asenapine and schizophrenia" example to discuss on how to search for the best evidence (Tripping for Evidence Part 1 and Part 2). So last night I just re-run the same search for "schizophrenia and asenapinelast" on Trip Database and I got 20 hits (search results as of March 12, 2012). The "Qnexa and obesity" search on the same site returned 32 hits total.

So we got thirty percent more hits (ie, publications) for a drug that is yet to get FDA approval.

But it gets even more interesting than this: from the 20 asenapine results about 15% (N=3) were news reports. For Qnexa 100% (N=32) of the hits are news results.

Granted, this are proxi measures at best. However, as a indirect measure of the buzz out there when it comes to different public health issues, in this case, schizophrenia and obesity, the results are pretty telling.

And the story they tell is that as a society we seems to be overinterested in issues related to weight and body image. That in itself might be part of the problem.

© Copyright Adrian Preda, M.D.

Schizophrenia and CBT

A new study by Grant et al. (2012) indicates that for a fairly treatment resistant schizophrenia population hour long weekly cognitive behavioral therapy (CBT) might help.

The study assessed how low functioning patients with schizophrenia and prominent negative symptoms respond to the addition of weekly CBT to treatment as usual. And surprise: patients did get better! Why the surprise? As low functioning and negative symptoms when part of the clinical picture in schizophrenia are traditionally though of indicative of treatment-resistance. In other words, the consensus is that for this patient group nothing works. Typically, this are patients who don't spend much time with anyone - partly because they don't have an interest in socializing, partly because most people also have difficulties connecting with them.

fMRI study of working memory in schizophrenia
By Kim J, Matthews NL, Park S. via Wikimedia Commons

When it comes to psychotherapy the clinical encounters tend be brief and mostly supportive.

In a strange way, the social isolation that seems to be the crux of the problems, is not fought against but kind of reinforced by the brevity of the therapy sessions and other types of social intercourse, including support groups, ACT, day programs etc., where more times than not these patients are allowed to simply fade into the background.

Well, this study tells a slightly different story. We learn that treatment resistant patients, when socially engaged for about one hour on a weekly basis, contrary to all expectations, actually improved over time. This runs contrary to our current understanding of prognosis and treatment response. We don't expect this patients to respond to anything, yet they do. We don't expect them to benefit from social interactions, yet they do. And the catalyst of change, surprisingly, is not some other pill but time spend week after week, with someone who cares and keeps engaging the patient not for a few minutes but for almost a full hours.

The study has a number of limitations. There is no comparable control group, which makes it difficult to ascertain if the reported effect is due to the specificity of CBT or other non-specific study factors, related to the more intense social interactions in the active group.

Also, strangely enough, even if the subjects were randomized, somehow the CBT group gathered patient with a more favorable prognostic profile at baseline: the CBT patients were younger, had a shorter duration of illness, a higher rate of schizoaffective disorder (which carries a better prognosis than schizophrenia), and were treated with less cognitively impairing medications (higher rate of atypical) and lower doses (also presumably with less need for higher doses and cognitive side effects). This is a constellation of factors that unfortunately weakens the study conclusions as presumably the reported effect might in part be a result of more favorable risk profile.

Nevertheless this remains a thought provoking study. First and foremost  in that it offers a glimmer of hope for a group of patients whose sufferance has been commonly deemed as irredeemable. Secondly for pointing out that even when facing disarming levels of chronicity and severity, everything else being equal, doctors still have a duty to hold dear hope up rather than throwing in the towel. And last but not least, for reminding us all about the importance of human connection, that universal ingredient of any effective therapy, which sometimes gets forgotten in our approach to treating schizophrenia.

© Copyright Adrian Preda, M.D.

Further Reading:
Schizophrenia: Causes, Symptoms, Signs, Diagnosis and Treatments - Revised Edition - Illustrated by S. Smith

Surviving Schizophrenia: A Manual for Families, Patients, and Providers

The Center Cannot Hold: My Journey Through Madness

Psychosis is Toxic for the Brain

There is an ongoing debate about how early one should intervene to prevent mental illness from unfolding.  Prophylaxis or prevention is universally agreed as better than post diagnosis intervention in medicine.  However when it comes to psychiatry prophylaxis is a bit of a Pandora box.

Edvard Munch The Scream

Universal prophylaxis - as in measures promoting mental hygiene - raises the issue of regimentation.  Forcing people in some ideal template of perfect mental state is a controversial project as there as there is no universal agreement on what the "ideal mental state" might be in a first place.  When science alone is not sufficient to clearly define what mental health is, objectivity gives was to subjectivity, scientific judgment to value judgment, and emotion fueled morality and politics instead of the coolly headed science end up taking the center stage.

Specific prophylaxis has its own thorny issues.  To this day, society still mistakes psychiatry definitions as judgment labels and then proceeds to stigmatize accordingly.  This being the case for people who meet diagnostic criteria, how would anyone go about potentially labeling patients who, while being at risk for a disorder, do not in fact meet the required criteria?  Choosing to prevent something that might occur is a very different proposition than slapping a prophylactic, yet stigmatizing label, on someone that might have never got it otherwise - and this the core the ethical dilemma that preventive psychiatry faces day in and day out.

Add the anti-psychiatry movement contention that the whole idea of mental illness is just a social construct. with the implication that treating mental illness with medications is literary a toxic and as such deeply unethical proposal and you will understand why studies of untreated patients are essential for our field.

The idea is simple.  Here it is what one needs to do to understand the natural history of a mental illness: take people who have a psychiatric diagnosis follow them free of psychiatric intervention ("toxicity", medications, hospitalizations, etc.) for some time and then see who got worse, who got better, or who ended up somewhere in between.

If all got better you can throw away your prescription pad and join the anti-psychiatry convention. If all got worse and the doctor in you should remember your primun non nocere Hippocratic Oath, and acknowledge that if doing nothing actually harms your patients than you'd better do something about it. Which is, well, TREAT.

That is why I appreciate a study like Thirthalli et al.  when one comes along. A rare study where patients who had a diagnosis of psychosis for quite some time where started on medications and then followed for up to a year. “The quite some time” part – with some patients with long duration of untreated psychosis (DUP) - in rare in modern day clinical psychiatric research, where most patients get rapidly diagnoses and treated.

Briefly, in this retrospective-prospective study, the newly treated patients showed that their symptoms severity and degree of dysfunction one year later correlated with the duration of untreated psychosis (DUP). In other words, the longer one was sick prior to treatment, the worse the shape they were going to be in one year later.  Now, this is not a controlled, randomized study. There are missing details in describing the study population. We also don’t know if people treated with different medications improved differently, which would have been very helpful to put things in context. However as most of the patients took one of two newer antipsychotics the clinical changes do not seem to be due to medications. Yet, weaknesses considered, the double correlation of both functional and symptoms severity scores at follow up exclusively with the duration of untreated illness, strongly suggests that one should not wait but treat psychosis as early as possible.

While this does not answer general questions about early intervention for mental illness, when it comes to psychosis the message is clear.

Brain toxicity is a result of untreated psychosis.

Medications for psychosis make things better not worse.

Treating early is a good idea.

Remember primun non nocere? Not to treat is to harm. Therefore treat.

References:

Thirthalli J, Channaveerachari NK, Subbakrishna DK, CottlerLB, Varghese M, Gangadhar BN.Prospective study of duration of untreatedpsychosis and outcome of never-treated patients with schizophrenia in India. Indian J Psychiatry. 2011 Oct;53(4):319-23

© Copyright Adrian Preda, M.D.

Polypharmacy for Schizophrenia

This is what people out there have been doing for a long time. However, the evidence base of this type of practice is not substantial. A new paper published by Essock and colleagues in the July 2011 issue of the green journal tries to answer the question. Contrary to expectations, polypharmacy, while not as well tolerated as monotherapy, seems to be preferred. Due to lack of blinding, it is not clear though, if this is due to the patient's or provider's preferences (or biases) or both.

On my Faculty of 1000 review of the paper (which we can also find HERE on the Faculty of 1000 site - subscription required) this paper got a 6 and was considered a new finding. Here is the entire text of the comment:

"Is polypharmacy all that bad? Polypharmacy with more than one antipsychotic is generally not recommended but is often prescribed as a result of 'desperation' in response to the failure of monotherapy. Such failures may be due to a combination of poor or partial response and/or adverse effects resulting in partial compliance. This paper by Essock et al. may signal the beginning of a paradigm change where future polypharmacy randomized controlled trials (RCTs), already informing practice in other medical disciplines (e.g. oncology, neurology and infectious diseases/AIDS), can address some of the complex questions that psychiatrists face on a daily basis. In addition, Essock et al.'s study shows that engrained expectations -- the official dogma -- can and should be challenged.

Directly challenging the traditional textbook-based psychopharmacological wisdom of 'less is more', Essock et al. compared continuing schizophrenia patients on two antipsychotics with switching to a single antipsychotic. Using a naturalistic randomized control trial design, Essock et al. found that, on average, time to discontinuation or change in medication was shorter in the monotherapy group, suggesting that, at least for some patients, polypharmacy might be better than monotherapy, although this was not reflected by an increase in general symptoms or more hospitalizations in those that switched. Importantly, most patients (69%) were successfully switched to monotherapy. Switchers lost weight (decreased body mass index [BMI] by 0.5 points), while the polypharmacy group gained 0.3 points. So, switching to monotherapy works for the majority of patients and on average results in weight loss. At 6 months, 86% of patients continued on polypharmacy versus 69% who stayed on monotherapy, suggesting that, regardless of practice guidelines, at least for some patients two antipsychotics can work better than one.

While these findings are thought-provoking, future studies looking at mono- versus polypharmacy comparisons should carefully address the issue of potential bias due to unblinded switching, which is a potential confounder in Essock et al.'s study. Further research is clearly indicated to tease out what were the hidden benefits of combination therapy."

© Copyright Adrian Preda, M.D.

Cognitive Remediation in Schizophrenia

My Faculty of 1000 review of Wikes and collegues recently published meta-analysis:
http://f1000.com/9528958


I am glad to see that there is some signal for a non-pharmacological intervention who can move us more in the direction of adressing functional deficits.

© Copyright Adrian Preda, M.D.

International Congress of Schizophrenia Research

Just came back from ICOSR. A brilliant meeting where great minds get together to solve the mystery of schizophrenia. I thought it would be interesting to see how the themes of the meeting inform about the current view of schizophrenia.
And here they are:
1. Biology continues to have the upper hand. The vast majority of the communications (oral and posters) were from the biological camp.
2. Fundamental research (or basic science) has the upper hand. Clinical research is playing catch up.
3. Psycho-social research is making a comeback by changing its theoretical allegiance from a psychological to a biological perspective. In other words psychosocical research appears to regain status while conceding to the view that the mind is a brain epiphenomenon. Thus, the gold standard psycho-social assessments and interventions are to be measured against is their ability to measure/change brain states, rather then mind states or social functioning.
4. Cognition in schizophrenia is on the rise. It has been steadily consolidating prior gains and is now rubbing elbows with the major league players (genetics and functional imaging).  In fact cognition might end up stealing the show as it is ideally positioned at a crossroad between biological, psychological and social theories as applied to both assessment and intervention research.

© Copyright Adrian Preda, M.D.

Tripping for Evidence - Part 1

Take a Trip!

You search Trip Database for "asenapine and schizophrenia".

One of the nice things about Trip is its color-coding of what it finds based on the quality of the evidence.

Green is best. This includes evidence based synopses, guidelines and systematic reviews. Why is this best? Because people who know what they do already reviewed the available evidence, graded it and summarized it - all in all, less work for you!

Blue is for original research, i.e. research that you need to directly review and asses according to "best evidence" criteria.

Red and brown is for textbook based evidence (otherwise known as background evidence), news etc. - evidence that maybe informative but it's harder to asses in terms of validity and bias.

You would hope that you will find evidence clustering towards blue. In this instance though Trip doesn't find any "best evidence". You find only 3 articles, all original research. From those, there is only one clinical trial comparing asenapine (Saphris) with risperidone (Risperdal) in schizophrenia (Potkin 2007).

Good try but you need to move to step 2: SUMSearch.

N.B. In the future, if you want to try your own "trips" from this blog, you can go under the "search this" box and simply click on Trip Database.

For Part 2 of Tripping for Evidence please go HERE.

References:

Potkin SG, Cohen M, Panagides J. Efficacy and tolerability of asenapine in acute schizophrenia: a placebo- and risperidone-controlled trial. J Clin Psychiatry. 2007 Oct;68(10):1492-500.

© Copyright Adrian Preda, M.D.