Youth's Social Problems Contribute To Anxiety And Depression

ScienceDaily (Mar. 25, 2008) — Socially successful children tend to have fewer symptoms of anxiety or depression, while children with problems such as anxiety and depression tend to have difficulties forming relationships and being accepted by friends. However, it is difficult to determine whether the anxiety and depression lead to the social problems, or vice versa. New research suggests that social problems are more likely to contribute to anxiety and depression than the reverse. The research also shows that this is particularly likely during the transition from adolescence into young adulthood.

Using data from Project Competence, which has followed a group of 205 individuals from middle childhood (ages 8 to 12) over 20 years into young adulthood, the researchers used detailed interviews with participants and reports from their parents, teachers, and classmates to create measures of so-called internalizing problems (anxiety, depressed mood, being withdrawn) and social competence (how well one functions in relation to other people, particularly with respect to getting along with others and forming close relationships). They then examined how these measures related to each other over time, taking into account the stability of each (in other words, that children who have social problems at the start of the study may continue to have them over time).

The researchers found that young people who had more internalizing problems (such as anxiety and depression) at the start of the study were more likely to have those problems in adolescence and young adulthood. Those who were socially competent at the start of the study were socially competent as they grew up. However, in addition to this evidence of continuity, the study found evidence of spillover effects, where social problems contributed to increasing internalizing symptoms over time.

Children who were less socially competent in childhood were more likely to have symptoms of anxious or depressed mood in adolescence. Similarly, young people who were less socially competent in adolescence were at greater risk for symptoms of anxiety and depression in young adulthood. The findings remained the same when the researchers took into account some other possible explanations, such as intellectual functioning, the quality of parenting, social class, and such problems as fighting, lying, and stealing. And the results were generally the same for both males and females.

"Overall, our research suggests that social competence, such as acceptance by peers and developing healthy relationships, is a key influence in the development of future internalizing problems such as anxiety and depressed mood, especially over the transition years from adolescence into young adulthood," explains Keith Burt, assistant professor of psychology at the University of Vermont and the study's lead author. "These results suggest that although internalizing problems have some stability across time, there is also room for intervention and change. More specifically, youth at risk for internalizing problems might benefit from interventions focused on building healthy relationships with peers."

Summarized from Child Development, Vol. 79, Issue 2, The Interplay of Social Competence and Psychopathology Over 20 Years: Testing Transactional and Cascade Models by Burt, KB (University of Vermont), Obradoviæ, J, Long, JD, and Masten, AS (University of Minnesota). The study was funded, in part, by the National Science Foundation and the National Institute of Mental Health.

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Tuesday, August 4, 2009

Abilify Runs Amok, Runs Stealth Safety Campaign in Medical Journal

Furious Seasons has a rather distressing piece of news from a recent Bristol-Myers Squibb conference call. To sum it up quickly, BMS claims that 10.6% of depressed patients are now receiving atypical antipsychotics. Of those 10.6%, 21.7% are taking Abilify. So that would mean roughly 10-11 in 100 depressed patients are taking antipsychotics and 2 of them are on Abilify. I shudder to think how many are on Seroquel. Or Zyprexa. It made me think of a post I wrote a few weeks ago in which I described the marketing of Abilify for depression. A huge market of depressed people just ripe for the picking.

Going along with this, BMS is pushing back on the issue of akathisa, the side effect that has garnered the drug much bad publicity (at least in the blog world; 1, 2, 3) via a medical journal article that distracts attention from Abilify as an akathisia-inducer. More on that to come soon. Ghostwriters, ignoring contradictory evidence; basically, an attempt to completely obscure the evidence on the topic. It's not the first time BMS has successfully placed a study with major flaws into a medical journal (1, 2). Details will be forthcoming.

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Wednesday, April 29, 2009

APA Monitor: We Don't Need No Stinking Evidence

The American Psychological Association publishes two monthly publications for members, the well-regarded journal American Psychologist, and the APA's newspaper, Monitor on Psychology. I've been having issues with The Monitor for as long as I can remember. At times, I think the magazine makes claims that are not at all substantiated by evidence, which really bothers me. Why? Because psychology is supposed to be a science; it is what separates psychologists from life coaches or snake oil salesmen. I usually skim the Monitor for about 30 seconds per month, but when I saw the cover for this month's issue, my intuition told me to look out for voodoo. The title: Brain imaging: New technologies for research and practice.

So I browsed through the glossy pages, looking for something to catch my eye. Then, on page 36, there it was...

A pacemaker for your brain? Electric brain stimulation may give hope to people with unremitting depression

Oooh. Sounded promising, so I gave it my full attention. Keep in mind that this was in the "Science Watch" section. The article begins:

It's about the size of the letter "o" in this sentence and may have the power to lift deep, unrelenting depression.

OK, there's the attention-grabber. It then goes on to describe deep brain stimulation (DBS). Before long, I ran across:

Since 2005, more than 60 people worldwide have received DBS for treatment-resistant mood disorders. For about 60 percent of them, there's a "striking improvement in their symptoms of depression," says Andres Lozano, MD, PhD, a neuroscientist at the University of Toronto who performs DBS surgery.

Well, that practically screams "valid scientific findings," asking a surgeon if his technique works. What was he gonna say, "Nah, I think DBS is a bunch of hooey. I only do it because it pays really well." I'm willing to bet that physicians who practiced bloodletting were also quite confident that the majority of their patients showed "striking improvement," which is why we conduct controlled trials rather than rely on subjective opinion. Later in the article, the author notes that the results from DBS are "dramatic and promising." The author also notes that

A number of other behavioral and mood disorders might also benefit from DBS. Benjamin Greenberg, MD, PhD, a psychiatrist at Brown University in Providence, R.I., is using DBS to treat obsessive-compulsive disorder, with success rates similar to [Helen] Mayberg's and Lozano's. Also similar is Greenberg's claim that OCD people who've had DBS are then able to tolerate and respond to behavioral therapy.

This broad success leads Mayberg to believe that DBS is establishing itself as an important tool for treating disorders that otherwise won't budge.

OK, so Lozano claims that 60% of people make "striking improvement"; what about others? As mentioned above, Helen Mayberg has done some research on this topic. The article describes one of her studies. Here comes the most convincing evidence I've ever witnessed:

The initial trial included six people who met diagnostic criteria for major depressive disorder. The two researchers and their colleagues implanted electrodes in the white matter adjacent to their patients' subgenual cingulate cortexes and fired up their pacemakers. All the patients, who were awake during the procedure, reported a "sudden calmness or lightness," Mayberg and Lozano reported in the paper.

The researchers followed up with the patients by administering monthly depression scales. After six months, four of the six showed significantly fewer depressive symptoms. To make sure they weren't getting a placebo effect, Mayberg and Lozano secretly switched off the electrodes in their best-responding patient. After about two weeks, the patient's scores began to drop. After about a month, his depressive symptoms had returned. The researchers switched it back on and six weeks later he was back up to non-depressive levels.

So the author of the article, based on the subjective opinion of a psychiatrist and a neurosurgeon, along with and an uncontrolled study of six people concludes that DBS:

  • Has shown "broad success"
  • "A number of other behavioral and mood disorders might also benefit from DBS"
  • "May have the power to lift deep, unrelenting depression"
  • Has shown "dramatic and promising" results

The author threw in a few caveats about side effects (though he essentially gave it a clean bill of health), and also noted that DBS should be reserved for patients with longstanding depression and who have not shown positive results with other treatments. So it stopped short of being a blanket endorsement of DBS, yet it did really make it sound like a fantastic treatment for longstanding depression despite the very meager evidence cited in its support. I often complain about poorly designed studies, suppression of negative data, or misinterpreted results leading to drugs being touted as unrealistically safe and effective. But this article shows that it doesn't necessarily take drug company involvement to pimp a treatment well beyond the scientific evidence.

For all I know, DBS may turn out to be The Holy Grail in treating depression of all shapes and sizes. I cast no aspersions on the researchers mentioned in the article, as searching for ways to treat seemingly intractable cases of depression is doing God's work. But the writer did a horrendous job of overblowing the evidence in favor of DBS. This kind of article feeds the popular notion that psychologists are a bunch of flakes who know nothing about science. The APA Monitor can do much better than this.

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Wednesday, March 25, 2009

Abilify, Depression, and the Memory Hole

ResearchBlogging.org
The Primary Care Companion to the Journal of Clinical Psychiatry has a piece on Abilify for depression that illustrates many of psychiatry's woes. Full text of the article is here. The journal published an article titled "Examining the efficacy of adjunctive aripiprazole in major depressive disorder: A pooled analysis of two studies." The paper combines data from two previously published studies which examined the addition of Abilify to existing antidepressant treatment (1, 2). One of psychiatry's big-name academics, Michael Thase, signed on as lead author. I'm hoping that he didn't actually write the paper. Actually, there are eleven authors of the paper, which seems a little ridiculous given that the paper is an analysis of data which had already been collected for two previously published clinical trials. Seven of the authors are employees of Bristol-Myers Squibb (BMS) or Otsuka, which both market Abilify. Wait... If you look closely, you can see my favorite disclosure... In the fine print on the first page...


In case you can't read the fine print: In defense of Thase and the other academic authors, they may have not actually written any of the paper. Much or all of the writing appears to be creditable to Ogilvy Healthworld Medical Education. On their site, they note that they perform:
Clinical Development and Publications Management
Experienced medical writers work closely with authors, editors and publishers to provide our clients with a full range of publishing options.
Whatever BMS/Otsuka paid you for this one simply was not enough. Why? Because whomever wrote this thing did an admirable job of focusing on the positive and completely ignoring the negative.

Erasing the Patient's Opinions: Remember, the article's title states that it examines the efficacy of adjunctive Abilify (adding Abilify to existing antidepressant treatment). So you'd think the article would mention all of the relevant depression data from the two relevant studies. Well, no. In the two stuides which are discussed in the article, patients were assessed on depression using the following measures:
  • Montgomery Asberg Depression Rating Scale (MADRS)
  • Inventory of Depressive Symptoms-Self Report Scale (IDS)
  • Quick Inventory of Depressive Symptoms Self-Report Scale (QIDS)
Using the MADRS, the authors conclude that adding Abilify to antidepressant treatment is more effective than adding placebo to antidepressant treatment. OK, fine, though it's not by a particularly huge margin. Mysteriously, the authors do not even mention that the self-report scales (IDS and its subscale, the QIDS) were used in the two trials. And why would they? In both trials, Abilify was not significantly better than placebo on these measures. A letter to the editor pointed out this glaring weakness in Abilify's claims of efficacy, the response to which was weak:
Noting that Abilify did not outperform placebo on the self-report measure in the trial, he wrote that "this may be due to the lower sensitivity" of the measure. So the drug wasn't the failure -- blame the rating scale instead. The people at BMS picked the scale and when it doesn't give results they like, then suddenly it's a poor measurement of depression. I bet Dr. Berman would not have complained about the instrument had it yielded results in favor of Abilify.
In the publications of each of the two clinical trials, the authors tried to downplay the fact that Abilify was no better than placebo according to patient self-reports. Then, when publishing an analysis that combined the results of the two trials, the authors go a step further by not even mentioning that patients completed a self-report. Right down the memory hole. In my opinion, any reasonable academic author writing about such research would want to note the strengths and limitations of Abilify in treating depression. The lack of benefit on patient-rated measures is a major weakness. Yet several big-time academics signed off on this paper despite its complete scrubbing of negative data. For that, I hereby nominate each author for a coveted Golden Goblet Award. And I credit the ghostwriter at Ogilvy with a fantastic job of serving his/her corporate clients. You, sir or ma'am, deserve kudos for a marketing job well-done.

The instructions for authors who submit to the Primary Care Companion to the Journal of Clinical Psychiatry state: "Conclusions should flow logically from the data presented, and methodological flaws and limitations should be acknowledged." Um, does completely scrubbing negative data count as failing to acknowledge limitations? I can see that the peer reviewers and/or editor really paid close attention to this paper.

Safety: The authors note that "adjunctive aripiprazole is relatively well-tolerated in patients with MDD." Relatively? Relative to what -- being hit with a baseball bat repeatedly? They note that akathisia occurred in 25% of patients on Abilify compared to 4% of patients on placebo. Restlessness: 12% vs. 2%; insomnia: 8% vs. 3%; fatigue: 8% vs. 4%; blurred vision: 6% vs 1%. The authors report that akathisia resolved in 52% of patients by the end of the study, which would also mean that for 48% of patients with akathisia, they were stuck with it at the end of the study. But don't worry, it's "relatively well-tolerated."

Overall, another example of a "research" publication being little more than a puff piece in favor of a drug. With big-name academics signed on as authors to add credibilty and just a fine print mention of a ghostwriter.

I thank an anonymous reader for alerting me to this study.

Citation:

Thase ME, Trivedi MH, Nelson JC, Fava M, Swanink R, Tran Q, Pikalov A, Yang H, Carlson BX, Marcus RN, Berman RM (2008). Examining the efficacy of adjunctive aripiprazole in major depressive disorder: A pooled analysis of 2 studies Primary Care Companion to the Journal of Clinical Psychiatry, 10, 440-447

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Tuesday, March 10, 2009

Abilify For Depression: I'm Not the Only Skeptic

ResearchBlogging.org

In April 2008, findings were published in the Journal of Clinical Psychopharmacology which claimed that the atypical antipsychotic aripiprazole (Abilify) was an effective add-on treatment for depression. I heartily disagreed with the study's conclusions, noting that the patient-rated depression measure did not demonstrate an advantage over placebo, an inconvenient result that the authors tried to explain away as if was unimportant. I also pointed out that the study design was biased in favor of Abilify:

Study Design. Patients were initially assigned to receive an antidepressant plus a placebo for eight weeks. Those who failed to respond to treatment were assigned to Abilify + antidepressant or placebo + antidepressant. Those who responded during the initial 8 weeks were then eliminated from the study. So we've already established that antidepressant + placebo didn't work for these people -- yet they were then assigned to treatment for 6 weeks with the same treatment (!) and compared to those who were assigned antidepressant + Abilify. So the antidepressant + placebo group started at a huge disadvantage because it was already established that they did not respond well to such a treatment regimen. No wonder Abilify came out on top (albeit by a modest margin).

Here's an analogy. A group of 100 students is assigned to be tutored by Tutor A regarding math. The students are all tutored for 8 weeks. The 50 students whose math skills improve are sent on their merry way. That leaves 50 students who did not improve under Tutor A's tutelage. So Tutor B comes along to tutor 25 of these students, while Tutor A sticks with 25 of them. Tutor B's students do somewhat better than Tutor A's students on a math test 6 weeks later. Is Tutor B better than tutor A? Not really a fair comparison between Tutor A and Tutor B, is it?
Some commenters agreed with my take on the matter while others did not. Two letters to the editor published in the latest Journal of Clinical Psychopharmacology raised concerns about the study. Alexander Tsai, from UCLA, wrote that he was concerned that the advantage for Abilify was small (2.8 points on the Montgomery-Asberg Depression Rating Scale ) and that the study design was biased in favor of Abilify (agreeing with my earlier point).

Dr. Bernard Carroll, wrote in his letter that:
  • The advantage of Abilify over placebo was small
  • There was no advantage on the patient-rated measure
  • Due to the notable side effect profile of Abilify, clinical raters could likely distinguish patients who were taking Abilify from those who were taking placebo, which could have biased their ratings. Thus, he questions if the study was truly double-blind.
  • The authors did not report whether the occurrence of several side effects were more common on Abilify than placebo. Dr. Carroll calculated that akathisia, fatigue, restlessness, and insomnia were all significantly more common on Abilify and wondered why the authors did not include such data in their report.
  • The authors did not note the relationship between akathisia (severe restlessness/tension) and suicide, which is concerning given that Abilify produces akathisia in droves.
The Defense: Robert Berman from Bristol-Myers Squibb wrote back to defend the study. His points were not impressive. Noting that Abilify did not outperform placebo on the self-report measure in the trial, he wrote that "this may be due to the lower sensitivity" of the measure. So the drug wasn't the failure -- blame the rating scale instead. The people at BMS picked the scale and when it doesn't give results they like, then suddenly it's a poor measurement of depression. I bet Dr. Berman would not have complained about the instrument had it yielded results in favor of Abilify.

Adverse Events: As for not reporting adverse events, well, there's a perfectly good explanation hidden somewhere in here...
...we have clearly reported rates of spontaneously reported treatment-emergent events that occurred at a rate of 5% or greater in any treatment group. As this study is not designed to collect adverse events in a systematic manner, statistical comparison between treatment groups is not appropriate.
So let me get this straight. They discussed "spontaneously reported" events, which would refer to the events reported by the patients without much questioning. Everyone knows that spontaneous reports are a joke because most side effects are not spontaneously reported. Based on spontaneous report, the rate of sexual side effects in SSRI's is quite low. But when you bother to ask people taking SSRIs questions about their sexual functioning, the rates of sexual problems increase drastically. So when Dr. Berman goes on to write that no suicide-related adverse events were reported in the study, keep in mind that the study investigators were not asking about such events. So it may be more accurate to say that nobody committed suicide during the study, but nobody was tracking suicidal ideation unless patients reported such problems themselves. Yes, suicidal ideation was covered a little bit by measures used in the study, but a more systematic assessment would have been helpful. To give the authors credit, at least they did include a couple measures of extrpyramidal symptoms, from which we gathered that akathisia happened in 25% of patients. Yikes.

Saying that the study was not designed to collect adverse event data in a systematic manner is frightening. If adverse event collection was not systematic, then the authors writing in the study report that "adverse events were generally mild to moderate" is meaningless. You can't say that adverse event data were not collected in any sort of systematic manner then also say that the study is "safe," as the authors claim in their paper. This is the definition of duplicitous. In any case, the authors should have reported that several adverse events were significantly more likely to occur on Abilify than placebo rather than making the ridiculous claim that comparing adverse event rates between treatment and placebo is not appropriate.

Dr. Berman does not address the less than 3-point benefit for Abilify over placebo. There is also no real explanation to address the concerns of Dr. Tsai and myself, who noted that the study design was biased in favor of Abilify.

Kudos to Dr. Caroll and Dr. Tsai for taking the time to write excellent letters which addressed quite problematic issues in this study. Every time I see a commercial pimping Abilify for depression, I cringe. It's good to know that some people in the medical community are seeing through the weak research that "supports" the use of Abilify as an antidepressant.

Citation for the offending study below:

Ronald N Marcus et al. (2008). The Efficacy and Safety of Aripiprazole as Adjunctive Therapy in Major Depressive Disorder Journal of Clinical Psychoopharmacology, 28 (2), 156-165

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Tuesday, January 27, 2009

 
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