In the News

And Now for the Rest of the Story

Tue, 31 Aug 2010 10:49:32 -0400

Check out the story that appeared on August 30 on CNN.com titled “Growing Up Bipolar,” and the one on August 31 in the New York Times’s science section, titled “Lasting Pleasures, Robbed by Drug Abuse.” Both reveal a lot about the selective story-telling that forms our societal beliefs about mental disorders and psychotropic drugs. The CNN story tells of how psychiatrists are getting better about diagnosing bipolar disorder in children, and how, once it is properly diagnosed, medications can be such a big help. But if you read the article closely, you’ll see that both of the children in this story were treated iitially with an antidepressant, which led to a manic episode in one child and to a further deterioration in behavior in the second child, and it was then they were diagnosed with bipolar disorder. Before psychiatry began prescribing stimulants and antidepressants to children, juvenile bipolar illness was unknown. Researchers regularly concluded that bipolar disorder (or manic depressive illness, as it was called in the past,) simply didn’t occur in prepubertal children. But then psychiatry began prescribing those drugs to children and youth, and the juvenile bipolar boom followed. Indeed, when researchers have surveyed juvenile bipolar patients, they have found that the overwhelming majority had been treated with a stimulant or an antidepressant prior to their being diagnosed with bipolar disorder. In other words, the CNN story should perhaps have been titled: “Creating the Bipolar Child: The Risks of Prescribing Antidepressants to Youth.” In the New York Times article, Weill Cornell Medical College psychiatrist Richard Friedman tells of how illicit drugs like cocaine and methamphetamine activate the brain’s reward system by releasing dopamine. However, he notes, the brain then tries to compensate for the drug’s presence, and it does by becoming less sensitive to dopamine release. The brain may end up with a “less responsive reward circuit,” which never fully repairs itself even after the drug use stops, he writes. The result is that the person may then be condemned to “endure a dulled life.” All of that may be true. But here is what is missing from this article. Ritalin and the other stimulants used to treat ADHD in children also activate the “dopamine system.” Ritalin, in fact, does it in much the same manner that cocaine does, and with equal potency. The difference is that Ritalin is not cleared from the body as quickly as cocaine, and thus a dose of Ritalin has longer-acting effects than cocaine. In response, the stimulant-using brain undergoes changes that make it less sensitive to dopamine release—it is trying to compensate for the drug’s presence. And so now the obvious question. If this process, in those who use cocaine or other illicit drugs, may lead to a “less responsive reward circuit,” which never fully repairs itself even after the drug use stops, isn’t there a similar risk with putting children on Ritalin or other stimulants? Is this treatment that may then lead children to “endure a dulled life” as adults? It seems like a question that psychiatry—based on this article by Richard Friedman in the New York Times—should ask.

The STAR*D Scandal: A New Paper Sums It All Up

Sat, 28 Aug 2010 16:41:58 -0400

The story of how the STAR*D results were misreported has been coming together for some time now, step by step, and a paper recently published in Psychotherapy and Psychosomatics, along with a review of that paper published by Medscape Medical News on August 24, leads to an inescapable conclusion: This is a story of a scientific scandal, one that the public needs to know about. The STAR*D trial, which was funded by the NIMH at a cost of $35 million and took six years to conduct, was touted as as the "largest antidepressant effectiveness trial ever conducted." As it was designed to study treatment strategies for helping people recover and then stay well, with a one-year followup, it would produce results, the investigators announced at the start of the trial, that would have "substantial public health and scientific significance." As the public well knows now, pharmaceutical funding of antidepressant trials produced scientific literature that was biased and profoundly misleading, a tale of persistent scientific misconduct that has now been reviewed by many authors. But STAR*D was a publicly-funded trial, and of course we would hope and expect that the results would be honestly reported. So, with the new paper authored by Edmund Pigott, Allan Leventhal, Gregory Alter, and John Boren as a guide, let's go through the scientific sins. The results consisted primarily of two data sets, the percentage of patients whose depression remitted, and then the percentage of remitted patients who stayed well during the one-year followup, and thus we can review whether the NIMH and the STAR*D investigators accurately reported those results, and also disclosed the relevant data. A. The percentage of patients whose depression fully remitted What was reported The STAR*D trial was designed to test whether a multistep, flexible use of medications could produce remission in a high percentage of depressed outpatients. Those who didn't get better with three months of initial treatment with an SSRI (citalopram) then entered a second stage of treatment, in which they were either put on a different antidepressant or given a second drug to augment an antidepressant. Those who failed to remit in step two could go on to a step three, and so on; in total, there were four treatment steps. In a November 1, 2006 press release the NIMH announced the positive news. "Over the course of all four levels, about 70% of those who did not withdraw from the study became symptom free." In an article published at the same time in the American Journal of Psychiatry, the researchers -- in the abstract of the article -- told a similar story. "The overall cumulative remission rates was 67%," they wrote. In the text of the article, they did note that this was a "theoretical" remission rate, as "it assumes that those who exited the study would have had the same remission rates as those who stayed in the protocol." Still, the 67% figure was the bottom-line message being communicated to physicians and the public, and in a paper published in 2007, titled "The STAR*D Project Results: A Comprehensive Review of Findings," the researchers emphasized this bottom line: "With all steps included, almost 70% of participants who remained in the study experienced remission. Patients and clinicians are encouraged not to give up." The actual results Now the investigators did publish charts with data on the number of patients who stayed in the trial and actually remitted, and after I plowed through those charts, I calculated that 1854 of the 3671 patients (50.5%) who entered in the trial remitted at some point during these four steps of treatment. (I wrote about this in an earlier blog.) However, as Pigott and his collaborators make clear in their paper, even this percentage, from a scientific standpoint, is an inflated number. When the investigators designed the study, they stated that the Hamilton Rating Scale for Depression (HRSD) would be the primary tool used to measure depressive symptoms, and that all patients, in order to be eligible for analysis, would have to have an entry HRSD score ≥ 14. Yet, their reported results strayed from those study parameters in two ways, both of which inflated remission rates. First, during the trial, the researchers also used the Self-Reported Quick Inventory of Depressive Symptoms (QIDS-SR) to periodically assess depressive symptoms. Higher remission rates were found with this assessment tool than with the HRSD scale, and the researchers then highlighted this higher remission rate in their published articles. Using the more lenient QIDS-SR scale, Pigott and his collaborators found, added more than 200 patients to the remitted group. (In essence, highlighting the QIDS-SR remission rates is a form of post-trial cherry-picking of data.) Second, the investigators enrolled 607 patients into the study who had a baseline HRSD score ≤14 (and thus were only mildly depressed), and, in several published reports, they included these patients when announcing a "67% cumulative remission rate," even though -- based on study criteria -- they were "ineligible" to be included in the analysis. Naturally, these mildly depressed patients were more likely to remit than those with higher baseline HRSD scores, and so including them in the published studies inflated the remission numbers. In their paper, Pigott and his collaborators determined that there were 3,110 patients who began the study with an HRSD score of ≥ 14, and found that 1,192 of this group remitted during the study, based on a HRSD score of ≤ 7. Thus, if the study protocol had been followed and the results honestly reported, the researchers would have announced that 38% of the patients remitted during the four steps of treatment, and that the remaining 62% either dropped out or failed to remit.  b) The percentage of remitted patients who stayed well throughout a year of "continuing care." What was reported When the STAR*D investigators designed the study, they sought to maximize the stay-well rate during a one-year period of "continuing care." During this stage of the study, physicians could change the patients' medications, alter dosages, and add new medications. Patients were paid $25 each time they had their symptoms assessed, as it was thought this would help keep patients in the study. In their reports, the STAR*D investigators announced that 33.5% to 50% of the remitted patients relapsed during this period of continuing care, with the lower percentage for those who remitted in stage one of treatment and the higher percentage for those who remitted in stage four of treatment. Thus, it seemed that a majority of the remitted patients had stayed well, which was fairly encouraging. And if you did a rough back-of-the envelope calculation -- multiplying the percentage of patients who remitted times the percentage stay-well rates during the followup -- it appeared that the 12-month stay-well rate for all of the patients who had entered the trial was around 40%. The actual results When I was researching and writing Anatomy of an Epidemic, I did my best to figure out the precise number of patients who remitted and stayed well throughout the trial. In particular, I puzzled over "figure 3" on page 1913 of a 2006 article on long-term outcomes, as it appeared the numbers might be there, but the data was presented in such a confusing manner I gave up. Ultimately, all I could determine was that of the 3,671 patients in the trial (including the 607 who had baseline HRSD score ≤ 14,) 737 had remitted and then reported, at some point during the 12-month followup, they were still well. The remaining 80% of the patients had either never remitted, relapsed during the followup, or dropped out at some point. This was not such an encouraging number, but, it turned out, my calculations were once again too kind. In a 2009 paper, Allan Leventhal and David Antonuccio were able to make sense of that mysterious graphic on page 1319, and they reported that only 108 patients -- out of the initial cohort of 3,671 -- had a "sustained remission." In other words, only 3% of the patients who entered the trial remitted, and then stayed well and in the trial during the year-long followup. But, as Pigott and his collaborators explain, even this number may be a bit high. They noted that many of the 108 stay-well patients may have come from the group of 607 patients who had a baseline HRSD score ≤14, and shouldn't have been included in the analysis in the first place. Moreover, since relapse was defined as a HRSD score ≥ 14, it was possible that some of the 108 patients actually had a higher HRSD score during the followup period (say a score of 13) than they did at baseline (say a score of 12), and yet would still have been reported as having remitted and stayed well throughout the 12-month period. Why This Is A Scandal This is my fourth post on the STAR*D results, and thus it may seem I am a bit obsessed about the study. And in a sense, I am. This was a publicly funded study, and the bottom-line message conveyed to the doctors and to the public was that it had shown that antidepressants enabled 67% of depressed outpatients to recover. That's what The New Yorker reported in an article published on March 1 of this year, adding that this "effectiveness rate" was "far better than the rate achieved by a placebo." Now let's sum up the scientific sins used to create that false impression: • The STAR*D investigators reported a "cumulative" remission rate of 67% in the abstract of an article, when in fact this was simply a "theoretical" rate.  • They reported remission rates based on the QIDS-SR scale, even though the pre-specified primary outcome scale was the HRSD, and this switch inflated the remission numbers.  • They included remission numbers for patients who weren't depressed enough at baseline to meet study criteria, and thus weren't eligible for analysis.  • They reported that 33.3% to 50% of remitted patients relapsed during the 12-year followup, which suggested -- when combined with the inflated 67% remitted rate -- that perhaps 40% of all patients who entered the trial had recovered and stayed well, when in fact only 3% of the entering patients had a "sustained remission" (and stayed in the trial.) As Medscape Medical News noted, the real results "point to a lack of long-term efficacy for antidepressants." But the fake results pointed to medications that were "far more effective" than placebo.  A STAR*D Investigator Responds In her article, Medscape Medical News writer Deborah Brauser asked STAR*D investigator Maurizio Fava, who is a prominent psychiatrist from Massachusets General Hospital, whether the published analysis by Pigott and his collaborators was correct. "I think their analysis is reasonable and not incompatible with what we had reported," he said. His answer is revealing for two reasons. First, he is acknowledging that the low remission and stay-well rates reported by the Pigott group are accurate. Those are indeed the real results. Second, he is acknowledging that the STAR*D investigators knew this all along, and that, in fact, this information was in their published reports. And in a sense, that is true. If you dug through all of the published articles, and spent weeks and months reading the text carefully and intently studying all the data charts, then maybe, at long last, you could -- like Pigott's group -- ferret out the real results. But that is not the way that honest science is supposed to work.

Charlie Rose and the “Mentally Ill Brain”

Fri, 13 Aug 2010 13:50:50 -0400

On a recent PBS television show hosted by Charlie Rose on the "mentally ill brain," Columbia University's Jeffrey Lieberman presented a series of brain scans of a person with schizophrenia, which showed enlarged ventricles and thus, as Lieberman told the audience, "loss of brain gray matter. (See minute 29:30 of video.) The idea being presented by Lieberman was that schizophrenia is a neurodegenerative disease, characterized by brain tissue loss. In the discussion, Lieberman also implied that antipsychotic medications, in some way, protect against this neurodegenerative process. The drugs "stabilize the illness," he said. But when people "stop taking the medicines, they get sick again, and when this happens, they have repeated insults to the brain . . . and this leads to a progression, and the progression, like somebody who has multiple little strokes, can lead to some decline in which people are not able to recover to the same level. And if you actually take brain scans over time, you can see the subtle, perceptible loss of brain grey matter." To the public, this is a new paradigm for understanding why antipsychotics are an essential treatment for schizophrenia. Schizophrenia is a neurodegenerative illness, characterized by brain tissue loss, and antipsychotics are "neuroprotective" agents that thwart that pathological process in some way. Given that this idea is taking hold, it seems worthwhile to check the literature to see if it is well grounded in science.  MRI Scans Making sense of MRI studies of schizophrenia patients can be a difficult task, partly because the results can be so inconsistent, and partly because the results are confounded by exposure to antipsychotics. However, earlier this year, Joanna Moncrieff and Jonathan Leo brought new clarity to this topic by analyzing the studies based on the patients' exposure to antipsychotics. Here is a summary of their findings, which they published in Psychological Medicine. Studies of chronic patients never exposed to antipsychotics  They identified three studies of schizophrenia patients who were ill for extended periods of time and were never exposed to antipsychotic medications. In comparison to the "controls" in the studies, these never-exposed patients showed "no major differences in global cerebral, grey-matter, ventricular, or CSF (cerebrospinal fluid) volumes."   Studies of first-episode patients with limited exposure to antipsychotics A number of studies have found brain abnormalities in first-episode schizophrenia patients, and these findings have been seen as proof that the abnormalities must be due to the disease and not the treatment. But as Moncrieff and Leo noted in their paper, many of the patients in the first-episode studies had been on antipsychotics for months, and there is evidence that antipsychotics may induce changes in brain structures in a short period of time. As such, the results from first-admission studies -- as a group -- are confounded by drug exposure. To counter this problem, Moncrieff and Leo analyzed the results from studies of schizophrenia patients who were either drug naïve or had limited exposure to antipsychotics (on average less than four weeks.) They found 18 such studies (in addition to the three studies discussed above.) In 13 of them, researchers did not find any differences between the patients and controls in whole-brain volumes, total grey matter, and CSF volumes. Of the five studies that did show differences in brain volumes, one included a subset of patients that had taken antipsychotics for up to 24 weeks, which could have confounded the results. A second study reported differences in an initial sample of 18 patients, but then, in a larger sample of 51 patients, no global differences were found. The remaining three studies found a difference in the size of the "third ventricle only;" a "trend level reduction in whole-brain volume;" and "smaller cerebellar volumes."  Longitudinal studies of patients treated with antipsychotics In 14 of 26 MRI studies of schizophrenia patients treated with antipsychotics for periods ranging from eight months to 10 years, the patients "showed a greater reduction in whole-brain, cortical or grey-matter volumes, or a greater increase in CSF or ventricular volumes, compared with controls." Several of the 14 studies quantified the brain-volume loss. In adult patients, "grey matter, whole-brain or cerebral volume showed a decline of 1.2% to 2.9% per year."  Summing Up The MRI Studies With the MRI literature parsed in this way, it's easy to see that the studies do not provide convincing evidence that schizophrenia patients, if they were not treated with antipsychotics, would regularly suffer "a loss of brain gray matter." A reduction in whole brain volumes is not regularly seen in first-episode patients with limited exposure to neuroleptics, and it was not seen in the three longitudinal studies of never-exposed patients. The fact that it shows up in the majority of studies of drug-treated patients simply leads to this possibility: It could be due to a disease process, or it could be due to the medication, or it could be due to a combination of the two. The Effect of Antipsychotics on Brain Volumes To best assess the long-term effects of antipsychotics on brain volumes and to distinguish drug effects from disease processes, you would need to run a long-term study that compared brain volumes in four groups: healthy people on the medications, healthy people off the drugs, schizophrenia patients on the drugs, and schizophrenia patients off the drugs. But you can't put healthy people on antipsychotics and it is considered unethical to withhold antipsychotics from schizophrenia patients for long periods, and so you can't run studies of that type. However, animal research and MRI studies of medicated schizophrenia patients do provide evidence that antipsychotics may cause "brain gray matter loss." In animal studies, typical antipsychotics have been found to cause neuronal loss and gliosis in the striatum, hypothalamus, brain stem, limbic system and cortex. In a study of non-human primates (macaque monkeys), a daily dose of haloperidol or olanzapine for 18 months led to an 8% to 11% reduction "in mean fresh brain weight compared to controls." Next, as Moncrieff and Leo reported, a majority of studies of schizophrenia patients on the drugs for longer periods found that they had reduced brain volumes, while in the three longer studies of never-exposed patients, there was no such finding. Furthermore, researchers have found that gray matter loss varies according to whether a typical or atypical antipsychotic is prescribed, and if the drugs did not affect brain volumes, there shouldn't be this variability. Lieberman and others recently conducted a study of this type, mapping the cortical changes seen in 36 first-episode schizophrenia patients treated with either haloperidol or olanzapine for one year. Here are their results, which they published in 2009: • In the haloperidol patients, "a dynamically spreading wave of significant gray matter loss was detected . . . progressive gray matter reduction began in lateral parietal-temporal cortices by three months, spreading into the dorsolateral, medial frontal and prefrontal cortices by six months, and involving most of the frontal cortex by one year after the first psychotic episode." The "total loss is severe by 12 months." • In the olanzapine patients, "regions of significant progressive gray matter loss were found at all time points, but these were less intense and widespread. These changes also evolved in a distinct antatomical trajectory" compared to the haloperidol-treated patients.   So how should these results be interpreted? Given the effects of haloperidol and olanzapine in macaque monkeys, you might conclude that both drugs cause brain gray matter loss in schizophrenia patients, with olanzapine perhaps less toxic than haloperidol. However, since there was no control group in this study and thus no mapping of gray matter loss in unmedicated schizophrenia patients, the researchers concluded that it was also possible that olanzapine was "neuroprotective," i.e. that it slowed down the loss seen in the haloperidol patients (which presumably was due mostly to the disease.) But, they wrote, without a control group "it is difficult to be sure that the effect is either due to toxic effects of one drug versus protective effects of another (among other interpretations), and it cannot be determined what the normal trajectory of such change is in schizophrenia."  The Bottom Line While the public may be hearing that schizophrenia is a neurodegenerative disease characterized by a loss of brain gray matter, with atypical antipsychotics neuroprotective against that process, even a quick review of the scientific literature reveals that it is unclear whether the gray matter loss is due to the disease, or to the drug, or to a combination of both.  Here's what Moncrieff and Leo wrote in their conclusion : "Overall, there seems to be enough evidence to suggest that antipsychotic drug treatment may play a role in reducing brain volume and increasing CSF or ventricular spaces . . . although it remains possible that the underlying disease process also causes brain volume changes, we suggest that antipsychotic drug treatment may be responsible for some of the changes that are usually attributed to schizophrenia."

Psychotropic Drugs and Children

Thu, 8 Jul 2010 14:24:20 -0400

I recently was asked to give a talk to a group called “Science for the Public” on psychotropic drugs and children. A video of that talk was posted on WGBH’s website. http://forum-network.org/lecture/psychotropic-drugs-and-children