10/17/17

Tell It Like It Is

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Recently I saw one of the ubiquitous “ask your doctor if … is right for you” commercials for Rexulti. The slick 90-second ad tells you that when Rexulti is added to your antidepressant, it has been shown to reduce symptoms of depression. The smiley faces used by the actors illustrate how: “Even when you’re taking an antidepressant, you may still be struggling with depression.” You learn that 2 out of 3 people taking an antidepressant may experience unresolved symptoms of depression; and that antidepressants can cause unusual changes in behavior, worsening depression and thought of suicide, especially in those 24 and younger. But you never learn that Rexulti is not an antidepressant.

The commercial never claims Rexulti is an antidepressant, but it clearly leads its viewers in that direction. Counter intuitively, in order to make the case for using Rexulti, it not-so-subtly tells you that antidepressants alone aren’t always effective, since 67% of people taking them have “unresolved symptoms” of depression. But then you learn Rexulti has been shown to reduce symptoms of depression when it is added to an antidepressant. The message is that Rexulti is effective relieving symptoms of depression. But let’s deconstruct what the commercial is telling you even further.

In the mix of the marketing rhetoric, you hear a litany of possible adverse medication side effects. The initial side effects are found with antidepressants: there could be unusual changes in behavior, worsening depression, even thoughts of suicide. “Antidepressants can increase these in those 24 and younger.” This information is legitimately about the side effects from antidepressant medications. See “Antidepressant Misuse Disorder” and “Antidepressants: Their Ineffectiveness and Risks” on this website.

Actually, Rexulti is an atypical antipsychotic or neuroleptic; in the same drug class as Abilify, Zyprexa, Seroquel and Risperdal. The other described side effects and warnings in the commercial are commonly found with atypical antipsychotics. See “Adverse Effects of Antipsychotic Medications” by Muench and Hamer for further information.

Looking further, the commercial said: “Elderly dementia patients taking Rexulti have an increased risk of death or stroke.” Antipsychotics were being used to control behavior problems in elderly patients with dementia. Then research demonstrated there was an increased risk of death in the elderly patients given antipsychotics. So the FDA issued a black box warning to that effect. There was also evidence that antidepressants increased the risk of stroke with elderly patients, thus the Rexulti warning. See “Seniors and Antipsychotics” and “Stroke Risk in Elderly Treated with Antipsychotics” for more information on this.

“Uncontrollable muscle movements” in the commercial is likely referring to tardive dyskinesia, a serious and potentially permanent neurological side effect from antipsychotics. The risks for developing metabolic syndrome (high blood pressure, high blood sugar, excess body fat at the waist, and abnormal cholesterol levels) are mentioned as well. Tardive dyskinesia and metabolic syndrome are widely acknowledged as potential adverse effects from antipsychotics, but not antidepressants. Try “Blind Spots with Antipsychotics,” Part 1 and Part 2 for a discussion on metabolic syndrome and other side effects from antipsychotics. Stiff muscles, confusion, and high fever are symptoms of “a possible life threatening condition” known as Neuroleptic Malignant Syndrome (See “Neuroleptic Malignant Syndrome”).

So you wouldn’t know Rexulti was an atypical antipsychotic or neuroleptic drug from listening to the commercial unless you knew the above were typical side effects with that class of drug. And you may not even discover this from reading the required Medication Guide, unless you knew what to look for. The FDA’s highlights of prescribing information for Rexulti, all 38 pages worth, does have a more complete discussion of the warnings and precautions as well as the adverse reactions. And Rexulti is referred to there as an atypical antipsychotic. However, in the shorter, two page medication guide, that is made available to individuals filling a prescription for Rexulti, there is no explicit reference to it being an atypical antipsychotic or neuroleptic.

The Rexulti Medication Guide does describe tardive dyskinesia, “problems with your metabolism” and Neuroleptic Malignant Syndrome as possible side effects, which are all potential side effects from antipsychotic or neuroleptic medications. But the only place in the medication guide that the word “antipsychotics” is used is in the section “What should I tell my healthcare provider before taking Rexulti?” There, the medication guide advised that if you become pregnant while taking Rexulti, you should “talk to your healthcare provider” about registering with the National Pregnancy Registry for Atypical Antipsychotics. The only place in the Rexulti medication guide the word “neuroleptic” in mentioned is when it notes how Neuroleptic Malignant Syndrome is a possible side effect.

This rhetorical sleight-of-hand is also present in the medication guides for three other antipsychotics approved by the FDA as adjunct medications for depression. Aripiprazole (Abilify), Olanzapine (Zyprexa) and Quetispine (Seroquel) all use the same descriptive technique of avoiding reference to the drugs as antipsychotics or neuroleptics in their medication guides. And several have an extended discussion of information on antidepressants. Again, someone not familiar with the medications might think they are taking an antidepressant rather than an antipsychotic medication.

The rational for this would appear to be because the initial market for antipsychotics, treating schizophrenia, is limited. Atypical antipsychotics are now the largest-selling class of drugs in the U.S. with more than $14.6 billion in annual sales for 2014. They also are the class of psychiatric drugs with the most side effects. See “Wolves in Sheep’s Clothing” and “Abilify in Denial” for more on these observations.

Another piece of information about Rexulti in contrast to the other antipsychotics approved as adjunct medications for depression is that it is the only one still on patent. Rexulti patents don’t expire until February of 2027 Abilify, Zyprexa, and Seroquel have all been approved as generics.  So Otsuka Pharmaceutical Company Ltd. has the potential for much greater profits from Resulti over the next ten years than the generic pharmaceutical companies have for the off-patent atypical antipsychotics.

There seems to be a general trend when discussing psychiatric medications to avoid any reference to them as atypical antipsychotics or neuroleptics. You can even see this in the FDA press release for the approval of Rexulti in July of 2015. This means a consumer looking for information on the potential adverse effects from an atypical antipsychotic may have some difficulty finding and then understanding what the risk is for them to take the drug.

For clarity’s sake, I think the FDA should require all consumer medication guides to clearly identify the drug class for approved psychiatric medications. They should also direct a patient to where they can find a more complete discussion of the potential adverse effects of the medication than what is contained within the brief summary of the medication guide. Confusing discussions of depression, its symptoms and the side effects from antidepressants included in antipsychotic medication guides should be clarified or removed entirely by the FDA. Additionally, there should be a truth in advertising requirement that tells it like it is for all psychiatric drug advertisements. An antipsychotic by any other name is still an antipsychotic and the commercials should say so.

10/6/17

Is Ketamine Really Safe & Non-Toxic?

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An article in The Morning Call, a newspaper for Allentown and the Lehigh Valley area of Pennsylvania, announced that a local company, the Lehigh Center for Clinical Research, would be conducting clinical trials for two pharmaceutical companies to gain FDA approval for modified versions of ketamine as a treatment for depression. The psychiatrist running the trials said the drugs could hit the market in the next few years. He said: “It’s exciting and promising but I think we have to wait to see it used in the widespread population to know whether it’ll be safe and non-toxic.” I thought the safety and toxicity of a new drug was supposed to be assessed BEFORE the FDA approved its release into the wider population.

There have been waves of excitement and concern over the past few years about the development and use of ketamine and ketamine-like drugs to treat depression. Ketamine has been an FDA approved medication since 1970, where it was used as an anesthetic in the Vietnam War. It is classified as a Schedule III Controlled Substance by the DEA, meaning it has a potential for moderate to low dependence or high psychological dependence. Ketamine is also a recreational drug known as Special K because of its dissociative properties. “Due to the detached, dreamlike state it creates, where the user finds it difficult to move, ketamine has been used as a ‘date-rape’ drug.” See: “Falling Down the K-Hole” and “Family Likeness in Depression Drugs?”

The excitement over ketamine, as a treatment for depression, centers on its rapid relief of depressive symptoms; sometimes within hours of it being administered. But the effects fade rapidly and require frequent, repeated treatments. Currently ketamine is administered intravenously, similar to its use as an anesthetic. There is an intranasal spray version (Esketamine) in the works. See: “Psychedelic Depression,” Ketamine to the Rescue?,” and Ketamine Desperation.”

The clinical trails being done by the Lehigh Center for Clinical Research would appear to be for Esketamine, by Janssen Research and Development, and Rapastinel, by Allergan. While Esketamine is a nasal spray, Rapastinel is administered by weekly IV injections. Both are currently in Phase 3 clinical trials. This involves randomized, double blind testing in several hundred to several thousand patients. Upon successful completion of their Phase 3 trials, a pharmaceutical company can request FDA approval for marketing their drug. Somewhere around 70 to 80 percent of drugs that make it to Phase 3 are eventually approved.

Although Esketamine and Rapastinel are similar to ketamine in several ways, they are still distinct NMEs (new molecular entities), patented by their respective pharmaceutical companies. Ketamine was first developed in the 1960s and has been off patent for decades, meaning there is no profit in Pharma companies pursuing ketamine-based treatment for depression. But since ketamine is an FDA approved drug, it can be used off label to treat depression. And there are a growing number of ketamine treatment facilities around the U.S. and Canada that do just that.

Earlier in 2017 All Things Considered on NPR featured a story on the off-label use of ketamine to treat depression, “Ketamine for Severe Depression.” Psychiatrist Gerard Sanacora said over 3,000 patients have treated at dozens of clinics with ketamine for depression. He has personally treated hundreds of people with low dose ketamine. Sanacora said when he is asked how he can offer it to people on the limited amount of available information and without knowing the potential long-term risk, he responds “How do you not offer this treatment” to individuals likely to injure or kill themselves, who have unsuccessfully tried the standard treatments?

Sanacora and others authored “A Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders” that was published in JAMA Psychiatry in April of 2017. They noted how several smaller studies have demonstrated the ability for ketamine “to produce rapid and robust antidepressants effects in patients with mood and anxiety disorders that were previously resistant to treatment.” It also cautioned that while ketamine may be beneficial to some patients, “it is important to consider the limitations of the available data and the potential risk associated with the drug when considering the treatment option.”

Zorumski and Conway published “Use of Ketamine in Clinical Practice” in the May 2017 issue of JAMA Psychiatry. They also noted the increasing evidence from small studies that ketamine has rapid antidepressant effects in patients with treatment-resistant depression. They commented how ketamine is having a major effect on psychiatry. “If clinical studies continue to support the antidepressant efficacy of ketamine, psychiatry could enter an era in which drug infusions and deliveries with more rapid responses become common.” They indicated the cautions of Sanacora et al. were noteworthy and should be emphasized.

Because of the limited data to guide clinical practice, these limitations extend to almost every recommendation in the consensus statement, including, perhaps most importantly, patient selection. The bulk of the literature describes the effects of ketamine in patients with treatment-refractory major depression. The definition of treatment-refractory major depression and where treatments such as ketamine fall in the algorithm for managing treatment-refractory depression remain poorly understood. . . . It is unclear whether patients with depression that is not treatment-refractory or patients with other psychiatric illnesses are appropriate candidates for ketamine treatment, and extreme caution must be exercised in patients with psychotic or substance use disorders.

So then comes the Short et al. study in the journal Lancet Psychiatry in July 2017, “Side Effects Associated with Ketamine Use in Depression.” It was the first systematic review of the safety of ketamine in the treatment of depression. After searching MEDLINE, PubMed, PsycINFO, and Cochrane Databases, they identified 60 out of 288 articles that met their inclusion criteria. “Our findings suggest a selective reporting bias with limited assessment of long-term use and safety and after repeated dosing, despite these being reported in other patient groups exposed to ketamine (eg, those with chronic pain) and in recreational users.”

Science Daily reported that the lead author for the study said there were major gaps in the research literature that should be addressed before ketamine was widely used as a clinical treatment for depression. “Despite growing interest in ketamine as an antidepressant, and some preliminary findings suggesting its rapid-acting efficacy, to date this has not been effectively explored over the long term and after repeated dosing.” Given that ketamine will likely involve multiple, repeated doses over an extended time period, “it is crucial to determine whether the potential side effects outweigh the benefits to ensure it is safe for this purpose.”

Commenting on the Short et el. Study for Mad in America, Peter Simons also noted the expressed concern with the selective reporting bias and a limited assessment of long-tem use and safety after repeated dosing. Researchers are generally careful to report safety and side effect data on studies of ketamine used recreationally or for chronic pain. However, depression research tended to ignore the safety and side effect concerns with ketamine, often not reporting such issues at all.  “Most people receiving ketamine had acute side effects.” Studies that did report adverse events said that after acute dosing, patients in ketamine treatment reported more frequent side effects.

Common side effects led a number of patients to withdraw from the study. Suicidal thoughts were common and there was one suicide attempt reported. Previously reported potential long-term adverse effects from ketamine include: urinary tract problems, liver toxicity, ulcerative cystitis, neurocognitive deficits and memory problems, and dependence or addiction. Some of the many additional side effects that were reported included:

 

  • Worsening mood
  • Anxiety
  • Emotional blunting
  • Psychosis
  • Thought disorders
  • Dissociation
  • Depersonalization
  • Hallucinations
  • Increased blood pressure
  • Increased heart rate
  • Decreased blood pressure
  • Decreased heart rate
  • Heart palpitations/arrhythmia
  • Chest pain
  • Headaches
  • Dizziness
  • Unsteadiness
  • Confusion
  • Memory loss
  • Cognitive impairment
  • Blurred vision
  • Insomnia
  • Nausea
  • Fatigue
  • Crying/tearfulness

Because of the extensive list of potential adverse effects, as well as the unknown possibility for harm from long-term use, the authors of Short et al. recommended large-scale clinical trials with multiple doses of ketamine. Long-term follow up to assess the safety of long-term regular use was also recommended. “As it stands, the safety of ketamine treatment for depression is unknown—and that is largely due to inadequate and biased reporting of safety issues.”

I hope that these concerns are seriously considered and factored into the FDA’s assessment process for approving Esketamine and Rapastinel. Otherwise, the real safety and toxicity assessment of these drugs will be done on the first wave of depression sufferers prescribed the new drugs for treatment-resistant depression. Given the short length of clinical trials, the long-term effectiveness and impact on a patient’s quality of life, including potential misuse of the drugs, will not be clear  for either Esketamine or Repastinel until Phase 4 Post Marketing Surveillance Trials are completed … after the drugs are on the market. Will they live up to their therapeutic promise or become another example of the Pharma patent medicine show?

09/26/17

Demolishing ADHD Diagnosis

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The Harvard psychologist, Jerome Kagan, sees ADHD as more of an invented condition than a serious illness. Further, he thinks it was invented for “money-making reasons” by the pharmaceutical industry and pro-ADHD researchers. He believes the drastic increase in the number of children diagnosed with ADHD has more to do with “fuzzy diagnostic practices” and relabeling. Fifty years ago, a 7-year-old child who was bored and disruptive in class was seen as “lazy.” Today he is seen as suffering from ADHD.

Every child who’s not doing well in school is sent to see a pediatrician, and the pediatrician says: “It’s ADHD; here’s Ritalin.” In fact, 90 percent of these 5.4 million kids don’t have an abnormal dopamine metabolism. The problem is, if a drug is available to doctors, they’ll make the corresponding diagnosis.

In his interview with Spiegel Online, Kagan went on to say that the inflated diagnosis of ADHD and other so-called childhood mental health disorders means more money for the pharmaceutical industry, psychiatrists and the people doing research. “We’re up against an enormously powerful alliance: pharmaceutical companies that are making billions, and a profession that is self-interested.” As he said, he’s not the only psychologist who is saying this.

Parenting expert and family psychologist, John Rosemond, agrees with Kagan. In 2009 he co-authored The Diseasing of American’s Children where they argued that ADHD and other childhood behavior disorders “were inventions of the psychological-psychiatric-pharmaceutical industry.” They went further than Kagan in saying that ADHD does not exist; that it is a fiction. In his April 9, 2017 article, “ADHD Simply Does Not Exist,” Rosemond referred to Kagan’s declaration on ADHD, noting that he and other psychologists studied Kagan’s books and research papers on children and child development when they were in graduate school. In The Diseasing America’s Children, Rosemond said:

Science depends on verifiable, objective evidence and experimental results that can be replicated by other scientists. Where ADHD is concerned, neither verifiable, objective evidence nor replicable experimental results exist to support the claims of the ADHD establishment.”

Rosemond and his co-author, Bose Ravenel, believe that childhood behavior disorders like ADHD are manifestations of “dysfunctions of discipline and lifestyle” endemic to modern family culture. Once these problems are identified, they can be easily corrected. And once corrected, the errant behavior “usually recovers to a state of normalcy within a relatively short period of time.” They believe children do not need a psychologist when they misbehave, they need discipline—“firm, calm and loving discipline.”

In Debunking ADHD, educational psychologist Michael Corrigan said ADHD is a negative label that does not exist. “Not unlike the many wonderful stories about unicorns, fairies, and leprechauns, the diagnosis of ADHD is a brilliant work of fiction.” He noted that many of the common childhood behaviors (or supposed symptoms) associated with ADHD are also used to identify giftedness in children. When these behaviors are harnessed and focused, they can help children become “incredibly creative, insightful, and successful individuals in adulthood.” If children don’t learn to harness the power of the behaviors ADHD and giftedness have in common, “such behaviors when displayed might seem annoying and immature.” He said:

My biggest reason for writing this book is my desire to show you that the practice of medicating children for acting like children in the name of ADHD is, in two words, wrong and dangerous. Despite the grandiose claims of the mega-pharmaceutical companies selling ADHD drugs to concerned parents, prescribing pills to young children trying to learn how to become young adults is just a quick fix void of any long-term benefits.

Corrigan described eating lunch with a group of children who had just taken their ADHD medication at school. They were now supposedly “good to go” (sufficiently medicated) for an afternoon of learning. It was the longest lunch period he had ever experienced. “Comparing the kids at my table to others in the cafeteria, and slowly watching these playful, creative, energetic, and funny children go from kids being kids to near expressionless robot-like entities, made me sick to my stomach.”

The total number of children on ADHD medication “skyrocketed” from 1.5 million in 1995 to 3.5 million in 2011. “Sales of prescription stimulants quintupled from 2005 to 2015.” The rising rate of ADHD diagnosis has been described as “an unreal epidemic” and a “national disaster of dangerous proportions” by well-known professionals like Allen Frances and Keith Conners. Frances was the chair of the DSM-IV. Conners, now an emeritus professor of medical psychology at Duke University, “spent much of his career in legitimizing the diagnosis of ADHD.”

Allen Frances was one of four authors of an article in the International Journal of Qualitative Studies on Health and Well-Being, “ADHD: A Critical Update for Educational Professionals.” When the DSM-IV was published in 1994, the prevalence of ADHD was estimated to be 3%. Since then, parent-reported ADHD diagnosis increased to 7.8% in 2003; 9.5% in 2007; and to 11% in 2011. Nearly one in five high school boys had been diagnosed with ADHD and around 13.3% of 11-year-old boys were medicated for ADHD.

Teachers and other school personnel are often the first to suggest a child might be “ADHD.” Research suggested teachers felt insecure about dealing with behavioral problems and hesitated to accept responsibility for students with special needs. Frances and his coauthors described six scientifically grounded issues that educational professionals should be aware of when they are confronted with inattention and hyperactivity in the classroom.

First: birth order matters. Several studies have shown “That relative age is a significant determinant of ADHD diagnosis and treatment.” The youngest children in the classroom are twice as likely to be diagnosed with ADHD and receive medication. They suggest teachers take the child’s relative age into account when judging the child’s behavior. “Seeing ADHD as the cause of inattention and hyperactivity is in fact a logical fallacy as it is circular.”

Second, there is no single cause of ADHD. “There are no measurable biological markers or objective tests to establish the presence or absence of ADHD (or any other given DSM syndrome).” ADHD is a description of behavior and is based on “criteria that are sensitive to subjectivity and cognitive biases.” Multiple factors have been associated with ADHD, without necessarily implying causality. Those factors include: divorce, poverty, parenting styles, lone parenthood, sexual abuse, lack of sleep, artificial food additives, mobile phone use and growing up in areas with low solar intensity. “All these factors and more may play a role when a particular child exhibits impairing hyperactive and inattentive behaviours, and there is no conclusive cause of ADHD.”

Third, most children exhibiting “ADHD behavior” have normal-looking brains. Studies that do show small differences in terms of brain anatomy do not apply to all children diagnosed with ADHD. Individual differences refer to slower anatomical development. “They do not reveal any innate defect as is illustrated by the fact that many people with an unusual anatomy or physiology do not experience ADHD related problems.” Also, the test subjects in many brain-related studies are rigorously screened and don’t represent all individuals diagnosed with ADHD.

The samples do not comprise an accurate representation of their respective populations, meaning an average child with a diagnosis of ADHD and an average “normal” child. This problem is particularly urgent since the DSM 5 has lowered the age of onset criterion, as well as the impairment criterion compared to the previous version, the DSM-IV. Alongside the lowered threshold, the potential to generalize earlier research findings has lowered as well.

Fourth, the claims of ADHD being inherited may be overestimated.  The claims vary widely and are subject to debate because of methodological issues used in calculating the heritability coefficient in twin, familial and adoption studies. There is significant difficulty separating genetic influences from environmental ones, such as poverty, parenting styles and divorce, in these studies. “In genetic association studies that really analyse genetic material and that are more powerful when separating the influence of genetics from other etiologic sources, associated genes show only very small effects.” When combined, they explain less than 10% of variance.

This means they occur only slightly more often in diagnosed individuals than in controls, and they do not explain nor predict ADHD behaviours. For educational professionals, this is important to consider as an ADHD label might give a false sense of security with regard to the alleged (genetic) cause of a child’s behaviour and the preferred cure (medication).

Fifth, medication does not benefit most children in the long run. Follow up studies of the long-term effects of the MTA (Multimodal Treatment of Attention Deficit Hyperactivity Disorder) study showed a convergence of outcomes over time between medicated and non-medicated children. Other studies also report either no long-term benefits, or even worse benefits. “While medication may help a small group of children in the long run, most will not benefit from long-term pharmaceutical treatment.”

The sixth and final issue that educational professionals should be aware of when confronted with inattention and hyperactivity in the classroom is the reality that a diagnosis can be harmful to children. A CDC MMWR Report indicated only 13.8% had severe ADHD, with 86.2% having mild (46.7% or moderate (39.5%) ADHD. The authors pointed out a DSM diagnosis opened the door for additional reimbursement to the school for treatment and school services, perhaps promoting a search for pathology in relatively mild cases. “The question is whether in these mild cases the merits of a confirmed diagnosis—such as acknowledgement of problems and access to help—outweigh possible demerits.” Some known disadvantages of a diagnosis are: lower teacher and parent expectations that turn into self-fulfilling prophecies, prejudice and stigmatization of diagnosed children, a more passive role towards problems, difficulties getting life and disability insurances later on in life, and others.

The Allen Frances article linked above was the most accepting of ADHD as a legitimate “neuro-developmental disorder.” Yet it cautioned there was no single cause for ADHD, medications to “treat” ADHD did not have long-term benefits, and there was a problem with its over diagnosis. Jerome Kagan thought 90% children were wrongly diagnosed with ADHD because of “fuzzy diagnostic practices and relabeling.” Michael Corrigan, John Rosemond and questioned the validity of ADHD as a neuro-developmental disorder. Corrigan said it pathologized normal childhood behavior; and medicating these children was wrong and evil. It’s time to demolish the ADHD treatment empire.

Additional articles on ADHD can be found on this website here: “National ADHD Epidemic,” “Misleading Info on ADHD,” “Tip of the ADHD Iceberg,” and “Is ADHD Simply a Case of the Fidgets?” You can also read a longer paper: “ADHD: An Imbalance of Fire Over Water of a Case of the Fidgets?

09/15/17

Dysfunctional fMRIs

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Neuroscientists at Dartmouth placed a subject into an fMRI machine to do an open-ended mentalizing task. The subject was shown a series of photographs depicting human social situations with a specific emotional reaction. The test subject was to determine what emotion the individual in the photo must have been experiencing. When the researchers analyzed their fMRI data, it seemed like the subject was actually thinking about the pictures. What was unusual about this particular fMRI study was that the subject was a dead Atlantic salmon.

Craig Bennett and other researchers wrote up the study to warn about the dangers of false positives in fMRI data. They wanted to call attention to the need to improve statistical methods in the field of fMRI research. But Bennett’s paper was turned down by several publications. However, a poster on their work found an appreciative audience at the Human Brain Mapping conference and neuroscience researchers began forwarding it to each other. The whimsical choice of a test subject seems to have prevented publication of the study, but it effectively illustrated and important point regarding the potential for false positives in fMRI research. The discussion section of their poster said:

Can we conclude from this data that the salmon is engaging in the perspective-taking task? Certainly not. What we can determine is that random noise in the EPI time series may yield spurious results if multiple comparisons are not controlled for. Adaptive methods for controlling the FDR and FWER are excellent options and are widely available in all major fMRI analysis packages.  We argue that relying on standard statistical thresholds (p < 0.001) and low minimum cluster sizes (k > 8) is an ineffective control for multiple comparisons. We further argue that the vast majority of fMRI studies should be utilizing multiple comparisons correction as standard practice in the computation of their statistics.

According to Alexis Madrigal of Wired, Bennett’s point was not to prove that fMRI research is worthless. Rather, researchers should use a set of statistical methods known as multiple comparisons correction “to maintain most of their statistical power while keeping the danger of false positives at bay.” Bennett likened the fMRI data problems to a kind of darts game and said: “In fMRI, you have 160,000 darts, and so just by random chance, by the noise that’s inherent in the fMRI data, you’re going to have some of those darts hit a bull’s-eye by accident.” So what, exactly, does fMRI measure and why is understanding this important?

The fundamental basis for neural communication in the brain is electricity. “At any moment, there are millions of tiny electrical impulses (action potentials) whizzing around your brain.” When most people talk about ‘brain activity,’ they are thinking about the activity maps generated by functional magnetic resonance imaging (fMRI). Mark Stokes, an associate professor in cognitive neuroscience at Oxford University said fMRI does not directly measure brain activity. Rather, fMRI measures the indirect consequences of neural activity, the haemodynamic response, which permits the rapid delivery of blood to active neuronal tissues. This indirect measurement is not necessarily a bad thing, if the two parameters (neural activity and blood flow) are tightly coupled together. The following figure from “What does fMRI Measure?” illustrates the pathway from neural activity to the fMRI.

A standard fMRI experiment generates thousands of measures in one scan (the 160,000 darts in Bennett’s analogy), leading to the possibility of false positives. This wealth of data in an fMRI dataset means that it is crucial to know how to interpret it properly. There are many ways to analyze an fMRI dataset, and the wealth of options may lead a researcher to choose one that seems will give him or her the best result.  The danger here is that then the researcher may then only see what they want to see.

Anders Ecklund, Thomas Nichols and Hans Knutson said that while fMRI was 25 years old in 2016, its most common statistical methods have not been validated using real data. They found that the most commonly used software packages for fMRI analysis (SPM, FSL, AFNI) could result in false positive rates up to 70%, where 5% was expected. The illusion of brain activity in a dead salmon discussed above was a whimsical example of a false positive with fMRI imaging.

A neuroscientist blogging under the pen name of Neuroskeptic pointed out that a root problem uncovered by Ecklund’s research is spatial autocorrelation—“the fact that the fMRI signal tends to be similar (correlated) across nearby regions.” The difficulty is well known and has software tools to deal with it, but “these fixes don’t work properly.”  The issue is the software assumes the spatial autocorrelation function has a Gaussian shape, when it fact, it has long tails, with more long-range correlations than expected. “Ultimately this leads to false positives.” See Neuroskeptic’s article for a graph illustrating this phenomena.

There is an easy fix to this problem. Ecklund and colleagues suggested using non-parametric analysis of fMRI data. “Software to implement this kind of analysis has been available for a while, but to date it has not been widely adopted.” So there is still value in doing fMRI research, but a proper analysis of the dataset is crucial if the results are to be trusted.

Neuroskeptic also discussed an analysis of 537 fMRI studies done by Sprooten et al. that compared task-related brain activation in people with a mental illness and healthy controls. The five diagnoses examined were schizophrenia, bipolar disorder, major depression, anxiety disorders and obsessive-compulsive disorder (OCD). The analysis showed very few differences between the disorders in terms of the distribution of the group differences across the regions of the brain. “In other words, there was little or no diagnostic specificity in the fMRI results. Differences between patients and controls were seen in the same brain regions, regardless of the patients’ diagnosis.”

Sprooten et al. speculated that the disorders examined in their study arose from largely overlapping neural network dysfunction. They cited another recent meat-analysis by Goodkind et al. that also found “shared neural substrates across psychopathology.” Sprooten et al. said: “Our findings suggest that the relationship between abnormalities in task-related networks to symptoms is both complex and unclear.”

Neuroskeptic didn’t think there was a need to assume this transdiagnostic trait was an underlying neurbiological cause of the various disorders. He wondered if something like anxiety or stress during the fMRI scan could have been captured by the scan.

It’s plausible that patients with mental illness would be more anxious, on average, than healthy controls, especially during an MRI scan which can be a claustrophobic, noisy and stressful experience. This anxiety could well manifest as an altered pattern of task-related brain activity, but this wouldn’t mean that anxiety or anxiety-related neural activity was the cause of any of the disorders. Even increased head movement in the patients could be driving some of these results, although I doubt it can account for all of them.

A paper in NeuroImage by Nord et al. commented how numerous researchers have proposed using fMRI biomarkers to predict therapeutic responses in psychiatric treatment. They had 29 volunteers do three tasks using pictures of emotional faces. Each volunteer did the tasks twice one day and twice about two weeks later. While the grouped activations were robust in the scanned brain areas, within-subject reliability was low. Neuroskeptic’s discussion of the study, “Unreliability of fMRI Emotional Biomarkers,” said these results could be a problem for researchers who want “to use these responses as biomarkers to help diagnose and treat disorders such as depression.”

Neuroskeptic asked one of the researchers if it was a “real” biological fact that activity in the brain areas studied actually varied within subject, or was the variability a product of the fMRI measurement? He didn’t know, but thought it wasn’t simply a measurement issue. He also thought it was perfectly possible “that the underlying neuronal responses are quite variable over time.”

Grace Jackson, a board certified psychiatrist, wrote an unpublished paper critiquing how fMRIs and other functional brain scans are being presented to the public as confirming that psychiatric disorders are real brain diseases. She pointed out the failure of media discussions to point out that functional imaging technologies, like fMRI, “are incapable of measuring brain activity.” They assess transient changes in blood flow. She also commented on the existing controversy of using this technology for diagnosis. “Due to theoretical and practical limitations, their application in the field of psychiatry is restricted to research settings at this time.”

She said even if abnormal mental activity could be objectively defined and reliably determined, “it remains unclear how any functional imaging technology could differentiate the brain processes which reflect the cause, rather than the consequence, of an allegedly impairing trait or state. She concluded with a quote from a position paper drafted by the American Psychiatric Association that said imaging research cannot yet be used to diagnose psychiatric illness and may not be useful in clinical practice for a number of years. “We conclude that, at the present time, the available evidence does not support the use of brain imaging for clinical diagnosis or treatment of psychiatric disorders…”

No current brain imaging technology, including fMRI, can be used to diagnose or treat psychiatric disorders. fMRI technology does not directly measure neural activity and has a demonstrated tendency to generate false positives, especially if the statistical analysis of the fMRI dataset is done incorrectly. Given the limitations of functional imaging technology, it is unclear how fMRI—or any other functional imaging technology—will be able to clearly distinguish between brain activity that causes an impaired neural trait or state, and brain activity that is a consequence of an impaired neural trait or state. And yet fMRI scans are presented to the public, by some individuals, as measuring brain activity and proving the existence of some psychiatric disorders. In their hands fMRI technology has become dysfMRI: dysfunctional MRI technology.

09/1/17

Circle the Pfizer Wagons

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The U.S. Preventive Services Task Force (USPSTF) recommended that all adults, including pregnant women and women who have recently given birth, be screened in primary care settings for depression. The screening would be done by: general practitioners, family physicians, nurse practitioners or physician assistants. USPSTF said screening adults for depression in primary care settings was accurate, it was effective in relieving depressive symptoms and the likelihood of harm from screening and treatment was small. The problem is that over 60% of individuals diagnosed with depression in primary care did not meet the DSM criteria for major depressive disorder. This rises to 80% with individuals over 65.

Albert Siu and the USPSTF published “Screening for Depression in Adults” in the January 2016 issue of JAMA. The authors said: “The USPSTF found convincing evidence that treatment of adults and older adults with depression identified through screening in primary care settings with antidepressants, psychotherapy, or both decreases clinical morbidity.” Commonly used screening instruments included the Patient Health Questionnaire (PHQ) in its various forms, as well as several others. But the USPSTF did not believe these instruments were getting as many false positives as noted above. “The accuracy of screening tests in the general adult population was established in the 2002 and 2009 USPSTF reviews and found to be convincing.”

Psychiatrist Vivek Datta pointed out the USPSTF guidelines did recommend that screening occurred when there were “adequate systems in place” for further evaluation and treatment. However, “55% of all US counties do not have a single mental health provider.” He noted that many of the symptoms screened for are nebulous and include “symptoms that are quite common in the general population and do not necessarily indicate a mental disorder requiring treatment.” They could represent the effects of a chronic medical problem. Moods are influenced by a variety of factors, such as our level of physical activity, what we eat, our financial security, alcohol and drug use, to name a few.

Symptoms of depression can occur as a result of lifestyle factors, substance use, medical illness, life events, interpersonal difficulties, and as a consequence of wider social policies. Comprehensive assessment frequently does not occur because of the lack of adequate services for those with mental health problems. The recommendation to screen all adults for depression ignores the social matrix in which depression occurs, will lead to further overdiagnosis and overtreatment of minor morbid mental states, and further overburden mental health services.

A Glut of Antidepressants” was published on August 12, 2013, in The New York Times. It mentioned an April 2013 study published in the journal Psychotherapy and Psychosomatics that found almost 62% of 5,639 individuals “who had been given a diagnosis of depression within the previous 12 months did not meet the criteria for major depressive episode.” Several other studies have reported that: “diagnostic accuracy is low in general practice offices.” The study’s lead author said: “The vast majority of individuals diagnosed with depression, rightly or wrongly, were given medication.” Doctors must resist the temptation “to take out the prescription pad and write down an antidepressant and hand it to the patient.”

The NYT article did indicate that not only are doctors prescribing more medication, their patients are demanding it more. I think this is a likely an outcome of the decision to permit direct-to-the-consumer advertising for pharmaceuticals in 1997. See “Pharma and Advertising” or “Not Everything is As It Appears” for more on this topic. If anything at all was done to “confirm” the patient’s or doctor’s impression that there was a depressed mood state, using a quick screening instrument seems likely given the short time period most patients spend with medical staff in a primary care setting.

James Davies, the co-founder of the Council for Evidence-Based Psychiatry, wrote “The Sedated Society,” where he commented on how a BBC radio program had failed to mention the problem with the PHQ-9 (mentioned above) and the GAD-7, which he said two of the most powerful questionnaires in the NHS (National Health Service). He said they have been used throughout the primary care system in the UK to assess whether or not a person has depression or anxiety. He said: “They set a very low bar for what constitutes having a form of depression or anxiety for which a drug should be prescribed.” He said the tens of millions of people who filled out these screening questionnaires don’t know that Pfizer Pharmaceuticals paid for their development and continues to hold the copyright for them. Their distribution throughout the NHS was paid for by Pfizer, which incidentally makes two of the most prescribed antidepressant and anti-anxiety drugs in the UK.

Although the BBC didn’t get Davies’s message out about the PHQ-9 and GAD-7, several news outlets did. At Vice, Hannah Ewens said “a few of us in the office” took the test, with everyone except one person got at least a score of mild depression. She personally scored within the “moderately severe depression” range, but doesn’t have depression at the moment. “If I have trouble sleeping ‘on several days’ or ‘nearly every day’ that bumps up my score significantly. And herein lies the problem: all of the indicators are symptoms of a modern lifestyle as well as signals of depression.” Ewens added that James Davies believes reliance on these questionnaires is becoming too commonplace because GPs don’t have the time to do proper interviews.

The Telegraph, another UK media outlet, echoed the Davies concern that the threshold for identifying possible depression was too low. Henry Bodkin noted that a PHQ chart was likely present in almost every GP consulting room over the last 20 years. He also said critics like Davies have said the GAD-7, also developed by Pfizer to screen for anxiety, sets the diagnosis bar too low. “These forms have a very low criteria for anxiety and depression. . . . Millions of people have filled them in and got medication, but did they know they were developed by Pfizer?”

Pfizer enlisted two “rock stars” in the field of psychiatric diagnosis to develop the PHQ-9 and GAD-7: Robert Spitzer and Janet Williams. Spitzer was the chairperson for the seminal changes incorporated into the DSM-III. Originally Williams was his text editor; later she became his wife and collaborator. Listen to an All Things Considered broadcast on Spitzer and the DSM, “The Man Behind Psychiatry’s Diagnostic Manual.”

In the September of 2001 issue of the Journal of General Internal Medicine, Kurt Kroenke, Robert Spitzer and Janet Williams published “The PHQ-9.” Their article examined “the validity of a brief, new measure of depression severity” called the PHQ-9. They concluded that data from their two studies provided “strong evidence for the validity of the PHQ-9 as a brief measure of depression severity.” Kroneke et al. also said brief measures were more likely to be used in the busy setting the typical medical practice. The brevity of the PHQ-9 was thought to make it “an attractive, dual-purpose instrument for making diagnoses and assessing severity of depressive disorders.” The Acknowledgements section said the development of the PHQ-9 was underwritten by an educational grant from Pfizer US Pharmaceuticals. Scrolling down further you’ll see:

From the Primary Care Evaluation of Mental Disorders Patient Health Questionnaire (PRIME-MD PHQ). The PHQ was developed by Drs. Robert L. Spitzer, Janet BW Williams, Kurt Kroenke, and colleagues. . . . PRIME-MD is a trademark of Pfizer Inc. Copyright 1999 Pfizer Inc.

Then in the May 2006 issue of JAMA Internal Medicine, the same three authors introduced the GAD-7, a brief self-report scale to identify generalized anxiety disorder (GAD). Not surprisingly, they concluded: “The GAD-7 is a valid and effective tool for screening for GAD and assessing its severity in clinical practice and research.” They expected the GAD-7 to have “considerable utility in busy mental health settings and clinical research.” Once again is an acknowledgement that the development of the GAD-7 was underwritten by an unrestricted educational grant from Pfizer Inc.

If you want to see or use copies of these scales, Pfizer’s lawyers have been clearly involved in dialing back the company’s responsibilities if the scales don’t live up to their creator’s optimistic expectations. On the Pfizer website, on the “Terms of Use” page for the two scales, is the following. Pfizer said since the questionnaires relied on patient self-report, all responses should be verified by the clinician. A definitive diagnosis should be made on clinical grounds, “taking into account how well the patient understood the questionnaire, as well as other relevant information from the patient.” Diagnoses should rule out normal bereavement, Bipolar Disorder, and other potential causes of depressive symptoms. Then there is the following disclaimer. The “all caps” formatting is in the original.

PFIZER MAKES NO WARRANTIES OR REPRESENTATIONS OF ANY KIND AS TO THE ACCURACY, CURRENCY, OR COMPLETENESS OF THE INFORMATION ACCESSED AND USED THROUGH THIS WEB SITE.
YOU AGREE THAT ACCESS TO AND USE OF THE PHQ AND GAD-7 SCREENERS IS AT YOUR OWN RISK. PFIZER DISCLAIMS ALL WARRANTIES, EXPRESS OR IMPLIED, INCLUDING WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE. NEITHER PFIZER NOR ANY PARTY INVOLVED IN CREATING, PRODUCING, OR DELIVERING THE PHQ/GAD-7 SHALL BE LIABLE FOR ANY DAMAGES, INCLUDING WITHOUT LIMITATION, DIRECT, INCIDENTAL, CONSEQUENTIAL, INDIRECT, OR PUNITIVE DAMAGES, ARISING OUT OF ACCESS TO, USE OF OR INABILITY TO USE THE PHQ/GAD-7, OR ANY ERRORS OR OMISSIONS IN THE CONTENT THEREOF.

The rhetoric about the GAD-7 and PHQ-9 and its variations related by their creators, Spitzer, Williamson and Kroneke seems to have been negated by Pfizer. Instead of the PHQ-9 being “an attractive, dual-purpose instrument for making diagnoses and assessing severity of depressive disorders” and the GAD-7 being “a valid and efficient tool for screening for GAD and assessing its severity in clinical practice and research,” Pfizer disclaimed all warranties expressed or implied for a particular purpose. Pfizer nor any party involved in creating the PHQ/GAD-7 will be liable for any damages from access or use of these questionnaires. Any users access and use the PHQ and GAD-7 does so “at your own risk.”

It seems that Pfizer circled their wagons to avoid any corporate liability coming from the use of these questionnaires despite the fact they paid for their development and continue to market them aggressively to general practitioners in the US and the UK. But the potential for the over diagnosis and over treatment of depression through the PHQ-9 has now reached a new height. Psychiatry Advisor reported in August of 2017 that Google announced whenever someone searches for ‘clinical depression,’ they have an option to take the PHQ-9. Google partnered with NAMI, the National Alliance on Mental Illness, to make depression screening with the PHQ-9 part of searching for ‘depression’ on the site. NAMI said: “We hope that by making this information available on Google, more people will become aware of depression and seek treatment to recover and improve their quality of life.”

So where did all that effort with the PHQ-9 and GAD-7 get Pfizer? Pfizer currently hold the rights to the brand rights for Xanax (alprazolam), an anti-anxiety drug, and Zoloft (sertraline), an antidepressant. Both have been available as generics for a number of years. And although The Telegraph article didn’t name Pfizer’s top selling antidepressant and anti-anxiety drugs in the UK, they must be the same two. Up-to-date yearly sales data for psychiatric drugs is hard to come by, unless you pay an organization like IMS for access to their sales data. But there is data available from 2013.

IMS Health listed the top 25 dispensed prescriptions in the US in 2013. Xanax and its generic, alprazolam, was the 13th most prescribed medication. Zoloft and its generic, sertraline, was the 18th most prescribed medication. Among the psychotropic medications listed they were number one and number three respectively. PsychCentral reported similar findings, with the added information that Xanax was the number one prescribed psychiatric drug in 2005, 2009, 2011 and 2013. Zoloft sank as low as the 4th most prescribed psychiatric drug in 2009 and the 3rd most in 2011.

08/22/17

It Takes Away Your Soul

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In case you missed it in July, there was an annual day of awareness … for the problems that result from the prescription and use of benzodiazepines. World Benzodiazepine Awareness Day (W-BAD) is on July 11th. The first W-BAD was in 2016, so it’s just getting started. The need for greater awareness of the adverse effects from benzos can be seen in the 2016 W-BAD promotional video, here. It’s over 24 minutes long, so be prepared to spend some time. If that’s too much time for you to take at the moment, here’s one take away quote from Wendy in Melbourne Australia about her experiences while on and then getting off of benzos: “It takes away your soul.”

I was pleasantly surprised to see an extended quote on the dangers of benzodiazepines from Dr. Neil Capretto was used in the 2016 W-BAD video. Dr. Capretto is the Medical Director for Gateway Rehabilitation Center, a drug and alcohol treatment program I’m familiar with in Western Pennsylvania, Dr. Capretto said:

People were innocently put on this medication [benzodiazepines] and in some instances it works out well. [But] there is a significant risk and we see it all of the time. Many people who have lost many years of their lives, who have lost jobs, been on the verge of suicide. I’m aware of cases where people have committed suicide. The drug can be dangerous, it can be fatal. During withdrawal the heart rate can go up, they may have a seizure, sometimes the body temperature can go up and in some cases it’s fatal.

The W-BAD video has individuals from around the world, telling about their experiences while using benzos, when tapering off them, and the ongoing protracted withdrawal experiences they suffered through. For some individuals, those adverse effects lasted months and in some cases were permanent. There were three W-BAD objective listed towards the end if the video, which are listed below.

To encourage the establishment of a mandatory maximum prescribing period of no more than 4 week, including taper period (based on the Committee on Safety of Medicines’ 2-4 week prescribing guidelines).

To encourage the establishment of ‘specialized’ withdrawal facilities for those who so desperately need them.

To encourage the provision of proper training for doctors and medical staff and to help them learn more about proper tapering practices to discontinue the drugs as well as about the serious implications of benzodiazepines.

The Committee on Safety of Medicines is an independent advisory committee that advises the UK Licensing Authority on the quality and safety of medicines. In 2005 it was replaced by the Commission on Human Medicines, combining the functions of the Committee on Safety of Medicines and the Medicines Commission. The Committee issued guidelines for UK physicians and medical professionals on the use of benzodiazepines in January of 1988. Pause for a minute. These concerns were evident almost thirty years ago.

The original document said there had been concerns regarding benzodiazepine dependence for several years, and cited a British Medical Journal article from 1980 to support the claim. It noted that withdrawal symptoms could include anxiety, confusion, insomnia, depression, and perceptual disorders. These symptoms could occur even when following therapeutic doses over SHORT periods of time (emphasis in the original). “These may sometimes be difficult to distinguish from the symptoms of the original illness.”

They discouraged the use of benzodiazepines to treat insomnia, unless it was severe and subjecting the person to extreme distress. If used, they should be used intermittently. “The use of benzodiazepines to treat short-term ‘mild’ anxiety is inappropriate and unsuitable.” When the anxiety is severe, disabling or subjecting the person to unacceptable distress they can be used for short-term relief—“two to four weeks only.”  The Committee then gave the following quote from the above noted article in the March 29, 1980 issue of the British Medical Journal. The point of all this is these concerns and recommendations with benzodiazepines have been know since the 1980s, but have been largely ignored on a global scale, as illustrated in the 2016 W-BAD video linked above.

The committee further noted that there was little convincing evidence that benzodiazepines were efficacious in the treatment of anxiety after four months’ continuous treatment. It considered that an appropriate warning regarding long-term efficacy be included in the recommendations, particularly in view of the high proportion of patients receiving repeated prescriptions for extended periods of time.It further suggested that patients receiving benzodiazepine therapy be carefully selected and monitored and that prescriptions be limited to short-term use.

Finding a “specialized” withdrawal facility can be difficult. Be careful of what the centers promise and their cost. Do your homework when searching for a “specialized benzodiazepine withdrawal facility.” A mere “benzodiazepine withdrawal facility” search will net multiple residential drug and alcohol treatment centers. Not every person who has been using benzodiazepines long enough to need medical inpatient detoxification support has been abusing benzos, and treatment at a drug and alcohol treatment center is often inappropriate. Plus the withdrawal protocol is often too rapid.

The New Beginnings Recovery Center in North Palm Beach Florida is an example of a treatment program that uses a protracted withdrawal method. I have no experience with their treatment program and can’t endorse it. But what I’ve seen of their methods fits with a patient or client-centered method of withdrawal, which I do think is best with benzodiazepines. Here is a link to the New Beginnings page on their Benzodiazepine Withdrawal Treatment Program. Here is a short YouTube video clip discussing the Heather Ashton Method for benzodiazepine withdrawal used at the New Beginnings Recovery Center.

Going slowly, at a pace controlled by the individual withdrawing from benzos, is the method most likely to produce positive results. It will take several weeks, months, and even in some cases, years. I’ve run across two medical professionals who advocate for this protracted withdrawal method, Dr. Peter Breggin and Dr. Heather Ashton.

I am personally familiar with Dr. Breggin’s work and have read many of his resources, including two that would be helpful for benzodiazepine withdrawal: Your Drug May Be Your Problem and Psychiatric Drug Withdrawal. Start with Your Drug May Be Your Problem for personal information on the process and try Psychiatric Drug Withdrawal for more technical discussions, if that’s needed. Both books discuss withdrawal from multiple classes of psychiatric drugs. There is a YouTube channel for Peter Breggin. He also has his own website with more information at: breggin.com.

The Ashton Protocol, or Ashton Method, is new to me, but from what I’ve reviewed it fits with the protracted withdrawal process I’m familiar with in Dr. Breggin’s material. Here is a YouTube clip, “Dr. Heather Ashton- Benzodiazepine Withdrawal.” You can see several other YouTube videos about her method with a “Dr. Heather Ashton” search on YouTube. Dr. Ashton also wrote “Benzodiazepeines: How They Work and How to Withdraw,” which has become known as “The Ashton Manual.”  A digital copy is available here on benzo.org.uk for free. A printed copy can be ordered.

From the brief review I’ve done so far, it seems likely to be a very helpful resource for individuals looking for assistance in getting off of benzodiazepines. Within a documentary by Shane Kenny, “The Benzodiazepine Medical Disaster,” which is linked below, Dr. Asthton said she wrote the manual for patients who weren’t getting help from the doctors. They seemed to know better what to do than the doctors. “It was for them. And the interesting thing is, although patients from all over the world have snapped it up, doctors still don’t read it.”

Protracted withdrawal will extend far beyond any acute medical withdrawal phase, and ongoing medical and therapeutic support on an outpatient basis is advisable. Getting medical support for protracted benzodiazepine withdrawal as an outpatient could be challenging. You may have to educate a willing physician on the necessity of an extended, rather than a shorter-term withdrawal. You can use the material recommended above from Peter Breggin and Heather Ashton to first educate yourself, and then any physician or psychiatrist willing to work with you on a protracted benzodiazepine withdrawal.

There are also many online information and support groups, such as: benzo.org.uk, which as been around since July of 2000. “Benzo.org.uk is dedicated to sufferers of iatrogenic benzodiazepine tranquilliser addiction.” In addition to the link to The Ashton Manual noted above, it has a wealth of information, including a FAQ document and links to online benzodiazepine withdrawal support groups on a support page. They also called out a specific support group called BenzoBuddies.

BenzoBookReview.com is a website with a list of books on benzodiazepine withdrawal. Information there includes memoirs and how-to guide books, with reviews and summaries of each book. The site is for anyone interested in information about benzodiazepine misuse and how to help benzodiazepine sufferers. That includes their families, doctors, psychologists, psychotherapists, drug counselors, and all professionals.

Other helpful resources include: Benzodiazepine Information Coalition, Beyond Meds, and Mad in America. Search the Mad in America site for “benzodiazepines.” Information on their “Withdrawal Resources” page will include a scientific literature review on withdrawal from benzodiazepines, as well as other classes of psychotropic drugs. Mad in America linked a short video by the group Benzodiazepine Recovery, “Benzodiazepine Withdrawal Symptoms” where individuals shared their top three most debilitating benzodiazepine withdrawal symptoms.

There are several helpful YouTube resources, such as Benzo Brains, by Jocelyn Pedersen. W-BAD also has a YouTube channel and a website: w-bad.org. Their YouTube channel has a short informational video (almost 3 minutes) on the risks of taking benzodiazepines. Start there to begin the education process with someone.

Look under Resources on w-bad.org for the Documentaries link. You will find information on “As Prescribed” by Holly Hardman, which is in production. Scrolling further down you will see a link to another documentary, “The Benzodiazepine Medical Disaster” by Shane Kenny. It features an in depth interview with Heather Ashton. Also remember what Melanie said about why this information on benzodiazepines is so important: “It takes away your soul.”

08/11/17

Drug Bust

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The FDA approval of Addyi (flibanserin) to treat hypoactive sexual desire disorder (HSDD) in premenopausal women on August 18, 2015, to a large extent, was due to the efforts of the marketing campaign of an organization called Even the Score.  A press release applauding the approval of Addyi listed 26 organizations, including the National Organization for Women, who were supporters of Even the Score. “Even the Score was established to serve as a voice for American women who believe that it’s time for the FDA to level the playing field when it comes to the treatment of hypoactive sexual desire disorder (HSDD).” But less than two years since its assistance in bringing about “a breakthrough moment for women’s health,” the organization is gone; vanished.

The Even the Score press release that celebrated the approval of Addyi noted there had been a steady drumbeat of support for women’s sexual dysfunction treatment from lawmakers, women’s rights groups, medical experts and consumer organizations. See the press release for a listing of these organizations. The Chair of the Even the Score campaign, Susan Scanlan, said: “Women deserve the safety and peace of mind that comes with access to FDA-approved medical treatments for HSDD.” Dr. Lisa Larkin, the Scientific Co-Chair of Even the Score said:

We applaud the FDA for acknowledging the clear science that supported approval of flibanserin, for starting a conversation that will define the next generation of progress in sexual rights and sexual health, and for empowering women to take control of their health in ways they never thought possible.”

But according to Alycia Hogenmiller, Alessandra Hirsch and Adriane Fugh-Berman, Even the Score was a fake feminist group created by Sprout Pharmaceuticals “so that they could get a bad drug approved by the Food and Drug Administration.” Writing for The Hastings Center in “The Score is Even,” the co-authors described how Sprout Pharmaceuticals hired Blue Engine Media, a PR firm, to create Even the Score. The Hastings Center is a nonpartisan bioethics research institute. And the coauthors of “The Score is Even” are affiliated with PharmedOut, a research and education project of the Georgetown University Medical Center that “promotes rational prescribing and exposes the effect of pharmaceutical marketing on prescribing practices.”

The Even the Score ad campaign hired two women who were both well-known to women’s groups. “Even the Score recruited and paid consumer advocacy groups to pressure the FDA into approving flibanserin for Hypoactive Sexual Desire Disorder—a condition previously created by industry to sell another drug.” The coalition did a Viagra commercial parody in 2014, which it said was “created to highlight the absurdity of the continued gender disparity in sexual health.” There is a link to the video in the press release. Members of Even the Score called Addyi: “the biggest breakthrough for women’s sexual health since the pill.” It was suggested there was possible “unconscious gender bias at the FDA.”

Two days after the approval of Addyi, Sprout sold the drug to Valeant Pharmaceutical for one billion dollars. Although Even the Score promised “to be there every step of the way” in the fight for true gender equality in sexual health, the victory video posted the day after Addyi was approved was the last posting on the Even the Score site. Completely dormant for many months, it disappeared entirely several months ago ( I couldn’t find it either). The last tweet from @eventhescore was from January 29, 2016 (I looked). The last post to the Even the Score Facebook page was January 28, 2016 (I looked there too).

In an earlier article for The Hastings Center on flibanserin, “The Drug that Cried ‘Feminism’”, Hirsch, Fugh-Berman and Rebecca Holliman described the drug as “Spanish fly, or horny goat weed, or one of the other aphrodisiacs that have been disappointing humans for millennia.” They noted how Sprout managed to convince the public and some women’s groups that flibanserin was a feminist cause. First, they created a narrative that branded anyone opposed to flibanserin as anti-woman. Then they hired two feminists to lobby women’s groups. They convinced NOW to join the cause. When there was some opposition from feminist groups about their feminist rhetoric, Even the Score and Sprout focused on the “scientific” evidence for flibanserin.

The point at which Sprout Pharmaceuticals’ innovative marketing bends sinister is in its misappropriation of feminist concepts. An oft-heard argument for approving flibanserin is “choice,” with the unstated subtext that women should decide about the risks and benefits of a drug on their own, sans pesky government interference. This implies that the FDA, the government agency charged with protecting the public from unsafe and ineffective drugs, is superfluous. That’s the way it was in the 19thcentury, pre-FDA, when we were giving children cocaine toothache drops.

A similar critique of Addyi (flibanserin) can be found in “Flibanserin: The Female Viagra is a Failed Me-Too Antidepressant.” The article was co-authored by Emily Wheeler, Madeline Brodt, Shannon Peters, and Lisa Cosgrove. The authors noted that HSDD (Female Sexual Interest/Arousal Disorder or FSI/AD in the DSM-5) is a classic example of disease mongering—creating a disease to promote a drug to treat it. A former president of the American Psychiatric Association admitted the possibility of such action in an article he wrote for the Harvard Review of Psychiatry:

The flexible boundaries of many psychiatric diagnostic categories, in the absence of definitive diagnostic tests, may encourage expansive definitions of affected populations and create opportunities for industry to promote treatments for people who would not previously been seen as having a disorder.

The empirical data supporting the diagnosis is weak, as is the clinical trial data used to approve Addyi (flibanserin). “Numerous researchers, clinicians, and policy experts, have questioned the validity of FFD and HSDD.” A systematic review and meta-analysis by Jaspers et al. in JAMA Internal Medicine, concluded that the benefits of flibanserin were marginal, particularly when the concurrent adverse effects are considered. “Treatment with flibanserin, on average, resulted in one-half additional SSE per month while statistically and clinically significantly increasing the risk of dizziness, somnolence, nausea, and fatigue. Overall, the quality of the evidence was graded as very low.”

Sprout admitted the effect is mild, only increasing the number of “satisfying sexual events” by less than one event per month. These events could include masturbation, but not necessarily orgasm. One of the statistics used in the Even the Score ad campaign, stating that 43% of women experience sexual dysfunction was from an older, highly criticized study. The often-repeated statistic of 1 in 10 women having HSDD was from a study funded by the pharmaceutical company that developed flibanserin, Boehringer Ingelheim. They sold the rights of the drug to Sprout Pharmaceuticals. The researchers conducting the study were either employees of Boehringer Ingelheim or paid consultants for the company.

The clinical effectiveness of Addyi (flibanserin) is questionable. The marketing campaign by Even the Score had significant influence on its approval process with the FDA. The so-called disorder it treats is mythical. But the numerous side effects from the drug are real. These potential side effects are so serious, that the FDA required special training and certification before providers could prescribe it. When flibanserin was approved, Janet Woodcock, the director of the FDA’s Center for Drug Evaluation and Research (CDER), said:

Because of a potentially serious interaction with alcohol, treatment with Addyi will only be available through certified health care professionals and certified pharmacies . . . Patients and prescribers should fully understand the risks associated with the use of Addyi before considering treatment.

Addyi can cause hypotension (severely low blood pressure) and loss of consciousness. These risks are increased and become more severe when used with alcohol, or when Addyi is taken along with CYP3A4 inhibitors such as: Prozac (fluoxetine), Luvox (fluvoxamine), and grapefruit juice. Here is a list of CYP3A4 inhibitors. Common side effects include dizziness, sleepiness, nausea, fatigue insomnia and dry mouth. Because of the sedation effects, it is recommended to take flibanserin at bedtime. Stop and think a minute. Addyi is a drug to treat sexual desire disorder that you take before going to bed … BECAUSE IT MAKES YOU SLEEPY!

The head of the National Women’s Health Network, Cindy Person, said: “This is a risky drug about which women and their doctors don’t get enough information.” Her organization produced an abysmal “report card” for Addyi. Among the listed concerns were that Addyi shouldn’t be taken with common medicines used to treat yeast infections, Chlamydia, syphilis, HIV and Hepatitis C. And taking hormonal birth control increased the risk of serious complications with Addyi. Writing for STAT News, Ed Silverman said: “Although some had great expectations for the drug, Addyi has, so far, been a bust.”  For more on Addyi, see “A Pill for a Mythical Ill.”

08/1/17

Repeating Past Mistakes

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At 4:45 a.m. on September 1, 1939, 1.5 million German troops invaded Poland. Two days later Britain and France declared war on Germany and World War II had begun. This “blitzkrieg” strategy became a blueprint of how Hitler intended to wage war. Generally unknown, one of the key tools in the success of the German Wehrmacht was their use of a methamphetamine called Pervitin. The troops were literally on cloud nine about Pervitin, as were their commanders.

Reports from the front lines on the drug included the following glowing testimonies:

Everyone fresh and cheerful, excellent discipline. Slight euphoria and increased thirst for action. Mental encouragement, very stimulated. No accidents. Long-lasting effect.The feeling of hunger subsides. One particularly beneficial aspect is the appearance of a vigorous urge to work. The effect is so clear that it cannot be based on imagination.

Not surprisingly, addiction became a problem. In April and May of 1940 alone, the Nazis shipped 35 million units of Pervitin and similar medications to its troops. Troops at the front sent letters home begging for more Pervitin. “Everybody, from generals and their staffs to infantry captains and their troops, became dependent on methamphetamine.” A lieutenant colonel leading a Panzer division wrote the following in a report:

Pervitin was delivered officially before the start of the operation and distributed to the officers all the way down to the company commander for their own use and to be passed on to the troops below them with the clear instruction that it was to be used to keep them awake in the imminent operation. There was a clear order that the Panzer troop had to use Pervitin.

“Speed” or amphetamine is in ADHD medications like Adderall (amphetamine/dextroamphetamine), Vyvanse (lisdexamfetamine). Methylphenidate (Concerta, Ritalin, Daytrana) is their close chemical relative. By the way, don’t be fooled by the creative spelling done by Shire for Vyvanse: “lisdexamfetamine” instead of “lisdexamphetamine.” Writing for The Guardian, Alexander Zaitchik noted  how the phonetic sleight-of-hand of Shire with Vyvanse and its aggressive marketing contributed to its success in getting the FDA to approve Vyvanse to treat “Binge Eating disorder.”

The company’s neo-phoneticism is intended to put more distance between its new golden goose and the deep clinical literature on speed addiction, not to mention last century’s disastrous social experiment with widespread daily speed use, encouraged by doctors, to temper appetites and control anxiety.

What follows is a history of amphetamines gleaned primarily from two sources: a paper on Amphetamines from the Center for Substance Abuse Research (CESAR) of the University of Maryland and a 2008 article by Nicolas Rasmussen for the American Journal of Public Health, “America’s First Amphetamine Epidemic 1929-1971.”

Amphetamine was first synthesized by a German chemist in 1887, but its stimulant effects weren’t noticed until the early 1930s, when it was rediscovered by accident. The chemist was trying to make ephedrine, a decongestant and appetite suppressant. Branded as Benzedrine, amphetamine was marketed as an inhaler for nasal congestion by the pharmaceutical company, Smith, Kline & French starting in 1933. It didn’t take some people long to figure out how to use Benzedrine for its euphoric effect. They cracked the container open and swallowed the Benzedrine-coated paper strip or steeped it in coffee.

Its use grew rapidly as medical professionals recommended amphetamine for alcohol hangover, depression, narcolepsy, weight-loss, hyperactivity in children and morning sickness in pregnant women. “The use of amphetamine grew rapidly because it was inexpensive, readily available, had long lasting effects, and because medical professionals purported that amphetamine did not pose an addiction risk.” During World War II, amphetamines or methamphetamine (a derivative of amphetamine) were used by both Allied and Axis troops to increase their alertness and endurance, as well as to improve their mood.

By 1945, over 500,000 civilians were using amphetamine psychiatrically or for weight loss. Between 1945 and 1960 commercial competition drove amphetamine use higher. After a patent expired in 1949, the FDA estimated the production of amphetamine and methamphetamine rose almost 400% by 1952. By 1962, production of amphetamines was approaching 43 standard 10-mg doses per person. This compares to concerns with the 65 doses per year in the present decade that social critics of our cultures point to as evidence of the overuse of psychotropic medications.

The adverse effects of amphetamine were becoming more evident by 1960. Amphetamine psychosis had been known since the 1930s, but was initially attributed to the drug unmasking latent schizophrenia. This claim is eerily similar to current interpretations of antidepressant activation unmasking latent bipolar disorder, rather than being seen as an adverse side effect of antidepressant medication. There were also concerns that amphetamines were addictive. But this didn’t stop individuals like President John F. Kennedy from using regular injections of vitamins, hormones and 15 mg of methamphetamine to help maintain his image of youthful vigor.

Large quantities of amphetamines were dispensed in the 1960s directly by diet doctors and weight loss clinics. Calculations of amphetamine use and misuse in 1970 estimated that at least 9.7 million Americans had used the drugs in the past year. And of those 9.7 million users, 3.8 million do so for nonmedical reasons and 2.1 million of those abused the drugs. Rasmussen said this first amphetamine epidemic was iatrogenic, “created by the pharmaceutical industry and (mostly) well-meaning prescribers.”  The current problem with the misuse of amphetamines has reached the peak of the original epidemic, namely about 3.8 million past-year nonmedical amphetamine users, with an estimated 320,000 of whom are addicted.

Parallel to this trend has been the surge in the legal supply of amphetamine-type ADHD medications such as Ritalin, Adderall and Vyvanse. American doctors, unlike those in other countries, have found it hard to resist prescribing these drugs. According to DEA production data, since 1995 medical consumption of these drugs has quintupled. In 2005, it exceeded the amphetamine consumption of 2.5 billion 10-mg amphetamine base units for medical use in 1969—compared to 2.6 billion base units in 2005. The following graph, taken from Rasmussen’s article, illustrates this increase. The data is based upon DEA production quotas and expressed as common dosage units of 10-mg amphetamine and 30-mg methylphenidate.

Rasmussen downplayed a causal connection between childhood stimulant treatment for ADHD and later nonmedical amphetamine consumption, but others don’t (See more on this below). However, he did think the wide distribution of ADHD stimulants, noted in the above graph, created a hazard. He cited data from a study that indicated 600,000 reported using stimulants other than methamphetamine nonmedically in the past month. So, “legally manufactured attention deficit medications like Adderall and Ritalin appear to be supplying frequent, and not just casual, misusers.”

An analysis of stimulant abuse in recent national household drug surveys found that half of the 3.2 million reporting past-year nonmedical use of stimulants in the U.S. only used psychiatric stimulants. And 750,000 of those reported they had never used anything but attention deficit pharmaceuticals in their entire lives. “On this evidence alone, one can fairly describe the high production and prescription rates of these medications as a public health menace of great significance.”

Another problem is the widespread acceptance of prescription amphetamines as a legal and relatively harmless drug that can be given to small children. Rasmussen said it is difficult to make a convincing case that the same drug is harmful if used nonmedically. Therefore he concluded any attempt to deal harshly with methamphetamine users today in the name epidemic control, without touching medical stimulant production and prescription was practically impossible and hypocritical.

There is some evidence of a connection between childhood stimulant treatment and later abuse or use of stimulants. See “ADHD: An Imbalance of Fire Over Water or a Case of the Fidgets?” on this website for a discussion of the association of addiction and ADHD medications as well as other adverse effects.

Nadine Lambert did a longitudinal study of ADHD children and normal controls. Her participants were followed through their childhood and adolescence and then evaluated three times as young adults. “ADHD was also significantly associated with amphetamine dependence.” However, being diagnosed with ADHD did not increase the odds of lifetime use of stimulants. She found that treatment with stimulants increased the odds of lifetime use of amphetamine and cocaine/amphetamines.

Commenting on Lambert’s findings in Brain Disabling Treatments in Psychiatry, Peter Breggin said:

It is not ADHD but the treatment for ADHD that puts children at risk for future drug abuse. This conclusion is entirely consistent with the fact that animals and humans cross addict to Ritalin, amphetamine and cocaine and that exposure to Ritalin in young animals causes permanent changes in the brain.

Hitler and his generals wanted victory at any cost and Pervitin (methamaphetamine), was part of that solution. German pilots called it “pilot’s chocolate”; soldiers on the front called it “Panzerschokolade” or “tank chocolate.” But towards the end of WW II, Vice Admiral Hellmuth asked German pharmacologists to develop a miracle drug. They had a wonder drug with Pervitin, but now they needed a miracle drug. So Gehard Orxzechowski synthesized D-IX. It was supposed to keep soldiers ready for battle even when they were asked, “to continue beyond what was considered normal.” It contained 5 mm of cocaine, 3mm of Pervintin and 5mm of morphine. It seems it was a good thing the war ended before they could distribute it widely to their troops.

We have a lesson to learn from the German Wehrmacht’s failure to make a better, smarter, stronger soldier through chemicals. The American war on drugs needs to recognize its greatest casualties are now coming from within—as with ADHD medications. And I think we need to reflect on the words of George Santayana in The Life of Reason: “Those who cannot remember the past are condemned to repeat it.”

07/21/17

Blind Spots with Antipsychotics, Part 2

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The American Journal of Psychiatry published an article by Goff et al. that addressed concerns that antipsychotic medications can adversely effect long-term outcomes of people with schizophrenia. Their conclusion was that there was little evidence to support “a negative long-term effect of initial or maintenance antipsychotic treatment on outcomes,” when compared to withholding medication treatment. Additionally, the researchers said while a subgroup of patients may benefit from “nonpharmacological treatment approaches,” they warned of the potential for an “incremental risk of relapse” and recommended the need for further research into the question. But did these researchers have a blind spot in how they evaluated their evidence?

In part one of this article, I reviewed some of the research evidence that supported concerns with long-term antipsychotic treatment. There was evidence supporting a link between long-term antipsychotic use and adverse cardiovascular events, brain shrinkage, and dopamine supersensitivity, as well as questions regarding the efficacy of antipsychotic maintenance treatment. There also seemed to be a disregard in Goff et al. of the evidence for the risk of metabolic syndrome with long-term antipsychotic use in their risk-benefit analysis of antipsychotic use. Yet health concerns from metabolic syndrome have been connected to the glaring difference in a shortened life expectancy, with persons suffering with serious mental illness dying 25 years earlier than the general population.

My previous encounters with Dr. Jeffrey Lieberman, who was the lead researcher for Goff et al., have led me to be cautious of his assertions without further investigation. I believe he has a serious blind spot when it comes to assessing and interpreting information counter to his position. See (“A Censored Story of Psychiatry, “Part 1, Part 2;  “Psychiatry, Diagnose Thyself!” Part 1, Part 2) for more on my concerns with Dr. Lieberman. So if there was a blind spot in Goff et al., what do other experts have to say about their conclusions?

Joanna Moncrieff wrote a response to Goff et al. on the Mad in America website, which can be accessed here. Moncrieff is a practicing psychiatrist, academic and author. She is one of the founding members and current co-chair person for the Critical Psychiatry Network, “a group of psychiatrists from around the world who are sceptical of the idea that mental disorders are simply brain diseases and of the dominance of the pharmaceutical industry.” She has written extensively on this issue, including a recent book on the troubling story of antipsychotic drugs entitled: The Bitterest Pill. You can read more about her thinking and her background on her website. She said she was shocked by how Goff et al. dismissed the concerns with long-term antipsychotic treatment and the evidence of brain impacts.

It is riddled with distortion, ignores the most pressing criticisms, and is shot through with the unexamined presumption that the multitude of problems currently labelled as schizophrenia or psychosis will one day be revealed to be due to a specific brain abnormality that is targeted by antipsychotics.

She doesn’t dispute the usefulness of antipsychotics for treating acute psychosis, what Goff et al. called initial antipsychotic treatment. Yet she noted where “decades of research into early intervention has not demonstrated that early antipsychotic treatment improves long-term outcomes.” She pointed out where Goff et al. stated the effectiveness of maintenance treatment has been well established, but then failed to acknowledge that randomised trials of maintenance treatment were typically maintenance treatment versus sudden withdrawal. “Thus they completely fail to address concerns that effects of withdrawal of long-term treatment inevitably confound such studies.”

The most worrying thing about the Goff et al. paper to Moncrieff was the minimization of the evidence that antipsychotics produce brain shrinkage. They claim that shrinkage of brain grey matter has been shown to be part of schizophrenia, claiming that brain differences were detected long before the introduction of antipsychotics. The paper they cited was a 1985 study by Bogerts and Schonfeldt-Bausch, which was a post mortem study done long after antipsychotics had been introduced.

The presence of differences between the brains of people with schizophrenia and controls does not establish that there is progression of brain volume loss, which is what has been clearly demonstrated in people and animals taking antipsychotics. There are no studies that show progressive brain changes in people diagnosed with schizophrenia or psychosis in the absence of antipsychotic treatment.

Dr. Moncrieff concluded her article by saying:

I still think antipsychotics can be useful, and that the benefits of treatment can sometimes outweigh the disadvantages, even in the long-term for some people. However, it does no one any service to pretend that they are innocuous substances that somehow magically transform (hypothetically) abnormal schizophrenic brains back to normal. Psychiatrists need to be fully aware of the detrimental effects of antipsychotics on the brain and body. They also need to acknowledge the way these drugs make life so miserable for many people, even for some who might have been even more distressed were they to be without them… Psychiatrists need to support people to evaluate the pros and cons of antipsychotic treatment for themselves and to keep doing this as they progress through different stages of their problems. To do this they need to be able to acknowledge the real nature of these drugs, and not sweep inconvenient truths under the carpet!

Miram Larsen-Barr also wrote a response to Goff et al. that appeared on Mad in America, which can be accessed here. She is a clinical psychologist with the University of Auckland, New Zealand. Larsen-Barr created and is the Service Director for Engage Aotearoa, an initiative that aims to make recovery information more easily accessible to the general public. She has “lived experience” of recovery from trauma, depression and suicidality. Her doctoral research explored experiences of taking, and attempting to stop, antipsychotic medication.

For her doctoral research she talked to 144 people who take or have taken antipsychotics. One-third thought antipsychotics had relieved their symptoms and given them back their lives—but another third said quite the opposite. She said the claim that the benefits of antipsychotic medications conclusively outweigh the adverse effects is just not true. It is true for some; entirely the opposite for others; and a mixed bag for the remaining individuals. You can access a copy of her thesis research here.

In my study, overall subjective experiences ranged on a continuum from life-saver” to hell” and every point between (Larsen-Barr, 2016). Around a third reported overall positive experiences such as A major relief from the monsters […] for me they have saved my life” and Helped me get through an unstable period of my life. And around a third of the participants reported mixed experiences such as, A short term help when needed then a burden” and A double edged sword. They help me with my bad experiences but they also take away the wind in my sails.”Another third reported wholly negative experiences such as, The worst experience of my life […] affected every aspect of my health and wellbeing. The therapeutic benefits certainly did not outweigh the costs for those who described the overall experience of taking antipsychotics as The ruin of my life or said they were Helpful to a point but […] robbed me of everything I value in myself as a person.

Larsen-Barr reported that few people in her study reported being well-informed of the potential benefits and risks before antipsychotic treatment. While about one-third reported beneficial results, 79% overall did contemplate stopping their medication, with 73% making at least one attempt. She said her study suggested the desire to stop antipsychotic medications was not just because of negative experiences. These decisions were primarily based upon whether or not taking AMs helped the person to “function in daily life.”

A full third of her survey sample had discontinued medications at the time of the study, which was similar to the stable discontinuation rate found in Harrow’s long-term study. Larsen-Barr found half of 105 survey participants who attempted to stop remained AM-free for one year or more; some over five years ago. Her research showed “withdrawal often entails a lack of information, poor support, and a range of physical, emotional, cognitive, social and functional disruptions that can be difficult to cope with, and which may include exacerbation of symptoms to the point of relapse.” For more on the Harrow study and concerns with antipsychotics, see “The Case Against Antipsychotics” by Robert Whitaker and “Worse Results with Psych Meds” on this website.

In part 1 of this article there was a discussion of how Carrie Fisher’s sudden cardiac death may have been associated with her use of psychiatric medications. Yet the possibility of her medications being a contributing factor to her death seemed to be overlooked in many articles about her unexpected death. For example, writing for Scientific American, Tori Rodriguez raised the possibility that Fisher’s bipolar disorder played a role in her death. Not the medication used to treat her bipolar disorder, but the disorder itself.

Did Carrie Fisher’s Bipolar Disorder Contribute to Her Death?” noted several possible connections to her bipolar disorder, but only made an oblique comment about how the medications may cause adverse effects like weight gain, diabetes higher triglycerides and even sudden cardiac death. Rodriguez noted how Fisher’s earlier substance abuse and struggles with her weight have been speculatively raised as contributing factors to her death. But she said one possibility that has been overlooked was the connection between bipolar disorder and cardiovascular disease and mortality. Individuals with bipolar disorder are twice as likely to develop or die from cardiovascular disease. The onset of cardiovascular disease occurs up to 17 years earlier in persons with bipolar disorder than in the general population. But as we’ve seen, that connection seems to be with the medications and not the disorder itself.

Rodriguez said Carrie Fisher “fit the bill” for several of the risk factors for sudden cardiac death at different points in her life. Then she said: ‘There is no definitive way to know whether her bipolar disorder or addiction history contributed to her death.” Yet there does seem to be a strong likelihood that not only did her use of antipsychotic medications help her be a better mother, friend and daughter, it may have contributed to her sudden cardiac death as well.

07/11/17

Blind Spots with Antipsychotics, Part 1

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Carrie Fisher was flying back to her home in Los Angeles on December 23, 2016 when she went into cardiac arrest. She was removed from the plane and later died in the hospital. Her daughter, Billie Lourd, said: ““She was loved by the world and she will be missed profoundly.” She was a well-known actress, writer and humorist. She wrote six books, some of which described her life, loves and adventures, which included drug addiction and bipolar disorder. A series of articles lamented that she was taken too soon, but there wasn’t anything said about a possible connection between her sudden cardiac death (SCD) and the medication she took for her bipolar disorder.

Fisher was a vocal mental health advocate and talked freely about her bipolar disorder and over the years. An article contained the following statements made by Fisher about her mental health and use of medication. In an interview with Diane Sawyer in December of 2000, she said: “I am mentally ill. I can say that. I am not ashamed of that. I survived that, I’m still surviving it, but bring it on. Better me than you.” At a February 2001 rally in Indianapolis for increased state funding for mental health and addiction treatment, she said: “Without medication I would not be able to function in this world. Medication has made me a good mother, a good friend, a good daughter.”

Writing for Mad in America, Corinna West raised the question of whether Fisher’s too soon passing was related to her use of psych meds. West referred to an article in the European Heart Journal by Honkola et al. that concluded: “The use of psychotropic drugs, especially combined use of antipsychotic and antidepressant drugs, is strongly associated with an increased risk of SCD at the time of an acute coronary event.” Variety reported Carrie Fisher was taking Prozac (an antidepressant), Abilify (an antipsychotic) and Lamictal (a mood stabilizer).

This study confirms that combining antidepressants and old school [first generation] antipsychotics causes an 18-fold increase in death during a cardiac event. Combining antidepressants with any antipsychotic causes an over 5-fold increase in relative risk of death during a cardiac incident.

To put this into some context, West noted: “Vioxx was pulled from the market for a 2-fold increase in relative risk factor of strokes and heart attacks.” It may have led to the death of 50,000 to 70,000 people while it was on the market. She then did some speculative calculations and suggested psych meds may contribute to 74,191 additional heart attacks annually and 33,386 deaths from SCD per year.

She also noted how people with serious mental illness have a 25-year lower life expectancy than others and a significantly greater risk of myocardial infarction. The NASMHPD “Morbidity and Mortality Report” said that it has been known for several years that people with serious mental illness die younger than the general population. “In fact, persons with serous mental illness (SMI) are now dying 25 years earlier than the general population.” The report also said people with SMI also suffer from a greater percentage of modifiable risk factors associated with cardiovascular disease, such as obesity, smoking, diabetes, hypertension and dyslipidema (high cholesterol). Corrine West noted the data from the “Morbidity and Mortality Report” showed that psychiatric drugs increased 4 of the top 5 normal risk factors for cardiac disease. Smoking was included as a risk factor because many individuals using psych meds find the nicotine helps relieve some of the numbness caused by the meds. See the following chart from the report.

There is increasing evidence of multiple adverse effects from the long-term use of antipsychotics in addition to the risk of SCD. Murray et al. concluded there was a lack of evidence for the long-term effectiveness of prophylactic (maintenance) antipsychotic use; and a growing concern with the cumulative effects of antipsychotics on physical health and brain structure. “There is enough evidence concerning the adverse effects of antipsychotics on physical health to compel psychiatrists to act.”

Murray et al. said long-tem maintenance treatment with antipsychotics was “based on hope rather than evidence.” They pointed to two serious methodological problems. First, studies claiming that antipsychotic maintenance treatment substantially reduced the risk of relapse were often limited to two years of follow-up. Second, the studies compared schizophrenic patients continuing on antipsychotics with those who stopped taking antipsychotics, not individuals who never used the drugs. So the withdrawal effect from antipsychotics in the discontinuation group influenced the higher relapse rates, making it a confounding variable to the supposed positive results with antipsychotic maintenance treatment.

The Murray et al. researchers did think there was no clear link between antipsychotic-associated changes in brain structure and cognitive decline or functional impairment. However, studies like that of Ho et al. suggested antipsychotics can “have a subtle but measurable influence on brain tissue loss over time.” Ho et al. said there was also a problem with dopamine receptor supersensitivity in some antipsychotic users. This supersensitivity could be a factor in the decreased efficacy of antipsychotics with continued prescription; and it may contribute to relapse when an individuals stops using antipsychotics. “There is an urgent need for neurochemical imaging studies addressing the question of dopamine supersensitivity in patients.”  In their conclusion, the researchers gave the following recommendations.

[The wise psychiatrist] will treat acute psychosis with the minimum necessary dose of antipsychotics, employing weight sparing antipsychotics wherever possible; dopamine partial agonists have this property and may also be less likely to induce dopamine supersensitivity. Following recovery, the psychiatrist should work with each patient to decrease the dose to the lowest level compatible with freedom from troublesome psychotic symptoms; in a minority of patients, this level will be zero.

You can read a summary review of the study by Justin Karter on Mad in America here.

Not all of the above-cited researchers agreed with the conclusions of each other. But collectively they pointed to evidence of a link between antipsychotics and adverse cardio vascular events, brain shrinkage, and dopamine supersensitivity.  Murray et al. also suggested that studies of long-tem antipsychotic maintenance treatment unfairly stacked their results in favor of antipsychotic maintenance by using patients who were withdrawn/discontinued from using antipsychotics as their control group. So when the recent press release from Columbia Medical Center regarding Goff et al. concluded the benefits of antipsychotics outweigh the risks was disconcerting and confusing at first. The Goff et al. abstract asserted: “Little evidence was found to support a negative long-term effect of initial or maintenance antipsychotic treatment on outcomes, compared with withholding treatment.”

The press release acknowledged the above concerns that antipsychotic medications have been said to have toxic effects and negatively impact long-term outcomes. However it went on to say that if this view was not justified by data, it had the potential to “mislead some patients (and their families) to refuse or discontinue antipsychotic treatment.” Therefore a team of researchers led by Jeffrey Lieberman, the Lawrence C. Kolb Professor and Chairman of Psychiatry at Columbia University College of Physicians and Surgeon, undertook “a comprehensive examination of clinical and basic research studies that examined the effects of antipsychotic drug treatment on the clinical outcomes of patients and changes in brain structure.” Lieberman was liberally quoted in the Columbia press release with regard to their findings supporting how the benefits of antipsychotics outweigh the risks. He said:

The evidence from randomized clinical trials and neuroimaging studies overwhelmingly suggests that the majority of patients with schizophrenia benefit from antipsychotic treatment, both in the initial presentation of the disease and for longer-term maintenance to prevent relapse. . . . Anyone who doubts this conclusion should talk with people whose symptoms have been relieved by treatment and literally given back their lives.

Lieberman went on to suggest that only a very small number of individuals recover from an initial psychotic episode without the use of antipsychotic maintenance treatment. “Consequentially, withholding treatment could be detrimental for most patients with schizophrenia.” He acknowledged where rodent studies suggested antipsychotics can sensitize dopamine receptors, but “there is no evidence that antipsychotic treatment increases the risk of relapse.” Further, although antipsychotic medications can increase the risk of metabolic syndrome, which is linked to heart disease, diabetes and stroke, their study did not include a risk benefit analysis of this concern.

Wait a minute. Why didn’t their study include a risk benefit analysis for metabolic syndrome? It seems to be one of the most reliably documented adverse effects, as noted above. Could it be that the intended message of the research—namely how strong evidence supports the benefits of antipsychotic medications—would not have been as clearly communicated if the risk benefit analysis concluded there was a substantial risk of metabolic syndrome? By the way, according to the Mayo Clinic,

Metabolic syndrome is a cluster of conditions — increased blood pressure, high blood sugar, excess body fat around the waist, and abnormal cholesterol or triglyceride levels — that occur together, increasing your risk of heart disease, stroke and diabetes. Having just one of these conditions doesn’t mean you have metabolic syndrome. However, any of these conditions increase your risk of serious disease. Having more than one of these might increase your risk even more. If you have metabolic syndrome or any of its components, aggressive lifestyle changes can delay or even prevent the development of serious health problems.

Dr. Lieberman has been a vocal advocate of modern psychiatry and equally critical of those who question many of its claims, as with those documented here. My previous encounters with his presentation of evidence and data, like his discussion of the conclusions of Goff et al. above, have led me to be skeptical of his conclusions without further investigation. I believe his fervent desire to defend modern psychiatry and current psychiatric methods has distorted how he interprets and presents conflicting evidence. He seems to have a blind spot when assessing and interpreting evidence counter to his position. The above question about the failure to include a risk benefit analysis of metabolic syndrome is one illustration of what I mean.

So what do others have to say with regard to the Goff et al. study? We’ll look at some of those critiques in part 2 of this article.