02/24/17

Misdiagnosing Substance Use

© adiruch | 123rf.com

Allen Frances doesn’t like the DSM-5 and you can hear him say so here.  He said our mental health system was in a mess. And he is afraid that with DSM-5, it will get even worse. “People who are essentially normal are being diagnosed with mental disorders they don’t have.” Small changes in the diagnostic system can result in tens of millions of normal people qualifying for a diagnosis. He used himself as an example, stating how he would qualify for several of the DSM-5 disorders. Typical symptoms of grief over his wife’s death, lasting beyond two weeks, would have signified him as having a Major Depressive Disorder.

Anther mistake was combining what had been two different diagnoses of substance use in the DSM-IV—Substance Abuse and Substance Dependence—into one: Substance Use Disorder. Substance Abuse was when someone had recurrent, but intermittent, trouble from recreational binges. Substance Dependence was a continuous and compulsive pattern of use, often with tolerance and withdrawal. The majority of substance abusers “never become addicted in any meaningful sense.”

The two DSM IV diagnoses have radically different implications for treatment planning and for prognosis. Artificially lumping them together in DSM-5 forces inaccurate diagnosis, loses critical clinical information, and stigmatizes as addicts, people whose substance problem is often temporary and influenced by contextual and developmental factors.

Hasin et al., “DSM-5 Criteria for Substance Use Disorders: Recommendations and Rationale,” presents the rationale used by the DSM-5 workgroup for substance use disorders for its changes, particularly combining abuse and dependence into one disorder. They recommended the combination as well as dropping one diagnostic criteria (legal problems) and adding one (craving). Two criteria are required to diagnose a Substance Use Disorder. The number of criteria met will indicate mild (2 to 3 criteria), moderate (4 to 5), and severe disorders (6 or more). The following chart, taken from the article, illustrates the changes from DSM-IV to DSM-5.

Frances is not alone in seeing value with two distinct types of substance use disorder. Carleton Erickson in The Science of Addiction noted how the distinction allowed for the differentiation between individuals with drug-related problems who could stop using when they wished (substance abusers), and others who had the disease of chemical dependence. Chemically dependent people have a dysregulation of the mesolimbic dopamine system and generally cannot stop using drugs without intensive intervention into their drug use problems. “According to these criteria, drug abuse in intentional, ‘conscious,’ or voluntary. Drug dependence is pathological and unintended.”

In his article, “DSM-5 Made a Mistake Eliminating Substance Abuse,” Allen Frances indicated the DSM-5 workgroup for substance use disorders based its rationale for dropping Substance Abuse on studies suggesting the distinction was hard to make. He said the results of the studies were not definitive. Moreover, their interpretation was flawed by what he said was a basic DSM-5 misunderstanding of the nature of psychiatric diagnosis. “All DSM disorder overlap with other DSM disorders and also frequently with normality.” Fuzzy boundaries among near diagnostic neighbors are common and not a sufficient excuse to collapse clinically valuable distinctions.

Carleton Erickson’s discussion of the degrees of severity with drug problems helps to illustrate this misunderstanding. He indicated there were mild, moderate and severe forms of both drug abuse and drug dependence. Most people don’t think in terms of severity with substance use problems. You either have a problem or you don’t; you either abuse drugs or you don’t. He then illustrated their relationship to drug-seeking behavior as follows.

Drug Abuse

Drug Dependence

Drug-Seeking

Mild

Little/None

Moderate

Some

Severe

Mild

A Lot

Moderate

Even more

Severe

All the Time

The overlap referred to by Frances occurs between severe drug abuse and mild drug dependence. The inability of psychiatric diagnosis to make a clear distinction here seems to have led to the decision to collapse the abuse and dependence diagnoses into one category in the DSM-5.

I think another overlap between drug abuse and drug dependence happens with regards to self-control. A distinction is necessary between self-control of thoughts, feelings and behavior when drinking and control of the drug intake itself. Any substance use can lead to a loss of self-control over an individual’s thoughts, feelings and behavior. When that loss of control results in recurrent, intermittent trouble, there is a drug abuse problem. The severity of this type of loss of self-control and the related intermittent trouble varies.

Not everyone who abuses a drug experiences the classic sense of losing of control over how much of the drug they use. A loss of control over drug intake—a continuous and compulsive pattern of use—is only evident within drug dependence. And again, the severity of this loss of control over drug intake varies. So I’d adopt Erickson’s degrees of severity with drug abuse and dependence problems as seen below.

Loss of Self-Control in Abuse

Loss of Control over Drug Intake in Dependence

Mild

Moderate

Severe

Mild

Moderate

Severe

A substance abuse problem with severe trouble related to loss of self-control may be indistinguishable from a substance dependence problem with mild loss of control over drug intake. Both people would look at their severe “trouble” and attribute it to drinking or drugging too much. Given an equal motivation to avoid further “trouble,” the substance abuser would likely have an easier time maintaining abstinence. Carleton Erickson said chemical dependence is not a “too much, too often, withdrawal” disease; it’s a “I can’t stop without help disease.” There is a pathological, compulsive pattern to substance use.

There does seem to be a “fuzzy boundary” between Substance Abuse and Substance Dependence. Nevertheless, the distinction still carries some clinical and diagnostic value. I agree with what Allen Frances said: “The change was radical, creates obvious harms, and provides no apparent benefit.” What should clinicians do? Frances suggested they simply ignore the DSM-5 change. He said it was appropriate and clinically preferable to continue making the distinction.

There is nothing sacred or official about the DSM-5 choices — I know because I made the choices for DSM-IV. The ICD coding system is official; the DSM codes are just one groups’ fallible adaptation of them. It is of great significance that the official coding in ICD-10-CM does not follow the DSM-5 decision to eliminate Substance Abuse. Instead, ICD-10-CM retains the DSM-IV terminology and continues to provide separate Substance Abuse and Substance Dependence codes for each of the major classes of substances.

The ICD-11 workgroup, currently in the final stage of development before field tests, will continue to separate Substance Dependence and Harmful Substance Use. The guidelines for dependence are revised and simplified into three diagnostic features: impaired control over substance use; increasing priority in life and physiological features. Severity qualifiers were suggested only for alcohol intoxication. They also introduced a new diagnostic category, with no equivalents in ICD-10 or DSM-5: single episode of harmful use. Frances commented:

The DSM-5 mistake thus places it out of line with ICD-10, ICD-11, previous DSM’s, and well established clinical practice. Clinicians remain truer both to clinical reality and to ICD coding when they ignore the new DSM-5 lumping of substance use disorders and instead continue to distinguish Substance Abuse from Substance Dependence. DSM’s are explicitly meant to be used only as guides, not worshiped as bibles. Clinicians are free to ignore DSM whenever it makes mistakes that go against clinical common sense and the International coding system.

01/24/17

Herding Pharma “Cats”

© mdfiles | stockfresh.comAfrica

The Chinese government released a report in September of 2016 by the State Food and Drug Administration (SFDA) that found fraudulent clinical trial practices on a massive scale. The SFDA concluded that over 80% of clinical trial data was fabricated. The scandal was the result of a “breach of duty by supervision departments and malpractice by pharmaceutical companies, intermediary agents and medical staff.” More than 80% of the applications for the mass production of new medications have been cancelled, with warnings by the SFDA that further evidence of malpractice might still emerge.

Radio Free Asia also reported the SFDA indicated much of the clinical trail data was incomplete at best. But it also failed to meet basic analysis requirements or was untraceable. “Some companies were suspected of deliberately hiding or deleting records of adverse effects, and tampering with data that did not meet expectations.” Apparently, this came as no surprise to industry insiders. “Clinical data fabrication was an open secret even before the inspection.”

Many of the new drugs were combinations of existing ones. Clinical trial outcomes were written beforehand, and their data presented so it agreed with the fabricated outcomes. A doctor at a top Chinese hospital said the problem lay with the failure to implement regulations governing clinical trial data. “Guangdong-based rights activist Mai Ke said there is an all-pervasive culture of fakery across all products made in the country.” Reporting for Pharmafile, Ben Hargreaves said:

The root of the issue is then not regulation, with regulation for clinical trials running on similar lines to Western practises, but in the lack of adherence to them. China’s generic drug industry has struggled with quality problems and therefore there is a temptation for companies to manipulate data to meet standards. The report found that many of the new drugs were found to be a combination of existing drugs, with clinical trials outcomes written beforehand and the data tweaked to fit in with the desire outcomes.

Sadly, clinical trial problems are not unique to China. An editorial published in the British journal The Lancet Psychiatry described multiple issues beginning with how subjects are recruited, moving on to determining what the control group should be, and ultimately defining meaningful outcome measures. Sometimes, trial recruits receive “care” they didn’t agree to. “Researchers and ethics review boards need to examine the ethical arguments and practical procedures from other areas of medicine where consent is problematic.” If such trials are done, regular and rigorous monitoring is essential. Patient safety and autonomy needs to be a priority.

In his discussion of the editorial, Justin Carter elaborated on one of the problems with recruiting subjects. An individual was recruited into a study on three antipsychotics while under a forced commitment order from a judge. “The psychiatrist who recruited him was in charge of the study and was his treatment provider and was also empowered to report on the patient’s progress to the judge.” The individual died by suicide during the drug trial.

The work of Irving Kirsch and others has shown the problem with inert placebos (sugar pills). The side effects from medication make it easy for participants to guess which study group they are in.

And when the trial is over and the data in, do the outcome measures really provide something meaningful for people’s lives? If the ultimate goal is for people to fell better and resume their prior level of functioning, should outcome measures by primarily patient self-reports, clinical assessment, or differences shown by imaging or the as-yet-to-be-clearly-identified biomarkers?

Given the problems running and interpreting psychiatry trials, it is essential to learn how even the most successfully tested interventions work in real clinics with the broad patient population. Implementation, uptake, and effectiveness in real-life settings must be analysed, and delivery of new innovations modified accordingly. Future research should be thought of not as a plain linear process from innovation to trial to implementation, but as a virtuous circle where research feeds into the clinic and vice versa.

Another issue pointed to by Carter was the validity and reliability of the diagnosis or classification system used to determine who to include and who to exclude from the trials. The DSM system, now in its fifth edition (DSM-5), is the current “bible” for assessing and diagnosing problems the psychiatric medications in clinical trials are supposed to “treat” in the U.S. Yet there have been questions about the reliability and validity of the DSM dating from an argument raised by Robert Spitzer and others in the 1970s that ushered in changes still embedded in the DSM-5. Rachel Cooper gave a brief history of the reliability questions with the DSM in “How Reliable is the DSM-5?” You can also refer to “Psychiatry Has No Clothes,” “Where There’s Smoke …”, and  “The Quest for Psychiatric Dragons,” Parts 1 and 2.

A few weeks before the release of the DSM-5, Thomas Insel, then the NIMH Director, announced the NIMH would be “reorienting” its research away from DSM categories. The agency’s new approach is called the Research Domain Criteria (RDoC) project. For now, RDoC is a research framework and not a clinical tool. But NIMH has high hopes for it: “RDoC is nothing less than a plan to transform clinical practice by bringing a new generation of research to inform how we diagnose and treat mental disorders.” While Tom Insel has moved on to work for Alphabet (Google), RDoC is alive and well within NIMH. You can keep up with news about RDoC on the “Science News About RDoC.”

The Science Update for February 16, 2106 noted the March 2016 issue of the journal Psychophysiology would be devoted to the RDoC initiative. Dr. Bruce Cuthbert said the special issue was a unique opportunity for researchers to engage with one another and reflect on work being done in various laboratories throughout the country. He thought it was encouraging to see many investigators already engaged in the kind of work RDoC advocates. “What this shows is that while the RDoC acronym may be new, the principles behind RDoC are certainly not new to psychiatric research.”

If the principles behind RDoC are not new to psychiatric research, how can it bring “a new generation of research to inform how we diagnose and treat mental disorders” in order to transform clinical practice? It sounds a lot like using the same deck of cards to just play a new card game. RDoC may not be the transformative framework it’s touted to become.

Added to these issues is the failure of pharmaceutical companies to publically report the results of clinical trials, as they are required by law to do. New reporting rules will take effect on January 18, 2017. But advocates for transparency in clinical research have cautioned the success of the new rules will depend upon the willingness and vigor of government enforcement of those rules. The failure to enforce the existing rules, which went into effect in 2008, led to widespread noncompliance with reporting requirements. If the FDA had fined the violators, they could have collected an estimated $25 billion.

Reporting for STAT News, Charles Piller said studies have indicated only a small fraction of trials will comply with the law. Yet there are no current plans to increase enforcement staffing at the FDA and NIH. That’s a big problem, according to Ben Goldacre, an advocate for full disclosure in clinical research. Francis Collins, the NIH director said they are serious about this and will withhold funds, if needed. “It’s hard to herd cats, but you can move their food, or take their food away.”

The legislation that created ClinicalTrials.gov emerged from numerous cases of drug manufacturers withholding negative trial results, making drugs look more effective and less harmful. Efforts to market the antidepressant Paxil for teenagers more than a decade ago stimulated the push for better reporting. A recent analysis in the journal BMJ found that GlaxoSmithKline, Paxil’s manufacturer, failed to disclose 2001 data showing the drug to be no more effective than a placebo, and was linked to increased suicide attempts by teens.

Writing for Time, Alexandra Sifferlin reported on a new study that suggested many of the medical reviewers for the FDA go to work for the drug companies they oversaw while working for the government. One of the study’s authors said: “I don’t think there is overt collusion going on, but if you know in the back of your mind that a major career opportunity after the FDA is going to work on the other side of the table, I worry it can make you less likely to put your foot down.”

Returning to the Francis Collins metaphor, it seems that the willingness to try and herd Pharma cats is dependent on whether or not you are afraid they will scratch you in the attempt.

09/2/16

Antidepressant Scapegoat

5169097 - goat. photo based illustation. the scapegoat was a goat that was driven off into the wilderness as part of the ceremonies of yom kippur, the day of atonement, in judaism during the times of the temple in jerusalem. the rite is described in leviticus 16.

© Elena Ray | 123rf

The Hamilton Depression Rating Scale (Ham-D) is the most widely used clinician-administered assessment scale. In use since the 1960s, it is seen as the “gold standard” for assessing depression. As such, it was the assessment tool of choice when antidepressant clinical trials were being done. The only problem was many, if not most, of the antidepressants that came to market had a statistically significant effect on the Ham-D that was not observable clinically. Irving Kirsch called this a “dirty little secret.” Both the pharmaceutical companies bringing the drugs to market and the FDA knew there was essentially no difference between the effects of the drug and the placebo used in the clinical trial.

Kirsch’s research into the placebo effect with antidepressants has been established and repeatedly replicated; it wasn’t a fluke, one-and-done study. Search his name in Google or start here with “Dirty Little Secret,” “Modern Alchemy with Antidepressants,” or “Do No Harm with Antidepressants.” Kirsch showed clearly that study participants were able to regularly break the double blind methodology of the clinical trials because the researchers continually used inert placebos. The real drugs given to study participants produced side effects; the inert placebo pills didn’t. All you had to do was pay attention to any side effects you may or may not exhibit to have about a 75% chance of accurately predicting whether you were in the experimental group of the control group.

But Swedish researchers suggested that the reason SSRI antidepressants haven’t performed better than placebo was because they were measured incorrectly. Heironymus et al. said that if 16 of the 17 items in the Ham-D were ignored and only the single item assessing depressed mood was utilized, “scientifically valid support for the tested drug being antidepressant” could be shown. They said their decision to focus on depressed mood was because it was one of the two key symptoms required by the DSM-IV definition of depression; and it is given particular importance by the FDA when the agency evaluates the efficacy of an antidepressant.

While not claiming that assessing depressed mood only is the optimal way of recording symptom severity, or that other symptoms are irrelevant, we do suggest that a treatment faithfully outperforming placebo in reducing depressed mood can hardly be regarded as ineffective.

Perceived flaws with the Ham-D have been pointed out by previous researchers. In 2004, Bagby et al. looked at the psychometric properties of the Ham-D and found the internal, interrater, and retest reliability estimates overall were mostly good. However, many of the individual scale items were poor contributors when measuring the severity of depression. Some had poor interrater and retest reliability. “For many items, the format for response options is not optimal.” They concluded that:

Evidence suggests that the Hamilton depression scale is psychometrically and conceptually flawed. The breadth and severity of the problems militate against efforts to revise the current instrument. After more than 40 years, it is time to embrace a new gold standard for assessment of depression.

They said many of the individual items were poorly designed and add up to a total score whose meaning was unclear. At the very least, they thought the Ham-D needed a complete overhaul of its items. The researchers thought it was time to retire the Ham-D, as it is measuring a conception of depression that is several decades old. “The field needs to move forward and embrace a new gold standard that incorporates modern psychometric methods and contemporary definitions of depression.” In other words, the new gold standard needs to include current DSM symptoms.

I wonder if the Bagby et al. study may be suggesting we set aside the Ham-D prematurely. A cursory comparison of the Ham-D and the current edition of the DSM, the DSM-5, suggested there is a good bit of overlap. An article by Michael Schreiner, “Major Depressive Disorder DSM 5 Criteria,” gives the DSM-5 diagnostic criteria; the Ham-D is described here in a NIH document.

The DSM-5 lists nine potential symptoms of depression, five of which are required to exist within a two-week period of time for a diagnosis of major depression. The symptoms have to cause clinically significant distress or impairment in social, occupational or other important areas of functioning. Every one of the nine symptoms is mentioned one way or another within the Ham-D.

The nine DSM-5 symptoms are:

1. Depressed mood most of the day, almost every day, indicated by your own subjective report or by the report of others. This mood might be characterized by sadness, emptiness, or hopelessness.
2. Markedly diminished interest or pleasure in all or almost all activities most of the day nearly every day.
3. Significant weight loss when not dieting or weight gain.
4. Inability to sleep or oversleeping nearly every day.
5. Psychomotor agitation or retardation nearly every day.
6. Fatigue or loss of energy nearly every day.
7. Feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) nearly every day.
8. Diminished ability to think or concentrate, or indecisiveness, nearly every day.
9. Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a   specific plan for committing suicide.

There are clear differences between them as well. The Ham-D scale devoted three items to sleep disturbance; the DSM-5, only one. Some items in the Ham-D, like agitation and retardation (slowness of thought and speech) were mixed into two different symptoms in the DSM-5. Hypocondriasis was in the Ham-D, but not the DSM-5. The Ham-D item on “work and activities” was broken into a symptom of fatigue and also appeared in a separate category B: “Symptoms cause clinically significant distress or impairment in social, occupational or other important areas of functioning.”

The case for a more psychometrically sensitive depression scale, one that has a greater correspondence to how depression is currently diagnosed, makes some sense. But is the problem really that a more effective diagnostic scale needs to be developed? Perhaps the issue is that the Ham-D hasn’t had a very good track record in demonstrating the effectiveness of antidepressant drugs. So researchers and pharmaceutical companies would like a scale that more clearly demonstrates efficacy with medications than the Ham-D. Or maybe the Ham-D is being scapegoated for the failures of antidepressant drugs. Then again, maybe the problem is trying to “treat” a complex human condition like depression by manipulating one or two neurotransmitters with antidepressants.

07/15/15

Pathologizing Grief

© Kzenon | stockfresh.com

© Kzenon | stockfresh.com

In January of 2015, an article on “Complicated Grief” was posted in The New England Medical Journal blog. The author described complicated grief as “intense grief after the death of a loved one that lasts longer than expected according to social norms and causes functional impairment.” While it was said that psychotherapy is a first-line treatment, the author reported that antidepressant medication is commonly used. This is just the latest stage in a rather complicated refashioning of grief from a normal human experience into a mental disorder.

The symptoms of complicated grief were said to be: “persistent, intense yearning, longing, and sadness.” Along with these “symptoms” can be a sense of disbelief or failure to accept the reality of the person’s death. Persistent thoughts or images of the deceased can occur. Ruminating on the circumstances of the death, with feelings of anger or guilt was said to be common. Avoiding situations that remind the person of the loss is common. Holding on to the deceased by repeated reminiscing, viewing, touching or smelling the deceased person’s belongings can occur as well.

People with complicated grief often feel shocked, stunned, or emotionally numb, and they may become estranged from others because of the belief that happiness is inextricably tied to the person who died. They may have a diminished sense of self or discomfort with a changed social role and are often confused by their seemingly endless grief.

Complicated grief is not a psychiatric diagnosis, although you wouldn’t know that from reading the above description. It explicitly uses diagnostic-like language in its discussion in an attempt to gain legitimacy for “Prolonged Grief Disorder” to be included in the International Classification of Diseases, 11th edition, due for release in 2017. The boat has passed on inclusion in the DSM, which went through its own controversy over grief when the DSM-5 removed the bereavement exclusion (BE) from the existing Major Depression Disorder (MDD) in 2013.

Within the DSM, the bereavement exclusion meant that a diagnosis of MDD could not be made if the loss of a loved one was a better explanation for the observed symptoms of depression. However, the time frame to avoid the grieving process from qualifying as MDD has been progressively shrinking. Within the DSM-III, the BE was one year; within the 4th edition, it was two months. Now in the DSM-5, bereavement is no longer an excuse. If you meet the diagnostic criteria for MDD over a two-week time period, you are just as depressed as anyone else, according to the DSM.

Joanne Cacciatore, who has specialized in the psychotherapeutic treatment of grief and bereavement for almost twenty years, has been an outspoken critic of these changing guidelines and pseudo-diagnoses. In March of 2012 she wrote an essay opposing the proposed elimination of the BE from the DSM-5. Her eloquent essay reached 100,000 readers in two weeks. She stated her opposition to both of the above ‘time limits’ for grief, and pointed to the historical movement of the DSM to medicalize normal human emotion. She said:

We should not, ethically or morally, medicalize grief.  To do so is to medicalize love.  We rarely mourn for that which we do not love. I can only begin to imagine what the sages, and mystics, and shamans of the past might think of a society which does so.

Allen Frances was also openly critical of the DSM-5 and its changes with regard to bereavement. In his own blog on the Huffington Post in March of 2012, he published Dr. Cacciatore’s open letter to the Board of Trustees of the American Psychiatric Association. She pointed to the arbitrariness of the two-week time frame, stating that it not only contradicts common sense, but rests on weak scientific evidence. To her knowledge there was no empirical evidence to support it.

One thing in which the literature is clear: long-term psychological distress is common in this population and other populations suffering traumatic deaths. In my experience both as a researcher and clinician in the field and also as a bereaved parent, the DSM-5 proposal is radical, unnecessary, challenges what it means to be human, and for some may be dangerous.

But the APA was not moved. Frances tried again in January of 2013, as the DSM-5 was preparing to go to press at the end of the month. He said: “The American Psychiatric Association has just four more weeks to reverse this dreadful mistake that flies in the face of clinical common sense and is unsupported by the limited available science.” He put together his own top ten list of harmful changes in the DSM-5, and medicalizing grief was number two. In case you aren’t aware, Dr. Frances’ credibility in voicing these concerns come from his long career as a psychiatrist and as the person selected by the APA to chair the DSM-IV. He said:

After 40 years and lots of clinical experience, I can’t distinguish at two weeks between the symptoms of normal grief and the symptoms of mild depression — and I challenge anyone else to do so. This is an inherently unreliable distinction. And I know damn well that primary care doctors can’t do it in a 7-minute visit. This should have been the most crucial point in DSM-5 decision-making because primary care docs prescribe 80 percent of all antidepressants and will be most likely to misuse the DSM-5 in mislabeling grievers.

Returning now to the essay “Complicated Grief,” let’s look at Dr. Cacciatore’s response. She commented how the bereaved were again at risk of being diagnosed and “treated” for “absolutely normal feelings and experiences” after a painful and traumatic loss. Responding to the above description of complicated grief, she said:

Ha! Social norms? Around grief? Talk about pathology! Western culture’s “social norms” and expectations around grief, especially when traumatic, are as abnormal and avoidant as any society could get. The average bereavement leave is three days, many bereaved parents are medicated within days or weeks after a traumatic loss (even in the presence of data to suggest these medications can be harmful and iatrogenic), and mourners are expected, and then pressured, to get back to ‘life-as-usual’ often within weeks or mere months, even after traumatic death. And our social networks often fail as others’ tolerance wanes in the months and years that follow.

Perhaps there is better guidance for conceiving a time frame for grief and bereavement in the book of Ecclesiastes (3:1-8) than in the DSM. There the Preacher said there is a season and a time for everything under heaven. Notice that he doesn’t try and quantify “season” or “time.” A time to be born and a time to die; a time to weep and a time to laugh; a time to mourn and a time to dance; a time to keep silent and a time to speak. When weeping turns to laughing, when mourning is replaced by dancing, then the season of grief has run its course. However, when individuals attempt to pathologize human emotion by blurring the line between grief and psychiatric disorder, it is a good thing that people like Joanne Cacciatore and Allen Frances choose to speak up and not remain silent.

04/22/15

A Drug in Search of a Disorder

© Sergey Nivens | 123RF.com

© Sergey Nivens | 123RF.com

When the DSM-5 was published in May of 2013, binge eating came out of the closet of Appendix B, the section for potential “disorders” needing further study. “Binge Eating Disorder” became a psychiatric diagnosis (Code: 307.51) in its own right. Before that time, binge eating had received a backhanded diagnosis under the rubric of “eating disorder not otherwise specified.”  Without official standing as a coded eating disorder, binge eating suffered from diagnostic insecurity and poor self-esteem. It didn’t have an official diagnostic category like anorexia and bulimia or an FDA-approved medication to treat it. But now, less than two years since it became an official psychiatric disorder, that is no longer the case.

The American Psychiatric Association (APA) defined binge eating disorder as: “recurring episodes of eating significantly more food in a short period of time than most people would eat under similar circumstances.” Some episodes would include marked feelings of a loss of control. A binge eater might eat too quickly, even when not hungry. They may feel guilty, embarrassed or disgusted. They may binge eat alone to hide the behavior. “This behavior is associated with marked distress and occurs, on average, at least once per week over three months.” There is a more complete description of the diagnostic symptoms here in “Promoting Amphetamines for Over-Eating.”

On January 30, 2015, the FDA announced that the ADHD drug Vyvanse (lisdexamfetamine dimesylate) was approved to treat binge-eating disorder in adults. It is the first such drug approved to treat this condition. “Vyvanse was reviewed under the FDA’s priority review program.” Expedited reviews can be done to treat a serious condition, especially if it’s seen to provide “a significant improvement” over available therapies. But, “Vyvanse is not approved for, or recommended for, weight loss. Its efficacy for weight loss has not been studied.”

Common side effects from Vyvanse include: dry mouth, insomnia, increased heart rate, jittery feelings, constipation, and anxiety. More serious, but less common side effects include: “psychiatric problems and heart complications, including sudden death in people who have heart problems or heart defects, and stroke and heart attack in adults.”  Vyvanse might also cause “psychotic or manic symptoms, such as hallucinations, delusional thinking, or mania, even in individuals without a prior history of psychotic illness.” Oh, and it’s a Schedule II controlled substance with a high potential for abuse. In fact, OxyContin, fentanyl and cocaine are also Schedule II controlled substances. The DEA said these drugs are considered dangerous, “with use potentially leading to severe psychological and physical dependence.”

The FDA Adverse Events Summary for Vyvanse reported the following adverse events out of 14,311 consumers to its FDA Medwatch reports between 2004 and 2012: off-label use; insomnia; DECREASED APPETITE; aggression; headache; anxiety; nausea; DECREASED WEIGHT; irritability; fatigue; SUICIDAL  IDEATION; depression; agitation; overdose; feeling abnormal; abnormal behavior.

The New York Times reported that the marketing strategy for Vyanse sheds light on how pharmaceutical companies seek to “influence the treatment and diagnosis of a medical condition” in order to make billions of dollars in sales. Shire, the pharmaceutical company dispensing Vyvanse, seems to have followed a familiar drug industry method of promoting awareness of a disorder before more directly marketing its treatment.

Soon after Shire won FDA approval of its drug to treat Binge Eating Disorder, Monica Seles began to make the rounds of television talk shows such as “Good Morning America” and “The Dr. Oz Show” to relate her personal struggle with binge eating. She was also interviewed by People Magazine. Seles said that one of the reasons she decided to do this campaign was “to raise awareness that binge eating is a real medical condition.” Seles is a paid spokesperson for Shire. She declined to say what she’s getting paid by Shire.

Shire CEO Flemming Ornskov said that about five years ago researchers noticed the similarities between ADHD and binge eating, so they decided to study Vyvanse for the condition. As early as 2011, Shire’s CEO said that the company hoped to generate “multiple billions of dollars” from expanding Vyvnase use into new areas of illness, like schizophrenia, depression and binge-eating. International Business Times reported that in 2014 Vyvanse made $1.5 billion for Shire in sales for 2014. The company hoped to grow its revenue from the $4.91 billion it made in 2013 to $10 billion by 2020 And Vyvanse is a significant part of that projection. Shire’s current patents for Vyvanse don’t expire until 2023. The approval of Vyvanase for BED means that Shire will gain an additional three years of exclusivity with the drug.

In her article for The New York Times, Katie Thomas quoted Dr. Timothy Walsh of Columbia University, as saying: “Once a pharmaceutical company gets permission to advertise for it, it can often become quite widely prescribed, and even tend to be overprescribed, and that’s a worry.”

There were 3 clinical trails in process for additional potential drug treatments for BED:  Cymbalta (Eli Lily), Lamictal (GlaxoSmithKline), and Nuvigil. Cosgrove et al. reported that the DSM-5 work group that approved binge eating as a diagnosis included three individuals with financial ties to Eli Lily, three people with relationships to GlaxoSmithKline and one person with a relationship to Shire.

Several articles have noted a variety of concerns with the FDA approval of Vyanse to “treat” Binge Eating Disorder. International Business Times quoted Sandy Walsh of the FDA office of media affairs as saying they had no direct evidence of how Vyvanse worked in BED: “The exact mechanism of action of the drug in reducing the symptoms of BED is … unknown.”  Melissa Gerson, the clinical director of an outpatient treatment center specializing in eating disorders, said she would not recommend a drug alone to treat BED. “I can’t imagine how you would see any long-term improvements in the symptoms.”

A Shire website, BingeEatingDisorder.com noted how someone could talk to their doctor about BED. They provided a Doctor Discussion Guide, saying on its link, “Not sure how to start the conversation with your health care provider?” A tip at the bottom of the homepage suggested that the individual could “Print, e-mail, or take a screen shot of this page, and bring it to discuss with your health care provider.”  The New York Times reported that some experts were concerned that the content appeared to coach patients on how receive a diagnosis or shop for a new doctor if they weren’t successful.

Some drug safety experts questioned why the FDA fast tracked approval of Vyanase—even foregoing a review by an advisory committee. For decades, amphetamines like Vyanase, have been known to be a widely abused class of drugs when prescribed for obesity. The marketing end run done by Shire to avoid this pitfall was to promote Vyanase for binge eating and acknowledge that about 80% of the people with BED are overweight or obese WHILE COMPLETELY IGNORING the history of amphetamine abuse with weight loss. Don’t forget that weight loss and appetite suppression are already known to be common side effects when taking Vyanase and other amphetamines. And the FDA didn’t see this move or call them on it?

A spokesperson for the FDA said that Vyanase was granted priority approval because there was no other drug treatment available for BED. “And it did not ask an advisory committee to review the issue because Vyanase is already sold as an ADHD drug and its safety profile is well known.” REALLY?  Dr. Daniel Carlatt said:

I’m concerned that the FDA’s approval of Vyvanse for binge eating disorder is going to worsen our problems with stimulant abuse. . . . Vyvanse is a derivative of Dexedrine. We’ve seen epidemics of Dexedrine abuse in the past when it was used to help people diet. I predict that the FDA has just opened the gates to another similar epidemic – after all, binge eating disorder is a subjective diagnosis that could be potentially expanded to cover many millions of people.

12/24/14

Where There’s Smoke …

As much as 4 ½ years before the publication of the DSM-5, there was growing public criticism of the American Psychiatric Association (APA) and the process they used to develop it. The amazing thing about this criticism is that it was from within the ranks of psychiatry itself … by psychiatrists who had been in charge of previous revisions of the DSM.

In a 2008 article, Benedict Carey of the New York Times pointed out the importance of the DSM as a “medical guidebook and a cultural institution.” It is used to help doctors make diagnoses and to provide diagnostic codes to insurance companies. The National Institute of Mental Health made the use of DSM criteria a requirement for funding research. But for the first time, the APA required its DSM contributors to sign a nondisclosure agreement.

Research psychiatrist Robert Spitzer said that when he first heard about the agreement, he went “bonkers.” Spitzer said: “Transparency is necessary if the document is to have credibility, and, in time, you’re going to have people complaining all over the place that they didn’t have the opportunity to challenge anything.”

Robert Spitzer, the chair of the “landmark” third edition of the DSM, has been hailed as the rescuer or savior of psychiatry. Allen Frances, the chair of the 4th edition of the DSM said in his book, Saving Normal, that Spitzer was a rare man. “Without Robert Spitzer, psychiatry might have become increasingly irrelevant.” Even critics of modern psychiatric diagnosis, such the authors of the book Mad Science, acknowledge Spitzer’s importance to psychiatry: “Robert Spitzer was a most unlikely rescuer of American psychiatry.”

On June 26, 2009, Frances published an article in the Psychiatric Times where he identified what he saw a grave problems with the DSM-5. He also was critical of the lack of transparency. Pointing to his own efforts with the DSM-IV, he said their goal had been to ensure that everyone would understand what they were doing and how they were going about it. “There was explicit accountability for decision making on all changes.” He cautioned against the stated ambition to effect a “paradigm shift” in psychiatric diagnosis with the DSM-5.

So long as psychiatric diagnosis is stuck at its current descriptive level, there is little to be gained and much to be lost in frequently and arbitrarily changing the system. Descriptive diagnosis should remain fairly stable until, disorder by disorder, we gradually attain a more fundamental and explanatory understanding of causality.

Frances specified his concerns with the DSM-5 process, which included the following: 1) there was no scientific basis to justify a paradigm shift in psychiatric diagnosis at this time; 2) there was a failure to provide clear methodological guidelines on the level of empirical support for the changes; 3) there was a failure to be open to wide scrutiny and useful criticism; 4) there was a failure to set and meet clear timelines; there was a likelihood that time pressure would lead to an unconsidered rush on last-minute decisions.

The members of the APA working on the DSM-5, including the DSM-5 Chair, David Kupfer, responded APA to Frances on July 1, 2009. They suggested that both Spitzer and Frances were repeating “factual errors and assumptions” about the development of the DSM-5. After their refutation of the concerns expressed by Frances, they stated:

Both Dr. Frances and Dr. Spitzer have more than a personal “pride of authorship” interest in preserving the DSM-IV and its related case book and study products. Both continue to receive royalties on DSM-IV associated products. The fact that Dr. Frances was informed at the APA Annual Meeting last month that subsequent editions of his DSM-IV associated products would cease when the new edition is finalized, should be considered when evaluating his critique and its timing.

Robert Spitzer responded to the criticisms raised about Allen Frances and himself on July 2, 2009. Spitzer noted how the DSM-5 debate had taken an ugly turn, by suggesting that he and Frances were critiquing the DSM for financial reasons. He limited his comments to what he saw as the core issue of transparency. After raising a series of questions with regard to the opaqueness and “empty rhetoric” on the DSM-5 as the most open and inclusive DSM ever, Spitzer saw two possible reasons for the lack of transparency. First, the answers to his questions were known, but for some reason, the DSM leadership was withholding it; perhaps to shield themselves from criticisms. A second possibility was that the DSM-5 leadership didn’t know the answers to his questions. “Given their plan to publish DSM-V in May 2012, if the second possibility is the case, it is inconceivable that this publication deadline could realistically be met. “

Both Spitzer and Frances continued their challenges to the process of review and approval of the DSM-5 by the APA and gained more support and even some victories. You can also read a more detailed description of the dispute here. The publication of the DSM-5 was delayed until May of 2013, but the controversy merely grew. Allen Frances became one of the most vocal critics of the DSM-5, with multiple blogs and articles looking at the problems and concerns. He’s even written two books, Saving Normal and Essentials of Psychiatric Diagnosis as a result of this controversy. You can scroll through some of his articles on the Huffington Post for starters.

Oh and with regard to the veiled accusation of Spitzer and Frances criticizing the DSM-5 for financial reasons, David Kupfer, Chair of the DSM-5 Task Force, has been outed for failing to report financial interests in Adaptive Testing Technologies, a company that designs tests and implements large scale adaptive testing systems for mental health assessment. After an investigation, the APA said (Letter-to-Assembly-20140114.pdf): “Dr. Kupfer should have disclosed to APA his interest in PAI in 2012.” However, it did not find that his interest in PAI had any influence on DSM-5’s inclusion of dimensional measures for further study in Section 3. One blogger, 1 Boring Old Man said:

It seems like Dr. Kupfer et al. are pursuing a strategy of only acknowledging this particular Conflict of Interest when forced, as in the situation with JAMA Psychiatry, and avoiding talking about it otherwise – mirrored so far by the APA President and Board of Trustees.

 

10/15/14

Psychiatry’s Mythical Phoenix

Prominent research psychiatrists are beginning to sound like their “antipsychiatric” critics. They are saying the current DSM diagnostic system isn’t valid; that something new, something scientifically sound and useful for treating patients is needed. One of these research psychiatrists is Thomas Insel, the Director of the Director of the National Institute of Mental Health (NIMH). He dropped a bombshell last year when he announced that the NIMH would be “re-orienting its research away from DSM categories.” The New York Times quoted Insel as saying: “As long as the research community takes the D.S.M. to be a bible, we’ll never make progress. . . . People think that everything has to match D.S.M. criteria, but you know what? Biology never read that book.”

So the NIMH has developed a new research strategy to classify mental disorders based upon “dimensions of observable behavior and neurobiological measures.” This strategic plan is known as: Research Domain Criteria (RDoC). The long-term goal is for RDoC to be “a framework to guide classification of patients for research studies.” It was not meant to be a useful clinical tool. “It is hoped that by creating a framework that interfaces directly with genomics, neuroscience, and behavioral science, progress in explicating etiology and suggesting new treatments will be markedly facilitated.”

RDoC is in search of the holy grail of psychiatry: reliable biomarkers (measurable indicators of a biological state or condition) for mental disorders. This search for biomarkers has been going on for decades. David Kupfer, the chair of the DSM-5 Task Force said: “We’ve been telling patients for several decades that we are waiting for biomarkers. We’re still waiting.” Susan Kamens suggested that the imminent discovery of biomarkers has been “the driving expectation of psychiatry since its birth in the 18th century.” But there are some problems with the RDoC quest.

What RDoC proposes is to replace the DSM diagnoses used currently to frame mental health research with broad categories based upon cognitive, behavioral and neural mechanisms. This means that the NIMH will be supporting research projects that look across or sub-divide existing DSM categories. But this very same DSM is what is used to assess the potential of future NIMH-funded research under RDoC.

In an article found in Nature, “Psychiatry Framework Seeks to Reform Diagnostic Doctrine,” Nassir Ghaemi said: “It is very hard for people who have been following the DSM their entire professional lives to suddenly give it up.” Ghaemi has felt shackled by the DSM. He wanted to do some research that cut across DSM categories. But his colleagues warned him against straying too far from the DSM structure when he applied for funding from the NIMH, because peer reviewers tended to insist on research structured by the DSM. So he held off from applying.

Steven Hyman, a former NIMH director, blames the DSM for hampering research into the biological or genetic basis of psychiatric illness. He said it was “a fool’s errand” to use symptom-based DSM diagnosis with little basis in nature to try and find a biomarker. Hyman urged the NIMH to think about how biomarkers identified by RDoC would be incorporated into mental health practice with the DSM. “It would be very problematic for the research and clinical enterprises to wake up in a decade to a yawning gulf.”

But Susan Kamens sees a deeper problem with blaming the DSM for hampering the search for biomarkers—it takes for granted that the biomarkers exist. In other words, it presumes what it seeks to find. According to Kamens:

“The main difference is belief versus doubt in the hypothesis that what we call mental disorder is primarily a disorder of biology. We treat that hypothesis as unfalsifiable, as if the proof [that mental disorder is biological] arrived before the evidence. We don’t test whether the hypothesis holds; we test whether and how to make the data fit it. When critics raise doubts, they’re often accused of ignoring the very same evidence that psychiatric researchers have recently declared to be utterly insufficient.”

Kamens noted that the RDoC “blueprint” is no less theoretical that the DSM-5. While the RDoC constructs are more measurable than the categories listed in the DSM, they are “essentially no more than basic human emotions and behaviors.”  She asked how RDoC would make clinically meaningful determinations into its “domains” and “constructs”? How would the research reveal anything beyond the coordinates of normal psychological processes? “In other words, how is RDoC anything beyond basic (nonclinical) neuroscience?”

RDoC is developing a new research model that will undoubtedly yield unprecedented data, but it focuses on the biogenetic correlates and normative mapping of basic psychological processes like visual perception, language, fear responses, and circadian rhythms. The idea is to create interventions for psychological and physiological processes that deviate from the norm. For this reason, RDoC is less likely to save psychiatry than it is to resurrect eugenics.

The quest for biomarkers in psychiatry can be likened to the legend of the phoenix, a mythological bird that repeatedly rises out of the ashes of its predecessor. The DSM seems to be near end of its life-cycle. Now psychiatry is building an RDoC “nest” that it will eventually ignite, reducing both the DSM and RDoC to ashes. And from these ashes, it is hoped, a new diagnostic system—a new phoenix—will arise.

Also see my blog post, “Psychiatry Has No Clothes.”

09/3/14

Psychiatry Has No Clothes

On April 29th of 2013, there was an astounding blog post by Thomas Insel, the Director of the National Institute of Mental Health (NIMH). He said that although the DSM-5 was due to be released in a few weeks, the NIMH would be “re-orienting its research away from DSM categories.” He noted that while the DSM has been referred to as a “Bible” for the field of mental health, “It is, at best, a dictionary, creating a set of labels and defining each.” Did you get that? The Director of the NIMH said the DSM was a “dictionary” that created “labels.” It was not, then functioning adequately, in his opinion, as its title suggests: as a Diagnostic and Statistical Manual of Mental Disorders! (emphasis added)

Insel said its strength had been “reliability”, meaning that it provided a way for clinicians to use the same terms in the same way. Its weakness was that it lacked validity. DSM diagnoses are based upon a consensus about clusters of symptoms and not any objective laboratory measure. “In the rest of medicine, that would be equivalent to creating diagnostic systems based on the nature of chest pain or the quality of fever.”

Insel was not using “reliability” in a statistical sense. In “The Myth of the Reliability of DSM,” Stuart Kirk and Herb Kutchins demonstrated conclusively that the DSM-III and DSM-IIIR were not statistically reliable. In fact, using the same statistic that Robert Spitzer used to justify the major changes to the DSM in the 1970s, they demonstrated that:

The reliability problem is much the same as it was 30 years ago [before the DSM-III]. Only now the current developers of the DSM-IV have de-emphasised the reliability problem and claim to be scientifically solving other problems.

Unfortunately, the tables in Figures 1 and 2 have been removed from the online version of their article. But the tables are still available in the original article found in the Journal of Mind and Behavior, 15 (1&2), 1994, p. 71-86. These tables plainly showed how the DSM statistical reliability was not what it was claimed to be. The Selling of the DSM (1992) by Stuart Kirk and Herb Kutchins has the tables. And there is a graphic comparison of the data within Mad Science (2013) by Stuart Kirk, Tomi Gomory, and David Cohen.

Insel went on in his blog to say that the NIMH will be supporting research projects that “look across current categories” or sub-divide them in order to begin to develop a better system. “We are committed to new and better treatments, but we feel this will only happen by developing a more precise diagnostic system.” In order to work towards that goal, the NIMH launched the Research Domain Criteria (RDoC). RDoC is only a research framework for now; a decade-long project that is just beginning. You can learn more about RDoC here (on the NIMH website).

Robert Whitaker, author of Anatomy of an Epidemic, said in a March 2014 interview that Insel stating that the DSM lacked validity was an acknowledgement the “disease model” has failed as a basis for making psychiatric diagnoses.

When Insel states that the disorders haven’t been validated, he is stating that the entire edifice that modern psychiatry is built upon is flawed, and unsupported by science. That is like the King of Psychiatry saying that the discipline has no clothes. If the public loses faith in the DSM and comes to see it as unscientific, then psychiatry has a real credibility problem on its hands.

Two weeks later on May 13, 2013, a joint press release was made by Thomas Insel and Jeffrey Liebermann, the President-elect of the American Psychiatric Association (APA). They said that the NIMH and the APA had a shared interest to ensure that patients and healthcare providers had “the best available tools and information” to identify and treat mental health issues.

Today, the American Psychiatric Association’s (APA) Diagnostic and Statistical Manual of Mental Disorders (DSM), along with the International Classification of Diseases (ICD) represents the best information currently available for clinical diagnosis of mental disorders. . . . The National Institute of Mental Health (NIMH) has not changed its position on DSM-5. As NIMH’s Research Domain Criteria (RDoC) project website states: “The diagnostic categories represented in the DSM-IV and the International Classification of Diseases-10 (ICD-10, containing virtually identical disorder codes) remain the contemporary consensus standard for how mental disorders are diagnosed and treated.”

The DSM and RDoC were said to be complementary, not competing frameworks. As research findings emerge from RDoC, they may be incorporated into future DSM revisions. “But this is a long-term undertaking. It will take years to fulfill the promise that this research effort represents for transforming the diagnosis and treatment of mental disorders.”

Saul Levine, the CEO and Medical Director of the APA said on May 5, 2014 that the DSM and the RDoC will “begin to come together” as the research from NIMH is included into the way they diagnose mental illness. They know that mental illness and substance use disorders are a bio-psycho-social illness. “We work very well together with NIMH. And I think that the whole field is looking to the science coming out of NIMH to include it as a way to help get better treatment for patients in this country.”

So the APA and NIMH affirm they are working towards the same goals as complementary research frameworks. Someday the research findings of RDoC may even be included into the DSM. But until then, the NIMH will have to continue to “ooh and aah” at the APA’s DSM and ignore the nay-sayers crying: “Look at the DSM; look at the DSM!”

Does it seem that psychiatry is trying to promote an unreliable, invalid—perhaps invisible—system of diagnosis?

Also see my blog post, “Psychiatry’s Mythical Phoenix.”