Tag: Mad in America

03/1/22

Withdrawal or Relapse When Tapering Antidepressants?

© sangoiri |123rf.com

The number of antidepressant prescriptions written in primary care has continued to increase, and patients are remaining on them for longer durations of time. Yet research into maintaining or discontinuing antidepressants (ADs) in this setting has been almost nonexistent. “Maintenance or Discontinuation of Antidepressants in Primary Care,” published in September of 2021 in The New England Medical Journal, examined the relapse rates of primary care patients who expressed a desire to discontinue their antidepressant. The researchers, G. Lewis and L. Marston et al, found that patients who chose to discontinue their antidepressant therapy had a higher risk of relapse than those who maintained their current medication. However, others believed the results were misleading, because the authors misinterpreted withdrawal effects as relapse.

Lewis, Marston et al found that patients assigned to discontinue their antidepressant medication had a higher frequency of depression relapse than those who maintained their medication through the 52 weeks of follow-up done by the study. Eligible patients were between 18 and 74, and had reported at least two prior episodes of depression. All patients had been receiving and adhering to their daily regimens and had been taking their ADs for more than two years. The main exclusion criterion for the study was current depression. They investigated three SSRIs, fluoxetine (Prozac), citalopram (Celexa) and sertraline (Zoloft), which have similar pharmacologic profiles and similar mechanisms of activity, and mirtazapine (Remeron).

Relapse occurred in 39% of the patients in the maintenance group, while 56% of the patients in the discontinuation group relapsed. Quality-of-life measures and symptoms of depression, anxiety, and medication withdrawal were generally worse in patients who discontinued their ADs. “By the end of the trial, 39% of the patients in the discontinuation group had returned to taking an antidepressant prescribed by their clinician.” See the figures below.

In a critique published in The BMJ of Lewis, Marston et al, Mark Horowitz, Joanna Moncrieff and Beth Parkin said their conclusion that continuing antidepressants reduced the chance of relapse was not warranted. “Because the authors neglected to account for the possibility of antidepressant withdrawal effects being mis-classified as relapse, a fundamental problem in discontinuation trials.” Although the antidepressants were discontinued more slowly than in previous studies, the 8 weeks of discontinuation was still a relatively short taper for patients who had been taking the drugs for more than 2 years. While the approach was consistent with recommendations at the time of the trial (half the dose for one month, then half the dose every second day for one month, before stopping), they are no longer in line with the current guidance from the Royal College of Psychiatrists on Stopping antidepressants.

Antidepressant withdrawal symptoms overlap with most domains of the depression scale used to detect relapse in the study. There was also a high correlation between mean differences on the withdrawal scale and means differences on the depression scale and anxiety scale. “Together, with the overlap of withdrawal symptoms with measures of mood and relapse, this suggests that the withdrawal symptoms may account for the increase in symptom scores and relapse rate.” The reverse would be unlikely, since withdrawal symptoms included physical symptoms that were not intrinsically related to depression—dizziness, electric shocks, and headache. “Occam’s razor would suggest one condition causes several symptoms rather than requiring several conditions.”

Confounding withdrawal with relapse is consistent with the finding that most relapses occurred when withdrawal effects were at their peak, “within 6-12 weeks of when the drugs were stopped (at week 8).” Ninety percent of the total difference in relapse rates between the two arms of the study were present 12 weeks after the drugs were stopped, although this accounts for only 27% of the total follow-up time. Additionally, patients stopping fluoxetine had fewer withdrawal effects than other antidepressants, likely because of its longer elimination half-life. These patients relapsed 25% less than people stopping citalopram and sertraline, “again suggesting withdrawal effects.”

Anxiety and depression scores were the same for both groups at the end of the study. While 44% of the discontinued group had returned to their medication by this time, there was no difference in symptom scores—even with twice as many people on antidepressants in the maintenance group. “This suggests that discontinuation of antidepressants did not worsen mood after the period in which withdrawal symptoms had settled.” There were only small differences in DESS scores (Discontinuation-Emergent Signs and Symptoms) by the end of the 52 week study. Lastly, 71% of the patients in the discontinuation group correctly guessed their allocation to placebo; possibly because of experiencing withdrawal symptoms and then expecting they would get worse.

As there was no effort made to manage the potential confounding of relapse by withdrawal the current study suffers the same flaws as previous discontinuation studies and cannot provide evidence of the benefits of long-term treatment, only the difficulties of stopping it. The authors could resolve some of these concerns by analysing the correlation of withdrawal symptoms with mood scores and relapse amongst individual patients to verify if withdrawal symptoms might account for relapse. They could also re-analyse their data by excluding patients who experienced significant withdrawal symptoms (e.g. modified DESS ≥ 2) from qualifying for a diagnosis of relapse. This would provide a more robust measure of relapse, reducing the potential for the misclassification of relapse as withdrawal. They could also test whether unblinding was associated with relapse.Uncritical interpretation of this study may lead to the erroneous conclusion that antidepressants should be continued to prevent relapse, when in reality all they may be doing is preventing withdrawal symptoms. The more accurate conclusion would be that such symptoms are temporary withdrawal symptoms that can be minimised by stopping the drug more gradually, as recognised by the authors in media interviews, although not in the published paper.

Additional responses in The BMJ supported these points. Bryan Shapiro said, “Dr. Horowitz offers a valid critique of this discontinuation trial—that is, the confounding of illness relapse with antidepressant withdrawal symptoms.” Gary Singh Marlowe said, “For many patients who have been on anti-depressants for more than a few years a 2-month tapering period is insufficient.” Singh Marlowe said practitioners like him have “become increasingly aware that many of the symptoms these patients experience on stopping their anti-depressants are due to the drug withdrawal itself rather than a return of the ‘illness.’” See “Withdrawal Symptoms Cloud Findings of Antidepressant ‘Relapse’ Trial” by Peter Simon on the Mad in America website for more discussion of the Horowitz, Moncrieff and Parkin critique.

Concern that antidepressant withdrawal symptoms are being confounded with relapse symptoms of depression are not just coming from Mad in America and Horowitz, Moncrieff and Parkin. The Mental Elf reported on a systematic review done by the Cochrane Common Mental Health Disorders group on studies where antidepressants were taken for 6 months or more and then discontinued. Relapse rather than discontinuation was the primary outcome for 31 of 33 studies. Only one study reported data on withdrawal symptoms.

All included trials were at high risk of bias. The main limitation of the review is bias due to confounding withdrawal symptoms with symptoms of relapse of depression. Withdrawal symptoms (such as low mood, dizziness) may have an effect on almost every outcome including adverse events, quality of life, social functioning, and severity of illness.

Because of this flaw, the Cochrane group was not able to conclude whether any of the discontinuation strategies were safe and effective, also noting none of them employed tapering protocols beyond a few weeks. The Cochrane authors also doubted the validity of the evidence base for antidepressant continuation, as it depended “on the same and similar studies thoroughly confounded by withdrawal, which is probably mistaken for relapse.”

Consequently, it is unclear to what degree misclassified withdrawal symptoms contributed to “relapse” rates. Research suggests this could pertain to most relapses (El-Mallakh 2012; Greenhouse 1991; Hengartner 2020; Recalt 2019; Rosenbaum 1988). Moreover, withdrawal symptoms may have an effect on almost every outcome including adverse events, quality of life, social functioning, severity of illness, and anxiety and depression scores. For example, low mood and other withdrawal symptoms may register on the Hamilton Rating Scale for Depression (HAM-D) – the prioritised measure for depressive symptoms – and may result in people falsely allocated to having “severe” depressive symptoms.

Based on the review, the Cochrane review authors advised clinicians that:

  • Because of confounds, the evidence is unreliable for either discontinuation approach or risk of relapse after discontinuation.
  • It is unclear how long antidepressant treatment has to be maintained after remission. Current guidelines are based on consensus rather than evidence.
  • Evidence is lacking for appropriate discontinuation approaches for those who do not have “recurrent” depression, the elderly, and those taking antidepressants for anxiety.
  • The effect of short tapering regimens (≤ 4 weeks) was similar to abrupt discontinuation. Clinicians should expect to taper much slower, perhaps using liquid drug forms or tapering strips, while closely monitoring for withdrawal symptoms.
  • To taper effectively, clinicians will need to recognise withdrawal symptoms. Withdrawal symptoms differ from relapse or recurrence in timing of onset (within days rather than weeks), a rapid reversal after reintroduction of the antidepressant, and the emergence of somatic and psychological symptoms different from the original illness (e.g. shock-like sensations, dizziness, pronounced insomnia). Utilising the Discontinuation-Emergent Signs and Symptoms (DESS) Scale (PDF) may be helpful in monitoring reductions in dosage. When the patient’s DESS score returns to baseline after a reduction, further reduction is appropriate.
  • Mark Horowitz, who is a researcher and psychiatrist, was quoted in an article discussing the Cochrane review on Mad in America. He said:

For me, this is such a critical issue both from a personal and a professional perspective. I’m one of the hundreds of thousands of people who have had or are having long, difficult, and harrowing battles coming off long-term depressants because of the severity of the withdrawal effects. And yet, rather than being able to find or access any high-quality evidence or clinical guidance in this situation, I could only find useful information on peer support sites where people who had gone through withdrawal from antidepressants themselves have been forced to become lay experts. Since then, the Royal College of Psychiatrists has taken a great step forward in putting out guidance on Stopping Antidepressants in 2020. However, there is still a lack of research and, therefore, evidence in this area on what works for different people. I want other people to have the evidence base to come off without the same trouble I had.

American psychiatry has fallen behind Britain in protecting its citizens from the potential for iatrogenic harm of antidepressants. In May of 2018, the All-Party Parliamentary Group for Prescribed Drug Dependence published “Antidepressant Dependency and Withdrawal.” At the bottom of the first page is a disclaimer that says this is not an official publication of the House of Commons or the House of Lords. Yet it seems to have influenced the Royal College of Psychiatrists to make public the above linked information for anyone who wants to know more about “Stopping Antidepressants in 2020.”

The Executive Summary of “Antidepressant Dependency Withdrawal” said it was incorrect to view antidepressant withdrawal as largely mild, self-limiting (typically resolving between 1-2 weeks) and of short duration. Available research showed that antidepressant withdrawal reactions are widespread, with incidence rates ranging from 27% to 86%. Nearly half of those experiencing withdrawal described it as severe. Approximately 25% of antidepressant users experienced withdrawal reactions for at least 3 months after cessation; many experienced AD withdrawal for longer than 6 months.

Antidepressants fulfill the criteria for dependency-forming medications within the DSM, the ICD, and the WHO’s definition of dependency. “It is more reasonable to classify antidepressants as potentially dependency-forming medications than not.” Not only do they cause withdrawal in a large proportion of users, there is evidence antidepressants generate tolerance in up to 25% of users. About a third of antidepressant users report being “addicted”, according to their own understanding of the concept.

“The escalation of long-term antidepressant use combined with the misdiagnosis of withdrawal reactions warrants serious concern.” The length of AD use has doubled over the past decade, fueling a rise in prescriptions for the drugs. The evidence suggests this lengthening duration may be partly rooted in “the underestimation of the incidence, severity and duration of AD withdrawal reactions.” This underestimation may have led to many withdrawal reactions being misdiagnosed as relapse or as failure to respond to treatment with AD medications.

There is one final observation to make about the Lewis, Marston et al study. “Maintenance or Discontinuation of Antidepressants in Primary Care,” was of 150 general practices in the United Kingdom, and yet it was published in the prestigious American journal, The New England Journal of Medicine. I wonder if the researchers were attempting to reach a more receptive and less critical audience than if they had published in a prestigious British journal like The BMJ, which did publish the critique of Horowitz, Moncrieff and Parkin.

06/22/21

Drugs Do Not Fix Chemical Imbalances

© lightwise | 123rf.com

Researchers at Harvard’s McLean Hospital observed that the public perception of mental illness was increasingly understood in neurobiological and genetic terms. There is some evidence that these explanations had an unintended consequence of reducing optimism for recovery among individuals with depression. Despite this, very little is known about how these beliefs interact with the treatment process and outcomes in a psychiatric treatment setting. They wanted to know if the language used affected treatment protocols and patient expectations. They found that believing depression was caused by a chemical imbalance was related to poorer treatment expectations.

In fact, they found that more depressed individuals showed a stronger relationship between chemical imbalance beliefs and lower treatment expectations. In “The dangers of the chemical imbalance theory of depression,” Derek Beres noted while the chemical marker serotonin is correlated with depression, it does not cause depression. “Decade after decade, however, we’ve been marketed the idea that chemical imbalance is the culprit behind depression.”

Instead of doctors diagnosing patients, they increasingly confirm what the patient suspected all along. The patients self-diagnose because they saw an advertisement or listened to a friend. Doctors too often comply without further investigating of the reasons for their reported distress. Medicalizing mental health softens the stigma of depression, but it also disempowers the patient. In “Stressors and chemical imbalances: Beliefs about the causes of depression in an acute psychiatric treatment sample,” the McLean researchers wrote:

More recent studies indicate that participants who are told that their depression is caused by a chemical imbalance or genetic abnormality expect to have depression for a longer period, report more depressive symptoms, and feel they have less control over their negative emotions.

Doctors, media, and advertising come together with a similar message. Everyday blues is a real medical condition, everyone is susceptible to clinical depression, and drugs correct the underlying physical conditions. Counseling aimed at self-insight seems to serve little purpose. The McLean team of researchers found patients expected little from psychotherapy and a great deal from pills. “When depression is treated as the result of an internal and immutable essence instead of environmental conditions, behavioral changes are not expected to make much difference.”

Doctor Ronald Pies referred to and cited “Stressors and chemical imbalances” in his January article in Psychiatric Times, “What We Tell Patients about Depression, and What They Say They Have Been Told.” Pies said the study found that the most commonly endorsed explanations for depression were psychosocial explanations, not “the chemical imbalance notion.” He said popular beliefs about the cause of depression could be adopted from a variety of sources, including television advertisements and anti-stigma campaigns promoting biogenetic explanations. These beliefs could also come from individual treatment experience. “All of this is simply to note that popularization of the chemical imbalance canard is almost certainly an over-determined effect, in which the role of psychiatrists (or other clinicians) is but 1 possible causal factor.”

But he seems to have glossed over the primary finding of “Stressors and chemical imbalances.” Patients who believe a chemical imbalance or genetic abnormality caused their depression do worse. The results of the study’s abstract said:

We found that although psychosocial explanations of depression were most popular, biogenetic beliefs, particularly the belief that depression is caused by a chemical imbalance, were prevalent in this sample. Further, the chemical imbalance belief related to poorer treatment expectations. This relationship was moderated by symptoms of depression, with more depressed individuals showing a stronger relationship between chemical imbalance beliefs and lower treatment expectations. Finally, the chemical imbalance belief predicted more depressive symptoms after the treatment program ended for a 2-week measure of depression (but not for a 24-hour measure of depression), controlling for psychiatric symptoms at admission, inpatient hospitalizations, and treatment expectations.

“Stressors and chemical imbalances” was not critiquing psychiatry for spreading the chemical imbalance theory, which Pies has called a kind of urban legend. The researchers examined etiological beliefs about depression and studied how they were related to treatment expectations and outcomes. If you believed in the chemical imbalance theory of depression, you tended to have poorer treatment outcomes. But that isn’t the only problem with believing in this “urban legend.”

Consequences of Believing in a Chemical Imbalance

 

Dutch researchers interviewed people who were given medical advice to discontinue antidepressants. The participants’ use of antidepressants was determined to be “not indicated” based upon clinical practice guidelines. This meant that participants had no current mental health diagnoses, no history of recurring mental health problems, and they had been taking antidepressants longer than nine months. Reporting on the study for Mad in America, Peter Simons said that despite receiving advice to discontinue, more than half refused to stop taking their antidepressant. The researchers identified two significant barriers to discontinuation.

The first was fear that if they ever stopped taking antidepressants, they would not be able to cope with the rebound depression. One of the participants said: “That’s my biggest fear. The misery I was in, before I got these medicines. I never want to relive that. I never want to go back to how I felt then. And because of this fear, I just can’t attempt to stop them.” Another person said if she would remain well, she would quit tomorrow. “But . . . to go through the hell I went through again? No.”

The second barrier was a belief in the serotonin deficiency theory, the chemical imbalance theory. The participants described their antidepressant use as supplying a deficient substance they needed to function normally. This resulted in their acceptance of a lifelong dependency. “I just need it. For me, this isn’t a psychological illness, it’s physical. And my body isn’t able to make enough serotonin, so I take the pill to supply it.”

There was a comparison to diabetes by her doctor reported by one participant.

She (the GP) told me, you should see it like you have a deficiency in your brain, you miss a certain substance and the medicine supplies it. She told me it’s just like someone with diabetes who needs insulin for the rest of their life. Well, I kind of believe that, so never questioned my use since.

The Dutch researchers said the biological model for depression seemed to backfire:

Another important barrier was the notion that antidepressants are necessary to supply the deficient serotonin. This serotonin deficiency resulted in patients expecting continued use of their medication. Presumably this is the result of the explanation the GPs gave to their patients at first prescription, or at least what patients (choose to) remember. The biological model for depression seems to backfire, making it difficult to persuade the patient to discontinue the drug. This is an important and new finding. GPs must keep this in mind while explaining the course of treatment for depressive and anxiety disorders. On the other hand, uneasiness with the perception of a biological cause could enhance attempts to stop antidepressants.

The chemical imbalance theory of depression is a false, unfounded report. For decades, the idea has been falsely marketed to consumers that a chemical imbalance is the culprit behind depression. Even psychiatrists, as seen with Dr. Pies, want to distance themselves from this “canard.” This urban legend is associated with poorer treatment outcomes and leads individuals with no apparent clinical need to remain on antidepressants instead of tapering off of them. We need to ask, how did we get here?

In his interview for Scientific American, “Has the Drug-Based Approach to Mental Illness Failed?”, Robert Whitaker described his journey away from the conventional understanding that depression and schizophrenia were caused by chemical imbalances in the brain, to founding the webzine, Mad in America.

Whitaker said he is convinced that psychiatric medications cause net harm when used over the long term. “I wish that weren’t the case, but the evidence just keeps mounting that these drugs, on the whole, worsen long-term outcomes.” Increasingly, he is not sure the medications provide real a short-term benefit either. “When you look at the short-term studies of antidepressants and antipsychotics, the evidence of efficacy in reducing symptoms compared to placebo is really pretty marginal, and fails to rise to the level of a ‘clinically meaningful’ benefit.” His concern and the concern of Mad in America has grown beyond studies with psychiatric medications:

Mad in America’s mission is to serve as a catalyst for rethinking psychiatric care in the United States (and abroad). We believe that the current drug-based paradigm of care has failed our society, and that scientific research, as well as the lived experience of those who have been diagnosed with a psychiatric disorder, calls for profound change.

He thinks our society organized itself with regard to mental illness around a false narrative presented as a narrative of science. In the early 1980s, we began to hear that psychiatric disorders were cause by chemical imbalances in the brain; and that like insulin did for diabetes, there was a new generation of psychiatric medications that could fix those imbalances. “We came to believe that there was a sharp line between the ‘normal’ brain and the ‘abnormal’ brain, and that it was medically helpful to screen for these illnesses, and that psychiatric drugs were very safe and effective, and often needed to be taken for life.”

But what can be seen clearly today is that this narrative was a marketing story, not a scientific one. It was a story that psychiatry, as an institution, promoted for guild purposes, and it was a story that pharmaceutical companies promoted for commercial reasons. Science actually tells a very different story: the biology of psychiatric disorders remains unknown; the disorders in the DSM have not been validated as discrete illnesses; the drugs do not fix chemical imbalances but rather perturb normal neurotransmitter functions; and even their short-term efficacy is marginal at best.

The above quotes from participants in the Dutch study and the quote on how the biological model for depression backfired, are found in the research article published in Therapeutic Advances in Psychopharmacology, “Patients’ attitudes to discontinuing not-indicated long-term antidepressant use.”

01/5/21

In Search of a Disorder for Ketamine

K© niceideas | 123rf.com

Interest in getting ketamine approved to treat depression persists, even after the approval of esketamine (Spravato) in March of 2019. The rapid reversal of depression symptoms was first shown with ketamine. But as it was a generic drug, there was no financial motivation for the pharmaceutical industry to invest in its potential. There is still a mystery in knowing exactly how ketamine exerts its effects. Now there is some who theorize it may help with alcoholism.

Soon after the FDA approval of Spravato in 2019, a team of researchers at Weill Cornell Medicine revealed how ketamine induced changes in the brain circuits of mice. Carlos Zarate, who was not involved in the study, said: “It’s a remarkable engineering feat, where they were able to visualize changes in neural circuits over time, corresponding with behavioral effects of ketamine.” He thought the work would help guide what treatments should be doing before they are moved into the clinical setting. The study used cutting-edge technology to visualize and manipulate the brains of stressed mice. Mice subjected to stress display the equivalent of depressed behavior and with antidepressant treatment, they often improve.

In the new study, the researchers used light microscopes to observe tiny structures called spines located on dendrites (a neuron’s “input” wires) in the mPFC [medial prefrontal cortex] of stressed mice. Spines play a key role because they form synapses if they survive for more than a few days.

STAT News said the medial prefrontal cortex is an area of the brain that is thought to be involved in depression. Research has suggested chronic stress can affect the number of synapses in the brain. The Weill Cornell researchers wanted to see if ketamine could reverse those effects. “So they looked at what are known as dendritic spines, tiny projections that shoot off branches of neurons known as dendrites. Most dendritic spines contain functional synapses, so scientists consider them a sign of a connection between two neurons.”

After giving the mice a dose of ketamine, the effects on behavior were rapid. They were more likely to attempt to escape from an unpleasant situation, preferred sugar water over plain water and explored a maze. All three behaviors are indications the mice are not stressed. However, the effects on synapse formation were slower. New synapses did not appear until around 12 hours after a dose of ketamine. This suggested ketamine’s rapid effect was not dependent on the formation of new synapses.

The researchers then used a tool that caused the newly formed synapses to collapse. Within two days, some of the behaviors of the mice reverted back to the behaviors evident during chronic stress. This suggests the new synapses and their continuation are critical to maintaining at least some of ketamine’s effect on behavior.

Zarate noted one limitation of the study was there was only a single dose of ketamine, rather than the multiple doses that occur with human treatment. Might the spines remain after weeks of repeated treatments? “Ongoing effects with repeated administration, we don’t know.” That will be the next question asked in further research.

One caution to remember there is a big difference between stressed mice and depressed humans. Anna Beyler, a neuroscientist of the University of Bordeaux, France, also added: “There’s no real way to measure synaptic plasticity in people, so it’s going to be hard to confirm these findings in humans.” Stay tuned for more mice research.

However, ketamine research is not focused solely on depression. There was a study published in Nature Communications that investigated how maladaptive reward memories (MRMs) are associated with developing and maintaining the overconsumption of alcohol: “Ketamine can reduce harmful drinking by pharmacologically rewriting drinking memories.” The researchers found that a single infusion of ketamine combined with motivational enhancement (MET) counseling can help heavy drinkers curb their drinking. Ninety people who drank an average of four to five pints of beer a day were recruited for the study.

These findings demonstrate MRM reconsolidation interference by ketamine and rewriting of reward structures surrounding alcohol. The subsequent, lasting clinical benefits observed suggest that this one-session intervention approach should be pursued in the future treatment of alcohol related disorders.

The study’s lead researcher, Ravi Das said to Merrit Kennedy of NPR: “When people become addicted, they’re learning that kind of behavior in response to things in their environment.” He added that those memories can be long lasting and become ingrained. “Current treatments don’t target those.” Das and the other researchers thought ketamine might be able to target a heavy drinker’s memories of drinking triggered just before they received a dose of ketamine. The results were said to be a dramatic decrease in the amount of alcohol consumed. “Given the high levels of problematic drinking in the current sample, one may reasonably expect similar effects to be observed in a more severely dependent/treatment-seeking population and there is now a strong rationale to conduct such clinical trials in formally diagnosed populations.”

Peter Simons reviewed the study for Mad in America, “Ketamine for Harmful Drinking: A Look at the Data.” One of the first things he noted was while the article claimed “ketamine can reduce harmful drinking by pharmacologically rewriting drinking memories,” the results were more nuanced and not as positive as presented. “In fact, the group that did not receive ketamine had lower levels of alcohol use throughout the study.” The researchers based their experimentation on a memory-based theory of how problem drug abuse develops. According to the theory, memories of the rewards associated with drug use are triggered when a person sees the drug, which causes them to want more of it.

The theory underlying this study is that ketamine may cause short-term memory loss. But the research did not directly test this idea. Rather, the researchers looked at a broader idea—that a ketamine infusion may reduce problematic drinking.

There were three groups in the study. One group received a placebo instead of ketamine and also the alcohol memory task (RET+PBO), another ketamine and alcohol memory task (RET+KET), and the third group had no memory task and ketamine (NO RET +KET). The researchers found that the ketamine infusion and alcohol task group drank far less than their baseline levels. But they also began the study with a significantly higher baseline of drinking than the other two groups. All three groups did better over time and the group that received ketamine and the alcohol task (RET+KET), did worse than the other groups until the nine-month end point of the study, when all three groups were drinking about the same amount of alcohol. The researchers interpreted their findings as meaning that ketamine successfully reduced the amount of alcohol drank by the study’s participants. See the following chart.

However, as Peter Simon noted, “This finding is what would be predicted by chance.”

One statistical phenomenon that occurs by chance is called regression to the mean. In that phenomenon, groups that start at an abnormally high (or low) point on any scale are more likely to return to the average over time. For instance, let’s say an event occurs—like a wedding, or a holiday celebration, during which you drink much more than usual. You are most likely to return to your regular drinking amount afterward. And that’s what we see here.

The researchers do acknowledge this possibility, saying in their study, “We cannot rule out regression to the mean as a contributing factor to the observed reduction in alcohol consumption.” Yet they denied that regression to the mean was responsible for their results, calling that commonly occurring statistical phenomenon “highly unlikely.” Asserting the significance of their findings, the researchers said the lasting clinical benefits observed suggested this intervention approach should be pursued in the future treatment of alcohol use disorders.

There is another limitation to the significance of the findings in how they conceived harmful alcohol use. The researches understood problem drinking as fundamentally a learned behavior problem. “Overconsumption disorders such as harmful drinking, alcohol and substance use disorders (AUDs, SUDs), which represent leading causes of global preventable mortality and morbidity, are fundamentally acquired or learned behaviours.” Such a conception of substance use disorders is reductionistic. There is a clear element of learned behavior in the development of a drinking problem, and there is clear evidence of there being a physiological element for many individuals with alcohol use disorders (See “The Genetic Connection”).

Following the thinking of Carleton Erickson in The Science of Addiction, there is a distinction between what earlier editions of the DSM called drug abuse and drug dependence. “According to these criteria, drug abuse is intentional, ‘conscious,’ or voluntary. Drug dependence is pathological and unintended.” Alcohol dependent people have a dysregulation of the mesolimbic dopamine system and typically cannot stop drinking without intensive intervention. There is an overlap between individuals with an alcohol abuse problem and those with an alcohol dependence problem, illustrated by this chart derived from the first edition of The Science of Addiction:

Alcohol Abuse Alcohol Dependence Alcohol-Seeking
Mild Little/None
Moderate Some
Severe Mild A Lot
Moderate Even more
Severe All the Time

Alcohol Dependence was a continuous and compulsive pattern of use, often with tolerance and withdrawal symptoms, suggestive of a physical dysregulation. Most alcohol abusers “never become addicted in any meaningful sense.” The abuse/dependence distinction for substance use disorders was part of the DSM diagnostic system before the DSM-5. The DSM-5 collapsed the distinction between abuse and dependence, establishing a continuum of alcohol use disorder instead of two separate disorders of alcohol abuse and alcohol dependence. As a result, the above noted diagnostic distinction between abuse and dependence was lost or became unclear. The ability to discern diagnostically between learned substance problems and substance problems driven by physical dysregulation was muddled in the DSM-5.

Only individuals who were never formally diagnosed with a substance use disorder were included in the study. So, this meant that individuals who were most likely to exhibit symptoms of physical dependence, such as withdrawal, cravings and an inability to limit or control their alcohol use, were excluded from the study. Was the subject pool of participants unintentionally made up of individuals most likely demonstrate the study’s results? Were the individuals in the study heavy drinkers who were not on the way to developing what was called an alcohol dependence disorder? What works with undiagnosed heavy drinkers may not work with individuals who are alcohol dependent, who have a moderate or severe form of alcohol use disorder.

For more information on DSM diagnosis and substance use, see: Misdiagnosing Substance Use. For more information on ketamine, see: Ketamine to the Rescue?, Family Likeness In Depression Drugs? or Psychedelic Depression.

12/22/20

Psychiatry Is Different, Not Irrelevant

© lightwise | 123rf.com

The Vice article, The Movement Against Psychiatry, opened with a disturbing story about two women who sought help from the mental health system, but received very different and ultimately harmful results. One woman refused to take medication or see her therapist and her condition deteriorated until she was eventually psychotic and incarcerated. The second woman served as a sergeant in the Army and sought psychiatric help while she was receiving medical care in Germany when she learned her convoy hit a roadside bomb in Iraq. “I walked straight down the hallway to the psychiatry office because I thought that’s what you do when you need help.” That began 13 years of being treated with 45 different medications, up to 18 at the same time until she said enough.

“The Movement Against Psychiatry” by Shayla Love used these two women to illustrate the contrasting position at the center of the debate of how to fix—or to do away with—the way we treat mental illness: over and under medication. At the core of this issue are the differences between psychiatry and what is called anti-psychiatry or critical psychiatry. But Love does not give a very fair presentation of the so-called anti-psychiatry position. This assessment is shared by Robert Whitaker, the journalist, author, and founder of madinamerica.com, which Love said was probably “the most active and legitimate critical psychiatry platform that exists today.”

Whitaker wrote a response to the Love’s article, “Vice, MIA and The Movement Against Psychiatry,” in which he presented a three-pronged assessment of what Love wrote. First, he gave an explanation of the mission of Mad in America. Then he addressed a common criticism made against himself and the Mad in America website that Love repeated, namely that Whitaker and his webzine distort the scientific record of psychiatry. Lastly, he saw the article as an opportunity to illustrate how the media, represented by Vice, perpetuated the conventional narrative about psychiatry.

In a section of his article titled: “Understanding Mad in America,” Whitaker gave a description of how the webzine seeks to be a forum for developing a new narrative to guide society’s thinking and care about psychiatry and its drug treatments. He then went on in “Deconstructing the Vice Article,” to describe some surprising details about what seems to be Love’s failure to remain unbiased. Love did not interview Whitaker for her article, instead she contacted him by email one week before her article was to be published. Whitaker also invited her to contact the researchers whose work he was said to have misinterpreted in order to see whether they thought his reporting of their work was inaccurate.

It seems she also failed to do that as well. Whitaker said, “All she needed to do was read the studies, call Harrow or Jobe, and she could have had a blockbuster article, anchored by research that revealed there was a scientific rationale for a “movement against psychiatry.”

Martin Harrow and Thomas Jobe had investigated long-term outcomes of patients diagnosed with psychotic disorders. They found at the 15-year mark that the recovery rate for schizophrenia patients off medication was eight times better than those who were medication compliant. Whitaker noticed in their data that even patients with milder psychotic disorders who stayed on antipsychotics had worse long-term outcomes than those with schizophrenia who got off medications. Harrow and Jobe later published further analysis of their long-term data and cited him and Joanna Moncrieff among those who questioned the received narrative for long-term outcomes for those who were using antipsychotics. Harrow and Jobe said:

Overall, the longitudinal studies cited do not provide conclusive proof of a causal relationship between being off medications and being psychosis free. They do clearly indicate that not all schizophrenia patients need continuous antipsychotics for a prolonged period, providing extensive evidence of samples of medication-free schizophrenia patients with favorable outcomes.

Whitaker’s deconstruction of “The Movement Against Psychiatry” illustrates how the article reinforces the conventional narrative of psychiatry. Read an op-ed article for MedPage Today, “Why Anti-Psychiatry Now Fails and Harms,” if you want an example of what is meant by the conventional narrative. Coincidentally, two of the three authors of the MedPage Today article were cited or quoted by Love as supporting the conventional narrative.

The Vice article was presented as an exploration of the “movement against psychiatry,” and yet you can see, once it is deconstructed, how it told a story that surely pleased the promoters of the conventional narrative, and put the “critics” on the defensive at almost every turn.

The concluding comments in Whitaker’s article appear to invite further dialogue between psychiatry and so-called “anti-psychiatry,” but he seems to be frustrated with the way many media outlets—Vice being the example here—protect and perpetuate the conventional narrative of psychiatry:

I hope that deconstructing this article—and revealing the journalistic standards that are on display—helps reveal the depth of the challenge for those who would like to see “psychiatry reimagined.” Unfortunately, this struggle is regularly hindered by the fact that media are often poised to report in ways that protect the conventional narrative, and look askance at those who would challenge it. But as is the case in any struggle, it’s always good to know what you are up against.

It also seems that Love may have misrepresented more than just Whitaker and Mad in America. Awais Aftab, a psychiatrist and author of an interview series for Psychiatric Times,” was prompted to clarify the context surrounding Love’s quotes of him the day after “The Movement Against Psychiatry” was published in: “The VICE Story: Beyond Anti-psychiatry.” Dr. Aftab appeared to be attempting a corrective against the potential for “the VICE Story” to lead too far into a “polarizing discourse.” He said he does not identify as a “critical psychiatrist,” because he does not think “critical” serves well as an identity function. He also said “anti-psychiatry” is an imperfect term because very few individuals today self-identify their views as being anti-psychiatry. Nevertheless, “one can still recognize the tremendous need for reform, and acknowledge the valid ways in which an exclusive emphasis on medical conceptualization can be harmful.”

This is a delicate and qualified position and navigating a dialogue from such a position is subject to the constant pressure for the dialogue to collapse into one polar position or another. I do not always succeed in that, but I try. That has precisely been the function of my interview series for Psychiatric Times, “Conversations in Critical Psychiatry”, where I try to engage with various critical and philosophical perspectives.

Attempting to maintain that dialogue, he noted how Love recognized the need to resist a polarizing discourse in her article. He pointed out that Love said it was nearly as useless to be steadfastly pro-psychiatry as it was to be anti-psychiatry. He concluded by saying: “One can recognize the need for meaningful criticisms and structural reform without delegitimizing the medical basis of psychiatry.”

Although Shayla Love did not interview Robert Whitaker for her article, John Horgan did interview him for an opinion piece published online for Scientific American, “Has the Drug-Based Approach to Mental Illness Failed?” When asked if he saw himself as a journalist or an activist, Whitaker said he didn’t see himself as an activist at all. He then quoted the mission statement for Mad in America, which said its mission was to serve as a catalyst for rethinking psychiatry. The current psychiatric paradigm has failed. Scientific research and the lived experience of those who have been diagnosed with a psychiatric disorder both call for a profound change.

The usual practice in “science journalism” is to look to the “experts” in the field and report on what they tell about their findings and practices. However, while reporting and writing Mad in America, I came to understand that when “experts” in psychiatry spoke to journalists they regularly hewed to a story that they were expected to tell, which was a story of how their field was making great progress in understanding the biology of disorders and of drug treatments that—as I was told over and over when I co-wrote the series for the Boston Globe—fixed chemical imbalances in the brain. But their own science, I discovered, regularly belied the story they were telling to the media. That’s why I turned to focusing on the story that could be dug out from a critical look at their own scientific literature.

Dr. Aftab’s comment above, about doing meaningful criticism and structural reform without delegitimizing the medical basis of psychiatry, may have captured the essence of the struggle between psychiatry and “anti-psychiatry.” Psychiatry wants to hold on to its identity as a medical specialty and sees the critique of Whitaker and others as a distinct threat to that identity. Perhaps the way forward lies with Lisa Cosgrove’s remarks quoted in “The Movement Against Psychiatry.” She said the fact that there are not any biomarkers doesn’t make psychiatry irrelevant as a medical discipline. “It just makes it different from other subspecialties in medicine.” Psychiatry needs to embrace its difference.

09/25/18

Rewiring the Adolescent Brain with Antidepressants

A depressed teenager walking towards the light

Research has shown that the earlier in life a person begins to use drugs, the more likely they are to develop serous problems as they mature. The interaction of early social and biological risk factors needs to be considered in assessing the developmental progression of later in life problems like addiction. “The fact remains that early use is a strong indicator of problems ahead, including addiction.”  While this is a noncontroversial perspective on how recreational drug use effects adolescent brain development, what about the effects of antidepressants and other psychiatric drugs on the developing brains of adolescents?

As our brains develop, our experiences reduce excess neural connections while simultaneously strengthening those that are used more often. The more we repeat any thinking or behavior pattern, the more it becomes habitually entrenched. If we repeatedly have a specific thinking pattern or do a particular behavior over and over again, the neurons in our brains strengthen that learning sequence, becoming what we refer to as a habit. “The more we actually do of whatever we do, the more ‘habitual’ that learning will become.” This is known as Hebbs Law, “Neurons that fire together, wire together.” When you combine Hebb’s Law with early drug use and the still maturing adolescent brain, you have a ready-made recipe for disaster.

image credit: NIDA

The above images of brain development are found in the NIDA (National Institute on Drug Abuse) discussion of “Drug Use and Addiction.” The images are for normal children and teens from the age of 5 to 20. Scientists think the process of brain maturation, depicted as the yellow to blue transition, corresponds to the steady reduction in gray matter volume seen during adolescence.  Note that the pre-frontal cortex is the last area of the developing brain to mature. Environmental forces, like drug use, help determine which connections wither and which are reinforced. This is a process that can “cut both ways” as not every habit reinforced by Hebb’s Law is desirable.

One of the brain areas still maturing during adolescence is the prefrontal cortex—the part of the brain that allows people to assess situations, make sound decisions, and keep emotions and desires under control. The fact that this critical part of a teen’s brain is still a work in progress puts them at increased risk for making poor decisions, such as trying drugs or continuing to take them. Introducing drugs during this period of development may cause brain changes that have profound and long-lasting consequences.

There is a euphoric effect from drugs that is still poorly understood, but it seems to be related to surges of neurotransmitters in parts of the brain’s reward circuit (i.e., the basal ganglia and amygdala). Some drugs cause a surge of neurotransmitters that are significantly greater than the normally occurring bursts produced naturally with healthy pleasurable activities such as eating, or social interaction. “Just as drugs produce intense euphoria, they also produce much larger surges of dopamine, powerfully reinforcing the connection between consumption of the drug, the resulting pleasure, and all the external cues linked to the experience.”  Simply put, surges of dopamine “teach” the brain to seek drugs at the expense of other goals and activities.

For the brain, the difference between normal rewards and drug rewards can be likened to the difference between someone whispering into your ear and someone shouting into a microphone. Just as we turn down the volume on a radio that is too loud, the brain of someone who misuses drugs adjusts by producing fewer neurotransmitters in the reward circuit, or by reducing the number of receptors that can receive signals. As a result, the person’s ability to experience pleasure from naturally rewarding (i.e., reinforcing) activities is also reduced.

One of the brain’s areas within its pleasure or reward center is the amygdala, which regulates emotions such as anxiety and depression, as well as having a role in the development of recreational drug addiction discussed above. While antidepressants won’t “shout” at the reward center in the same way cocaine or alcohol does, the individual who uses an antidepressant will experience a similar, if less radical, adjustment of their neurotransmitters and/or receptors. Consider what this could mean in the developing brain of an adolescent using an antidepressant that inhibits the uptake of serotonin (SSRI) or serotonin and norepinephrine (SNRI).

I have no training in medicine or neuroscience. But it seems logical to infer from the above that the long-term use or abuse of any drug which influences the neurotransmitter and/or receptor balance of the brain—cocaine, alcohol, antidepressants or other psychiatric medications—will influence brain function in the way described above. If studies show that “long-term drug use impairs brain functioning,” which the NIDA article claimed, this is equally true for recreational or psychiatric drugs. The question is, to what extent does the use of psychiatric medications like antidepressants effect the development of the adolescent brain?

A study by Lugo-Candelas et al. published in JAMA Pediatrics looked at the association between fetal brain development and prenatal exposure to SSRIs. Their findings suggested there was an association between prenatal SSRI exposure and fetal brain development, “particularly in brain regions critical to emotional processing.” The researchers said there was a need for “further research on the potential long-term behavioral and psychological outcomes of these neurodevelopmental changes.” In her review of the Lugo-Candelas et al. study for Mad in America, Bernalyn Ruiz said: “Overall, this study presents evidence that prenatal exposure to SSRI’s can affect infant neurodevelopment and may be associated with increased susceptibility to anxiety disorders, hyperactivity and maladaptive processing.”

A 2016 study by Cipriani et al. published in The Lancet concluded that the risk-benefit profile of antidepressant use in the acute treatment of major depression with children and adolescents did not seem to offer a clear advantage. The researchers said that fluoxetine (Prozac) was probably the best pharmacological treatment option. The study did not look at long-term antidepressant use as there has not been enough previous research to analyze, according to Cipriani. A STAT News review of the Cipriani et al. study quoted child psychiatrist Jon Jureidini as saying the study’s evidence for Prozac’s effectiveness was weak. He said the vast majority of children do not need to be medicated for depression.

What we’re up against is the marketing enterprise of the pharmaceutical industry combined with wishful thinking on the part of doctors and parents that there might be a good, simple solution for adolescent distress. . . . It’s something we need to take very seriously, but we don’t need to make it into a medical condition when it most times isn’t.

David Healy, Joanna Le Noury and Jon Jureidini wrote about their review of the benefits and risks of the use of antidepressants in children and adolescents for the International Journal of Risk & Safety in Medicine. They examined a total of 20 pediatric antidepressant studies conducted since 1990 and classified them as positive or negative according to the studies’ primary outcomes. In a review of the Healy, Le Noury and Jureidini study for Mad in America, Rebecca Troeger noted the authors found that all 20 trials performed between 1990 and 2005 were negative on primary outcome measures. That included the two fluoxetine (Prozac) trials “that provided the foundation for the drug’s regulatory approval” for use with children and adolescents. There was also evidence of an “excess of suicidality on active treatment” with these trials. “Of the 15 studies conducted since 2006 reviewed by the authors, nearly all were negative on primary outcome measures.”

At a global health conference in Aberdeen Scotland, Dr. Healy said every one of these trials produced more harms than benefits. Children became suicidal who would not have been suicidal if they had been kept off of antidepressants. He said if you follow the evidence, no one should be using these drugs. “At the same time, in teenagers, these drugs have become the most commonly used drugs.” The available evidence seems to question the wisdom and effectiveness of antidepressant use with children and adolescents.

06/22/18

Corrupted Clinical Trials

© ironstealth | stockfresh.com

Dr. Jason Fung opened his article, “The Corruption of Evidence Based Medicine—Killing for Profit” with the following: “The idea of Evidence Based Medicine (EBM) is great. The reality, though, not so much.” He said if the evidence base was false or corrupted, then evidence-based medicine was completely worthless. “It’s like building a wooden house knowing the wood is termite infested.” He’s not alone in this opinion and he quoted three current or former editors of the two most prestigious medical journals in the world who corroborated his statement.

Richard Horton, editor in chief of The Lancet said: “The case against science is straightforward: much of the scientific literature, perhaps half, may simply be untrue.”

Dr. Marcia Angell, former editor in chief of the New England Medical Journal (NEJM) said: “It is simply no longer possible to believe much of the clinical research that is published, or to rely on the judgment of trusted physicians or authoritative medical guidelines. I take no pleasure in this conclusion, which I reached slowly and reluctantly over my two decades as an editor.”

Dr. Arnold Relman, the former editor of the NEJM, said: “The medical profession is being bought by the pharmaceutical industry, not only in terms of the practice of medicine, but also in terms of teaching and research. The academic institutions of this country are allowing themselves to be the paid agents of the pharmaceutical industry. I think it’s disgraceful.”

Dr Fung said: “Physicians and universities have allowed themselves to be bribed.” He went on to say the examples in medicine are everywhere. For instance, medical research is typically paid for by pharmaceutical companies. “Trials run by industry are 70% more likely than government funded trials to show a positive result.” Among the issues he described were: the selective publication of clinical trials, rigging the outcomes of those trials, publication bias and industry payments to medical journals and their editors.

Clinical trials with negative results are likely to be suppressed. Using the company Sanofi to illustrate the problem, Dr. Fung noted the company completed 92 studies in 2008, but only published the results of 14. He acknowledged how it would be financial suicide to publish data that would harm your company. “But knowing this, why do we still believe the evidence based medicine, when the evidence base is completely biased?”

With antidepressants, a review of the published literature published in the NEMJ suggested 94% of the trials conducted were positive. Among FDA-registered trials, 31% were not published and only 51% showed positive results. The authors said:

We cannot determine whether the bias observed resulted from a failure to submit manuscripts on the part of authors and sponsors, from decisions by journal editors and reviewers not to publish, or both. Selective reporting of clinical trial results may have adverse consequences for researchers, study participants, health care professionals, and patients.

Before the year 2000, pharmaceutical companies doing clinical trials did not have to declare beforehand what their primary outcomes would be. So they would “measure many different endpoints and simply figured out which one looked best and then declared the trial a success.” The government changed that requirement and after 2000, 8% of clinical trials showed good results when 57% of those before 2000 showed a positive result. Evidence of the evidence base was being corrupted by commercial interest.

If a journal publishes a positive article about a Pharma drug, the company would order several hundred thousand copies of the article to distribute to doctors in their marketing efforts. “It’s insanely profitable for journals to take money from Big Pharma.” The NEMJ gets 23% of its income from reprints; the Lancet gets 41%; and the American Medical Association gets 53%! “No wonder these journals are ready to sell their readers (ordinary physicians) down the river. It pays.” A cited study noted where 50.9% of the editors of prestigious medical journals received at least some payments from the industry, and in some cases “these payments were often large.”

We found that industry payments to journal editors are common and can be substantial. Moreover, many journals lack clear and transparent editorial conflicts of interest policies and disclosures. Given our findings, we would suggest that journals take several steps. Firstly, we would strongly argue that all journals should develop and implement a transparent, publicly accessible editorial conflicts of interest policy. Secondly, editors in chief should consider excluding those with considerable industry relations from editorial positions. While such a stance could be considered drastic, editors play a crucial role in research integrity; even an appearance of conflict can serve to undermine the clinical research enterprise.

In The Chronicle of Higher Education, Batt and Fugh-Berman noted where “Disclosing Corporate Funding Is Not Nearly Enough.” In the U.S. in 2015, industry spent $102.7 billion on health-related research, while federal agencies spent $35.9 billion. “The current administration attempted to further decrease NIH funding, but those efforts were unsuccessful.” They said reliance on industry money limits the scope of research; and “it weakens researchers’ ability to act as independent critics.” Pharmaceutical companies fund, publish and promote studies that that are favorable to their marketing goals and “suppress or attack research that threatens market share.”

Perhaps most troubling is that if the final results of a study do not support commercial goals, the full study may never be published. In general, industry-funded studies are less likely to be published than non-industry-funded ones. And contrary to expectations, the reason negative studies are unpublished is not because journals rejected them, but because they were never submitted for publication. Although many universities frown on agreements that give funders the right to suppress the publication of findings, policies regarding publishing are not uniform across colleges and universities. In any case, enforcement is nil: Colleges can’t force researchers to publish studies. Industry insiders tell us that when company representatives fail to prevent a researcher from publishing unfavorable results on a drug, they may attempt to persuade the researcher to “bury” the paper in an obscure journal. Or, under the guise of reviewing a manuscript for “accuracy,” a company may soften statements or insert subtle marketing messages into the article to mitigate harm to its marketing goals. We don’t know the extent to which industry funding distorts biomedical literature — and clinical decision-making — but a substantial body of evidence now shows that allowing industry to choose what scientific questions should be asked, and how findings should be analyzed, interpreted, and disseminated, has public-health costs. We need strategies to minimize industry influence on scientific questions, and the resulting impact on policies and medical practice.

Writing for Mad in America, Zenobia Morrill summarized a review article by three researchers, “Industry-corrupted psychiatric trials.” The authors quoted from Marcia Angell’s 2008 article for JAMA, “Industry-sponsored clinical research: A broken system,” where she said:

Over the past 2 decades, the pharmaceutical industry has gained unprecedented control over the evaluation of its own products. Drug companies now finance most clinical research on prescription drugs, and there is mounting evidence that they often skew the research they sponsor to make their drugs look better and safer.”

Amstersdam, McHenry and Jureidini, the authors of “Industry-corrupted psychiatric trials,” noted it was common knowledge that pharmaceutical companies “laundered” their promotional efforts through medical communications companies that “ghostwrite articles and then pay academic consultants to sign on to the fraudulent articles.”

The firms set up advisory board meetings with key opinion leaders and marketing executives in advance of the clinical trials. Once a trial is complete, the medical ghostwriter who is employed by the medical communications firm produces a draft of a manuscript – from a summary of the Final Study Report of the clinical trial – and seeks feedback from the corporate sponsor. It is at this stage in the manuscript production that misrepresentation of the trial data frequently occurs, since the medical ghostwriter is under the direction of marketing executives to “spin” the data. The medical ghostwriter then revises a number of drafts with input from the external academic “authors” and internal industry scientists, and once the corporate sponsor is satisfied that the final manuscript draft is “on message,” it is submitted by a corporate-designated lead author to a medical journal for peer review. Once the manuscript is submitted, the medical ghostwriter disappears or is acknowledged in the fine print for “editorial assistance.”

As a result, ghostwriting by the pharmaceutical industry has become a major factor in the “crisis of credibility” in academic medicine. “The integrity of science depends on the trust placed in individual clinicians and researchers and in the peer-review system which is the foundation of a reliable body of knowledge.” If academics allow their names to appear on ghostwritten articles, “they betray this basic ethical responsibility and are guilty of academic misconduct,” according to Amstersdam, McHenry and Jureidini. Ghostwriting extends to include an academic façade for research “that has been designed, conducted and analyzed by industry.” Yet the vast majority of ghostwritten publications won’t be revealed as such.

Key opinion leaders (KOLs) or “thought leaders” are academic physicians who are carefully vetted by the industry on the basis of their receptivity to the sponsor’s products. Pharmaceutical companies say they have engaged these KOLs for expert evaluation and feedback on marketing strategy. However, they essentially are highly paid “product champions” or marketers. “Few physicians and psychiatrists can resist the flattering offer by industry to become KOLs.” Medical journals are noted to be part of the problem here as well.

Medical journals are part of the problem rather than the solution to the problem. Instead of demanding rigorous peer review of a submissions and an independent analysis of the data, medical journal editors are pressured to publish favorable articles of industry-sponsored trials and rarely publish critical deconstructions of ghostwritten clinical trials. As medical journals and their owners have become dependent upon pharmaceutical revenue, the journals fail to adhere to the standards of science. Thus the publication of “positive” studies showing drug safety and effectiveness means more pharmaceutical advertising and more orders of reprints for dissemination by the sales force. In contrast, a “negative” study showing poor tolerability or ineffectiveness results in no such revenue.

“Industry-corrupted psychiatric trials” then went on to deconstruct how three studies, “SmithKline Beecham Paroxetine Study 329,” “Forest Laboratory Citalopram Study CIT-MD-18” and “SmithKline Beecham Paroxetine Study 352” all manipulated or misrepresented outcome data. The first two to support the use of the SSRI antidepressants paroxetine (Paxil) and citalopram (Celexa) for the treatment of childhood and adolescent depression. The third study, “Paroxetine Study 352,” misrepresented and manipulated outcome data in adults diagnosed with bipolar affective disorder. Morrill said: “Misconduct of this study was revealed when academics filed complaints of plagiarism and research misconduct against KOLs at medical research universities across the U.S. as well as pharmaceutical company executives.”  Read the review article for further details on how these three research studies were deconstructed to reveal how they manipulated or misrepresented outcome data.

In closing, let me remind you again of the opinion of Marcia Angell, former editor of the NEMJ:

It is simply no longer possible to believe much of the clinical research that is published, or to rely on the judgment of trusted physicians or authoritative medical guidelines. . . . Drug companies now finance most clinical research on prescription drugs, and there is mounting evidence that they often skew the research they sponsor to make their drugs look better and safer.

05/1/18

Psychiatric Scientism

© Bruce Rolff | 123rf.com

There is a curious phenomena within the debate over the evidence base of psychiatric drug treatment, namely whether psychiatry itself ever promoted or supported the chemical imbalance theory. Ronald Pies, an emeritus editor for Psychiatric Times, has repeatedly claimed that the chemical imbalance theory “was always a kind of urban legend—never a theory seriously propounded by well-informed psychiatrists.” Further, Pies said that to his knowledge, “No professional psychiatric organization has ever publically promoted a ‘chemical imbalance theory’ of mental illness in general.” But it seems his statements are incorrect.

The two above quotes by Ronald Pies were from blog articles he posted on the Psychiatric Times website in “Psychiatry’s New Brain-Mind and the Legend of the Chemical Imbalance,” and “Serotonin: How Psychiatry Got Over Its ‘High School Crush’”.  He claimed “the ‘chemical imbalance’ trope” has been used by the opponents of psychiatry and erroneously attributed to psychiatrists themselves. Yet Robert Whitaker commented in his response to “Serotonin: How Psychiatry Got Over Its ‘High School Crush’” that it is quite easy to find numerous instances where prominent psychiatrists, including leaders of the APA [American Psychiatric Association], informed the public that “mental illnesses—such as depression or schizophrenia—are not ‘moral weaknesses’ or ‘imagined’ but real diseases caused by abnormalities of brain structure and imbalances of chemical in the brain.” This quote was in a 2001 Family Circle article, “Unlocking the Brain’s Secrets,” by the president of the APA, Richard Harding.

Another example given by Whitaker was in a 2005 brochure published by the APA, “Let’s Talk Facts About Depression.” In the section “How Is Depression Treated?” it says: “Antidepressants may be prescribed to correct imbalances in the levels of chemicals in the brain.” In 2005 APA press release, “Mental Illness Stigmas Are Receding, But Misconceptions Remain,” the results of an APA survey indicated that although 75% of consumers believe mental illnesses are usually caused by a chemical imbalance in the brain, they are more likely to consult a primary care physician rather than a psychiatrist—“a specialist specifically trained to diagnose and treat chemical imbalances and other determinants of mental illness.”

Whitaker’s thesis is that since the publication of the third edition of the DSM in 1980, the APA has been committed to the position that mental disorders are diseases of the brain; and that drugs for those diseases are safe and effective. “The chemical imbalance story comprised the heart of this disease-model narrative: Psychiatric researchers were discovering the pathology of mental disorders, and its drugs fixed that pathology, like insulin for diabetes.”  He sees this narrative as serving psychiatry’s interests as a guild.

  • It told of how its disorders in DSM III had been “validated” as real diseases.
  • It told of a medical specialty that was making great scientific progress, which elevated its power and authority in our society.
  • It told of a medical specialty that had a product—e.g. drugs—that was of great worth in treating those diseases.
  • Most important of all, this narrative provided a reason for psychiatry, as a medical specialty, to have authority over this part of our lives.

Whitaker said our society has responded to this narrative by organizing itself around it, and assuming it is the legitimate “story of science.” In “The Scientism of Psychiatry,” Sami Timimi said this tendency has led mainstream psychiatric literature to prefer rhetoric to scientific accuracy. Psychiatric research and discourse, according to Timimi, “are now dominated and infected by scientism — the promotion of a belief … that because what you do and talk about sounds and looks like ‘science,’ it is ‘scientific’”.

In “What Is Scientism?” Thomas Burnett said philosopher Tom Sorell defined scientism as putting too high a value on natural science in comparison with other branches of learning. A more precise and extreme definition by physicist Ian Hutchinson was also quoted from his book: Scientism: Philosophy and the Infatuation with Science: “Scientism is a matter of putting too high a value on natural science in comparison with other branches of learning or culture.”  Hutchinson also said the health of science was jeopardized by scientism.

Burnett gave a brief history of scientism up through the logical positivism embodied in The Vienna Circle. “In this system, there are only two kinds of meaningful statements: analytic statements (including logic and mathematics), and empirical statements, subject to experimental verification. Anything outside of this framework is an empty concept.” However Karl Popper pointed out there were very few statements that could be completely verified in science. “A single observation has the potential to invalidate a hypothesis, and even an entire theory.” So he proposed that instead of experimental verification, “the principle of falsifiability should demarcate what qualified as science, and by extension, what can qualify as knowledge.” Timimi noted how this has been incorporated into scientific methodology as a process of rejecting or disproving the null hypothesis.

Science uses a methodological approach involving hypothesis generation and then testing the hypothesis through empirical methods. The best scientists can live with and accept uncertainty as a prerequisite to being objective in the pursuit of knowledge. Knowledge develops and builds through generating a hypothesis (often using results from previous research) and then carrying out an investigation aimed at proving that something called a ‘null hypothesis’ can’t be true. The null hypothesis is a general statement or default position that there is no relationship between certain measured phenomena. Rejecting or disproving the null hypothesis — and thus concluding that there are grounds for believing that there is a relationship and the actual hypothesis may be true — is a central task in the modern practice of science.

He then said one of the major problems with the current concepts used in psychiatry traces back to the basic assumptions on which much of psychiatric research rests. In order to scientifically evaluate a proposition that there is a natural category of dysfunction/disorder, we must start with the null hypothesis. Until proven otherwise, there is no characteristic relationship between what we are investigating (put the disorder of your choice here) and some measurable biological/neurological feature. “This is a foundational assumption behind the development of knowledge through the scientific method.” ADHD, Depression and essentially all other psychiatric disorders fail to meet this standard. “Until we have demonstrated that this basic null hypothesis can’t be true, then scientifically, we cannot proceed with research that assumes that ADHD [or any other diagnostic category] as a concept has explanatory power for the behaviours it describes.”

Mainstream psychiatry has been afflicted by at least two types of scientism. Firstly, it parodies science as ideology, liking to talk in scientific language, using the language of EBM [evidence based medicine], and carrying out research that ‘looks’ scientific (such as brain scanning). Psychiatry wants to be seen as residing in the same scientific cosmology as the rest of medicine. Yet the cupboard of actual clinically relevant findings remains pretty empty. Secondly, it ignores much of the genuine science there is and goes on supporting and perpetuating concepts and treatments that have little scientific support. This is a more harmful and deceptive form of scientism; it means that psychiatry likes to talk in the language of science and treats this as more important than the actual science.

Contrasting medical and psychiatric diagnosis, Timimi then said:

In medicine, diagnosis is the process of determining which disease or condition explains a person’s symptoms and signs. Diagnosis therefore points to causal processes. Making an accurate diagnosis is a technical skill that enables effective matching of treatment to address a specific pathological process. Pseudodiagnoses, like for example ADHD, cannot explain behaviours as there are only ‘symptoms’ that are descriptions (not explanations) of behaviours. Even using the word ‘symptom’ may be problematic, as in medicine ‘symptoms’ usually refers to patients’ suffering/experience as a result of an underlying disease process and is therefore associated in our minds with a medical procedure leading to an explanation for the ‘symptom.’ But psychiatric diagnoses do not explain symptoms.

Using ADHD as am example, Timimi said once we start interrogating basic assumptions like the validity of psychiatric diagnoses, it should be easy to see that much of the psychiatric literature is built on assumptions lacking validity. Since ADHD is a descriptive classification and not a medical diagnosis, we have no reliable empirical method for defining what qualifies as a case of ADHD. Determining what qualifies as a case of ADHD is then arbitrary and depends on the standards used by the person doing the diagnosis, “influenced by whatever prevailing ideology concerning diagnosis they have been exposed to.” So as a consequence, we cannot eliminate wide variation in ‘diagnostic’ practice.

Timimi said in Western culture, science has become a cosmology—“an ideology/faith that believes that science has an undeniable primacy over all other ways of seeing and understanding life and the world.” This makes us vulnerable to scientism. He suggested psychiatry keeps faith in scientism despite its flaws because of the value we place in our culture on technology and technological achievement; and because, “this connects with that broader ‘cosmology’ that wants to use ‘science’ to explain everything.” In order to have credibility and leverage in our society, “we are inclined to use technological/scientific-sounding language.” Michael Foucault and others have pointed out, “this is how institutional power builds up and get authority to create ‘regimes of truth’.” Robert Whitaker said if psychiatry is ever going to reform itself in a way that will serve the public, “rather than its own guild interests,” it has to confront its past.

Why did it tell this false narrative—of drugs that fixed chemical imbalances in the brain—to the public? Perhaps then it could understand that its duty, as a medical specialty, is to tell a narrative to the public that is consonant with the relevant science. If that were so, then the public would be hearing that the biological causes of psychiatric disorders remain unknown, and that its drug treatments are of marginal efficacy over the short term, and that over the long-term, outcomes for medicated patients are very poor.

03/9/18

Psychiatry Needs a Revolution

© Anna_Om | stockfresh.com

Peter Gøtzsche wrote a January 2018 editorial in the British Medical Journal, where he elaborated on why he thinks, “Psychiatry is a disaster area in healthcare that we need to focus on.” In his editorial, Gøtzsche said the prevailing paradigm in psychiatry was to say psychiatric drugs have specific effects against specific disorders; and that their actions do more good than harm. However, he asserted that as a consequence of its liberal use of psychiatric drugs, psychiatry actually does more harm than good. Gøtzsche and other so-called “antipsychiatry,” critics are often dismissed by psychiatry. But there was a study that surveyed the attitudes of medical teaching faculty towards psychiatry and psychiatrists; and the results had more in common with the antipsychiatrists than you might think.

Stuart, Sartorius and Linamaa published “Images of Psychiatry and Psychiatrists” in the open access journal, Acta Psychiatra Scandinavica. They surveyed 1,057 teaching medical faculty members from 15 academic teaching centers in the United Kingdom, Europe and Asia. The overwhelming majority of respondents held negative views towards psychiatry as a discipline, psychiatrists and psychiatric patients. Some of their findings were startling: 90% thought psychiatrists were not good role models for medical students; 84% thought psychiatric patients should be treated only within specialized facilities.

When the survey asked about the perception of psychiatry as a profession, 8.9% thought psychiatry was unscientific; 7.7% thought it was not evidenced-based; and 8.0% thought psychiatry was not a genuine, valid branch of medicine. Perceptions of psychiatric treatment thought psychiatrists had too much power over their patients (25.0%); treatments were not as effective as in other branches of medicine (22.6%); and most who receive treatments do not find them helpful (20.4%). Then 28.6% said they would not encourage a bright student to enter psychiatry; and 75.4% said many students at their medical school were not interested in pursuing psychiatry as a career.

Results highlight the extent to which non-psychiatrist medical faculty hold negative opinions of psychiatry as a discipline, psychiatric treatments, psychiatrists as role models for medical students, psychiatry as a career choice, psychiatric patients, and psychiatric training. The most outstanding findings were that psychiatrists were not considered to be good role models for medical students, and psychiatric patients were considered to be emotionally draining and unsuitable to be treated outside of specialized facilities or in general hospitals.

“In Search of an Evidence-Based Role for Psychiatry,” by Read, Runciman and Dillon noted this was not the only study indicating negative views of psychiatry by other medical professionals. They cited a study by Curtis-Barton and Eagles that found medical students were discouraged from choosing psychiatry as a career either a lot or a little because of a perceived lack of evidence base (51%); and the scientific basis of psychiatry (53%). Only 4-7% of UK medical students saw it as a ‘probable/definite’ career because of its poor evidence base. Commenting further on “Images of Psychiatry and Psychiatrists,” Read, Runciman and Dillon said:

Even more revealing than the survey findings was psychiatry’s response to it. The researchers themselves, including a former President of the World Psychiatric Association, wondered whether their colleagues’ opinions are ‘well founded in facts’ or ‘may reflect stigmatizing views toward psychiatry and psychiatrists’. Their own answer to that question becomes abundantly clear when, instead of proposing efforts to address the problems identified by the medical community, such as having little scientific basis, they recommend only ‘enhancing the perception of psychiatrists’ so as to ‘improve the perception of psychiatry as a career.’

The responses to the survey, all written by psychiatrists, dismissed each concern “and blamed everyone but their own profession, including their supposedly ignorant, prejudiced medical colleagues and the biased media.” Read, Runciman and Dillon then described problems with how mental health issues are conceptualized, what causes them and how to treat them. “Despite all this, biological psychiatry is trying to expand the reach of what others consider to be an unscientific, reductionistic, simplistic and pessimistic ‘medical model’.” A truly evidence-based psychiatry would recommend psychiatric medications at a last resort (and for a short time period). The adverse effects of medications should be fully disclosed and “no medical treatment should be forced on anyone against their will.”

Read, Runciman and Dillon said there were three core research areas that psychiatry should be demonstrating progress in, if it is a legitimate scientific, medical discipline. They are: conceptualization, causation and treatment of the disorders.

With regard to the conceptualization of psychiatric disorders, “psychiatry’s primary contribution is an ever expanding list of labels.” Many do not reach even minimal scientific reliability levels and calling them ‘diagnoses’ is often a misnomer. Significantly, the NIMH announced when the DSM-5 was about to be published that it was abandoning the DSM diagnostic approach to classifying mental health problems for its research to develop scientifically robust ‘research domains.’ See “Patients Deserve Better Than the DSM” for more information on this.

“In terms of causation, psychiatry has focused predominantly on chemical imbalances, brain abnormalities and genetics.” But has repeatedly failed findings of any substance in support of that premise. Genetics has an important role, if the research is done on constructs that actually exist. There is also “the role of epigenetic processes whereby genes are activated and deactivated by the environment.”

Research suggests that the safety and efficacy of psychiatric drugs has been grossly exaggerated. Documentation in support of this claim is overwhelming. See the websites for Mad in America, Peter Breggin, and David Healy and RxISK for starters. You can also search this website or start with: “In the Dark About Antidepressants,” “Blind Spots With Antipsychotics.”

Peter Gøtzsche similarly noted concerns with the “liberal use of psychiatric drugs.” He identified four concerns with the prevailing paradigm in psychiatry and gave supporting evidence for each.

  • First, the effects of the drugs are not specific. “They impair higher brain functions and cause similar effects in patients, healthy people and animals.” For instance, not only does serotonin (SSRI antidepressants influence serotonin levels) seem to have a role in maintaining mood balance, it can effect social behavior, appetite and digestion, sleep memory and sexual desire and function.
  • Second, research in support of the paradigm that psychiatric drug have specific effects against specific disorder is flawed.
  • Third, the widespread use of psychiatric drugs has been harmful for patients. In every country where the relationship has been examined, an increased use of psychiatric medications has accompanied an increase in the number of chronically ill people and the number of people on disability pensions.
  • Fourthly, all attempts to use brain scans to show that psychiatric disorders cause brain damage have failed. “This research area is intensely flawed and very often, the researchers have not even considered the possibility that any brain changes they observe could have been caused by the psychiatric drugs their patients have taken for years” Yet this has been shown repeatedly in many reliable studies, especially for neuroleptic drugs.

Peter Gøtzsche said the prevailing paradigm in psychiatry, that its drugs have specific effects against specific disorders, is unsustainable when the research in support of it is critically appraised. He said psychiatry needed a revolution; reforms were not enough. “We need to focus on psychotherapy and to hardly use any psychiatric drugs at all.” Dr. Gøtzsche is a medical researcher and the Director of the Nordic Cochrane Center. Along with 80 others, he helped start the Cochrane Collaboration in 1993, which is “a global independent network of researchers, professionals, patients, carers, and people interested in health.” The work of the Cochrane Collaboration is recognized as an international gold standard for high quality, trusted information.

12/5/17

Pick Your Poison: Diabetes and Psych Meds

© klenova | stockfresh.com

The American Diabetes Association said 30.3 million Americans, 9.4% of the population, had diabetes in 2015. There are 1.5 million news cases of diabetes diagnosed each year. It is the 7th leading cause of death in the U.S. with 79,535 death certificates in 2015 listing it as the underlying cause of death. A total of 252,806 death certificates listed diabetes as an underlying or contributing cause of death. If the number of deaths from diabetes were equal to 252,806, it would be the third leading cause of death in the US, according to the CDC … and psych meds increase the risk for diabetes.

SSRIs have been associated with an increased risk of diabetes, as Yoon et al. noted in “Antidepressant Use and Diabetes Mellitus.” The researchers ruled out depression itself as a potential confounding variable in the relationship between antidepressants and diabetes. Their findings suggested that antidepressant drug treatment and not the depression increased the risk of diabetes mellitus (DM). “Given the widespread use of antidepressants, the implications of the increased risk are serious.”

The authors noted that while there is disagreement as to the reason for the association between antidepressant use and DM risk, some studies “propose that antidepressants may bio-pharmacologically affect glucose homeostasis and insulin sensitivity.” In “Use of Antidepressants Linked to Diabetes,” Peter Simons of Mad in America noted a study that has supported that hypothesis. A study led by Raymond Noordam and published in The Journal of Clinical Psychiatry, found the use of SSRIs in nondiabetic participants was associated with lower insulin secretion and an increased risk of insulin dependence in type 2 diabetes in older adults.

It is biologically plausible that SSRIs decrease insulin secretion and that this might, therefore, be a mechanism underlying the previously observed association between SSRIs and increased risk of type 2 diabetes. Consequently, type 2 diabetes patients treated with SSRIs might also have a higher risk to develop insulin dependence, a condition associated with an increased risk of mortality.

The researchers also found that participants already diagnosed with diabetes who were taking antidepressants were twice as likely to start insulin treatment than those who did not take antidepressants. They said: “our data might suggest that progression of type 2 diabetes during the use of SSRIs is accelerated.” Simons commented how the higher mortality rate for individuals who require insulin treatments made this “a particularly alarming finding.”

This new study provides additional convincing evidence that although SSRIs are commonly believed to have fewer risks of adverse effects than TCAs, they still carry significant risk. This appears to be particularly relevant when it comes to patients with diabetes. Whenever antidepressant medication is considered, patients and prescribers should carefully weigh the potential risks and benefits.

There was an updated meta-analysis published in PLos One, “The Risk of New-Onset Diabetes in Antidepressant Users.” Their meta-analysis found an increased risk factor of 1.27 between exposure to antidepressants and new-onset diabetes. When they restricted the analyses to higher quality studies, the relative risk was higher. The researchers noted their findings were in line with two previous meta-analyses that reported “a 1.5-fold increase of diabetes among AD [antidepressant] users.” In an interview with Endocrinology Advisor, the lead investigator of the study extrapolated that given a 13% prevalence rate of antidepressant use in the US, a 1.3-fold increase in diabetes risk would translate to over 1 million cases of diabetes that could be due to concurrent antidepressant use.

Pharmacy Times reported in “Atypical Antipsychotic-Induced Type 2 Diabetes” that patients with schizophrenia were at an increased risk of developing metabolic disorders like type-2 diabetes mellitus (T2DM). Schizophrenic patients had a number of risk factors for T2DM, including family history, increased body mass index (weight gain), a sedentary lifestyle and the use of atypical antipsychotics. There have been several proposed mechanisms for the association of diabetes and atypical antipsychotics, one being the weight gain associated with the medications.

A 2006 study by Alvarez-Jiménez et al. found that 78.8% of patients taking atypical antipsychotics experienced a weight gains greater than 7%, the cut off for clinically meaningful weight gain in the study. In 2004 the FDA required a warning be placed in the medication guides of all atypical antipsychotics warning of the increased risk of hyperglycemia and diabetes.

 Patients with schizophrenia are at increased risk of developing metabolic disorders like type 2 diabetes. This is due to a number of factors, including the treatment of schizophrenia with atypical antipsychotics. There are several potential mechanisms behind antipsychotic-induced diabetes, including the weight gain associated with these medications, the effects on pancreatic receptors and/or glucose transporters, or some other cause not yet discovered. Most likely, it is a combination of these effects. Of the atypical antipsychotics, clozapine [Clozaril] and olanzapine [Zyprexa] are associated with the highest incidence of metabolic dysfunction, whereas ziprasidone [Geodon] and aripiprazole [Abilify] are considered to be the least risky.

In “Antipsychotic-Induced Diabetes Mellitus” published in U.S. Pharmacist, Chhim et al. reported there are several metabolic consequences with antipsychotic use, including weight gain, hyperglycemia (abnormally high blood glucose) and dyslipidemia (an abnormal amount of triglycerides, cholesterol and/or fat phospholipids in the blood). The association of type 2 diabetes mellitus (T2DM) and antipsychotic use is supported by retrospective epidemiologic studies as well as post-marketing assessment. Data indicate the prevalence of diabetes and obesity is 1.5 to 2 times higher in people diagnosed with schizophrenia or affective disorders than the general population.

The authors noted that diabetes was reaching epidemic proportions worldwide, and the contributions of medications to the development of hyperglycemia and other metabolic problems was getting more attention.  “Pharmacists are in a unique position to counsel and encourage appropriate self-monitoring in patients receiving certain drugs, such as antipsychotics, that can contribute to the development of weight gain, hyperglycemia, and dyslipidemia.” They can encourage patients to report adverse events to other health care providers and seek therapeutic substitutions, counseling, and/or treatment for the adverse events.

Another resource addressing these concerns, one that was cited in “Antipsychotic-Induced Diabetes Mellitus,” is the “Consensus Development Conference on Antipsychotic Drugs and Obesity and Diabetes.” This is a joint consensus statement from the American Diabetes Association, the American Psychiatric Association, the American Association of Clinical Endocrinologists, and the North American Association for the Study of Obesity to help reduce the risk of developing diabetes, cardiovascular disease, and other complications of diabetes.

There was a large longitudinal study done in Denmark by Rajkumar et al. that found in addition to the high risk for diabetes conferred by schizophrenia on individuals, “the risk is further increased by both first-generation and second-generation antipsychotics.” Reporting on the study for Mad in America, Bernalyn Ruiz said the authors said the prevalence of diabetes was 4 to 5 times greater in people diagnosed with schizophrenia. “After adjusting for potential confounders, the risk was elevated threefold compared to those without a schizophrenia diagnosis.” No differences were seen between first-generation and atypical antipsychotics.

This large nationwide study confirmed endogenous risk for diabetes among individuals diagnosed with schizophrenia, with risks increasing significantly when antipsychotics are prescribed.

The bottom line is that in addition to their other adverse effects, there is credible scientific evidence that antidepressants and antipsychotics increase the risk of diabetes among individuals taking them. So when you’re advised to use one of these classes of psychiatric medications, it’s a bit like being asked to pick your poison.

10/6/17

Is Ketamine Really Safe & Non-Toxic?

credit wellcomeimages.org

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?