01/5/18

In the Dark About Antidepressants

© tab62 | stockfresh.com

In 2011, antidepressants were the third most commonly prescribed medication class in the U.S. Mojtabai and Olfson noted in their 2011 article for the journal Health Affairs that much of the growth in the use of antidepressants was driven by a “substantial increase in antidepressant prescriptions by nonpsychiatric providers without an accompanying psychiatric diagnosis.” They added how the growing use of antidepressants in primary care raised questions “about the appropriateness of their use.” Despite this concern, antidepressant prescriptions continued to rise. By 2016, they were the second most prescribed class of medications, according to data from IMS Health.

A CDC Data Brief from August of 2017 reported on the National Health and Nutrition Examination Survey. The Data Brief provided the most recent estimates of antidepressant use in the U.S. for noninstitutionalized individuals over the age of 12. As indicated above, there was clear evidence of increased antidepressants use from 1999 to 2014. 12.7% of persons 12 and over (one out of eight) reported using antidepressant medication in the past month. “One-fourth of persons who took antidepressant medication had done so for 10 years or more.”

Women were twice as likely to take antidepressants. And use increased with age, from 3.4% among persons aged 12-19 to 19.1% among persons 60 and over. See the following figures from the CDC Data Brief. The first figure notes the increased use of antidepressants among persons aged 12 and over between 1999 and 2014. You can see where women were twice as likely to take antidepressants as men.

Figure 1

The second figure shows the percent of individuals aged 12 and over who took antidepressant medication in the past month between 2011 and 2014. Note how the percentages increase by age groups for both men and women, with the highest percentages of past month use for adults 60 and over for both men and women.

Figure 2

The third figure shows the length of antidepressant use among persons aged 12 and over. Note that while 27.2% reported using them 10 years or more, 68% reported using antidepressants for 2 years or more. “Long-term antidepressant use was common.” Over the fifteen-year time frame of the data, antidepressant use increased 65%.

Figure 3

The widespread use of antidepressants documented above is troubling when additional information about antidepressants is considered. A February 2017 meta-analysis done by Jakobsen et al., and published in the journal BMC Psychiatry, found all 131 randomised placebo-controlled trials “had a high risk of bias.” There was a statistically significant decrease of depressive symptoms as measured by the Hamilton Depression Rating Scale (HDRS), but the effect was below the predefined threshold for clinical significance of 3 HDRS points. Other studies have indicated that differences of less than 3 points on the HDRS are not clinically observable. See “Antidepressant Scapegoat” for more information on the HDRS. Jakobsen et al. concluded:

SSRIs might have statistically significant effects on depressive symptoms, but all trials were at high risk of bias and the clinical significance seems questionable. SSRIs significantly increase the risk of both serious and non-serious adverse events. The potential small beneficial effects seem to be outweighed by harmful effects.

In his review of the Jakobsen et al. study for Mad in America, Peter Simons noted where these results add to a growing body of literature “questioning the efficacy of antidepressant medications.” He pointed to additional studies noting the minimal or nonexistent benefit in patients with mild or moderate depression; the adverse effects of antidepressant medications; the potential for antidepressant treatment to potentially worsen outcomes. He concluded:

Even in the best-case scenario, the evidence suggests that improvements in depression due to SSRI use are not detectable in the real world. Given the high risk of biased study design, publication bias, and concerns about the validity of the rating scales, the evidence suggests that the effects of SSRIs are even more limited. According to this growing body of research, antidepressant medications may be no better than sugar pills—and they have far more dangerous side effects.

Peter Gøtzsche, a Danish physician and medical researcher who co-founded the Cochrane Collaboration, wrote an article describing how “Antidepressants Increase the Risk of Suicide and Violence at All Ages.” He said that while drug companies warn that antidepressants can increase the risk of suicide in children and adolescents, it is more difficult to know what that risk is for adults. That is because there has been repeated underreporting and even fraud in reporting suicides, suicide attempts and suicidal thoughts in placebo-controlled trials. He added that the FDA has contributed to the problem by downplaying the concerns, choosing to trust the drug companies and suppressing important information.

He pointed out a meta-analysis of placebo-controlled trials from 2006 where the FDA reported five suicides in 52,960 patients (one per 10,000).  See Table 9 of the 2006 report. Yet the individual responsible for the FDA’s meta-analysis had published a paper five years earlier using FDA data where he reported 22 suicides in 22,062 patients (which is 10 per 10,000). Additionally, Gøtzsche found there were four times as many suicides on antidepressants as on placebo in the 2001 study.

In “Precursors to Suicidality and Violence in Antidepressants” Gøtzsche co-authored a systematic review of placebo-controlled trials in healthy adults. The study showed that “antidepressants double the occurrence of events that can lead to suicide and violence.” Maund et al. (where he was again a co-author) demonstrated that the risk of suicide and violence was 4 to 5 times greater in women with stress incontinence who were treated with duloxetine (Cymbalta).

Although the drug industry, our drug regulators and leading psychiatrists have done what they could to obscure these facts, it can no longer be doubted that antidepressants are dangerous and can cause suicide and homicide at any age. Antidepressants have many other important harms and their clinical benefit is doubtful. Therefore, my conclusion is that they shouldn’t be used at all. It is particularly absurd to use drugs for depression that increase the risk of suicide when we know that psychotherapy decreases the risk of suicide. . . . We should do our utmost to avoid putting people on antidepressant drugs and to help those who are already on them to stop by slowly tapering them off under close supervision. People with depression should get psychotherapy and psychosocial support, not drugs.

Peter Breggin described “How FDA Avoided Finding Adult Antidepressant Suicidality.” Quoting the FDA report of the 2006 hearings, he noted where the FDA permitted the drug companies to search their own data for “various suicide-related text strings.” Because of the large number of subjects in the adult analysis, the FDA did not—repeat, DID NOT—oversee or otherwise verify the process. “This is in contrast to the pediatric suicidality analysis in which the FDA was actively involved in the adjudication.” Breggin added that the FDA did not require a uniform method of analysis by each drug company and an independent evaluator as required with the pediatric sample.

Vera Sharav, “a fierce critic of medical establishment,” the founder and president of the Alliance for Human Research Protection (AHRP), testified at the 2006 hearing. She reminded the Advisory Committee that the FDA was repeating a mistake they had made in the past.  She said in the past the FDA withheld evidence of suicides from the Advisory Committee. German documents and the FDA’s own safety review showed an increased risk of suicides in Prozac. “Confirmatory evidence from Pfizer and Glaxo were withheld from the Committee.”  Agency officials “obscured the scientific evidence with assurances.”

What the FDA presented to you is a reassuring interpretation of selected data by the very officials who have dodged the issue for 15 years claiming it is the condition, not the drugs. What the FDA did not show you is evidence to support that SSRI safety for any age group or any indication. They are all at risk. They failed to provide you a complete SSRI data analysis. They failed to provide you peer-reviewed critical analyses by independent scientists who have been proven right. FDA was wrong then; it is wrong now. Don’t collaborate in this. [But they eventually did]

Breggin commented that the FDA controlled and monitored the original pediatric studies because the drug companies did not do so on their own and failed to find a risk of antidepressant-induced suicidality in any age group. “Why would the FDA assume these same self-serving drug companies, left on their own again, would spontaneously begin for the first time to conduct honest studies on the capacity of their products to cause adult suicidality?”

In a linked document of two memos written by an Eli Lilly employee in 1990, Dr. Breggin noted where the individual questioned the wisdom of recommendations from the Lilly Drug Epidemiology Unit to “change the identification of events as they are reported by the physicians.” The person went on to say: “I do not think I could explain to the RSA, to a judge, to a reporter or even to my family why we would do this especially to the sensitive issue of suicide and suicide ideation. At least not with the explanations that have been given to our staff so far.” Those suggestions included listing an overdose in a suicide attempt as an overdose, even though (here he seems to be quoting from a policy or procedural statement) “when tracking suicides, we always look at all overdose and suicide attempts.” Eli Lilly brought the first SSRI, Prozac, to market in 1986.

Next time you hear someone say that the FDA studies only showed increased suicidality in children and young adults as opposed to adults, remember that the adult studies, unlike the pediatric studies, were not controlled, monitored or validated by the FDA. This is one more example of the extremes the FDA will go to in order to protect drug companies and their often lethal products.

The problems with antidepressants, most of which are SSRIs—selective serotonin reuptake inhibitors—were at least partially known as Prozac and its cousins were being developed and brought to market in the early 1990s. As the above discussion indicated, there seems to have been a disregard of the potential for multiple negative side effects from their use, up to and including the various forms of suicidality. The sleight-of-hand done by the drug companies, and apparently the FDA, means that many individuals are in the dark about the adverse side effects stemming from their SSRI medications.

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 tow 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.

06/9/17

Worse Results with Psych Meds

© Spectral | stockfresh.com

Psych meds are popular. One in six U.S. adults (16.7% of 242 million) reported filing at least one prescription for a psychiatric medication in 2013. That increased with adults between the ages of 60 and 85, where one in four (25.1%) reported using psych meds. Only 9% of adults between the ages of 18 and 39 reported using one or more psych drugs. Most psychiatric drug use was long-term, meaning patients reported taking these meds for two years or more; 82.9% reported filling 3 or more prescriptions in 2013. “Moreover, use may have been underestimated because prescriptions were self-reported, and our estimates of long-term use were limited to a single year.”

The above findings were reported in a research letter written by Thomas Moore and Donald Mattison in JAMA Internal Medicine. Their findings got a fair amount of media attention, including articles in Live Science (here), The New York Times (here), Mad in America (here), Psychology Today (here) and even Medscape (here).

Moore said the biggest surprise was that 84.3% of all adults using psychiatric medication (34.1 million) reported using these meds long-term, meaning over two years. He said the high rates of long-term use of psych meds raises the need for closer monitoring and a greater awareness of the potential risks.

Both patients and physicians need to periodically reevaluate the continued need for psychiatric drugs. . . This is a safety concern, because 8 of the 10 most widely used drugs have warnings about withdrawal/rebound symptoms, are DEA Schedule IV, or both.

The ten most commonly used psychiatric drugs in ranked order were:

  1. Sertraline (Zoloft, an SSRI antidepressant)
  2. Citalopram (Celexa, an SSRI antidepressant)
  3. Alprazolam (Xanax, a benzodiazepine for anxiety)
  4. Zolpidem tartrate (Ambien, a hypnotic prescribed for sleep)
  5. Fluoxetine (Prozac, an SSRI antidepressant)
  6. Trazodone (an antidepressant often prescribed for sleep)
  7. Clonazepam (Klonopin, a benzodiazepine for anxiety)
  8. Lorazepam (Ativan, a benzodiazepine for anxiety)
  9. Escitalopram (Lexapro, an SSRI antidepressant)
  10. Duloxetine (Cymbalta, an SNRI antidepressant)

Drawing on data from a different source in “Drugs on the Mind” for Psychology Today, Hara Estroff Marano said the Institute for Healthcare Informatics (IMS) reported there were 4.4 billion prescriptions dispensed in 2015, with total spending on medicines reaching $310 billion. “Over a million of the prescriptions written for a psychiatric drug were to children 5 years of age or younger.” There were 78.7 million people in the U.S. using psychiatric meds. Within this group, 41.2 million were prescribed one or more antidepressants; 36.6 million were given anti-anxiety medications; and 6.8 million were given antipsychotics.

These figures were different than the percentages reported above from the Moore and Mattison study. Moore and Mattison found that 12% (29 million) reported using antidepressants; 8.3% (20 million) reported using anxiolytics and 1.6% (3.9 million) reported using antipsychotics. Their 1 in 6 (16.7%) figure would then be 40.4 million people using at least one psychiatric medication. Regardless of which data source you use, there are millions of U.S. citizens taking at least one psychiatric drug and therefore at risk of experiencing the adverse effects associated with these drug classes.

Anatomy of an Epidemic by Robert Whitaker described how psychiatric drugs seem to be contributing to the rise of disabling mental illness rather than treating those who suffer from it. What follows is a sampling of comments from Anatomy that he made about benzodiazepines (anxiolytics), which are widely used to treat anxiety and insomnia. Whitaker said long-term benzodiazepine use can worsen the very symptoms they are supposed to treat. He cited a French study where 75 percent of long-term benzodiazepine users  “. . . had significant symptomatology, in particular major depressive episodes and generalized anxiety disorder, often with marked severity and disability.”

In addition to causing emotional distress, long-term benzodiazepines usage also leads to cognitive impairment (137). Although it was thirty years ago that governmental review panels in the United States and the United Kingdom concluded that the benzodiazepines shouldn’t be prescribed long-term … the prescribing of benzodiazepines for continual use goes on (147).

In her article for Medscape, Nancy Melville pointed out the CDC found zolpidem (a so-called “Z” drug) was the number one psychiatric linked to emergency department visits. As many as 68% of patients used it long-term, while the drug is only recommended for short-term use. Up to 22% of zolpidem users were also sustained users of opioids.

Among the concerns with antidepressants are that they are not more effective than placebos (see discussions of the research of Irving Kirsch, starting here: “Do No Harm with Antidepressants”). In some cases they contribute to suicidality and violence (see “Psych Drugs and Violence” and “Iatrogenic Gun Violence”) and they have a risk of withdrawal symptoms upon discontinuation.

In a systematic review of the literature, Fava et al. concluded that withdrawal symptoms might occur with any SSRI. The duration of treatment could be as short as 2 months. The prevalence of withdrawal was varied; and there was a wide range of symptoms, encompassing both physical and psychological symptoms. The table below, taken from the Fava et al. article, noted various signs and symptoms of SSRI withdrawal.

The withdrawal syndrome will typically appears within a few days of drug discontinuation and last for a few weeks. Yet persistence disturbances as long as a year after discontinuation have been reported. “Such disturbances appear to be quite common on patients’ websites but await adequate exploration in clinical studies.”

Clinicians are familiar with the withdrawal phenomena that may occur from alcohol, benzodiazepines, barbiturates, opioids, and stimulants. The results of this review indicate that they need to add SSRI to the list of drugs potentially inducing withdrawal phenomena. The term ‘discontinuation syndrome’ minimizes the vulnerabilities induced by SSRI and should be replaced by ‘withdrawal syndrome’.

Updating his critique of the long-term use of antipsychotics in Anatomy of an Epidemic, Robert Whitaker made his finding available in a paper, “The Case Against Antipsychotics.” There are links to both a slide presentation and a video presentation of the information included in his paper. The breadth of material covered was difficult to summarize or select out some of the more important findings. Instead, we will look at what Whitaker said was the best long-term prospective study of schizophrenia and other psychotic disorders done in the U.S. The Harrow study assessed how well an original group of 200 patients were doing at various time intervals from 2 years up until 20 years after their initial hospitalization for schizophrenia. In his paper, Whitaker reviewed the outcome for these patients after 15 and 20 years of follow up.

Harrow discovered that patients not taking medication regularly recovered from their psychotic symptoms over time. Once this occured, “they had very low relapse rates.” Concurrently, patients who remained on medication, regularly remained psychotic—even those who did recover relapsed often. “Harrow’s results provide a clear picture of how antipsychotics worsen psychotic symptoms over the long term.” Medicated patients did worse on every domain that was measured. They were more likely to be anxious; they had worse cognitive functioning; they were less likely to be working; and they had worse global outcomes.

There is one other comparison that can be made. Throughout the study, there were, in essence, four major groups in Harrow’s study: schizophrenia on and off meds, and those with milder psychotic disorders on and off meds. Here is how their outcomes stacked up:

As Whitaker himself noted, his findings have been criticized from several individuals. However, he answered those critiques and demonstrated how they don’t really hold up. Read his paper for more information. But his conclusions about the use of antipsychotic medications are not unique. In the article abstract, for “Should Psychiatrists be More Cautious About the Long-Term Prophylactic Use of Antipsychotics?” Murray et al. said:

Patients who recover from an acute episode of psychosis are frequently prescribed prophylactic antipsychotics for many years, especially if they are diagnosed as having schizophrenia. However, there is a dearth of evidence concerning the long-term effectiveness of this practice, and growing concern over the cumulative effects of antipsychotics on physical health and brain structure. Although controversy remains concerning some of the data, the wise psychiatrist should regularly review the benefit to each patient of continuing prophylactic antipsychotics against the risk of side-effects and loss of effectiveness through the development of supersensitivity of the dopamine D2 receptor. Psychiatrists should work with their patients to slowly reduce the antipsychotic to the lowest dose that prevents the return of distressing symptoms. Up to 40% of those whose psychosis remits after a first episode should be able to achieve a good outcome in the long term either with no antipsychotic medication or with a very low dose.

All three classes of psychiatric medications reviewed here have serious adverse effects that occur with long-term use. In many cases, they lead to a worsening of the very symptoms they were supposed to “treat.” Increasingly, it is being shown that the psychiatric drug treatments are often worse than the “mental illness” they allegedly treat.

12/23/16

Listening to Antidepressants

© willeecole |stockfresh.com

Prozac took the U.S. by storm when the FDA approved it in 1987.  It also had a similarly radical effect on the thinking of a forty year-old psychiatrist named Peter Kramer. In the Introduction of his now classic book, Listening to Prozac, Kramer described how people became “better than well” with Prozac and how they and he began to “listen” to what Prozac told them. Kramer said it “transformed my views about what makes people the way they are.” But even by 1993, when Listening to Prozac was published, the stories of violence and suicide after taking the first SSRI antidepressant were circulating as well.

Toxic Psychiatry by another psychiatrist named Peter Breggin, was published two years earlier and documented reports of suicidal behavior in both the popular press and the professional literature. “Suicidal Behavior Tied to Drug,” was published on February 7, 1991 in The New York Times. The article said two cases of suicidal behavior and fantasies (with no prior history) were reported in The New England Journal of Medicine that same day. Eli Lilly was facing more than 50 lawsuits at the time and of course denied that there was any scientific merit to the claim the medication could prompt suicidal or violent acts. The year before, “Emergence of Intense Suicidal Preoccupation During Fluoxetine Treatment,” was published in the February 1990 issue of The American Journal of Psychiatry. Its abstract read:

Six depressed patients free of recent serious suicidal ideation developed intense, violent suicidal preoccupation after 2-7 weeks of fluoxetine treatment. This state persisted for as little as 3 days to as long as 3 months after discontinuation of fluoxetine. None of these patients had ever experienced a similar state during treatment with any other psychotropic drug.

Breggin also seems to have predicted the rise of what is now called “treatment resistant depression” with SSRIs. He said: “If Prozac can indeed alleviate depression by making more serotonin available in the brain, then with time it may produce incurable depression by making the brain relatively unresponsive to any amount of serotonin.” In Talking Back to Prozac in 1995, Breggin “blew the whistle” on the newer antidepressants and antidepressant-induced violence, suicide and mania. Finally in 2004 the FDA finally required black box warnings to be placed on the newer antidepressants, warning of the potential for the increased risk of suicidal thoughts and behavior in children and adolescents.

Yes, Dr. Kramer did say as far back as Listening to Prozac that the chemical imbalance theory (the amine hypothesis) was at least incomplete and perhaps false. But then Kramer published Against Depression in 2005, arguing that the socio-economic costs of depression were so large, that modern societies should strive to eradicate it as they did with smallpox. On his blog in 2008 he argued that the chemical imbalance theory was prematurely declared dead, even though “the neurotransmitter theory is incomplete and not fully proven.”  He asserted that since 1993 the evidence for it had been steadily growing.

Jonathan Leo and Jeffrey Lacasse did an in depth critique of the evidence Dr. Kramer used to support the chemical imbalance theory. They noted several qualifications used when scientists discuss the biological basis of mood with other scientists. “Yet, in the popular press all these qualifications disappear and instead the public is inundated with declarations about ‘chemical imbalances causing mental illness.’” They said there were two different discussions going on about the theory—a simple, straightforward one in the media and advertisements, but a tenuous nuanced one in scientific circles. In scientific circles, the discussion was about the appropriateness of using the chemical imbalance theory with patients and not so much about the strength of the theory.

In the late 1990s, Irving Kirsch decided to research the placebo effect with the newer (SSRIs and SNRIs) antidepressants. He began with the assumption that there actually was a therapeutic effect with antidepressants, but he wanted to assess the placebo effect: “I was not particularly interested in the drug effect. I assumed that antidepressants were effective.” He was surprised to discover how small the drug effect was. Seventy-five percent of the improvement in the drug group also occurred with people who were given placebo pills with no active ingredient in them.

Critics of his findings said the meta-analysis he and his co-author had done was biased; that they had an unrepresentative sample of clinical trials. So Kirsch and three others replicated the original study with the identical data set used by the pharmaceutical companies for the FDA approval of six of the new generation antidepressants at the time. These six accounted for the bulk of antidepressant prescriptions being written at the time, 2002. “In the data sent to us by the FDA, only 43% of the trials showed a statistically significant benefit of drug over placebo. The remaining 57% were failed or negative trials.” The results here were that 82% of the response to antidepressants was due to the placebo effect.

Kirsch again did a replication in 2008 with a larger number of clinical trials and again found the 82% placebo effect. In both analyses, the mean difference between drug and placebo was less than two points (1.8) on the HAM-D depression scale, used in all the FDA clinical trials for antidepressants at the time. The difference was clinically insignificant. In other words, these miniscule differences were too small to be observable in a normal clinical setting with someone who was depressed. Others, including the FDA, have repeatedly replicated their results. The above history can be found in a 2014 article by Irving Kirsch, “Antidepressants and the Placebo Effect,” or in his 2010 book, The Emperor’s New Drugs. There he speculated:

Antidepressants may be nothing more than active placebos, producing side effects through chemical means and therapeutic effects through psychological means.

Twenty-three years after Listening to Prozac, Peter Kramer published his latest book, Ordinarily Well: The Case for Antidepressants. According to Jonathan Rosen, who wrote “The Assault on Antidepressants” for The Atlantic, Kramer said he believed in the utility of antidepressants, despite their flaws. He not only sought to make a case for antidepressants, he also tried to make a case for psychiatry as “a humanistic science that bridges the impersonal ideals of the laboratory and the pragmatic exigencies of clinical intervention.”

In a book review of Ordinarily Well for The New York Times, Jennifer Senior referred to the original Kirsch research and said Kramer was wary of these studies because they flew in the face of his clinical experience. Indicating that when his own patients asked if their improved mood could be due to a placebo effect, “Dr. Kramer’s answer is an unequivocal no.” And Ordinarily Well attempted to prove his belief. Senior indicated Kramer argued that Kirsch deliberately “’seemed to cull studies in which antidepressants underperformed,’ and treated some drugs as placebos even though they may have had antidepressant effects.” Either Senior or Kramer was unaware of, or failed to mention the above-described replications done by Kirsch and others. She did point out how Kramer used meta-analyses to make his own points, but failed to acknowledge that fact. Another area of concern for Kramer was the mechanism for recruiting subjects for clinical trials.

He is particularly devastating on the subject of recruiting test subjects. One of the most damning chapters features an unnamed facility where antidepressant trials are frequently conducted. Many of the participants are unemployed or underemployed — lonely, dispossessed and eager for the money. Suddenly, they’re getting paid, interacting with others and receiving the careful attention of doctors and nurses. “Even on placebo,” Dr. Kramer writes, “these patients ought to get better.”

There is an indication that evidence-based medicine has some flaws; and that the gold standard of meta-analysis can be undermined by flawed analysis, especially in psychiatric drug research. And there really is a problem with recruiting clinical trials subjects; and sometimes with the methodologies used by researchers in those clinical trials. But remember that if Kramer’s concerns are accepted (and I think they should be), then the newer antidepressants were approved using questionable scientific methods and an unreliable approval process. See “Evidence-Based Treatment … Lacks Evidence.”

If that is the case, where is the protection that FDA approval of pharmaceuticals is supposed to provide? And why aren’t more people pressing for regulatory reform of the FDA clinical trial process? If we accept Kramer’s arguments, we should also acknowledge that the clinical trials used for FDA approval of SSRIs were invalid. Kramer’s rationale for dismissing the evidence for the placebo effect with antidepressants also calls into question the methods used for their approval—and many of the studies afterwards touting their continued effectiveness.

A recent review article by Andrews et al., “Is Serotonin a Downer or an Upper?” challenged the assumptions of the therapeutic effects of SSRIs. “Although the idea that a single neurochemical is the cause of depression is now considered simplistic, the low serotonin hypothesis still lies at the foundation of most research on depression.” The authors noted how many types of depression seem to correspond to higher levels of serotonin, not lower ones. They proposed a radical new way of understanding the role of serotonin in the brain, according to Shannon Peters in, “How Do Antidepressant Really ‘Work’?” They suggest that serotonin coordinates metabolic processes with the storage, mobilization, distribution, production and utilization of energy resources.

Under this theory, there are higher levels of serotonin when there is a need to redistribute limited energy resources. “Serotonin cannot be simply described as an ‘upper’ or a ‘downer’; its symptomatic effects depend on the organism’s state,” write the authors.

When listening to antidepressants, we hear a history of effectiveness that can’t be clearly attributed to the therapeutic effect of the drugs. Expectation or placebo plays a significant role in whether or not these drugs will help an individual “overcome” their depression. Peter Kramer continues to hold on to a narrative that the chemical properties of SSRIs actually do help some depressed individuals, with “little of the benefit coming from the classical placebo effect.” But in debunking the science used to affirm the antidepressant placebo effect, he also calls into question the methods used to approve those same SSRIs in the first place.

What about Peter Breggin? He’s still around and critiquing the use of other classes of psychiatric drugs as well as antidepressants. He was recently the expert witness in a 2016 court case, awarding $11.9 million in a Paxil suicide malpractice case. He has a video series on YouTube, “Simple Truths About Psychiatry,” which is also linked on his website: breggin.com. There is plenty of additional material there to support the ineffectiveness and danger of antidepressants. In 2011, Dr. Breggin was the expert witness in a court case where Prozac was found to be a contributing factor to the murder of a teenager by his friend. “This was the first criminal case in North America where a judge has specifically found that an antidepressant was the cause of a murder.”

There’s more discussion of Irving Kirsch and the placebo effect here on my website. Start with: “Dirty Little Secret” or do a search of the website for his name.

11/22/16

Antidepressant Misuse Disorder

54164089 - antidepressant pills 3d rendering isolated on white background

© Olekii Mach | 123rf.com

Chances are you know someone who is using an antidepressant. But that doesn’t necessarily mean the person you know has a problem with depression. In 2015, Takayanagi et al. published a study in The Journal of Clinical Psychiatry found that: “Among antidepressant users, 69% never met criteria for major depressive disorder (MDD); and 38% never met criteria for MDD, obsessive-compulsive disorder, panic disorder, social phobia, or generalized anxiety disorder in their lifetime.” Their data indicate that antidepressants were commonly used in the absence of “clear evidence-based indications.”

Writing for Mad in America, Justin Karter noted that previous studies revealed antidepressants were being over-prescribed and prescribed off-label. But others countered that these studies underestimated the lifetime prevalence of so-called mental disorders. The Takayanagi et al. study sought to address this criticism by conducting in-depth interviews to estimate whether participants met criteria for “mental disorders” over their lifetime. The study also indicated an individual was more likely to be prescribed an antidepressant if they were a woman, white, reported physical pain or discomfort to their doctor, or had recently visited a mental health care facility.

Another 2015 report by Kanton et al. published in JAMA found that the percentage of Americans on antidepressants increased from 6.8% to 14% between 1999 and 2012. The report’s authors speculated that the increase could in part reflect shifting attitudes regarding depression. Commenting on this report, Justin Karter pointed out how the increase likely includes a large proportion of off-label use of antidepressants. As was noted above, 69% of antidepressant users did not meet the criteria for major depression.

A JAMA study published in May of 2016 by Wong et al. found that 45% of the prescriptions given for antidepressants were to treat anxiety disorders, pain, insomnia and various other conditions. The study, which was done in Quebec Canada, looked at all adult prescriptions written for antidepressants (100,000 patients) between January 1, 2006 and September 30, 2015. Prescriptions for monoamine oxidase inhibitors were excluded. Prescriptions were classified as on or off label depending upon whether the drug was approved by Health Care of Canada or the FDA for the indication noted by September 0f 2015. Physicians prescribed antidepressant off-label for anxiety disorders (18.5%), insomnia (10.2%), pain (6.1%) and panic disorders (4.1%).

An online survey of long-term antidepressant patients by Cartwright et al., published in Patient Preference and Adherence, found that almost 90% reported some degree of improvement, with 30% also saying they had moderate to severe bouts of depression during treatment.  Ten different adverse effects were reported by over 50% of the participants. The five most common were: withdrawal effects (73.5%), sexual dysfunction (71.8%), weight gain (65.3%), feeling emotionally numb (64.5%), and failure to reach orgasm (64.5%). “Between 36% and 57% of respondents experienced these adverse affects at either a moderate or severe level.” Additional adverse effects reported included: agitation (55.1%), feeling not like myself (54.4%), reduced positive feelings (45.6%), caring less about others (36.4%), suicidality (36.0%), and feeling aggressive (31.6%).

Some patients in this study were particularly concerned about severe withdrawal symptoms that undermined their confidence to discontinue should they wish to and therefore limited their choices. In line with this, 45% patients also believed that they had some level of addiction to the antidepressant. Some patients were also critical of the lack of information given by prescribers with regard to adverse effects, including withdrawal symptoms. Some also expressed disappointment or frustration with the perceived lack of support available to them in managing withdrawal.

Limitations of the study include the fact that the data were self-reported and that the study was not a randomized control study—the gold standard methodology for evidence-based medicine. However, there are relatively few long-term outcome studies of antidepressant use.

A 2009 systematic review published in the Journal of Affective Disorders, concluded that long-term outcomes in depression were poor, with no clear relationship between drug treatment and positive outcomes.  The outcomes for non-antidepressant treatment were no worse than those for antidepressant treatment.

Overall 40% to 85% of patients experienced a recurrence during follow-up. Average time to recurrence was around 3.2 years across eight studies that provided data on this outcome. Around 25% of patients achieved a global rating of well or improved at the end of the study and a similar number had a poor outcome marked by multiple recurrences or continuous impairment. Most participants recovered from the index episode, but experienced multiple recurrences.

The August 2016 issue of Psychotherapy and Psychosomatics published a literature review of long-term use of newer generation antidepressants (i.e., SSRIs and SNRIs and others) by Carvalho et al. While many side effects were transient, disappearing after a few weeks, other potentially serious adverse events may persist or occur later. The main adverse events related to using newer antidepressant drugs included the following:

  • Gastrointestinal issues
  • Weight gain and metabolic disturbances
  • Genitourinary issues (issues related to the genital or urinary organs)
  • Sexual dysfunction
  • Hyponatremia (low sodium level in the blood)
  • Osteoporosis and risk of fractures
  • Bleeding
  • Central nervous system issues
  • Sweating
  • Sleep disturbances
  • Affective disturbances
  • Suicidality
  • Discontinuation syndromes

You can read more information on the above adverse effects and others in the Carvalho et al. review. What follows is a brief discussion of their findings for weight gain and diabetes, bleeding, sleep disturbances, affective disturbances, suicidality, and discontinuation syndromes.

Several studies have shown that long-term use of antidepressants (more than 6 months) is associated with weight gain. Paroxetine (Paxil) may be the worst offender. A population-based study indicated the use of antidepressants could be associated with a higher risk of obesity. The association between antidepressants and diabetes mellitus is inconclusive. Some reports indicate a higher risk; others do not. But a recent review and meta-analysis found that SSRIs were associated with an increased risk of diabetes mellitus.

All SSRIs have been associated with an increased risk of bleeding. “The most likely mechanism responsible for these adverse reactions is a reduction of serotonin reuptake by platelets.” Fluoxetine (Prozac), paroxetine (Paxil), and sertraline (Zoloft) have a higher risk of platelet dysfunction than other SSRIs. Veniafaxine (Effexor) and mirtazapine (Remeron) have been associated with an increased risk of bleeding. SSRIs have been associated with a higher risk of bleeding during operations.

Sleep disturbances are one of the hallmark symptoms of depression. However,  studies have shown that SSRIs and Effexor are associated with increased REM sleep latency and an overall reduction in the time spent in REM sleep. These effects are usually associated with the initial period of treatment and may return to baseline after 8 weeks. Remeron and trazodone have been associated with improving sleep. In my clinical experience, trazadone is regularly used off-label to help promote sleep.

Many individuals taking SSRIs report they experience emotional blunting. They say their emotions have been “toned down.” Others say they just don’t care about issues that were significant to them before. “Evidence indicates that these adverse affective manifestations may persist even after the symptoms of depression have improved and can occur in patients of all ages.” Mania or agitation can occur. These response have been said to unveil unrecognized bipolar disorder. But since this can also occur in previously unipolar patients, the mania could be drug-induced. An activation syndrome, where patients experience anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness and impulsivity can occur.

Carvalho et al. limited the occurrence of these adverse effects to the first three months of treatment. However, psychiatrist Peter Breggin has documented the emergence of agitation and activation with antidepressants in Medication Madness and other writings. Carvalho et al. said using antidepressants could also be associated with the return of depressive symptoms during baseline treatment, and the appearance of new symptoms or paradoxically, exacerbate the baseline clinical picture. The occurrence of paradoxical effects was reported in random control trials with Prozac and Zoloft.

The emergence of suicidality and self-injurious behavior with antidepressant treatment is one of the most debated and controversial risks. Nevertheless, the FDA has required a black box warning regarding the risk of suicidality for children and adolescents using antidepressants since 2014. The incidence of successful and attempted suicide has been frequently underreported in antidepressant RCTs. Carvalho et al. said:

Two recent meta-analyses have not identified a clear increased risk of treatment-emergent suicidality in adult individuals treated with antidepressants in RCTs. Notwithstanding that the use of antidepressants is efficacious for the treatment of MDD in adults, there is no clear evidence for either specific protective effects or increased risk related to suicidality.

Often underappreciated, is the emergence of withdrawal symptoms of varying degrees with treatment discontinuation and/or interruption with almost all SSRIs and SNRIs. These reactions have been described as “discontinuation syndromes” in an attempt to avoid the suggestion of dependence that could effect marketing. A review suggested the dependence and withdrawal with newer antidepressants was comparable to those experienced with benzodiazepines. “Due to the severity and unpredictability of these manifestations, it has been recently suggested that the term ‘discontinuation syndrome’ should be replaced by ‘withdrawal syndrome.’” These symptoms can include:

flu-like symptoms, tremors, tachycardia, shock-like sensations, paresthesia, myalgia, tinnitus, neuralgia, ataxia, vertigo, sexual dysfunction, sleep disturbances, vivid dreams, nausea vomiting, diarrhea, worsening anxiety and mood instability.

In their conclusion, Carvalho et al. said the common belief of fewer side effects with the newer generation antidepressants (especially the SSRIs) only pertains to their safety in overdose. “On the contrary, the long-term use of SSRIs and SNRIs is likely to yield important side effects.” The likelihood of treatment-emergent adverse effects is related to the duration of antidepressant treatment—particularly with weight gain, diabetes, and osteoporsis. Some adverse side effects may persist long after discontinuation of the drug. Particularly following long-term use, antidepressants,

 … may increase the risk of experiencing additional psychopathological (e.g. treatment emergent affective switches and paradoxical symptoms), or medical (e.g. obesity and bleeding) problems that do not necessarily subside after discontinuation of the drug.

This leads to their conclusion that: “The findings of this review suggest that long-term treatment with new generation ADs should be avoided if alternative treatments are available.”

09/2/16

Antidepressant Scapegoat

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

© Elena Ray | 123rf

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

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

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

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

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

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

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

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

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

The nine DSM-5 symptoms are:

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

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

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

11/18/15

The Cycle of Antidepressant-Induced Helplessness

© Everett Collection, Inc. | dreamstime.com

© Everett Collection, Inc. | dreamstime.com

Lawyers for GlaxoSmithKline (GSK) recently referred to evidence presented by a well-respected expert, Dr. Joseph Glenmullen, as “junk science.” He was irrational enough to testify that there was a connection between suicidality (the likelihood of an individual completing suicide) and suicide attempts. The case is one where the widow of a lawyer sued GSK because her husband committed suicide shortly after taking a generic version of the antidepressant. “Since there is no way Dr. Glenmullen can establish causation based on suicide data, he relies instead on data on ‘suicidality’ and suicide attempts, which are not appropriate surrogates for reaching conclusions about suicide.”

The above was taken from a brief news report on Mad in America, “Paxil Manufacturer Calls Evidence of Suicide Risk ‘Junk Science.’” The article said GSK has routinely overstated the drug’s efficacy. A widely cited 2001 study funded by GSK known as “Study 329” was recently reanalyzed and these results then published in the British Medical Journal. The reanalysis showed that the original claim by Study 329 that Paxil (paroxetine) was safe and effective for adolescents was wrong. The September 16, 2015 BMJ press release also noted where GKS had been fined $3 billion ($1 billion criminal, $2 billion civil) for fraudulently promoting paroxetine, among other violations.

Using previously confidential documents, researchers reanalyzed the original data from Study 329 and found that paroxetine was not more effective than placebo in treating major depression in adolescents. They concluded: “paroxetine was ineffective and unsafe in this study.” And yet for fourteen years Study 329 has been cited as demonstrating the safety and efficacy of paroxetine to treat adolescent depression. The BMJ Editor-in-Chief said the publication of the reanalyzed data “set the record straight” while it also “shows the extent to which drug regulation is failing us.”

All antidepressant medications are required to include a warning similar to what follows, which was taken from the Medication Guide for Paxil:

PAXIL and other antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, or young adults within the first few months of treatment or when the dose is changed.

Psychiatrist Peter Breggin noted in “The Proven Dangers of Antidepressants” that the FDA warning cautioning about the risks of newer antidepressants (Prozac, Zoloft, Paxil, Luvox, Celexa, and Lexapro, as well as Wellbutrin, Effexor, Serzone, and Remeron) followed a public hearing with dozens of family members and victims testifying about suicide and violence committed by individuals taking these medications.

While stopping short of concluding the antidepressants definitely cause suicide, the FDA warned that they might do so in a small percentage of children and adults. In the debate over drug-induced suicide, little attention has been given to the FDA’s additional warning that certain behaviors are “known to be associated with these drugs,” including “anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia (severe restlessness), hypomania, and mania.

Breggin was himself an expert witness in a 2012 court case that awarded $1.5 million medical malpractice verdict to a family of a man who committed suicide. He testified how antidepressants such as Paxil and Effexor could increase suicide risk in adults.

After reviewing extensive records and interviewing Mr. Mazella’s wife Janice, I concluded that Dr. Beals was negligent in reportedly prescribing Paxil for 10 years without seeing the patient, in failing to warn the patient and his wife about the serious risks associated with Paxil, in his doubling the Paxil dose and adding Zyprexa by telephone, and then in abandoning the patient during his decline. I also concluded that a hospital psychiatrist was negligent in not recognizing that Mr. Mazella was suffering from adverse drug effects and in discharging him without proper follow up two weeks before his death.

In his discussion on “The Proven Dangers of Antidepressants” linked above, Breggin also commented how there has been little attention to the additional FDA warning that additional behaviors are known to be associated with antidepressants, including “anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia (severe restlessness), hypomania, and mania.” He noted how he has repeatedly documented how the stimulation and activation profile of antidepressants can lead to out-of-control behavior, including violence.

In his article, “Antidepressant-Induced Mania,” psychologist Philip Hickey described how circular reasoning about activation from antidepressants becomes evidence of “an underlying latent bipolar disorder.” He indicated that psychiatry retrospectively applies their explanation as follows: “Before the individual showed any signs of mania, he must have had bipolar disorder because he became manic at a later date.” The hypothesis cannot be verified because the occurrence of a manic or hypomanic episode is the primary criterion for the bipolar diagnosis.

Yet there has been recent evidence that manic/hypomanic episodes can be caused by the use of antidepressant medications. Hickey reviewed a Psychiatric Times article written by Ross Baldessarini that reported on a meta-analysis that he and his colleagues did on antidepressant-associated mood-switching. Bipolar disorder is often seen as beginning with at least one episode of major depression, followed by an episode of mania or hypomania. This ‘switching’ of mood may occur during treatment with an antidepressant or other mood-elevating agent. And it is especially common among juveniles and young adults using an antidepressant for a mood disorder (depression or anxiety) or a stimulant for attention. “Such pathological shifts of mood and behavior may represent adverse drug actions or a manifestation of undiagnosed bipolar disorder.”

Hickey noted that Baldessarini et al. found that manic or hypomanic episodes were 5.6 times more common per year for individuals diagnosed with major depression who were taking antidepressants and others with the same diagnosis who were not taking them. After citing several quotations from the Baldessarini et al. study and the Psychiatric Times article, Hickey said: “What the authors are pointing out here is that antidepressants are clearly implicated in the ‘excess’ incidents of mania/hypomania, and they have even raised the question of a direct causal link.”

Baldessarini even suggested that when antidepressant-related manic episodes occur, the continued use of antidepressants might contribute to recurrent manic episodes. Although it is widely assumed that mood-stabilizing drugs are highly effective in preventing antidepressant-associated mood switching, it is not conclusively proven to be true. “Moreover, there is very limited evidence that prolonged antidepressant treatment provides substantial protection against recurrences of bipolar depression and that it might contribute to emotional instability or rapid cycling.”

When you add the research of Irving Kirsch, who has shown that antidepressants have little or no therapeutic effect at all (See “Do No Harm with Antidepressants”), we are left with a class of drugs that are no more effective than the placebos used in their clinical trials. As we saw here, they could also activate what they are taken to prevent or stabilize—depressive symptoms such as suicidality. Moreover, their use could also lead to mania or hypomania and thus elevate the initial diagnosis of major depression to the more serious one of bipolar disorder. And the icing on the cake is that if antidepressants are continued, they may contribute to further emotional instability or rapid cycling. This is a cycle of what Peter Breggin called iatrogenic helplessness generated by antidepressants. Here is his description in Brain-Disabling Treatments in Psychiatry:

The concept of iatrogenic helplessness and denial includes the patient’s and the doctor’s mutual denial of the damaging impact of the treatment as well as their mutual denial of the damaging impact of the patient’s underlying psychological and situational problems. Overall, iatrogenic helplessness and denial accounts for the frequency with which psychiatry has been able utilize brain-damaging technologies, such as electro-shock and psychosurgery, as well as toxic medications.

Iatrogenic refers to something induced inadvertently by a physician, medical treatment or diagnostic procedures. Breggin has been challenging the iatrogenic nature of psychiatric treatment for essentially his entire professional career as a psychiatrist. In 1983 he wrote in The Iatrogenics Handbook that iatrogenic denial involved the infliction of brain damage and dysfunction upon the patient to encourage them to deny both the existence of his problems and the iatrogenic brain damage. “I developed the brain-disabling hypothesis which states that all the major psychiatric treatments disable the normal brain rendering the individual more helpless and hence easier to manage or to ignore.”

10/21/15

Dirty Little Secret

© ia_64 | stockfresh.com

© ia_64 | stockfresh.com

Quoting Steven Hollon, in his book The Emperor’s New Drugs, Irving Kirsch said it was a “dirty little secret” that there was only a small difference between the experimental and control groups for the patients who participated in the randomized clinical trials (RCTs) used to approve SSRIs. Be sure to get this: the pharmaceutical companies that produced the drugs AND the regulatory agencies that approved them, knew there was essentially no difference between the effects of the drug and the placebo. Yet the drugs were approved for use with humans. “Many have long been unimpressed by the magnitude of the differences observed between treatments and controls, what some of our colleagues refer to as the ‘dirty little secret’ in the pharmaceutical literature.”

Kirsch was originally interested in studying the placebo effect, and not the antidepressant drug effect. “How is it, I wondered, that the belief that one has taken a medication can produce some of the effects of that medication?” He was not surprised to find a substantial placebo effect of the medications on depression. But he was surprised to see how small the drug effect was. “Seventy-five percent of the improvement in the drug group also occurred when people were give dummy pills with no active ingredient in them.”

You can read an article by Kirsch describing the research process described here in: “Antidepressants and the Placebo Effect.”

He replicated the findings in another study published in 2002, using the data submitted to the FDA by the pharmaceutical companies in their process of obtaining approval for six new generation antidepressants. There were some advantages to using the FDA data set. First, they received data on the published and unpublished clinical trials conducted by the pharmaceutical companies. What was particularly important here was that: “The results of the unpublished trials were known only to the drug companies and the FDA, and most of them failed to find a significant benefit of drug over placebo.”

A second advantage was that the FDA trials all used the same primary measure of depression—the Hamilton depression scale (HAM-D). The third advantage was that the FDA data was the same data used for the approval of the medications. So if there had been anything wrong with the trials, one would think, the medications would not have been approved.

In the data sent to us by the FDA, only 43% of the trials showed a statistically significant benefit of drug over placebo. The remaining 57% were failed or negative trials. . . . The results of our analysis indicated that the placebo response was 82% of the response to these antidepressants.

One explanation for Kirsch’s results could be that the replication done in 2002 contained both the published and unpublished clinical trials. The inclusion of failed and negative trials would have lowered the positive results required by the FDA for approval of a medication. So the placebo response was greater in this replication than it was in their original study because of including the unpublished trials. Nevertheless, the majority of the trials failed to show positive results. Remember that the pharmaceutical companies themselves conducted these studies; and that they were the trials done in the process of gaining approval for their medications.

Getting approval of a drug by the FDA requires the submission of two studies showing the new drug is better than a placebo. It doesn’t matter if it takes you ten studies to get those two; only the two positive ones count for approval. The requirement is that two trials have to demonstrate the drug is more effective than a placebo, and that measurement has to be statistically significant. Kirsch’s analysis found just a 1.8-point difference on the HAM-D scale between drug and placebo—a difference that is not clinically significant, even though it may be statistically significant. The National Institute for Health and Clinical Excellence (NICE) has set the criterion for a clinically significant difference between drug and placebo to be at least three points on the HAM-D scale.

A criticism of Kirsch’s 2002 study was that the results were based on clinical trials conducted on subjects who were not very depressed. So Kirsch et al. (2008) reanalyzed the data in: “Initial Severity and Antidepressant Benefits.” They found that “the overall effect of new-generation antidepressant medications is below recommended criteria for clinical significance.” Only for the most extremely depressed patients was there evidence for clinical significance, according to the HAM-D scale. Yet they also concluded this difference was “due to a decrease in the response to placebo rather than an increase in the response to medication.”

So the question becomes, what do all these drugs have in common that gives them a slight, but statistically significant effect on depression over placebo? The answer is that they all produce side effects.

Clinical trials are all double-blind studies, meaning that neither the patient nor the doctor is supposed to know whether the patient is given the active drug or the placebo. Yet in one study, 80% of patients guessed correctly whether or not they were on the drug or placebo; and 87% of doctors also guessed correctly. So most patients and most doctors could break the blind by guessing according to the presence or absence of side effects to the medications. Additionally, “89% of the patients in the drug group correctly ‘guessed’ that they had been given the real antidepressant, a result that is very unlikely to be due to chance.”

So clinical trials are not really double blind studies if most patients can guess whether or not they have been given the real drug rather than the placebo. This ability to “break blind” has been known in the research literature since 1986 when Rabkin et al. published their study, “How Blind is Blind” in the September issue of Psychiatry Research. Yet drug trials continue to use inert placebos.

But what would happen if an active placebo were used in clinical trials? Active placebos have been used with antidepressants in other studies. See “Active Placebos Versus Antidepressants for Depression.”  Moncrieff et al. reported that: “differences between antidepressants and active placebos were small.” Kirsch noted that in the nine clinical trials discussed by Moncrieff et al. where an active placebo (atropine) was used, there was only a significant difference in two of the studies.

In the vast majority (78 percent) of the clinical trials in which active placebos were used, no significant differences were found between the drug and the placebo. So comparisons with inactive placebos are much more likely to show drug-placebo differences than comparisons with active placebos. This suggests that at least part of the difference that has been found between antidepressant and placebo may be due to the experience of more side effects on the active drug than on the placebo.

It’s good this dirty little secret is becoming more widely known. But unfortunately the horse has already left the barn. Too bad it wasn’t getting press fifteen years ago before the SSRIs started going off-patent. The pharmaceutical companies have already gouged the public with their SSRI profits and their drugs have gone generic.

Eli Liliy’s Prozac went off patent in 2001. GlaxoSmithKline’s Paxil has been off-patent since 2003. Forest Labs’ Celexa patent expired in 2003. Pfizer’s Zoloft patent expired in 2006. Wyeth’s Effexor (now marketed by Pfizer) went off-patent in 2006. Wellbutrin, developed by Burroughs Wellcome and later acquired by GlaxoSmithKline, lost its patent in 2006. Lexapro was developed by Forest Laboratories in conjunction with Lundbeck and they won two patent extensions. But it lost exclusivity in 2012.

09/2/15

Do No Harm with Antidepressants

© Jrabelo | Dreamstime.com

© Jrabelo | Dreamstime.com

In April of 2006, I first read Irving Kirsch’s 2002 article, “The Emperor’s New Drugs.” In that article, Kirsch described how 80% of the response to antidepressant medications was duplicated in placebo control groups. Kirsch’s analysis was of the very same clinical data submitted to the FDA between 1987 and 1999 for the approval of 6 widely prescribed antidepressants. The allusion to Hans Christian Andersen’s tale, “The Emperor’s New Clothes” was fitting. Kirsch played the role of the little boy in Andersen’s tale to my understanding of how antidepressants work. He pointed to antidepressants and said: “But they have little or no therapeutic effect at all!”

Since 2006 I’ve become familiar with the work of several individuals questioning the received wisdom of psychotropic medications, including Joanna Moncrieff. Her book, The Myth of the Chemical Cure, had its own “aha!” moment in the development of my thinking on the clinical use of psychiatric medications. A search of  “Faith Seeking Understanding” by their names will pull up other articles where I have referenced them.

Not too long ago, I saw a link to a new article by Joanna Moncrieff and Irving Kirsch, “Empirically derived criteria cast doubt on the clinical significance of antidepressant-placebo differences.” I’ve read previous articles written by Moncrieff and Kirsch, “Efficacy of antidepressants in adults” and “Clinical trials and the response rate illusion.” But still looked forward to reading their latest. It seems to have hammered home the final nail in the coffin of the ineffectiveness of antidepressants for me.

In “The Emperor’s New Drugs,” Kirsch found that the drug/placebo difference was less than 2 points on the Hamilton-D (HAM-D) scale, a scale often used in studies for assessing the effects of antidepressants. Even then, Kirsch et al. were saying that: “the clinical significance of these differences is questionable.” The spin put on his conclusions was that this was only to hold true only for individuals with mild cases of depression. Moderate to severe depression should still have antidepressants as a first-line treatment.

However, in “Efficacy of antidepressants in adults,” Moncrieff and Kirsch pointed out that the studies included in “The Emperor’s New Drugs,” were mainly with patients suffering with severe to very severe depression. They cited additional studies questioning the efficacy of antidepressants and concluded: “Recent meta-analyses show selective serotonin reuptake inhibitors have no clinically meaningful advantage over placebo;” and that “Claims that antidepressants are more effective in more severe conditions have little evidence to support them.”

In their most recent article, Moncrieff and Kirsch tackled the issue of how antidepressants have been shown to be statistically superior to placebo. This statistical significance has been true from the time of Kirsch’s work on “The Emperor’s New Drugs, ” where the authors said that: “Although mean differences were small, most of them favored the active drug, and overall, the difference was statistically significant.” Moncrieff and Kirsch commented that a three-point difference on the HAM-D scale could not be detected by clinicians. Clinically relevant drug-placebo differences would have to be 7 points or greater on the HAM-D scale. “Currently, drug effects associated with antidepressants fall far short of these criteria.”

These conclusions were built upon the work of German psychiatrist Stefan Leucht and his colleagues. You can read a less technical discussion of the importance of this research in Dr. Moncrieff’s blog, here. She said that a reduction of 2 points on the 52 point HAM-D scale, while statistically significant, seemed to be an insignificant amount. “Leucht et al. provide some empirical evidence to support that hunch.”

Given that there was little if any difference in clinically relevant effects between one treatment and another, Moncrieff and Kirsch suggested that patients and healthcare providers should be aware that all treatments, including placebo, produce some positive effect on symptom scales, “while none outperforms a pill placebo to a meaningful degree.”

The small differences detected between antidepressants and placebo may represent drug-induced mental alterations (such as sedation or emotional blunting) or amplified placebo effects rather than specific ‘antidepressant’ effects. At a minimum, therefore, it is important to ascertain whether differences correlate with clinically detectable and meaningful levels of improvement.

So where does this discussion lead us? Treating depressive symptoms with antidepressants should not be a first option. “Given the choice, most depressed patients prefer psychotherapy over medication.” Moncrieff and Kirsch suggest that decisions about treatment should include patient preference, safety and cost. With regard to safety, antidepressants should be a last choice for treatment alternatives.

Their article referenced a study by Andrews et al., “Primum non nocere” (first, do no harm), which noted a series of harmful effects from SSRIs. Serotonin has wide reaching effects on adaptive processes throughout the body and could have many adverse health effects. They described how antidepressants effect the proper functioning of homeostatic mechanisms in the body.  Long-term use is associated with a loss of symptom reducing effectiveness with SSRIs. This suggests that the brain is pushing back against the effects of SSRIs and trying to regain the homeostasis present before the use of antidepressants began. “Because of the complex role that serotonin plays in shaping the brain, antidepressants could have complex effects on neuronal functioning.”

Additional negative side effects included attention problems, driving performance, falling and bone fractures in the elderly, gastrointestinal problems such as diarrhea, constipation and irritable bowel syndrome. SSRIs may increase the risk of abnormal bleeding. They can related to an increase risk of cardiovascular events. There is concern that SSRIs can effect neonatal development. One study suggested SSRI use during pregnancy, especially the first trimester, led to an increased risk of Autism Spectrum Disorders. Andrews et al. summarized their findings here:

We have reviewed a great deal of evidence of the effects of antidepressants on serotonergic processes throughout the body. Some of the effects are widely known, but they have been largely ignored in debates about the utility of antidepressants. Indeed, it is widely believed that antidepressant medications are both safe and effective; however, this belief was formed in the absence of adequate scientific verification. The weight of current evidence suggests that, in general, antidepressants are neither safe nor effective; they appear to do more harm than good.

03/18/15

Modern Alchemy with Antidepressants

19867524_sA study published in the open access journal, PLOS One by Sugarman et al. once again replicated previous studies showing that there was very little clinical difference between an antidepressant and placebo. In a way this is old news. One of the study’s authors, Irving Kirsch previously reported these findings. You can read more on this antidepressant research here and here. I’ve also looked at a 60 Minutes broadcast that interviewed him in “Thor’s Psychiatric Hammer: Antidepressants.” Kirsch has also published a book on the topic: The Emperor’s New Drugs: Exploding the Antidepressant Myth. But here is the significance of the Sugarman et al. study. It was the first evaluation to use “a complete database of published and unpublished trials sponsored by the drug’s manufacturer.”

In 2004, GlaxoSmithKline  (GSK) was required as part of a lawsuit settlement to post online the results of all clinical trials involving its drugs. The 2004 lawsuit was because the company had withheld data on the ineffectiveness and potential danger of Paxil (paroxetine) when given to adolescents and children. But it doesn’t seem GSK learned their lesson. In 2014 the company agreed to plead guilty to criminal charges and pay $3 billion in fines for promoting its antidepressant drugs, Paxil and Wellbutrin for unapproved uses and failing to report safety data about Avandia. So Sugarman et al. were able to use the data GSK made available to do the research reported here.

The current analysis is the first evaluation of the efficacy of an SSRI medication in the treatment of multiple anxiety disorders, and the first to utilize a complete database of published and unpublished trials sponsored by the drug’s manufacturer. Our results indicated that paroxetine presented a modest benefit over placebo in the treatment of anxiety and depression, with mean change score differences of 2.3 and 2.5 points on the HRSA [Hamilton Rating Scale for Anxiety] and HRSD [Hamilton Rating Scale for Depression], respectively.

The study’s results found that individuals receiving placebo reported 79% of the magnitude of change with the individuals receiving paroxetine. This was consistent to previously reported magnitudes of 76% for placebo compared to paroxetine. Replicating this previous finding, namely greater than 75% of the drug response, suggested that: “the magnitude of the placebo effect is especially large in the treatment of anxiety and depression.” Given the similarities between paroxetine and other SSRIs, it is possible that similar magnitudes of placebo effects will be found with them. Further research is required to support this proposition. Nevertheless, “the current analysis indicates that the published literature represents an overestimate of the true efficacy of paroxetine in the treatment of anxiety.”

The glass-half-full reporting of the differences between drug and placebo have emphasized that statistically significant differences were found. The problem is, those differences were so small, that their clinical significance was questionable. According to the criteria of NICE, the National Institute of Health and Clinical Excellence, “the mean difference between paroxetine and placebo in the current analyses fell short of clinical significance for the treatment of both anxiety and depression.” Sugarman et al. reviewed these concerns and concluded that changes of three points or less on the HRSD did not correspond to a clinically detectable change and appeared to be “of marginal clinical significance.”

So paroxetine has only a slight benefit over placebo in treating symptoms of anxiety and supports previous work indicating that it has just a modest benefit over placebo when treating depression. Given the known side effects with standard medications used to treat anxiety and depression, their use as a first-line treatment for these problems seems questionable. “The obvious alternative for the treatment of both anxiety and depression is psychotherapy intervention.” But direct comparisons have not generally shown a significant difference between depression treatment modalities (medication or psychotherapy). Similarly inconclusive findings were noted for anxiety treatment.

Allen Frances said there were two differences between medieval alchemy and the pharmaceutical industry today. First is the well-oiled, massively financed, worldwide, and devastatingly effective marketing machine. Second is the requirement for a DSM diagnosis.

A significant portion of the $12 billion spent each year on antidepressants in the United States rewards the drug companies for promoting the overly widespread use of what to many patients are no more than highly advertised, oversold, and very expensive placebos prescribed for a fake diagnosis. (Allen Frances, Saving Normal)

In 2010, there was a study published a Scandinavian psychiatric journal with the provocative title: “Antidepressant Medication Prevents Suicide in Depression.”  It concluded from studying 18,922 suicides in Sweden between 1992 and 2003, “that a substantial number of depressed individuals were saved from suicide by postdischarge treatment with antidepressant medication.” Sixteen months after publication, it was formally retracted by the authors for “… unintentional errors in the analysis of the data.”

Psychologist Phillip Hickey reported that after a five month legal battle, he was able to get access to the correct data. The original study found that among completed suicides treated for depression in psychiatric care in the last five years before their suicide, 164 (15.2%) had antidepressants in their blood when they committed suicide. The corrected data indicated that 603 (56%) had antidepressants in them when they committed suicide. The “unintentional error” was huge—an increase of 439 people (268%).

And yet, the study’s author said that no conclusion from the study could be drawn “regarding antidepressants’ effects on suicide risk in any direction.” In other words, you couldn’t conclude that antidepressants prevented or facilitated suicide risk. Hickey reported that at the time of writing the original article, its author has financial ties to Lundback, Eli Lily and GSK (GlaxoSmithKline).

In another study, found in The British Journal of Psychiatry, a team of UCLA researchers randomized 88 participants into double-blind groups for 8 weeks of treatment (placebo or medication) with supportive care; and a separate group receiving supportive care alone. Expectations of medication effectiveness, general treatment effectiveness and therapeutic alliance were also measured. The groups receiving medication or placebo plus supportive care were not significantly different. However, both had significantly better outcomes than the supportive care alone group. Expectations of medication effectiveness were predictive of only the placebo response. Therapeutic alliance predicted participant response to both medication and placebo.

The lead author of the study, Andrew Lechter, said that the results indicated that if you think a pill is going to work, it probably will work. He noted that belief in the effectiveness of the medication was not related to the likelihood of benefitting from it. “Our study indicates that belief in ‘the power of the pill’ uniquely drives the placebo response, while medications are likely to work regardless of patients’ belief in their effectiveness.” He speculated that factors like direct-to-the-consumer advertising could be shaping peoples’ attitudes about medication. “It may not be an accident that placebo response rates have soared at the same time the pharmaceutical companies are spending $10 billion a year on consumer advertising.”

It seems that Lechter is saying that the drug response was independent of the expectations of medication effectiveness, while the placebo response was driven be the prior expectations of the participants, as they were influenced by factors like direct-to-the-consumer advertisings. If true, this would seem to challenge, to a certain extent, the results noted above and in Kirsch’s previous research. Replication of the results is needed before Lechter’s conclusions from his research are accepted. It should be pointed out that paroxetine (Paxil) was approved by the FDA in May of 1996, while direct-to-the-consumer advertising of medications did not begin until 1997. Therefore, it would not have had an effect upon the paroxetine data reported above. I would also feel more comfortable with Lechter’s interpretations of his data if he didn’t have as extensive an association with the pharmaceutical industry. See the “Declaration of interest” in the linked abstract from The British Journal of Psychiatry.