09/15/20

If TD Walks Like a Duck …

On April 10, 2020, Psychiatric Times published “Advances in Tardive Dyskinesia: A Review of Recent Literature.” The article was written as a supplement to Psychiatric Times and provided helpful information on the recent literature on tardive dyskinesia (TD), the signs and symptoms of TD, risk factors and epidemiology, treatment and screening. It also contained concise summaries of several studies of TD. Overall, it appears to be an accessible article with a wealth of information on TD. But like a pitch from a pharmaceutical sales rep, attached to the end of the article is the medication guide for Ingrezza (valbenazine), one of two FDA-approved medications to treat TD, and a full-page color ad by Neurocrine Biosciences for Ingrezza.

The attachment of the advertisement and medication guide for Ingrezza left me wondering whether “Advances in Tardive Dyskinesia” was truly a review of the recent literature or just an advertisement. I don’t know if the author knew his article would have these attachments, but they left me wondering how objective the article was. It was formatted like a journal article, but as it was not published in a peer-reviewed journal; it did not have to go through that process. So, I question the representativeness of the “concise summaries of selected articles” reviewed in the article and whether there is another perspective of TD and its treatment.

Peter Breggin M.D. has a “TD Resources Center” for prescribers, scientists, professionals, patients and families that presents an opposing view of TD. He considers TD to be an iatrogenic disorder, largely from the use of antipsychotic drugs. Breggin said: “TD is caused by all drugs that block the function of dopamine neurons in the brain. This includes all antipsychotic drugs in common use as well as a few drugs used for other purposes.” In what follows, I will compare selections from the “Advances in Tardive Dyskinesia” to information available on Dr. Breggin’s website.

“Advances in Tardive Dyskinesia” said the causes of TD were unknown, but likely to be complex and multifactorial. It suggested there is evidence that multiple genetic risk factors interact with nongenetic factors, contributing to TD risk. It quoted the DSM-5 definition of TD, which said it developed in association with the use of a neuroleptic (antipsychotic) medication. Note that TD is narrowly conceived as related to the use of antipsychotics. This then necessitate the existence of something called spontaneous dyskinesia, which is an abnormal movement in antipsychotic-naïve patients that is “indistinguishable from TD.” A review of antipsychotic-naïve studies found that the prevalence of spontaneous dyskinesia ranged from 4% to 40% and increased with age.

TD was said to be highly prevalent in patients treated with antipsychotics, but the rate of TD was lower, but not negligible, in patients treated with second-generation antipsychotics compared to those treated with first-generation antipsychotics (21% versus 30%). The cumulative duration of antipsychotic exposure was said to be an important consideration when estimating these TD rates, which can be diagnosed after as little as 3 months of cumulative antipsychotic treatment. TD can emerge more rapidly in some patients, especially the elderly.

Alternatively, Peter Breggin said TD is “a group of involuntary movement disorders caused by drug-induced damage to the brain.” As noted above, he conceives TD as caused by all drugs that block the function of dopamine in the brain. Included are all antipsychotics “as well as a few drugs used for other purposes.” He said TD begins to appear within 3-6 months of exposure to antipsychotics, but cases have occurred from one or two doses.

The risk of developing TD, according to Breggin, was high for all age groups, including young adults: 5% to 8% of younger adults per year who are treated with antipsychotics. The rates are cumulative, so that by three years of use, 15% to 24% will be afflicted. “Rates escalate in the age group 40-55 years old, and among those over 55 are staggering, in the range of 25%-30% per year.” One article by Joanne Wojcieszek, “Drug-Induced Movement Disorders,” said the risk factors for developing TD increase with advancing age. “In patients older than age 45 years, the cumulative incidence of TD after neuroleptic exposure is 26%, 52%, and 60% after 1, 2, and 3 years respectively.” There is more detailed information in his Scientific Literature section. Regarding the newer, second-generation antipsychotics , he thought they had similar rates to first-generation antipsychotics. Breggin said:

Drug companies have made false or misleading claims that newer antipsychotic drugs or so-called atypicals are less likely to cause TD than the older ones. Recent research [more information in his Scientific Literature section], much of it from a large government study called CATIE, have dispelled this misinformation. Considering how huge the TD rates are, a small variation among drugs would be inconsequential. All the antipsychotic drugs with the possible exception of the deadly Clozaril, cause TD at tragically high rates. Since all these drugs are potent dopamine blockers, there should have been no doubt from the beginning that they would frequently cause TD.

Psychiatric Times linked several articles on tardive dyskinesia together, including, “Not All That Writhes Is Tardive Dyskinesia” and others like “Tardive Dyskinesia Facts and Figures,” “A Practical Guide to Tardive Dyskinesia,” and others. The information in the articles generally seems to acknowledge TD as being associated with long-term exposure to dopamine receptor antagonists (Although “Not All That Writhes Is Tardive Dyskinesia” softened that association by making the TD-spontaneous dyskinesia distinction), which include both first and second-generation antipsychotics. In “Tardive Dyskinesia Facts and Figures,” Lee Robert said a survey of patients taking antipsychotics found that 58% were not aware that antipsychotics can cause TD. An estimated 500,000 persons in the US have TD. 60% to 70% of the cases are mild, and 3% are severe. “Persistent and irreversible tardive dyskinesia is most likely to develop in older persons. . . Tardive dyskinesia is not rare and anyone exposed to treatment with antipsychotics is at risk.”

GoodTherapy gave the following information on “Typical and Atypical Antipsychotic Agents.” The website noted antipsychotic medications, also known as neuroleptics or major tranquilizers, have both a short-term sedative effect and the long-term effect of reducing the chances of psychotic episodes. There are two categories of antipsychotics, typical or first-generation antipsychotics and atypical or second-generation antipsychotics. First generation antipsychotics were said to have a high risk of side effects, some of which are quite severe. “In response to the serious side effects of many typical antipsychotics, drug manufacturers developed another category referred to as atypical antipsychotics.”

Both generations of antipsychotics tend to block receptors in the dopamine pathways or systems of dopaminergic receptors in the central nervous system. “These pathways affect thinking, cognitive behavior, learning, sexual and pleasure feelings, and the coordination of voluntary movement. Extra firing (production of this neurotransmitter) of dopamine in these pathways produces many of the symptoms of schizophrenia.” The discovery of clozapine, the first atypical antipsychotic, noted how this category of drugs was less likely to produce extrapyramidal side effects (tremors, paranoia, anxiety, dystonia) in clinically effective doses than some other antipsychotics.

Wikipedia said as experience with atypical antipsychotics has grown, several studies have raised the question of the wisdom of broadly categorizing antipsychotic drugs as atypical/second generation and typical/first generation. “The time has come to abandon the terms first-generation and second-generation antipsychotics, as they do not merit this distinction.”

Although atypical antipsychotics are thought to be safer than typical antipsychotics, they still have severe side effects, including tardive dyskinesia (a serious movement disorder) neuroleptic malignant syndrome, and increased risk of stroke, sudden cardiac death, blood clots and diabetes. Significant weight gain may occur.

In another publication, “Tardive Dyskinesia,” Vasan and Padhy also said TD was caused by long-term exposure to first and second-generation antipsychotics, some antidepressants (like fluoxetine), lithium and certain antihistamines. They said there was some evidence that the long-term use of anticholinergic medications may increase the risk of TD. See “The Not-So-Golden Years” for more on anticholinergics. Vasan and Padhy said TD was seen in patients with chronic exposure to dopamine D2 receptor blockade and rarely in patients who have been exposed to antipsychotics less than three to six months. “A diagnosis of antipsychotic-induced tardive dyskinesia is made after the symptoms have persisted for at least one month and required exposure to neuroleptics for at least three months.”

They cautioned against the chronic use of first-generation antipsychotics, saying they should be avoided whenever possible. “Primary prevention of tardive dyskinesia includes using the lowest effective dose of antipsychotic agent for the shortest period possible.” The authors noted the FDA’s approval of Ingrezza (valbenazine) to treat TD, saying that early data indicated it was safe and effective in abolishing TDs. “However, the study was conducted by many physicians who also received some type of compensation from the pharmaceutical companies- so one has to take this data with a grain of salt until more long-term data are available.”

So, where does all of this leave us with regard to antipsychotics and tardive dyskinesia? Contrary to what “Advances in Tardive Dyskinesia” said, the cause of TD is known. According to Dr. Peter Breggin and others, TD is caused by drugs that block the function of dopamine receptors in the brain. The risk of developing TD is present for all ages, although older adults are at higher risk of suffering this adverse side effect. And the risk of TD increases with the continued use of antipsychotics, perhaps as high as 26%, 52%, and 60% after 1, 2, and 3 years respectively of cumulative use.

Narrowly defining TD (as the DSM does) leads to the confounding invention of spontaneous dyskinesia—that is said to be indistinguishable from TD. The logic here seems circular. If TD is defined as caused by antipsychotics (which seems to mean primarily first generation antipsychotics), then dyskinesia independent of antipsychotics can’t be TD, because TD is only found with antipsychotics.

The so-called first-generation antipsychotics and second-generation antipsychotics equally put the individual at risk of developing TD and should be used at the lowest possible dose for the shortest time—if at all. Dr. Breggin said: “Since all these drugs are potent dopamine blockers, there should have been no doubt from the beginning that they would frequently cause TD.” Disregarding the fact that this drug action common to all antipsychotics perpetuates what seems to be an unnecessary and inaccurate distinction between first-generation and second-generation antipsychotics. So, if it walks like a duck, and quacks like a duck, isn’t it a duck?

See “Downward Spiral of Antipsychotics” for more on the concerns with antipsychotics.

07/7/20

Rebranding Problems With Abilify

Abilify had a profitable and expansive run for Otsuka Pharmaceuticals since it was approved by the FDA for the treatment of schizophrenia in 2002. The FDA then expanded its treatment use to include bipolar disorder in 2005, irritability associated with autistic disorder in 2009 and Tourette’s disorder in 2014. It was also approved by the FDA as an add-on with antidepressants for treatment-resistant depression in 2007. Abilify is used off-label to treat insomnia, delusional disorders and anxiety. In 2013 this enlarged treatment market brought in $7.8 billion in global sales for Otsuka. FiercePharma noted the end of Abilify’s patent exclusivity in April of 2015 left a big revenue hole for Otsuka and Bristol-Myers Squibb, who marketed and promoted it in the U.S. But instead of quietly surrendering to the generic market, Abilify (aripiprazole) was rebranded into three new drug applications with the FDA: Abilify Maintena, Abilify MyCite and Aristada.

Abilify Maintena was approved as an extended-release once-monthly depot shot of aripiprazole for the treatment of schizophrenia in March of 2013. Otsuka said it was a new treatment option to address the need for relapse prevention in patients with schizophrenia. It was the first dopamine D2 partial agonist approved as a once-monthly injection. In July of 2017 its approved use was extended to include maintenance monotherapy treatment of Bipolar I Disorder in adults.

Abilify MyCite has an ingestible sensor embedded in aripiprazole tablets that records that the medication was taken. Approved by the FDA in November of 2017, it is the first drug in the U.S. with a digital tracking system. This was a second try for Otsuka, as the FDA initially failed to approve Abilify MyCite in April of 2016, saying it needs more information about the product’s use, and further human factor investigations. “The goal of human factors testing is to evaluate use-related risks and confirm that users can use the device safely and effectively.”

The pill’s sensor sends a message to a wearable patch that in turn transmits the information to a mobile application that allows the patient to track the ingestion of the medication on their smart phone. Patients can give their caregivers and doctors permission to access the information through a web-based portal. Mitchell Mathis, the director of the Division of Psychiatry Products in the FDA’s Center for Drug Evaluation and Research, said: “Being able to track ingestion of medications prescribed for mental illness may be useful to some patients.” Actually, the digital tracking capability of Abilify MyCite is a selling point for psychiatrists concerned with patient adherence. Getting people who are prescribed antipsychotics to stay on their drugs can be a challenge. See “Doublespeak With Abilify MyCite” for more information on this.

Aristada (aripiprazole lauroxil) was approved by the FDA as an extended release injectable form of aripiprazole to treat adults with schizophrenia on October 5, 2015. It is a prodrug, meaning it is a biologically inactive compound that is metabolized into a pharmacologically active drug within the body. Unlike Abilify MyCite and Abilify Maintena, its parent company is Alkermes, not Otsuka. Similar to the price of another Alkermes drug, Vivitrol, Aristada costs about $1,500 per month.

According to ProPublica, Alkermes has successfully marketed Vivitrol to the criminal-justice system, emphasizing its use in drug courts. The Atlantic wrote how the relationship between drug companies and the criminal-justice system has expanded in “Marketing Psychiatric Drugs to Jailers and Judges,” as drug companies realized the potential market behind bars. Free samples are distributed to detention facilities; jail and prison doctors attend free luncheons to learn about medications. Payments are made to doctors and criminal-justice employees, such as sheriffs and drug-court judges, to promote certain medications.

Alkermes and other drug companies have marketed not only to jailers but to judges as well. Earlier this year, at a conference for drug- and mental-health-court professionals in Maryland, Alkermes sponsored a closed-door promotional session about using long-acting shots in a court setting. Featured at the session was Richard Jackson, a former psychiatrist at the Women’s Huron Valley Correctional Facility in Ypsilanti, Michigan, and Ernie Glenn, a magistrate in Bexar County, Texas, who had helped defendants in his court get access to long-acting antipsychotic shots. While Glenn had received no payments from Alkermes, the company had paid Jackson more than $250,000 between 2015 and 2018 for speeches, travel and lodging, and meals, according to the Centers for Medicare and Medicaid Services’s open payments database. (Jackson also received $252,608 in payments from Otsuka from 2015 to 2018, and said he has continued receiving payments from drug companies in 2019; it wasn’t immediately clear whether Alkermes was one of them.) The conference program, as in the conference in Nashville, directed people to learn about Aristada at Alkermes’s exhibit booth.

The director of the ACLU’s National Prison Project, David Fathi, expressed concern that the marketing has been aimed at judges and prison officials instead of the incarcerated people themselves. A ProPublica analysis found that doctors who accepted money from pharmaceutical companies were more likely to prescribe those companies’ medications. Incarcerated patients may not feel they have a real ability to choose. In cases where patients choose to take a psychiatric drug, it may be a choice made under duress. “If you know you can be forcibly medicated, can you really make a free and noncoercive choice about medication?”

The makers of drugs like Abilify Maintena and Aristada are banking on long-acting injections as the future of schizophrenia treatment. A 2015 study found that patients who were given injections of long-acting risperidone were more likely to comply with treatment and led to better long-term outcomes. The lead author of the study, Kenneth Subotnik, said, “We know that not taking antipsychotic medication is the single greatest modifiable risk factor for psychotic symptoms returning.” Yet as Max Blau noted in The Atlantic, there is a possibility the side effects will last longer than with the pill form. The most common side effect with Aristada is akathisia (a feeling of inner restlessness and inability to stay still). Other side effects include: Neuroleptic Malignant Syndrome, Tardive Dyskinesia, Diabetes, weight gain and seizures.

In 2016 the FDA published a Safety Communication about impulse-control problems associated with aripiprazole (Abilify, Abilify Maintena and Aristada). They warned of reports of compulsive, uncontrollable urges to gamble, binge eat, shop, and have sex with the use of aripiprazole. The impulse-control problems were rare, but may result in harm to the patient or others. “These uncontrollable urges were reported to have stopped when the medicine was discontinued or the dose was reduced.”

Although pathological gambling is listed as a reported side effect in the current aripiprazole drug labels, this description does not entirely reflect the nature of the impulse-control risk that we identified. In addition, we have become aware of other compulsive behaviors associated with aripiprazole, such as compulsive eating, shopping, and sexual actions. These compulsive behaviors can affect anyone who is taking the medicine. As a result, we are adding new warnings about all of these compulsive behaviors to the drug labels and the patient Medication Guides for all aripiprazole products.

A search of the FDA Adverse Event Reporting System (FAERS) database and the medical literature identified 184 case reports with an association between arpiprazole use and impulse-control problems. Pathological gambling was the most common with 164 cases, “but other compulsive behaviors including compulsive eating, spending or shopping, and sexual behaviors were also reported.” None of the patients had a history of pathological gambling, compulsive sexual behavior, binge eating or compulsive shopping before starting arpiprazole treatment. None of the patients had concurrent substance abuse disorder or symptoms of mania at the time of developing the impulse-control problems.

Despite the problems with Abilify, Otsuka and Alkermes have repackaged it with digital tracking technology and a slow-release, depot injection and then promoted these products as improving treatment adherence, reducing the risk of overdose and improving relapse prevention and reducing rehospitalization rates.

Pharmaceutical companies seem to disregard the problems with antipsychotics like Abilify while they pursue their potential profits. Bristol-Myers Squibb paid $515 million to settle charges it illegally marketed Abilify for children and the elderly. See “Broken Promises with Ability” for more information on this issue. Persistence in addressing problems with nonadherence seems to ignore the larger issue of adverse side effects antipsychotics. See “Abilify in Denial,” “Pick Your Poison: Diabetes and Psych Meds,” “Downward Spiral of Antipsychotics,” “Pros and Cons of Antipsychotics” and “Biomedical Big Brother” for more on concerns with adherence and adverse side effects with Abilify and other antipsychotics. The rebranding Abilify as Abilify Maintena, Abilify MyCite and Aristada does not appear to address the concerns with aripiprazole and other antipsychotics.

04/21/20

Pros and Cons of Antipsychotics

Antipsychotic treatment is often associated with weight gain and metabolic syndrome, a cluster of symptoms that increases the risk of heart disease, stroke and diabetes, independent of other adverse effects like sexual dysfunction, drowsiness, dizziness, restlessness, and others. In The Lancet, Pillinger et al compared and ranked 18 antipsychotics on the basis of their metabolic side-effects. They found that antipsychotics varied widely in their effects on body weight, BMI, total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, and glucose concentrations. Olanzapine (Zyprexa) and clozapine (Clozaril) were ranked the worst for metabolic-related adverse effects, while ironically being identified as among the most effective antipsychotic drugs. Aripiprazole (Abilify, Aristada), brexpiprazole (Rexulti), cariprazine (Vraylar), lurasidone (Latuda), and ziprasidone (Geodon) were the most benign profiles.

In the same issue of The Lancet, Yoav Domany and Mark Weiser compared the results of this study with a network meta-analysis on the efficacy and adverse effects of antipsychotics. Clozapine was the most efficacious in reducing overall symptoms and amisulpride (Solian) was the most efficacious in reducing positive symptoms. “One would hope that data on efficacy and adverse events could be taken together with the detailed information on metabolic adverse events from this study to consider a personalized medicine approach in treating patients with schizophrenia.”

This approach could be part of a shared decision-making process, based on a discussion with the patient weighing the benefits and disadvantages of each treatment option. Such an approach is hampered by the fact that clozapine and olanzapine, which consistently come out among the best in terms of efficacy, are also consistently associated with the highest rates of metabolic adverse effects, hindering such a process at this stage.

One limitation of the Pillinger et al study was the studies in its meta-analysis were quite short, in the range of 2-13 weeks. The authors noted how randomized controlled trials are generally short and recommended that future studies should “examine antipsychotic-induced metabolic dysregulation in patients receiving long-term maintenance therapy.” Further, lifestyle and treatment factors (physical comorbidity, alcohol use, smoking, diet, exercise, and co-prescription of psychiatric—eg, mood stabilisers—or physical health medications—eg, statins or anti-glycaemic drugs) may have influenced metabolic outcomes. “Treatment guidelines should be updated to reflect differences in metabolic risk, but the choice of the treatment intervention should be made on an individual patient basis, considering the clinical circumstances and preferences of patients, carers, and clinicians.”

Standard treatment guidelines are that antipsychotic medications should continue indefinitely after someone has experienced more than one psychotic episode. But according to Sandra Steingard, there is less agreement treatment guidelines after a single psychotic episode. “Current guidelines recommend drug treatment for two to five years, the idea being that if a person remains well during that time, it might then be safe to stop the drug.” She said most psychiatrists assumed that by reducing risk of relapse you would improve long-term outcomes. But that assumption may not be correct. Not only are there risks of weight gain and tardive dyskinesia, antipsychotics seem to impair functional outcome. Robert Whitaker reported that Martin Harrow and Thomas Jobe did a long-term study of 200 psychotic patients. Patients who were off medication had better cognitive functioning and lower levels of anxiety than medicated patients. Patients on medication were more likely to be psychotic at follow-up. “Eighty-six percent of the medication-compliant patients were psychotic at the 4.5-year follow-up, compared to 21% of those who had stayed off antipsychotics. This dramatic difference remained throughout the study.” See the following chart.

Harrow also found that once patients who went off medication were stable, they were likely to remain stable for extended time periods. None of the stable, off-med patients stable at the 7.5-year follow-up relapsed in the next 7.5 years. Seventy to 90% of the unmedicated patients were working more than half time, compared to roughly 25% of the medicated patients. Those with milder disorders who continued taking medications had worse outcomes than schizophrenia patients who were off their medications.

Harrow discovered that patients off medication regularly recovered from their psychotic symptoms over time (2-year to 4.5-year outcomes), and that once this happened, they had very low relapse rates. At the same time, a majority of the patients on medication regularly remained psychotic, and even those who did recover often relapsed. Harrow’s results provide a clear picture of how antipsychotics worsen psychotic symptoms over the long term.

Schizophrenia monotherapy treatment is not always effective, and some individuals receive additional interventions, such as electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS) and psychological therapies. Ortiz-Orendain and others conducted a Cochrane review that compared antipsychotic monotherapy and combined treatment. The authors found low-quality evidence that combined antipsychotics improved the clinical response. The study indicated that more people who received combination therapy showed an improvement in symptoms. But there were no clear differences with other outcomes, such as relapse, hospitalization, adverse events, discontinuing treatment or leaving the study early. In her review of the Ortiz-Orendain et al study for The Mental Elf, Elena Marcus said it was a well conducted systematic review. However,

One of the main limitations of this review lies in the quality of included studies, with outcomes rated as low or very low quality which really questions our confidence in the reported estimates. There was a particularly high or unclear risk of reporting bias and attrition bias across studies and as authors included quasi-randomised trials there was a risk of selection bias in ~70% of studies. Whilst five studies were clearly quasi-randomised, for 39 studies there was not enough information to judge whether sequence generation was truly random, so the risk of bias here was unclear rather than high.

Users of antipsychotic medications also describe a distinctive experience, characterized by sedation, cognitive impairment, emotional blunting and reduced motivation. These are in addition to the various physical effects, including weight gain, sexual dysfunction and neurological consequences. Thompson et al described a synthesis of qualitative data about mental and behavioral changes associated with taking antipsychotics, and how these interact with symptoms of psychosis and people’s sense of self and agency. They found that neuroleptics interfered with people’s ability to carry out basic activities. But they also reduced the intensity of intrusive psychotic experiences and other symptoms, such as anxiety and insomnia.

Anything that changes our mental faculties is likely to impact on our sense of ourselves, and this is a common experience in relation to mood or experience-modifying agents. In the studies we reviewed, some participants felt neuroleptic-induced effects deprived them of important aspects of their personality; their drives, imagination or humour, for example. Others felt that by reducing the symptoms of psychosis, the drugs were able to restore them to a state in which they felt ‘themselves’ again. Similarly, some people were content to view themselves as having a disease requiring ongoing treatment, while others felt that taking neuroleptic medication symbolised a tainted identity. Schizophrenia or psychosis can disrupt people’s sense of self, and studies of personal recovery have described the importance of reconstructing a sense of self in a way that is distinct from symptom improvement. Therefore, although neuroleptics may effectively suppress symptoms, their effects can nevertheless be experienced as detrimental to sense of self and identity, with important implications for social functioning and achievement of life goals.

John Read and Ann Sacia of the University of East London surveyed 650 individual’s experiences with antipsychotics. Two-thirds (66.9%) of the participants said their experiences with antipsychotic drugs was more negative than positive, with 34.9% stating their experiences were extremely negative. Nearly a quarter (22.1%) of the participants said their experiences were more positive than negative, with 5.7% saying their experiences were extremely positive. The authors said at the point of prescription clinicians should provide a full range of information about antipsychotics, including potential benefits and harms, difficulties withdrawing, and information on alternative treatments, such as psychological therapies.

Implied in the above critique of antipsychotics is the view that psychiatric drugs are psychoactive substances in the same way alcohol or heroin are psychoactive substances. This is what Joanna Moncrieff refers to as the ‘drug-centered’ model of drug action. Conversely, the opening study by Pillinger et al seems to view antipsychotics according to a ‘disease-centered’ model of drug action. Moncreiff said the disease-centered model is borrowed from medicine and presents drugs through the prism of disease, disorder or the symptoms the drugs are thought to treat. The significant effects (or efficacy) are the ones the drugs exert on the diseased or abnormal nervous system. Any others are of secondary interest and referred to as above as side effects or adverse effects.

In contrast, the ‘drug-centred’ model suggests that far from correcting an abnormal state, as the disease model suggests, psychiatric drugs induce an abnormal or altered state. Psychiatric drugs are psychoactive substances, like alcohol and heroin. Psychoactive substances modify the way the brain functions and by doing so produce alterations in thinking, feeling and behaviour. Psychoactive drugs exert their effects in anyone who takes them regardless of whether or not they have a mental condition. Different psychoactive substances produce different effects, however. The drug-centred model suggests that the psychoactive effects produced by some drugs can be useful therapeutically in some situations. They don’t do this in the way the disease-centred model suggests by normalising brain function. They do it by creating an abnormal or altered brain state that suppresses or replaces the manifestations of mental and behavioural problems.

The above discussion suggests individuals being treated with antipsychotics should weigh the risks and benefits of the medication prescribed to them. They need to gather information on their medication, its potential side effects and then monitor how they respond to the drug. This is consistent with what Joanna Moncrieff called the drug-centered model of drug action. The Harrow study also indicated that the use of antipsychotics may not be the best long-term treatment protocol for schizophrenia. If you are using or considering the use of antipsychotics, weigh the pros and cons.

11/6/18

Nursing Homes Want Docile

photo by rawpixel.com from Pexels CCO license

The US population is aging. Between 2005 and 2015, the percentage of the population over 65 increased by 30%. “Older people now account for one in seven Americans: almost 50 million people, over 26 million women and over 21 million men.” As our population ages, the number of individuals with debilitating conditions like dementia is also increasing. By 2050, it has been estimated that as many as 15 million Americans could have Alzheimer’s. And in an average week, nursing facilities in the U.S. currently administer antipsychotic medications to over 179,000 people “who do not have diagnoses for which the drugs are approved.”

An extensive Human Rights Watch report, “They Want Docile,” described the inappropriate use of antipsychotics in older people with dementia in U.S. nursing facilities. The report found these dangerous medications were used without valid medical reasons, for the convenience of the staff, and without informed consent. Their use was often inconsistent with federal regulator requirements for the nursing facility industry. “They Want Docile” quoted a state inspector with a long career in long-term care as saying: “I see way too many people overmedicated. The doctor signs off and the nurse fills the prescription. They see it as a cost-effective way to control behaviors.”

Older people receive long-term care in various settings ranging from at home to institutional facilities. In-between settings like assisted living facilities, senior housing and retirement communities also exist. “The proportion of people living in institutional settings increases with age because care needs become more intensive.” Of the 6 million older people who receive long-term care around 4 million receive that care at home. Another 1.2 million live in nursing facilities and around 780,000 people live in other residential care communities.

The nursing facility industry is big business and Medicare and Medicaid is the financial foundation that supports it. “In 2015, the nursing facility industry, assisted living, and other types of long-term care recorded annual revenues of $156.8 billion, 41 percent of which came from Medicaid and 21 percent from Medicare.” The Nursing Home Reform Act of 1987 requires the nursing facility industry to meet certain standards, including certification of the care facility, to be paid by Medicare and Medicaid. CMS, the Centers for Medicare & Medicaid Services, contracts with state agencies to certify facilities and to guarantee “substantial compliance.”

With the growth in older populations and the increases in debilitating conditions such as dementia, the need for long-term care and support services will grow rapidly. Although some forms of dementia have earlier onset, the disease is associated with older age: increasing age is the “greatest known risk factor” for Alzheimer’s disease. Experts estimate that approximately 70 percent of people aged 65 and over will require long-term services and support, ranging from limited support in their own homes and communities to around-the-clock care in institutional settings.

The American Psychiatric Association (APA) has “Practice Guidelines” for the use of antipsychotics to treat agitation or psychosis in patients with dementia that indicated they should only be used as a last resort to minimize the risk of violence, patient distress and care giver burden. The APA then referenced two studies finding “the benefits of antipsychotic medications are at best small.” Contrary to these guidelines, nursing facility staff, individuals living in facilities, their families and others told Human Rights Watch “antipsychotic drugs are used sometimes almost by default for the convenience of the facility, including to control people who are difficult to manage.”

One facility social worker said that one of the most common “behaviors” leading to antipsychotic drug prescriptions was someone constantly crying out, “help me, help me, help me.” An 87-year-old woman reflected that at her prior facility, which gave her antipsychotic drugs against her will, “they just wanted you to do things just the way they wanted.” A social worker who used to work in a nursing facility said the underlying issue is that “the nursing homes don’t want behaviors.”

Among the people living in nursing homes interviewed by Human Rights Watch, a 62-year-old woman reported she had been given Seroquel without her knowledge or consent. She said it knocked her out; leading her to sleep all the time. She claimed the facility would crush and mix it in her food so she would refuse to eat food she suspected of having the drug. “Ms. D continued to object as well as she could to being administered antipsychotic drugs until her discharge from the nursing facility the day after Human Rights Watch interviewed her.”

Madeline C., an 87-year-old woman in a facility in Illinois, described the effect of antipsychotic medications administered in a prior nursing facility. She had been placed in a dementia unit. The woman said that when she “just about went crazy” from being in a locked unit with no activities, she “started speaking out, saying things were not right.” After that, she said, “suddenly I was very sleepy,” adding, “you feel like you’re going to die there.” She said she later learned that the facility had given her an antipsychotic drug. At the time of the interview, the woman was in a different facility that had discontinued the drug. “The fog lifted…. There’s the old Madeline again.” Being at the prior facility was “a very traumatic time.”Alma G., the sister and power of attorney of Mariela O., an 84-year-old woman with dementia who died in 2017, said that her sister’s nursing facility gave her an antipsychotic drug to ease the burden of bathing her. She said, “They give my sister medication to sedate her on the days of her shower: Monday, Wednesday, Friday—an antipsychotic. They give her so much she sleeps through the lunch hour and supper.”

“They Want Docile” described many additional examples of the misuse of antipsychotic medications at nursing facilities. The authors said many of their interviews supported the statement that antipsychotic medications were often given to nursing home residents for no valid reason. Some nursing home staff told Human Rights Watch antipsychotics were prescribed for screaming or calling out. A long-term care pharmacist said he regularly sees medication requests without an appropriate diagnosis—things like “‘Seroquel for dementia,’ or ‘Seroquel for anxiety,’ or ‘Seroquel for behavior dysfunction.’”

The report is disturbing and I’ve only scratched the surface of what it describes. It also had several recommendations to federal and state legislatures, and agencies. Here are just a couple. The CMS (Centers for Medicare & Medicaid Services) should strengthen the enforcement of existing regulatory requirements to end all inappropriate use of antipsychotics in nursing facilities, including when their use would amount to being used as a “chemical restraint.” It should also strengthen enforcement of existing regulatory requirements for informed consent and appropriate medication administration. Care planning should include the right of patients to refuse treatment; to be involved in their care planning; to be free from unnecessary drugs and chemical restraints. Medicaid fraud units should be required to investigate and prosecute abuse, including the use of chemical restraints, and neglect in nursing facilities.”

The Washington Post published an article, Why are nursing homes drugging dementia patients without their consent?, that was written by an individual who was part of the Human Rights Watch research. She noted how the use of antipsychotics as chemical restraints in nursing homes has a long history. A 1975 Senate report documented some of the same issues occurring today. While there are federal regulations stating residents have the right to be fully informed of their treatment and even to refuse treatment, nursing homes regularly ignore the rules because they are rarely held accountable.

Human Rights Watch found that in 97 percent of citations for violations related to antipsychotic drugs, the incidents were determined to have caused “no actual harm” to residents. As a result, in almost no cases did the government impose financial penalties, which correspond to the severity of harm caused by the noncompliance. The prospect of enforcement actions, and the rare sanctions issued, unsurprisingly had little deterrent effect, our analysis found. Nursing homes cited for antipsychotic-drug-related issues did not reduce their rates of drug use any more than facilities not cited.

Further limitations on holding nursing facilities accountable have ironically come as a result of the Trump administration’s Patient’s Over Paperwork deregulatory efforts. In response to an industry request, the instances in which inspectors can assess the heaviest fines was limited. That guidance now favors one-time sanctions rather than per-day sanctions, leading in many cases for facilities to face less significant consequences. And since November of 2016, “CMS imposed an 18-month moratorium on Obama-era revisions to some regulations — not updated since 1991 — intended in part to protect residents whose psychotropic medications are prescribed on an “as needed” basis.”

A JAMA Psychiatry study showed how a peer comparison letter could reduce off-label prescribing of an antipsychotic in older adults. The researchers found that “a peer comparison letter randomized across the 5055 highest Medicare prescribers of the antipsychotic quetiapine fumarate [Seroquel] reduced prescribing for at least 2 years.” The effects were larger than those found with large-scale behavioral interventions, possibly because the content of the peer letter “mentioned the potential for a review of prescribing activity.” Writing for Mad in America about the study, Bernalyn Ruiz said:

This study provides some hopeful evidence that a simple intervention that can reach a large group of prescribers effectively. Given the high rates of overprescribing, especially within this vulnerable population, effective ways of addressing this issue are needed.

In another article reflecting on the study by Ina Jaffe for NPR, Dr. Helen Kales, the head of the University of Michigan’s Program for Positive Aging, said stopping the overmedication of dementia patients was just the beginning. She pointed out how the use of mood stabilizers with dementia patients has also accelerated. “So any kind of fixation on one [drug] — it’s maybe winning the battle, but not the war.” Dr. Kales chaired an international committee of dementia specialists who published a consensus statement on the ways to treat dementia behaviors like agitation and wandering, and said it’s better to find out what triggers the behavior or modify the patient’s environment instead of prescribing medication. “The highest ranked and endorsed treatments are all non-pharmacological approaches.”

In closing, consider the following. The graphic below by Human Rights Watch shows the proportion of nursing home residents across the U.S. on antipsychotic drugs. The more intensely red areas indicate a higher percentage of antipsychotic use, with 45% being the highest. If you or a loved one were in a nursing home somewhere in the U.S. would you want it to be using antipsychotics to chemically manage you and your behavior?

12/5/17

Pick Your Poison: Diabetes and Psych Meds

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 7^th leading cause of death in the U.S. with 79,535 death certificates in 2015 listing it as the underlying cause of death. A total of 252,806 death certificates listed diabetes as an underlying or contributing cause of death. If the number of deaths from diabetes were equal to 252,806, it would be the third leading cause of death in the US, according to the CDC … and psych meds increase the risk for diabetes.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

11/3/17

Downward Spiral of Antipsychotics

Antipsychotic or neuroleptic drugs became big business for pharmaceutical companies about nine years ago, reaching sales of $14.6 billion in 2008. This made them the best selling therapeutic class of medications in the U.S. that year. Not only are they used to treat psychosis and bipolar disorder, several have been approved as an add-on medication to treat depression. Additionally they are used off-label with children and the elderly for behavioral control. And they are the primary cause for a serious neurological disorder called tardive dyskinesia.

Tardive dyskinesia (TD) is a group of involuntary movement disorders caused by drug-induced (iatrogenic) neurological damage, primarily from antipsychotic drugs and a few others that block the function of dopamine in the brain. “TD can vary from a disfiguring grimace to a totally disabling array of spasms and often bizarre movements of any part of the body.” If TD is not identified early on and the drugs stopped, “these disorders nearly always become permanent.” Both patients and their doctors often fail to recognize or diagnose its symptoms.

The above short introduction was gleaned from Dr. Peter Breggin’s “Antipsychotic Drugs and Tardive Dyskinesia (TD) Resources Center.” If you can spare a few minutes, watch a ten-minute TD video edited by Dr. Breggin from existing videos available on the Internet. The video contains a series of individuals with the three general types of tardive dyskinesia whose ages range from pre-adolescence to seniors. These types are: tardive dystonia, a series of involuntary movements that include painful muscle contractions or spasms; tardive akathisia, psychomotor agitation; and classic tardive dyskinesia, the rapid, jerky movements or uncontrollable head bobbing or movements of the arms, hands, feet fingers or toes. The following is a reproduction of a table from Psychiatric Drug Withdrawal by Peter Breggin more fully describing the symptoms of tardive dyskinesia.

Symptoms of Tardive Dyskinesia

Tardive Dyskinesia (Classic)

Rapid, irregular (choreiform), or slow and serpentine (athetoid) movements; often bizarre looking; involving any voluntary muscle, including:

Face, eyelids and eye muscles, jaw (chewing movements, tongue biting), mouth lips, or tongue (protruding, trembling curling, cupping)

Head (nodding), neck (twisting, turning), shoulders (shrugging), back, torso (rocking movements), or abdomen

Arms and legs (may move slowly or jerk out of control)

Ankles, feet and toes; wrists, hands, and fingers (sometimes producing flexion, extension or rotation)

Breathing (diaphragm and ribs; grunting), swallowing (choking), and speaking (dysphonis)

Balance, posture, and gait (sometimes worse when slow, often spastic)

Tardive Dystonia

Often painful sustained contractions (spasms) of any voluntary muscle group; potentially causing muscular hypertrophy, arthritis, and fixed joints; frequently involving the following:

Neck (torticolis, retrocollis) and shoulders

Face (sustained grimacing and tongue protrusion)

Mouth and jaw (sustained opening or clamping shut)

Arms and hands; legs and feet (spastic flexion or extension)

Torso (twisting and thrusting movements; flexion of spine)

Eye lids (blepharospasm)

Gait (spastic; mincing)

Tardive Akathisia

Potential agonizing inner agitation or tension, usually (but not always) compelling the patient to move, commonly manifested as the following:

Restless leg movements (when awake)

Foot stamping

Marching in place, pacing

Jitteriness

Clasping hands or arms

Inability to sit still

TD can impair any muscle functions that are partially or wholly under voluntary control such as the face, eye muscles, tongue, neck, back, abdomen, extremities, diaphragm and respiration, swallowing, and vocal cords. Coordination and posture can be afflicted. TD can cause tremors, tics, and paresthesias (e.g., burning sensations, numbness). TD can also afflict the autonomic nervous system, especially impairing gastrointestinal functioning.

TD sufferers are often exhausted by these unrelenting body movements; even when they are limited to one area of the body, such as the jaw, neck or feet. They become socially withdrawn and isolated—humiliated by the stigma of their uncontrollable movement disorder. One muscle group, such as the tongue or fingers, or various muscle groups can be afflicted. TD symptoms can also change over time from one muscle group to another. This can occur over a period of minutes, days, weeks or years. “Especially in the dystonic forms, the pain can be very severe, and the physical stress can cause serious orthopedic problems.” Antipsychotic drugs are the primary cause of this neurological disorder.

Antipsychotic drugs are also called neuroleptics. Prescribers often promote them in a misleading fashion as antidepressants, mood stabilizers, bipolar drugs, sleeping pills, and behavior control drugs in children. Recent ones include Risperdal (risperidone), Abilify (aripiprazole), Geodon (ziprasidone), Invega (paliperidone), Latuda (lurasidone), Rexulti (brexpiprazole), Risperdal (risperidone), Saphris (asenapine), Seroquel (quetiapine), and Zyprexa (olanzapine). Older antipsychotics include Haldol (haloperidol) and Thorazine (chlorpromazine). [See a more complete listing of antipsychotics here]

Drug companies have made claims that the newer, so-called atypical antipsychotic drugs are less likely to cause TD, but those claims are false or misleading. A 2008 study by Chouinard found a high prevalence of DIMD (drug-induced movement disorders). Nearly 50% of patients had a definite DIMD. The authors also said that DIMD persisted with atypical antipsychotics. “It is crucial to acknowledge that there is a persistence of DIMD with atypical antipsychotics, which are not recognized and confounded with psychiatric symptoms.” Caroff, Miller and Rosenheck reported in “Extrapyramidal Side Effects” that there were no significant differences in measuring the incident rates of TD and other DIMDs between atypical antipsychotics and an older antipsychotic, perphenazine (Trilafon).

According to Dr. Breggin, TD occurs around a rate of 5 to 8 percent per year in adults up to the age of 40, with an accumulating risk of 20% to 24% after four years. The rates increase rapidly over forty. “For a 40-year-old patient, the risk is 18% at 2 years [9% per year] and 30% at 4 years.” In patients over 45, “the cumulative incident of TD after neuroleptic exposure is 26%, 52%, and 60% after 1, 2, and 3 years, respectively.”

Recently the FDA approved two medications to treat TD. Let this sink in. A serious neurological disease, which is primarily caused by a class of psychiatric medications, is being treated with another medication. Neurology Advisor interviewed two experts medical experts on the current state of treatment for TD. One of the experts interviewed said:

The main issue in the “treatment” of TD is prevention. It is important to use offending agents only when the potential benefit is higher than this risk. Once it appears, the first step is to determine whether symptoms are bothersome or disabling to warrant treatment. If possible, either discontinue the offending agent, although this might not improve symptoms permanently, and they will probably worsen initially, or change to a similar agent less likely to cause TD. In terms of prescription medications for TD, I have observed significant variability in treatment approaches depending on physician choice. Over the last few years, I personally found tetrabenazine to be the most efficient agent.

Tetrabenazine (Xenazine) was approved to treat the movement disorder associated with Huntington’s chorea, but has been used off-label to treat TD. It is now off patent and available as a generic. On patent, it sold for $152,000 per year. The generic version is $96,000 per year. However, there have been two new drugs approved specifically to treat TD: Austedo (deutetrabenazine) and Ingrezza (vabenazine). Both are being priced at around $60,000 per year. All three medications carry “black box” warnings from the FDA because of their risk for depression and suicide. You can read more about these medications here, here, here and here.

In addition to TD, antipsychotics have been linked to adverse cardio vascular events, brain shrinkage, dopamine supersensitivity, weight gain, diabetes, a shortened life span and more. The risk-benefit ratio may see a need for short-term use of antipsychotics, but the long-term benefits of their use are questioned by many credible sources. There have been follow up studies that support that concern. See this blog post by Thomas Insel, the former director of the NIMH, the National Institute of Mental Health.

It seems to be stepping onto a downward spiral to use medications with serious side effects to treat TD, a serious side effect from antipsychotics. As the above quoted expert, suggested, the best treatment for tardive dyskinesia is prevention—avoid antipsychotics if at all possible. For more information on concerns and adverse effects with antipsychotics, see: “Blind Spots with Antipsychotics” Part 1 and Part 2, “Antipsychotic Big Bang”, “Wolves in Sheep’s Clothing” and “Hollow Man Syndrome.”

10/17/17

Tell It Like It Is

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

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

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

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

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

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

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

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

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

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

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

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

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

07/21/17

Blind Spots with Antipsychotics, Part 2

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

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

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

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

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

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

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

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

Dr. Moncrieff concluded her article by saying:

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

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

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

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

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

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

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

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

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

07/11/17

Blind Spots with Antipsychotics, Part 1

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

06/9/17

Worse Results with Psych Meds

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:

Sertraline (Zoloft, an SSRI antidepressant)
Citalopram (Celexa, an SSRI antidepressant)
Alprazolam (Xanax, a benzodiazepine for anxiety)
Zolpidem tartrate (Ambien, a hypnotic prescribed for sleep)
Fluoxetine (Prozac, an SSRI antidepressant)
Trazodone (an antidepressant often prescribed for sleep)
Clonazepam (Klonopin, a benzodiazepine for anxiety)
Lorazepam (Ativan, a benzodiazepine for anxiety)
Escitalopram (Lexapro, an SSRI antidepressant)
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.

Faith Seeking Understanding

Charles Sigler, D.Phil.

Tag: antipsychotics