09/15/20

If TD Walks Like a Duck …

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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.

11/3/17

Downward Spiral of Antipsychotics

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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.”