Flawed consensus statement for tardive dyskinesia

Intended as a statement of consensus to inform a standard of care in persons with tardive dyskinesia, this report, by authors of record Stanley Caroff, Les Citrome, and colleagues, published last spring in the Journal of Clinical Psychiatry (2020, March-April (81(2): 19cs12983), is presented as an investigational study, but it is not designed to test a null hypothesis, nor does it attempt to gather systematic observations in support of a falsifiable hypothesis that answers a scientific question.

It is, in fact, an opinion poll of a non-random sample of 30 participants selected by a non-random sample of 11 unspecified members of a steering committee created by a pharmaceutical firm with a wish to see its product advance from clinical trial to first-line treatment in a statement of consensus in just three years. Physician participants met the steering committee’s impromptu criteria for expertise apropos of tardive dyskinesia, but withal were supplied by the steering committee with a “core bibliography” on tardive dyskinesia that comprised a congeries of systematic studies, reviews, and case descriptions published no earlier than 2007 (rationale unspecified). The participants then engaged in two “rounds” of virtual, digital, anonymous interactivity (undescribed) intended to elicit their opinions on 153 clinical issues pertaining to tardive dyskinesia. Rounds were administered by a private contractor, pursuant to a “modified Delphi methodology,” not necessarily developed to elicit and reconcile differences of opinions of experts.

The first round was devoted to identifying whether the participants agreed with (or considered important) the 153 clinical “items.” (The items, not specified, reportedly pertained to screening, diagnosis, and treatment of tardive dyskinesia, and some participants responded to one or more presented in “multiple choice” format with respect to whether they agreed with the item (statement) or considered it important. An unspecified proportion of them responded on a Likert scale of ratings ranging from “strongly disagree” and/or “very unimportant” to “strongly agree” and/or “very important.” The authors do not describe the second of the two virtual rounds, except to note that it was confined to items about which 26 to 74 percent of the participants agreed (those with which 25-percent or fewer disagreed were excluded from the second round because opinions about them were considered irreconcilable; likewise, those with which 76-percent or more agreed were excluded because the items were considered to lack need for reconciliation of opinion), and the authors give no perspicuous explanation for the limits of either percentage range.). Agreement was assessed with the Likert scale in every participant of the second round. (Ratings in the first round that had been classified as “unanimous” (100-percent agreement), “consensus” (75- to 99-percent agreement), and “majority” (50- to 74-percent agreement) were converted to a Likert rating, for analysis of results at the end of the second round).

Data from the two rounds were handed off to sponsor’s designee(s} (not specified), who, in collaboration with the sponsor, collated, analyzed, and interpreted the results, and then used them to prepare an exposition of the study, which then was submitted as a paper for publication.

    The authors report that they performed a statistical analysis of change in agreement between rounds, but no statistical analysis accompanies their paper, and they do not disclose whether statistically significant increments of agreement were observed in any of the clinical items for which reconciliation was sought during the second round. Instead, they say that statistical “comparisons between Round 1 and Round 2 …were used for descriptive purposes only” (which they do not explain) and direct the reader to “comparison analyses” in “Supplementary Tables 1-3.” (Only a Table 1 is included in the text (along with “Boxes” and a Figure 1), of which none includes statistical comparison data.)  

    The authors report percentages of agreement among participants pertaining to some items about screening, diagnosis, and treatment of tardive dyskinesia. Overall, a majority of participants agreed on 66 percent of them. The evidence upon which they assented or demurred is not discussed, but appears in some instances to have been incorrectly understood, disbelieved, or not considered. (Examples include recommendations to suspect tardive dyskinesia in any person who develops “abnormal movements” of “any one body part” pursuant to the Abnormal Involuntary Movement Scale (which includes frowning, grimacing, increased eye-blinking, and tremor of any type) after no longer than one month after neuroleptic exposure; an assumption (not evidence-based) that anticholinergic agents worsen the movements of tardive dyskinesia and/or increase risk of new-onset tardive dyskinesia; that clozapine represents optimal first-line neuroleptic for substitution; and that tetrabenazine derivatives valbenazine or deutetrabenazine also represent first-line pharmacotherapy.



The authors’ do not discuss evidence favoring their recommendation of vesicular monoamine transport protein 2-inhibitors (VMAT-2 inhibitors) as first-line pharmacotherapy for tardive dyskinesia. Their recommendation is withal based upon a “core bibliography” (provided to participants by the sponsor’s steering committee) that excluded literature published earlier than 2007, when a preponderance of evidence was published about response rates and adverse effects of tetrabenazine (the parent drug of valbenazine and deutetrabenazine). They do not explain this significant omission, which broaches sponsorial bias via censorship of a half-century of clinical literature pertaining to tetrabenazine, and would have provided a larger, more accurate sample than that of the pre-approval clinical trial to inform participants’ experience with valbenazine and deutetrabenazine.

The authors’ leave out criteria for implementing VMAT2- inhibitors—that is, whether VMAT2-inhibitors should be started routinely, as a matter of course, or added only if a lower-risk, minimally-dosed, atypical neuroleptic regimen is ineffective. The authors’ consensus-level agreement among participants of their study (75-percent) favored initiating VMAT2-inhibitors after an optimally reduced-risk neuroleptic regimen had proved insufficiently effective.) They additionally recommend a trial of a second VMAT-2 inhibitor if the first proves ineffective (82-percent of participants agreed). The authors’ propose criteria for adequate response that consist of ratings heavily dependent upon subjective patient reports of improvement and feelings of well-being, which, if considered alone, could deprive clinical impressions sufficient basis for a conclusion of worsening or of improvement by clinical assessment or AIMS ratings (ironic, with respect to prior evidence suggesting that nearly 70 percent of patients were unaware of their symptoms or the causal association of them with neuroleptic medication at time of diagnosis).

    Other of the authors’ recommendations that warrant challenge include their preference for clozapine as a neuroleptic of first resort in patients who continue to need antipsychotics for control of psychotic or manic symptom;s, and, as mentioned, their presumption that evidence warrants an expectation of exacerbation of tardive dyskinesia by anticholinergic agents (agreed with by 74-percent of participants), and informs their recommendation that clinicians reduce dosage of anticholinergic agents as a matter of course (agreed with by 68-percent) and to eventually discontinue them.

The authors recommend a subgroup of previously reported risk factors with special relevance to tardive dyskinesia: cumulative exposure to neuroleptics, current or recent exposure to a first generation neuroleptic; age; acute extrapyramidal adverse effects, with an exclusion for akathisia (not explained and not evidence-based), and do not specify whether they intend to include any history of EPS with current or recent EPS.

Most of the previously reported factors of risk for development of tardive dyskinesia represent non-causal associations. Extrapyramidal adverse effects may or may not be—they may so prove, should someone demonstrate a common neuropathology of tardive dyskinesia and extrapyramidal adverse effects. Since the relationship of cumulative neuroleptic exposure is an established, causal risk factor for tardive dyskinesia, extrapyramidal adverse effects, which are bioavailabilty-related, should be considered factors of risk of tardive dyskinesia because both are more directly associated with high neuroleptic bioavailability. Some risk factors represent associations with susceptibility to a causal exposure; age may be one of them (perhaps by virtue of less efficient drug clearance). The more distant an association is from a proximal cause, the less predictive power it has, and risk factors of tardive dyskinesia should be so prioritized. Age, extrapyramidal adverse effects, cumulative exposure to neuroleptics, exposure to first-generation neuroleptics or risperidone (risperidone-treated persons having been reported to have a significantly higher annualized incidence of tardive dyskinesia), hyperprolactinemia, occurrence of gynecomastia, higher than required neuroleptic dosages, co-exposure to drugs that increase bioavailability of neuroleptic by virtue of pharmacokinetic drug-drug interactivity, history of brain disease or trauma that may increase permeability of the blood-brain barrier, non-tardive dyskinesias, dystonias, and parkinsonism—all are among established or clinically plausible risk factors for development of tardive dyskinesia.

   Recent systematic review and meta-analysis (by Johnathan Kane’s group at Hofstra and elsewhere) of 15,000 patients who had been treated with first-generation antipsychotics, clozapine, and/or second- and subsequent-generation atypical antipsychotics for chronic psychotic illnesses calculated diverse indices of risk for development of tardive dyskinesia (clozapine-treated patients who did or did not develop tardive dyskinesia over durations normalized for one year; clozapine-treated patients compared with patients taking other atypical antipsychotics except risperidone) (or all patients taking other atypical or typical antipsychotics) for durations normalized for one year who did or did not develop tardive dyskinesia; patients treated with clozapine versus those treated with olanzapine or quetiapine or aripiprazole. compared individually or collectively who did or did not develop tardive dyskinesia over durations normalized for one year), and found all indices of risk for developing tardive dyskinesia no lower in clozapine-treated patients than in patients taking olanzapine, quetiapine, or aripiprazole. (The mean yearly incidence of tardive dyskinesia for patients taking atypical antipsychotics was 2.5 percent, compared with 6.8 percent of patients treated with first-generation antipsychotics). The lowest mean annualized risk of tardive dyskinesia was observed in aripiprazole-treated patients; that of patients treated with olanzapine was five- to six-times higher. Aripiprazole, olanzapine, clozapine, and quetiapine had the lowest mean annualized risks among the atypical antipsychotics. The highest risks were observed in patients treated with risperidone and its active metabolite paliperidone.

Given that risk of tardive dyskinesia associated with clozapine is not distinctively low, but rather similar to risks of aripiprazole, olanzapine, and quetiapine, other adversities that may be more likely to be experienced by clozapine-treated patients (such as agranulocytosis, with a yearly incidence of 0.4 percent) and agranulocytopenia (yearly incidence of 3 percent),) or are not uncommon and comparatively more frequent in clozapine-treated patients (such as weight gain, hyperlipidemias, glucose intolerance) or are uncommon but not rare and pose severe complications and require immediate intervention followed by monitoring (such as peripheral antimuscarinic adverse effect syndromes, such as bowel obstruction, urinary retention, dysphagia) central anticholinergic delirium, myocarditis, and seizures), benefit-to-risk considerations do not justify unqualified preference of clozapine as a neuroleptic of first resort in persons with tardive dyskinesia. unless risk of suicide or severe psychotic or manic symptoms proved unresponsive to other atypical antipsychotics associated with lowest risk of tardive dyskinesia and/or electroconvulsive therapy. Risperidone warrants avoidance because of its comparatively high rates of EPS, its potential to induce tardive motor syndromes, and its demonstrated propensity to induce hyperprolactinemia and hormonal complications thereof (gynecomastia in males, menstrual abnormalities in females, putatively elevated risk of some kinds of breast malignancies). Olanzapine has a low propensity to induce tardive dyskinesia, similar to that of clozapine, but like clozapine is among the most likely to induce weight gain and metabolic adversity.

Optimality for neuroleptic substitution, when a neuroleptic is needed for continuing treatment of psychotic disorder or mania in persons with tardive dyskinesia appears most appropriately conferred upon aripiprazole, which so far appears to have the lowest risk among the atypical neuroleptics of inducing tardive dyskinesia, does not typically induce hyperprolactinemia, has a relatively low rate of inducing weight gain or other metabolic adversity, uncommonly induces extrapyramidal adverse effects, and is unlikely to induce sedation or prolongation of QTc duration. Quetiapine seems to run an intermediate-distance second: its propensity to induce tardive dyskinesia is among the lowest of the atypical neuroleptics; its likelihood of inducing weight gain and other metabolic adversity is less than those of clozapine and olanzapine. It is sedating at high dosages taken during the day.

The authors’ study is unusual with respect to the thoroughgoing involvement of its sponsor (Neurocrine, Inc., the manufacturer of valbenazine (Ingrezza), approved in 2017 for treatment of tardive dyskinesia). Disclosure accompanying the published study indicates that no one was involved in the study who was not an employee of, contractor hired by, consultant to, or speaker for Neurocrine or Teva (the manufacturer of deutetrabenazine (Austedo), which, with valbenazine, are the only drugs approved for tardive dyskinesia. By its own admission (per disclosure in the published paper of the study), the sponsor designed the study, hired a contractor to implement a controversial methodology for developing consensus and to collect the data, and then participated in “collating” and analyzing the data and influencing the exposition that was written up for publication by another contractor.

The contributions of the study’s authors are not specified. Opportunity for sponsorship bias therefore extended from start to finish, and motivation for it to have been brought to bear acquires relevance from the premise of the study, less an investigation than a solicitation of opinion of participants, pursuant to a 57-year-old methodology (Delphi method, modified) fraught with a history of consistent criticism of persistent flaws (arbitrary, non-random selection of topics and reference content permitted and of arbitrary criteria defining expertise, arbitrary selection of experts, vagueness of terminology, variable modes of assessment, and violations of anonymity, adding substance to impressions over its long history of “loose tolerances” better suited to evoking opinions than reconciling differences.). The authors do not discuss why the Delphi methodology was chosen for a purportedly scientific study that presumes to define a standard of care for an entire subspecialty, with an unusual propinquity and ubiquity of sponsorial involvement throughout.

Included in two pharmacotherapies cited by the authors of record as first-line treatment of tardive dyskinesia, one was the chemical class (VMAT2 inhibitors (infra)) comprising the sponsor’s product valbenazine and that of Teva, deutetrabenazine, prompting reasonable curiosity about whether Neurocrine Inc. (the manufacturer of the former) may have favored promotion of the study as a consensus statement for the purpose of endorsing its product to 25,000 psychiatrists as first-line treatment for approximately 500,000 persons in the U.S. who have tardive dyskinesia (and for whom the per patient yearly cost is $40,000). A consensus statement is understood by practitioners and by the public as tantamount to a standard of care at or above which prescribers must perform for the benefit of their patients (and from which they derive some measure of protection against medicolegal liability). 

    A very small percentage of those prescribers have had experience with valbenazine (designated a VMAT2 inhibitor, acronymic for vesicular monoamine transporter protein 2, which, when inhibited prevents uptake and sequestration of dopamine, other catecholamines, and indoleamines, such as serotonin, within intracellular storage vesicles, where they are protected from metabolism by monoamine oxidase). The eventual result of an inhibitor, such as valbenazine, is depletion of dopamine for synaptic release, which reduces synaptic dopamine concentrations, and decreases the likelihood of interactivity of dopamine with its postsynaptic receptor, thereby reducing or interrupting dopamine signaling. Tardive dyskinesia is purported to be the macroscopic manifestation of excessive postsynaptic dopamine signaling, resulting from proliferation of dopamine receptors in compensatory response to chronic reduction by neuroleptic of dopamine-receptor interactivity with its ligand. Whether valbenazine mitigates tardive dyskinesia by dint of that hypothetical mechanism of action is not certain. Yet, VMAT2 inhibitors deplete dopamine in the basal ganglia, and valbenazine was reported in its preapproval clinical trials data to induce or worsen adverse effect syndromes speculated to devolve from reduction of dopamine signaling: parkinsonism in up to 30-percent of patients, akathisia in about ten percent, clinically significant new-onset depression and exacerbation of diagnosed depression in 20 percent, and somnolence in up to 30 percent.

     Indeed, depletion of dopamine results in a functional equivalent of neuroleptic-induced reduction of dopamine signaling by dopamine receptor antagonism, and the latter may be the mechanism of action by which VMAT2 inhibition by tetrabenazine, valbenazine, and deutetrabenazine induce those syndromes. VMAT2 inhibitors have been shown by basic researchers to induce dopamine depletion and nigral degeneration in mice. An additional, speculative but compelling possibility is that added risk of oxidative stress-related intraneuronal degenerative changes in tetrabenazine-treated mice may result from intracellular accumulation of oxidative metabolites of dopamine, attributable to desequestration of dopamine by VMAT2 inhibitors. Oxidative stress, like dopamine receptor supersensitivity, has been invoked as a putative etiology of tardive dyskinesia and degenerative diseases of the central nervous system, generally.

Tetrabenazine is not a highly effective drug for tardive dyskinesia, nor are its significant adverse effects rare. It is no more a “turn-key” pharmaceutical than is reserpine, which has long been documented to induce clinically significant depression during its use as an antihypertensive. Reserpine, like VMAT-2 inhibitors, depletes intracellular dopamine, norepinephrine and indoleamines, such as serotonin, by interfering with storage of newly synthesized catecholamines and indoleamines. The search for a better tolerated substitute for reserpine led to the synthesis of dozens of derivatives. Tetrabenazine was born of that search in the late 1950’s and is chemically, pharmacologically and metabolically similar to valbenazine and deutetrabenazine. Tetrabenazine, like the latter, is prescribed for hyperkinetic movement disorders, including tardive dyskinesia, and has been since the 1960’s. It earned mixed grades for efficacy and tolerability, and whatever advantage once accrued to its use by dint of cost has long been exploded by increments that now sum to a yearly total of about one-third to one-half that of the per-year cost of valbenazine and deutetrabenazine.

  Fewer than half of valbenazine-treated patients have evinced clinically significant improvement of tardive dyskinesia. The results of Neurocrine’s phase 3 “Kinect” study of valbenazine were consistent with those of tetrabenazine’s sixty-year clinical history apropos of tardive dyskinesia: in Neurocrine’s Kinect study, forty percent of patients with tardive dyskinesia who were treated with valbenazine showed fifty-percent or greater reductions of tardive dyskinesia ratings. (In a randomized, controlled study some years ago, ginkgo biloba did about as well; and so, in another randomized, controlled study, did Vitamin E in a subgroup of younger persons with tardive dyskinesia whose symptoms were relatively mild). So, having satisfied FDA’s modest criteria for approval (more effective than placebo in a sponsor-supported study kept foul-free pursuant to “honor code” surveillance and enforcement (and more lenient for indications lacking established treatment).  

The authors acknowledge in their study that optimal treatment for most patients with tardive dyskinesia will continue to require continuing neuroleptic exposure, and include in their recommendations substitution of less potently risk-conferring second and subsequent generation neuroleptics at lowest effective dosages. Since their detection and characterization, neuroleptic-induced tardive motor syndromes have proved rapidly and potently suppressible by neuroleptics. The key refinement after onset of tardive dyskinesia is that those regimens be optimized for risk reduction. As earlier mentioned, the authors recommend clozapine as the preferred alternative neuroleptic for substitution.

Neither evidence nor logic supports that recommendation, given the distinctive risk of clozapine-induced agranulocytosis (with a yearly incidence of 0.4 percent) and granulocytopenia (yearly incidence, 3.0 percent), which prompts more frequent monitoring for agranulocytosis after its detection, along with evidence identifying clozapine with the highest propensity among the atypical neuroleptics to induce weight gain and other metabolic adversities, myocarditis, seizures, peripheral complications of antimucarinic activity (dysphagia, bowel obstruction, urinary retention) and central anticholinergic syndrome. Moreover, according to recent findings of comparative risk of tardive dyskinesia among atypical neuroleptics, the annualized incidence of tardive dyskinesia induced by clozapine is comparable to those of olanzapine and quetiapine and six-fold higher than that of aripiprazole, with the lowest within-class propensities to induce hyperprolactinemia and its endocrine-associated complications, such as gynecomastia in males and menstrual abnormalities in females, weight gain and metabolic adversities generally, lower rates of extrapyramidal adverse effects, fewer reports of complications of central and peripheral anticholinergic activity, and low likelihood of QTc prolongation, aripiprazole would seem a distinctively appropriate candidate for study as a preferred alternative for neuroleptic substitution.

Another error is the study’s admonition about anticholinergic agents, which it implies increase risk of and/or exacerbate tardive dyskinesia. Neither has been demonstrated over a long history of investigation or opportunity for spontaneous reportage, which has produced no systematic studies and has been limited to observational reports and individual impressions. Recently reviewed by the Cochrane organization, anticholinergic agents have not consistently affected the severity of tardive dyskinesia when initiated or discontinued from neuroleptic-treated patients with tardive dyskinesia; nor does any consistent evidence suggest that anticholinergic agents affect the rate of tardive dyskinesia among neuroleptic-treated patients. (A contributor to belief that anticholinergic agents convey risk of new-onset tardive dyskinesia or worsening of tardive dyskinesia may represent reification of a cholinergic-dopaminergic reciprocity hypothesis, wherein anticholinergic agents increase and cholinomimetic agents reduce dopaminergic signaling throughout the basal ganglia. The few pharmacologic examples that comport with the inverse reciprocity hypothesis represent a minute fraction of total cases wherein anticholinergic agents have not affected or in some cases mitigated abnormal movements (of parkinsonism) and/or dystonia that represented acute extrapyramidal effects in patients whose persistent psychotic symptoms required ongoing treatment with neuroleptics. A small number of persons with tardive dyskinetic movements withal have been reported to improve after dosing with anticholinergic agents (and failed to after acute intravenous doses of the cholinesterase inhibitor physostigmine or after oral doses of memantine).  The authors’ suspicion that antimuscarinic agents conduce to or exacerbate tardive dyskinesia is unfounded, and may eventuate in evidence-based harm, should the preponderance of persons with persistent need of neuroleptics be deprived of them or given inadequate dosages for acute extrapyramidal adverse effects. (Or when they are suddenly withdrawn from them and suffer from a week of “cholinergic rebound” symptoms, manifested principally as clinically significant gastrointestinal symptoms.)

Insufficient surveillance of anticholinergic agents increases risk of central nervous system anticholinergic toxicity and peripheral antimuscarinic activity conducing to dysphagia, bowel obstruction, and urinary retention. The latter have been observed in patients taking therapeutic and high dosages of clozapine and olanzapine, which are associated with increased bioavailability resulting from dosage increase or pharmacokinetic interactivity as may occur after sudden cessation of tobacco smoking (a potent inducer of CYP1A2, which, with CYP3A4, are the principal hepatic metabolic enzymes during clozapine and olanzapine clearances). Another scenario of risk may occur when anticholinergic agents are dosed aggressively for management of akathisia, for which they are less effective than they are for neuroleptic-induced parkinsonism and dystonia. (Beta adrenergic blocking agents or benzodiazepines can be substituted or coadministered with reduced risk of central or peripheral anticholinergic adverse effects.)

Not elaborated beyond mention of cumulative exposure as dosage, risk for developing tardive dyskinesia or other manifestation of drug exposure contributed by pharmacokinetic drug-drug interactivity is conventionally expressed by blood drug or drug metabolite concentrations per unit dose in fluid compartments in equilibrium with brain tissue concentrations. Preponderantly dependent during clearance upon hepatic metabolism by cytochrome enzymes CYPs 1A2, 2D6, and 3A4, of which they are substrates, neuroleptics may achieve higher bioavailabilities during coadministration of potent inhibitors of the latter. Decrements of comparable magnitude have been reported during coadministration of hepatic inducers of CYPs 1A2 and 3A4, and have potential to develop in CYP2D6 ultra-rapid metabolizers (whose incremental enzymatic activity devolves from an extra wild-type allele). Severity of clinical adversity is proportional to dose (exposure) within typical dosage ranges; it may accompany hepatic enzyme inhibition with increments of parent neuroleptic or hepatic-induction-related increments of neuroleptic metabolite concentrations, by dint of their own activity or in consequence of back-conversion to parent drug (as reported in association with clozapine-N-oxide, which has an affinity for dopamine receptor sites one fourth that of clozapine and withal is back-convertible to clozapine).

So, too, warranting mention is critical dependence of tetrabenazine upon CYP2D6 for hepatic metabolism during clearance. The (so far) single adequately powered investigation of tetrabenazine bioavailability in persons with diverse CYP2D6 alleles conveying poor, normal, extensive, or ultra-rapid rapid metabolic activity detected no clinically significant differences during gradual increase of tetrabenazine dosage increase. The most potent inhibitors of CYP2D6 among the psychiatric pharmaceuticals are bupropion, paroxetine, and fluoxetine, which have plausible potential to raise tetrabenazine bioavailability by clinically significant increments and conduce to tetrabenazine-induced adverse effects (somnolence, fatigue, depression, parkinsonism, and akathisia). Coadministering monoamine oxidase inhibitors with tetrabenazine has a potential to induce pressor effects and/or hyperthermic toxicity in association with increased extravesicular concentrations of catecholamines or indoleamines. During inhibition by tetrabenazine of vesicular monoamine transport protein 2, those amines cannot enter intracellular storage vesicles and be sequestered away from extravesicular monoamine oxidase; their concentrations rise, as do those of their toxic oxidative metabolites, which have been speculated to contribute to tetrabenazine-induced degenerative damage leading to parkinsonism.

The authors’ study of consensus development in the management of tardive dyskinesia showed no statistically significant effect of their intervention, and they concede that by their use of statistics as “purely descriptive” (that is, by failure to include levels of significance in their exposition). Other issues, above mentioned, require that this study be repeated under more favorable conditions and with a reliable methodology. Sponsorship bias, not unknown to studies of tardive dyskinesia, and to clinical studies of pharmaceuticals generally, seems probable in this study, by virtue not only of the extent of involvement and observation by the sponsor and its exclusive use of employees, contractors, consultants, and speakers to design, plan, administer and analyze results, but more seriously, by censoring a majority of animal and clinical studies of tetrabenazine published before 2007. Important recommendations in the authors’ consensus statement were not optimal because they were based on insufficient information and misinterpretation of evidence. (Knowing some of the authors, we wonder whether their ghosts rather than they wrote this paper.) The Journal of Clinical Psychiatry, which provided platform and vehicle for dissemination of this paper, missed or chose not to react to its conspicuous flaws. Whichever, it was asleep at the fiduciary switch, and if it wishes to avoid becoming another “throw-away journal,” it should investigate why and drain the swamps.

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