For several decades, neuroleptic drugs such as haloperidol and chlorpromazine have helped to reduce psychotic symptoms in patients suffering from a multitude of psychiatric conditions. Commonly referred to as "typical" antipsychotics, these drugs and others including perphenazine, loxapine, and thioridazine have been a mainstay of pharmacological treatment in psychiatric patients since chlorpromazine's development (marketed as Thorazine) in 1957.1,2 Though their use has declined in recent years with the creation of newer "atypical" antipsychotics, chlorpromazine and drugs like it still continue to be utilized in a variety of settings today.
The typical antipsychotics, though each has its own benefits and risks, all share a similar mechanism of action: blockade of dopamine receptors. Dopamine is a catecholamine neurotransmitter produced in the substantia nigra and several other areas of the brain.3 According to Dr. Lance Nickelson (Disease Processes and Therapeutics IV lecture, Feb 2010, University of Louisiana at Monroe College of Pharmacy), physiologic functions of dopamine are a result of dopaminergic neuron projection through four main pathways in the brain: the mesolimbic, mesocortical, nigrostriatal, and tuberinfundibular. The mesolimbic pathway controls behavior; hyperactivity of dopamine in this pathway is associated with increased "positive" symptoms of schizophrenia such as hallucinations and delusions. The mesocortical pathway is thought to be responsible for "negative" symptoms of schizophrenia such as avolition and social withdrawal. The nigrostriatal pathway is involved with movement, while the tuberinfundibular pathway regulates prolactin secretion. Five dopamine receptor subtypes exist: D1, D2, D3, D4, and D5. Therapeutic efficacy of the typical antipsychotics is most closely linked to dopamine blockade at the D2 receptor through the mesolimbic pathway.
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For many patients, the benefits of treatment with a dopamine-blocking neuroleptic agent outweigh the risks; there are, however, significant drawbacks to long-term treatment with a typical antipsychotic. Side effects are often related to their anticholinergic properties and can include dry mouth, sedation, constipation, urinary retention, and blurry vision.1 Dopamine blockade through the tuberinfundibular pathway can cause increased prolactin secretion, resulting in unwanted lactation and dysmenorrhea in women, or sexual dysfunction in both men and women. Less common but severe side effects include torsades de pointes, agranulocytosis, and drug-induced lupus erythematosus.1
Historically, some of the most dreaded adverse effects of these agents are the extra-pyramidal side effects (EPSE). Extra-pyramidal side effects are believed to be due to dopamine blockade in the nigrostriatal pathway and can manifest themselves in a variety of ways. Akathisia is defined as the "inability to sit still and as being functionally motor restless." Patients suffering from akathisia will often pace, shuffle, and tap their feet, while complaining of a general restless feeling or need to remain in constant motion. Akathisia has been treated to varying levels of efficacy with benzodiazepines, beta-blockers, or through a simple reduction in antipsychotic dosage. Dystonia is characterized by a state of abnormal muscle tone, often described simply as severe "muscle spasm." These prolonged tonic contractions usually occur within one to four days of treatment initiation or dosage increase of a neuroleptic agent and in some cases can be life-threatening, as seen with pharyngeal-laryngeal dystonias. Dystonias can be treated with intravenous or intramuscular anticholinergics or benzodiazepines. Psuedoparkinsonism is similar to idiopathic Parkinson's disease and is characterized by the four cardinal symptoms of Parkinson's disease (tremor, bradykinesia/akinesia, rigidity, and postural instability). Pseudoparkinsonism develops in most patients one to two weeks following treatment initiation or dosage increase of a neuroleptic agent. Anticholinergic medications such as benztropine and diphenhydramine are typically very effective in alleviating the symptoms of psuedoparkinsonism.4 Though the aforementioned adverse reactions all have a significant impact on the psychiatric patient, arguably the most severe extra-pyramidal side effect associated with the use of typical antipsychotics is tardive dyskinesia.
Tardive dyskinesia (TD) differs from other extra-pyramidal side effects in that its onset is typically seen months to years after treatment with typical antipsychotics, and in some cases the syndrome can be irreversible despite discontinuation of neuroleptic treatment. The buccal-lingual-masticatory (BLM) syndrome is the hallmark sign of tardive dyskinesia. Typically the first detectable sign of TD, BLM movements often begin mildly with lateral, forward, or backward movements of the tongue. More conspicuous displays such as lateral jaw movements, or thrusting, chewing, or rolling of the tongue may appear as the disorder progresses. These symptoms may negatively impact the patient's ability to speak, chew, or swallow. Other involuntary movements associated with tardive dyskinesia include lip smacking, facial grimacing, choreiform (spasmodic) movements and distal athetosis (writhing, slow movements) of the limbs, pelvic thrusting, unusual posture, and rocking or swaying. Stress may worsen symptoms of TD. Abnormal movements can disappear completely during sleep, or be voluntarily suppressed by the patient for a short period of time upon concentration on a task.4
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It is estimated that 15-30% of patients receiving long-term treatment with typical antipsychotic agents will develop tardive dyskinesia.5 Risk factors for the development of TD include increased duration of therapy with antipsychotic medications, increased daily dosage, increasing age, diagnosis with an organic mental disorder (such as schizophrenia), tobacco use, and diabetes mellitus. Diagnosis of tardive dyskinesia may be difficult and is often confused with withdrawal dyskinesias from short-term antipsychotic use, congenital torsion dystonia, Huntington's disease, or in the case of elderly patients, spontaneous orofacial dyskinesias. No standardized criteria for diagnosis of TD has been developed, though patients with one or more of the following are generally considered to be suffering from tardive dyskinesia: ">1 moderate movement or > 2 mild movements during or <4 weeks (8 for depot) after discontinuation of neuroleptic treatment of > 3 months (1 month if > 60 years of age)."5 Various rating scales have been devised to assess the severity of tardive dyskinesia symptoms, the most common of which being the Abnormal Involuntary Movement Scale (AIMS). The AIMS can be performed by the clinician in under 10 minutes and is used to quantify the severity of abnormal movements in the facial and oral area (facial muscles, jaw, tongue, lips and perioral space), upper extremity (arms, wrists, hands, fingers), lower extremity (legs, knees, ankles, toes), and trunk (neck, shoulders, hips). The AIMS also takes into account whether the patient is experiencing problems with denture use, and the degree to which the patient is aware of their abnormal movements.6
Despite its prevalence in psychiatric patients for decades, the exact pathogenesis of tardive dyskinesia remains unknown. One hypothesis suggests that blockade of dopamine receptors results in an upregulation of those receptors in the nigrostriatal pathway, causing tardive dyskinesia. Another more researched theory has implicated free radical activity in the pathogenesis of tardive dyskinesia.7 This theory is supported by the finding that the use of neuroleptic drugs results in increased catecholamine (specifically dopamine) metabolism, which leads to excessive formation of superoxide and hydroxyl radicals. These cytotoxic free radicals have been linked to neuronal loss in the substantia nigra, striatium, and other areas of the basal ganglia, as well as cell membrane destabilization through interaction with various membrane components.8 In an attempt to confirm this free radical hypothesis of TD formation, several clinical trials have been conducted to assess the efficacy of treatment with Î±-tocopherol (vitamin E). Vitamin E is a naturally occurring lipid-soluble vitamin found in various foods, such as spinach, sunflower seeds, nuts, olives, and asparagus. Vitamin E is notable for its powerful anti-oxidant properties and limited side-effect profile; common adverse effects of vitamin E such as nausea, diarrhea, and blurry vision are very rarely treatment-limiting and are usually associated with long-term use of high doses. Therapeutic uses of vitamin E include the treatment of age-related macular degeneration, dysmennorhea, rheumatoid arthritis, and scar reduction through topical use.9 According to the free-radical hypothesis, vitamin E may be able to reduce the severity of tardive dyskinesia symptoms both through prevention of peroxidation reactions that lead to tissue damage or death and through cell membrane stabilization.8
"A double-blind placebo-controlled study of Vitamin E Treatment of Tardive Dyskinesia" was one of the first major studies designed to measure the effect of vitamin E in treating tardive dyskinesia. Performed by James B. Lohr, M.D. and Michael P. Caligiuri, Ph.D., this study was published in 1996 and sought to build upon the results of many smaller studies published on the topic over the preceeding decade, the majority of which found a beneficial effect in using vitamin E to treat TD. Lohr and Caligiuri distinguished their study from those before it by utilizing a larger sample size and modified data collection techniques.
The study featured a double-blind, placebo-controlled, parallel-group design and included a total of 35 participants, all of whom were diagnosed with tardive dyskinesia through the Schooler and Kane criteria. To be eligible for inclusion, participants had to have been on a steady dose of neuroleptic medication for atleast one month prior to the beginning of the study. No constraints were placed on initial psychiatric diagnosis or time since onset of tardive dyskinesia. Subjects were excluded from the trial if at any time they required a neuroleptic medication dosage change or were nonadherent with their vitamin E or neuroleptic medication regimens. Active group subjects were administered a vitamin E dose of 800 IU twice daily for two months, while placebo group subjects received sesame oil gel caps on an equivalent schedule.
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Participants were assessed primarily through two methods: the modified AIMS (mAIMS) video scoring procedure and the instrumental assessment procedure. The mAIMS differs from the traditional AIMS in that it further breaks down abnormal movement rankings in terms of the magnitude (or amplitude) of the movement and the duration (or proportion) of time the movement is being exhibited. In describing the video scoring procedure, the researchers wrote: "The entire video procedure consisted of 15 minutes of split-screen recording, during which time the interviewer administered a standard AIMS rating procedure. During the interview, one half the video screen was dedicated to a full-body image, and the other half to close-up images of face, hands, and feet, lasting approximately 5 minutes per region." The instrumental assessment examined variations in the control of steady-state force from both the jaw and upper extremity. "Patients were instructed to exert pressure so that the resultant force signal matched a target displayed on a storage oscilloscope. They were further instructed to hold that pressure as steady as possible until told to rest." The reasoning behind the use of this method was that because TD patients are unable to exert a constant amount of force over time, the severity of their dyskinetic symptoms could be quantified through the variation in their force levels. Lohr and Caligiuri also found this technique useful because when compared to the AIMS it was less subject to influence by the voluntary suppression of abnormal movements demonstrated by some TD patients. The coefficient of variation (CV) was used as the principal outcome measure for the instrumental assessment method.
The researchers found that the active group showed greater reduction when compared to the placebo group in terms of both mAIMS and CV scores. The active group showed a 24% and 29% reduction in mean total mAIMS scores and total CV (hand + jaw) scores, respectively, though data was not provided to make a direct comparison with the placebo group. Another notable observation is that patients with tardive dyskinesia of more recent onset showed a greater response to the vitamin E therapy: subjects with TD of 5 years or less showed a 35% reduction in mean total mAIMS score while those with TD of greater than 5 years showed a reduction of 11%. In utilization of the mAIMS to compare sub scores for magnitude and duration of abnormal movement separately, the active group showed a greater reduction in both categories when compared to placebo, though this finding was only significant for the duration of abnormal movement. The trial also proved the instrumental assessment procedure as a valid tool for tardive dyskinesia patient evaluation: mean jaw CV scores showed a significant reduction in TD severity while the mean orofacial mAIMS scores did not.10
The next significant trial published on the topic was titled "Vitamin E Treatment for Tardive Dyskinesia." Conducted by Adler et al and published in Archives of General Psychiatry in 1999, this was a prospective, randomized, placebo-controlled trial. Upon reviewing published material on the treatment of tardive dyskinesia with vitamin E, Adler and associates felt that all of the previous studies lacked power because they contained a small sample size (37 or less), were conducted at only one site, and measured results over a short treatment period.
In response to this perceived insufficiency in the available literature, the researchers coordinated their study with 158 subjects across nine sites through the Veterans Affairs Cooperative Studies program. To be eligible for inclusion into the study, subjects had to meet Research Diagnostic Criteria for tardive dyskinesia at both screening and baseline, been diagnosed with a nonorganic psychosis (such as a delusional disorder, bipolar disorder, or schizophrenia), and have been on a stable dose of typical neuroleptic or risperidone for at least four weeks prior to enrollment, among other criteria. Some of the criteria for exclusion were subjects with TD of greater than 10 years, those with an illness which could interfere with TD or its assessment, or subjects taking either deprenyl or clozapine. In contrast to the previous study evaluated, adjustments of neuroleptic dose were allowed in this trial; the researchers reason that this decision was made to "address the possible benefits of vitamin E in its true clinical use." Subjects were given 400 IU vitamin E twice daily (or placebo) for a minimum of one year, and those who elected to continue with the study received treatment for the full duration of two years.
The researchers employed a number of clinical assessments to gather information on their participants. The AIMS was their primary data collection tool and was performed at each visit, scheduled for approximately every four weeks after the initial baseline visit. The Barnes Akathisia Scale was also conducted at each visit to assess akathisia. Signs of drug-induced parkinsonism were measured through the Modified Simpson-Angus (for Extrapyramidal Symptoms) Scale. Psychopathologic disorders were evaluated through the Brief Psychiatric Rating Scale, and the Global Assessment of Functioning Scale (GAF) was used periodically to assess the participant's overall level of functioning. Electromechanical assessments were also utilized at each visit; data through this procedure was collected and analyzed in the same manner as previously described in the study by Lohr and Caliguiri. Due to the fact that multiple data collectors were used over the course of the study, the researchers needed to ensure that differences in results were truly reliable and not the result of variations in technique between personnel. They found that reliability scores for the GAF were "excellent" (intraclass correlation coefficient of 0.90), while those for the AIMS, Barnes Akathisia Scale, and Brief Psychiatric Rating Scale were "moderate" (intraclass correlation coefficient of 0.73-0.75). Additionally, labs were taken at weeks 8, 24, and 52 of the treatment period to assay for neuroleptic and vitamin E levels. Data were analyzed through 2-tailed t tests at the .05 level, with AIMS scores also being analyzed using a linear mixed effects regression.
Adler and his colleagues found that vitamin E treatment had no effect on tardive dyskinesia. The vitamin E treatment group showed no significant difference in AIMS ratings, Modified Simpson-Angus (for Extrapyramidal Symptoms) Scale ratings, Barnes Akathisia Scale scores, GAF scores, or Brief Psychiatric Rating Scale scores. Though the linear mixed effects analysis found significance in results between sites, no significant difference was found in any of the other variables. The researchers acknowledge that their results conflict with the positive findings in previous studies, and that this discrepancy "highlights the importance of performing large-scale, long-term, multi-center trials."11
Despite the seemingly definitive results of the Veterans Affairs trial by Adler et al, research on the treatment of tardive dyskinesia with vitamin E continues to be performed. One of the most recent studies was conducted by Zhang et al and published in 2004 in Journal of Clinical Psychopharmacology. Titled "The Effect of Vitamin E Treatment on Tardive Dyskinesia and Blood Superoxide Dismutase: A Double-Blind Placebo-Controlled Trial," this study stands apart from those preceding it in two ways: its examination of superoxide dismutase and its use of non-Caucasian patients. Superoxide dismutase (SOD) is the primary enzyme responsible for the detoxification of free radicals and has been found to have reduced activity in patients with TD. The researchers chose to examine SOD as a means of determining whether vitamin E affects TD symptoms through direct radical metabolism or via changes in SOD levels, if at all. Chinese subjects were used to detect possible interethnic differences in response to vitamin E treatment.
The study consisted of 41 Chinese inpatients in Beijing's Hui-Long-Guan Hospital, 22 of which were randomized to the treatment group. Eligibility requirements for the study included DSM-III-R diagnosis of schizophrenia, tardive dyskinesia of atleast 1 year duration (as diagnosed through Schooler and Kane criteria), and stable neuroleptic dose for atleast 3 months. Subjects were excluded for having any neurologic disorder besides tardive dyskinesia or for receiving vitamin E within 1 month of the study's beginning. Subjects randomized to the treatment group received vitamin E 800IU/d for the first week, which was then increased to 1200 IU/d for the remainder of the 12 week treatment period. Neuroleptic medication doses were not modified during the trial.
The AIMS served as the primary method of tardive dyskinesia evaluation and was performed at baseline, week 6, and week 12. SOD samples were collected at baseline and posttreatment following an overnight fast and evaluated through radioimmunoassay. Subject psychopathology was also measured at baseline and posttreatment through the Positive and Negative Syndrom Scale (PANSS). Concerning statistical analysis, the researchers write:
The principal outcome analysis consisted of repeated-measures multivariate analyses of variance for the AIMS total score with a between-subjects factor of drug (placebo vs. vitamin E) and a within-subjects factor of time (baseline, week 6, and week 12). Secondary analyses consisted of analyses of covariance, with age, TD duration, baseline SOD levels, baseline AIMS, and neuroleptic dose used as the covariates. Thirdly, the relationships between change scores on the AIMS total score and potential response predictors were tested with Pearson product moment correlations.
Zhang et al found that subjects in the vitamin E treatment group showed a significant improvement (6.14 +/- 2.32 vs 3.32 +/- 1.26) in AIMS score between baseline and posttreatment, where those in the placebo group (5.88 +/- 1.89 vs 5.63 +/- 1.92) did not. Treatment group subjects also showed improvement in SOD levels where placebo group subjects did not; treatment group SOD levels were 545 +/- 172 ng/mg Hb at baseline vs 769 +/- 223 ng/mg Hb posttreatment while baseline placebo SOD levels were 565 +/- 182 ng/mg Hb compared to 607 +/- 214 ng/mg Hb posttreatment. However, the Pearson correlation analysis revealed no significant relationship between increased SOD levels and reduced AIMS in the treatment group. The researchers conclude that their results reinforce those of other studies showing the efficacy of vitamin E in treating tardive dyskinesia, with increased SOD levels in the treatment group providing further support for free radical involvement in the development and pathophysiology of TD.12
Paragraph or two on review articles.
Compare and contrast study designs and results, assign priorities, etc. Unknown mechanism may describe why vit E shows efficacy in short-term trials? Suggestions for future researchâ€¦.