New and emerging treatments for symptomatic tardive dyskinesia

Figures & data

Table 1 Summary of the evidence for treatment options of tardive dyskinesia

Authors	Study design	Regimen	Results	Adverse effects
Mentzel et al^Citation6	PubMed and Embase databases were searched on May 25, 2011 for English-language articles.	Search terms: “deep brain stimulation” AND “tardive”. 17 studies involving 50 patients with TD who underwent DBS were included.	77.5% improvement was seen on the Burke–Fahn–Marsden Dystonia Rating Scale.	1 patient experienced increase in depression and another experienced increased psychosis.
Woods et al^Citation7	Cohort study of TD incidence. N = 35 TD-free outpatients.	AIMS scores were taken twice at every visit along with Glazer-Morgenstern criteria for dyskinesia.	TD incidence with ATAs alone was similar to that of conventional therapy; the incident ratio was approximately 0.68.	N/A
Ragheb and Goldberg^Citation10	Double-blind dose-response study; N = 23 schizophrenic patients with and without TD.	100 mg, 300 mg, and 600 mg clozapine.	600 mg and 300 mg were significantly lower than baseline values; 100 mg was not. 100 mg dose showed worsening ADR scores. Switching from 600 mg to 300 or 100 mg resulted in loss of ameliorative effect.	N/A
Grimm et al^Citation21	Female rats; 3 months old.	Haloperidol decanoate (21 mg/kg) every 3 weeks for 24 weeks. Sesame seed oil (21 mg/kg) every 3 weeks for 24 weeks.	Haloperidol-treated animals: elevated VCM activity, approximately 140% above controls. Decreased ChAT cells in ventrolateral striatum and nucleus accumbens.	N/A
Kelley and Roberts^Citation22	N = 50 albino rats.	2.5 mg haloperidol/100 mL of water.	Haloperidol-treated rats had 26% decrease in ChAT immunoreactive neurons, with 29%–39% decrease of choline in high-VCM rats.	N/A
Pappa et al^Citation24	Double-blind, placebo-controlled crossover design. N = 22 patients with TD.	100 mg amantadine or placebo.	Total reduced score from 12.5 to 10.5 from amantadine treatment for orofacial dyskinetic symptoms. Average total AIMS reduction was 21.81%. No reduction was noted in the placebo treatment.	No adverse events or side effects were noted.
Ethier et al^Citation25	Young adult wild-type male mice and Nur77 knockout (Nur77 [−/−]) mice.	DHA (100 mg/kg/day), HX531 (20 mg/kg/day), haloperidol alone (1 mg/kg), haloperidol + DHA.	Nur77 (−/−) mice had high VCM activity along with wild-type mice that were given HX531. DHA alone had no effect on wild type mice or Nur77 (−/−) mice. Coadministration of DHA and haloperidol reduced VCMs in wild-type mice.	N/A
Busanello et al^Citation29	Albino Swiss mice weighing 27–32 g.	Reserpine (1 mg/kg) and resveratrol (5 mg/kg).	Reserpine increased VCM activity. Reserpine–resveratrol co-treatment showed lower VCM. No change in locomotors or exploratory activity was seen. Resveratrol alone did not modify VCM.	N/A
Busanello et al^Citation30	Rats weighing 270–320 g.	Fluphenazine enante (25 mg/kg) and resveratrol (1 mg/kg) for 21 days.	Fluphenazine increased VCM prevalence. Resveratrol reduced prevalence to 30% (P = 0.07), but not when administered alone.	N/A
Slotema et al^Citation32	Single-blind study. N = 12 patients with orofacial TD.	Botulinum toxin was injected at 40 mg. The dosage could be increased to 60 Mu or 80 Mu.	Patients who changed antipsychotic medication showed no change. Patients who did not change their antipsychotic medication showed a significant reduction (P = 0.035).	N/A
Zhang et al^Citation33	Double-blind study. N = 157 patients with TD.	Special GB extract (Egb-761) or placebo.	Improvement in AIMS score of greater than 30%; no deterioration of AIMS score was seen after 12 weeks.	No adverse side effects were noted.
Howland^Citation34	Literary review of causes and therapies of TD.	Articles on antipsychotic drug-induced motor syndromes, ATA drugs, DA-depleting drugs, DA-modulating drugs were searched.	Second-generation antipsychotic drugs should be used. DA-depleting drugs are effective along with DA-modulating drugs.	DA-depleting drugs have shown severe side effects such as depression, Parkinsonian effects, akathisia and orthostatic hypotension.
Guay^Citation35	Reviews the chemistry, pharmacology, pharmacokinetics, therapeutic use, tolerability, drug interaction potential, and dosing and administration of TBZ.	MEDLINE was searched (1950 to February 2010) for English-language articles investigating any aspect of TBZ. Search terms included “tetrabenazine,” “Ro 1–9569,” “Nitoman®,” “benzoquinolizines,” and “reserpine.”	Clinical studies suggest that TBZ may have therapeutic applications in a wide range of hyperkinetic movement disorders.	TBZ has been associated with numerous adverse effects, some of them serious and potentially fatal; these include Parkinsonism, other extrapyramidal symptoms (particularly akathisia), depression and suicidality, neuroleptic malignant syndrome, and sedation.
Kenney et al^Citation36	Retrospective chart review from 1997–2004. N = 448 patients with hyperkinesia, TD, dystonia, chorea, and myoclonus.	TBZ.	Majority of patients improved with TBZ treatment.	Adverse side effects included drowsiness (25%), Parkinsonism (15.4%), depression (7.6%) and akathisia (7.6%).
Thaker et al^Citation37	Double-blind, placebo-controlled, randomized crossover trial. N = 19 (mean age 39.14 years) chronically ill with TD were treated with neuroleptics.	Clonazepam: 11 patients were given 4–4.5 mg/day, 6 were given 3 mg/day, and 2 were given 2 mg/day.	Dyskinesia was reduced by 37.1% overall. Antidyskinetic effect was higher (41.5%) in patients with dystonic symptoms than those with choreoathetoid symptoms (26.5%). Long-term effect of clonazepam in 5 patients showed decrease in dyskinetic symptoms.	3 patients showed with ataxia, and one with nausea. 15–20 mmHg drop in diastolic and systolic BP was measured in one patient (reduction of dosage cured this). Increase in anxiety in one patient and dyskinetic symptoms in another were seen during placebo administration after clonazepam administration. Long-term treatment with clonazepam showed disappearance of antidyskinetic effect after 5–8 months. Withdrawal and readministration after 2 weeks cured this.
Howland^Citation38	Literary review of drug therapies for TD.	Articles on essential fatty acids, BCAAs, GABA-modulating drugs, cardiovascular drugs, antioxidant drugs were searched.	BCAA and GABA-modulating drugs are safe and provide some benefit for TD. Essential fatty acids have not been shown to be effective. Antioxidant therapies could be used together.	N/A
Littrell and Magill^Citation39	N = 12 with TD.	6 months of clozapine.	AIMS scores for 4 patients were 0, which was maintained for 12 months. 1 patient received a score of 2.	N/A
Bassitt and Louzã Neto^Citation40	N = 7 schizophrenic patients with severe TD.	392.86 mg/day of clozapine.	Mean reduction of 52% in ESRS scores after 6 months. One patient was completely remitted of dystonic movement while another showed 50% reduction.	Sialorrhea, excessive somnolence, blurred vision, and obstipation.
Louzã and Bassitt^Citation41	5-year follow-up study of 7 schizophrenic patients.	Dosage of clozapine after 3 years was 400 mg/day; after 5 years it was 428 mg/day.	87.5% decrease in ESRS scores for TD was seen after 5 years and 83% after 3 years.	No adverse side effects were noted.
Castro et al^Citation42	Randomized, double blind, placebo-controlled design. N = 7 patients with TD.	20 mg/day of melatonin.	2 patients showed more than 60% improvement. No differences were noted in the other 5 patients.	N/A
Shamir et al^Citation43	Double-blind, placebo-controlled crossover study; N = 22 patients with schizophrenia and TD.	10 mg/day melatonin for 6 weeks.	2.45 decrease in AIMS score for melatonin and 0.77 for placebo treatment (P < 0.001).	No adverse events or side effects were noted.
Nelson et al^Citation44	Literature found through MEDLINE (1966 to September 2002) and PsycINFO (1967 to September 2002).	Review articles, case reports/ series, and animal and human studies were taken into consideration.	Animal studies and several human case series describe an association between melatonin and TD. There are inadequate data at the present time to support the use of melatonin in patients with TD.	N/A
Iwata et al^Citation47	N = 11 patients with schizophrenia, bipolar affective disorder, schizoaffective disorder, mental retardation with TD.	50–100 mg/day of zonisamide.	AIMS total score decreased from 24.1 to 19.5 with 36% of subjects showing 20% or more decrease in AIMS score.	Well tolerated.
Woods et al^Citation50	Double-blind, placebo-controlled, randomized study. N = 50 patients with TD.	Levetiracetam 500 mg/day to 3,000 mg/day or placebo for 12 weeks.	AIMS total score decreased 43.5% from baseline score compared to 18.7% for placebo.	Emergent ataxia, impaired coordination.
Konitsiotis^Citation51	Open-label study. N = 8 with psychosis and antipsychotic-induced TD.	Levetiracetam at 1,000 mg, twice a day.	AIMS score significantly reduced from 15.8 to 8.3 and a total mean reduction of 44% was seen.	One patient presented with somnolence during treatment.
Emsley et al^Citation52	Single-blind, randomized trial. N = 45 patients with TD.	400 mg of quetiapine was given per day. haloperidol was given at 10mg per day.	Furthermore, a response rate (symptom reduction) of greater than 50% was seen in quetiapine than haloperidol.	No changes were recorded.
Richardson et al^Citation53	Double-blind placebo study. All males from a psychiatric center with long-standing TD.	Placebo. Low (56 mg/kg), medium (167 mg/kg), or high (222 mg/kg) BCAA.	Amino acid group showed a decrease of 36.5% in TD and placebo showed a 2.4% increase in TD movements.	N/A
Richardson et al^Citation54	N = 6 children and adolescents with TD symptoms.	222 mg/kg BCAA in 148 mL water, 3 times a day.	TD symptoms decreased in 5 of 6 patients from 40% to 65%.	1 patient showed worsening of TD symptoms over the 2-week trial.
Kimiagar et al^Citation55	N = 6 patients with buccolingual dyskinesia.	Combination of TBZ (50 mg), clonazepam (1 mg), and clozapine (25 mg).	All patients were free of TD symptoms within 4 weeks.	N/A
Thobois et al^Citation56	3 case studies of surgical lesion in the striatum.	Pallidotomy or thalamotomy.	Resulted in 78% decrease in AIMS score.	No major psychiatric side effects.
Welter et al^Citation57	N = 10 patients with refractory neuroleptic-induced TD.	DBS of the globus pallidus internus.	Average improvement of 56% and 61% on AIMS and ESRS scores, respectively.	N/A

Abbreviations: ADR, adverse drug reaction; AIMS, Abnormal Involuntary Movement Scale; ATA, atypical antipsychotics; BCAA, branched-chain amino acid; BP, blood pressure; DA, dopamine; DBS, deep brain stimulation; DHA, docosahexaenoic acid; ESRS, Extrapyramidal Symptom Rating Scale; GABA, γ-aminobutyric acid; GB, Ginkgo biloba; HX531, 4-(5H-2,3-(2,5-Dimethyl-2, 5-hexano)-5-methyl-8-nitrodibenzo-[b,e][1,4]diazepin-11-yl)benzoic acid; N/A, not applicable; TBZ, tetrabenazine; TD, tardive dyskinesia; VCM, vacuous chewing movement.

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