Transcript Evidence-based Guideline Update: NSAIDs, and other

Evidence-based guideline: Treatment
of tardive syndromes
Report of the Guideline Development
Subcommittee of the American Academy of
Neurology
©2013 American Academy of Neurology
Authors






Roongroj Bhidayasiri, MD, FRCP, FRCPI
Stanley Fahn, MD, FAAN
William J. Weiner, MD, FAAN
Gary S. Gronseth, MD, FAAN
Kelly L. Sullivan, PhD
Theresa A. Zesiewicz, MD, FAHA
©2013 American Academy of Neurology
Sharing this information
 The AAN develops these presentation slides as
educational tools for neurologists and other
health care practitioners. You may download and
retain a single copy for your personal use. Please
contact [email protected] to learn about
options for sharing this content beyond your
personal use.
©2013 American Academy of Neurology
Presentation Objectives
 To present the results of a systematic review and

analysis of the evidence regarding management
of tardive syndromes (TDS), including tardive
dyskinesias (TDD)
To present evidence-based recommendations
©2013 American Academy of Neurology
Overview
 Background
 Gaps in care
 American Academy of Neurology (AAN) guideline


process
Analysis of evidence, conclusions,
recommendations
Recommendations for future research
©2013 American Academy of Neurology
Background
 TDS are disorders that fulfill the following criteria:
• A history of at least 3 months’ total cumulative
neuroleptic exposure during which the exposure can
be continuous or discontinuous
• The presence of at least “moderate” abnormal
involuntary movements in one or more body areas or
at least “mild” movements in two or more body areas
• Absence of other conditions that might produce
abnormal involuntary movements1
©2013 American Academy of Neurology
Background, cont.
 Various involuntary movements, including oral

buccal-lingual masticatory movements, are
recognized as TDD symptoms.
TDS includes not only lingualfacialbuccal
dyskinesia but also the variant forms,
collectively termed tardive syndromes.28
In this guideline, TDD encompasses all forms of
persistent dyskinesia caused by dopamine
receptor blocking agents (DBRAs).
©2013 American Academy of Neurology
Background, cont.
 TDS prevalence is estimated to be 30% in

outpatients with schizophrenia treated with
neuroleptics.911
TDS develops at approximately a 5% rate yearly,
with a cumulative 5-year incidence of
approximately 20%–25%.12,13
©2013 American Academy of Neurology
Clinical Questions
 Is withdrawal of DRBAs an effective TDS




treatment?
Does switching from typical to atypical DRBAs
reduce TDS symptoms?
What is the efficacy of pharmacologic agents in
treating TDS?
Do patients with TDS benefit from
chemodenervation with botulinum toxin (BoNT)?
Do patients with TDS benefit from surgical
therapy?
©2013 American Academy of Neurology
AAN Guideline Process
 Clinical Question
 Evidence
 Conclusions
 Recommendations
©2013 American Academy of Neurology
Literature Search/Review
 Rigorous, Comprehensive, Transparent
Search
Search
Review abstracts
Review full text
Relevant
©2013 American Academy of Neurology
Select articles
AAN Classification of Evidence
 All studies meeting inclusion/exclusion criteria

defined a priori rated Class I, II, III, or IV
Five different classification systems
• Therapeutic
Randomization, control, blinding
• Diagnostic
Comparison with reference standard
• Prognostic
• Screening
• Causation
©2013 American Academy of Neurology
AAN Level of Recommendations
 A = Established as effective, ineffective, or harmful (or
established as useful/predictive or not
useful/predictive) for the given condition in the
specified population
 B = Probably effective, ineffective, or harmful (or
probably useful/predictive or not useful/predictive)
for the given condition in the specified population
 C = Possibly effective, ineffective, or harmful (or
possibly useful/predictive or not useful/predictive) for
the given condition in the specified population
 U = Data inadequate or conflicting; given current
knowledge, treatment (test, predictor) is unproven
 Note that recommendations can be positive or negative
©2013 American Academy of Neurology
Translating Class to
Recommendations
 A = Requires at least two consistent Class I



studies*
B = Requires at least one Class I study or two
consistent Class II studies
C = Requires at least one Class II study or two
consistent Class III studies
U = Assigned in cases of only one Class III study,
only Class IV studies, or evidence that is
conflicting and cannot be reconciled
* In exceptional cases, one convincing Class I study may suffice for an “A” recommendation if 1)
all criteria are met, 2) the magnitude of effect is large (relative rate improved outcome >5 and
the lower limit of the confidence interval [CI] is >2)
©2013 American Academy of Neurology
Applying the Process to the Issue
 We will now turn our attention to the guideline.
©2013 American Academy of Neurology
Methods
 The authors searched MEDLINE, EMBASE,



Cochrane Database of Systematic Reviews,
Science Citation Index, PsycLIT, and CINAHL from
1966–2011.
The preferred outcome measures are objective
clinical rating scales of TDS severity (e.g.,
Abnormal Involuntary Movement Scale).14
Two panelists reviewed abstracts and titles for
relevance and rated the evidence level of selected
studies using the AAN therapeutic classification
scheme.
Disagreements regarding classification were
resolved by consensus.
©2013 American Academy of Neurology
Methods, cont.
 Strength of recommendations was linked directly

to evidence levels.
Conflicts of interest were disclosed.
©2013 American Academy of Neurology
Literature Search/Review
 Rigorous, Comprehensive, Transparent
>2,000
abstracts
Inclusion criteria:
Studies on neuroleptic
withdrawal, anticholinergics,
benzodiazepines, betablockers, calcium channel
blockers, cholinergics,
GABAergic compounds,
neuroleptic medications, nonneuroleptic compounds that
impact the dopamine and
noradrenaline systems,
vitamin B6, and vitamin E
Exclusion criteria:
489
articles
©2013 American Academy of Neurology
- Case reviews, animal studies
AAN Classification of Evidence
for Therapeutic Studies
 Class I: A randomized, controlled clinical trial of the
intervention of interest with masked or objective outcome
assessment, in a representative population. Relevant
baseline characteristics are presented and substantially
equivalent among treatment groups or there is
appropriate statistical adjustment for differences. The
following are also required:
•
•
•
•
Concealed allocation
Primary outcome(s) clearly defined
Exclusion/inclusion criteria clearly defined
Adequate accounting for dropouts (with at least 80% of enrolled
subjects completing the study) and crossovers with numbers
sufficiently low to have minimal potential for bias.
©2013 American Academy of Neurology
AAN Classification of Evidence
for Therapeutic Studies, cont.
• For noninferiority or equivalence trials claiming to
prove efficacy for one or both drugs, the following are
also required*:
The authors explicitly state the clinically meaningful difference
to be excluded by defining the threshold for equivalence or
noninferiority.
The standard treatment used in the study is substantially
similar to that used in previous studies establishing efficacy of
the standard treatment (e.g., for a drug, the mode of
administration, dose and dosage adjustments are similar to
those previously shown to be effective).
The inclusion and exclusion criteria for patient selection and
the outcomes of patients on the standard treatment are
comparable to those of previous studies establishing efficacy of
the standard treatment.
The interpretation of the results of the study is based upon a
per protocol analysis that takes into account dropouts or
crossovers.
©2013 American Academy of Neurology
AAN Classification of Evidence
for Therapeutic Studies, cont.
 Class II: A randomized controlled clinical trial of the
intervention of interest in a representative population with
masked or objective outcome assessment that lacks one
criteria ae above or a prospective matched cohort study
with masked or objective outcome assessment in a
representative population that meets be above. Relevant
baseline characteristics are presented and substantially
equivalent among treatment groups or there is
appropriate statistical adjustment for differences.
 Class III: All other controlled trials (including well-defined
natural history controls or patients serving as own
controls) in a representative population, where outcome is
independently assessed, or independently derived by
objective outcome measurement.**
©2013 American Academy of Neurology
AAN Classification of Evidence
for Therapeutic Studies, cont.
 Class IV: Studies not meeting Class I, II, or III criteria
including consensus or expert opinion.
*Note that numbers 13 in Class I, item 5 are required for Class II in
equivalence trials. If any one of the three is missing, the class is
automatically downgraded to Class III.
**Objective outcome measurement: an outcome measure that is unlikely
to be affected by an observer’s (patient, treating physician,
investigator) expectation or bias (e.g., blood tests, administrative
outcome data).
©2013 American Academy of Neurology
Clinical Question 1
 Is withdrawal of DRBAs an effective TDS
treatment?
©2013 American Academy of Neurology
DRBA Withdrawal: Conclusion
and Recommendation
 Data are insufficient to support or refute TDS
treatment by DRBA withdrawal (Level U).
Clinical Context:
 The American Psychiatric Association Task Force
recommends antipsychotic withdrawal only in
patients who can tolerate it.15
 Psychotic relapse predictors include younger age,
higher baseline antipsychotic dosage, and shorter
hospitalization.16
©2013 American Academy of Neurology
Clinical Question 2
 Does switching from typical to atypical DRBAs
reduce TDS symptoms?
©2013 American Academy of Neurology
Switching to Atypicals:
Conclusion and Recommendation
 Data are insufficient to support or refute TDS
treatment by changing to atypical antipsychotics
(Level U, Class IV studies).
©2013 American Academy of Neurology
Clinical Question 3
 What is the efficacy of pharmacologic agents in
treating TDS?
©2013 American Academy of Neurology
Question 3: Agents Examined














Acetazolamide
Amantadine
First-generation antipsychotics
Second-generation antipsychotics
Electroconvulsive therapy
Dopamine-depleting agents
Dopamine agonists
Cholinergic drugs
Anticholinergic drugs
Biperiden (Akineton) discontinuation
Antioxidants
GABA agonists
Levetiracetam
Calcium channel blockers
©2013 American Academy of Neurology
Acetazolamide and Amantadine
Conclusions and Recommendations
 Acetazolamide and thiamine reduced TDS in one
Class III study.
 Amantadine reduced TDS when used conjointly
with a neuroleptic during the first 7 weeks (1
Class II study, 2 Class III studies).
 Data are insufficient to support or refute TDS
treatment with acetazolamide and thiamine
(Level U). Amantadine with neuroleptics may be
considered to treat TDS for short-term use (Level
C).
©2013 American Academy of Neurology
First-generation Antipsychotics
Conclusions and Recommendations
 Haloperidol possibly reduces TDS movements for
up to 2 weeks (2 Class II studies,17,18 1 Class III
study19) but is associated with increased akineticrigid syndrome (1 Class II study20). Data are
insufficient to support or refute the use of
thiopropazate in reducing oral dyskinesia (1 Class
III study19).
 Data are insufficient to support or refute the use
of thiopropazate, molindone, sulpiride,
fluperlapine, and flupenthixol in treating TDS
(Level U).
©2013 American Academy of Neurology
First-generation Antipsychotics,
cont.
Clinical Context
 Although haloperidol and thiopropazate possibly
reduce TDS, they are not recommended because
of the competing risk of akinetic-rigid syndrome.
 Safety data are unavailable concerning long-term
use of typical antipsychotics as TDS suppressive
agents, and these drugs themselves can cause
TDS; these significant risks outweigh the benefits
of any short-term use of typical antipsychotics.
©2013 American Academy of Neurology
Second-generation Antipsychotics
Conclusions and Recommendations
 Data are conflicting regarding the use of clozapine
(conflicting Class III studies). Risperidone (2 Class II
studies, 1 Class III study) is probably effective in
reducing TDD. Olanzapine is possibly effective in
reducing TDD (2 Class III studies). The safety of
risperidone and olanzapine as a TDS suppressant for
use beyond 48 weeks has not been addressed.21
 There is no evidence to determine the efficacy of
clozapine, quetiapine, ziprasidone, aripiprazole, and
sertindole in TDS treatment.
 Because neuroleptic agents may themselves cause
TDS and may mask its symptoms rather than treat it,
these drugs cannot be recommended for TDS
treatment (Level U). Caution is advised when using
risperidone or olanzapine to reduce TDS.
©2013 American Academy of Neurology
Electroconvulsive Therapy
Conclusion and Recommendation
 Only case reports have documented TDD
reduction with electroconvulsive therapy.
 Data are insufficient to determine the efficacy of
electroconvulsive therapy for TDD treatment
(Level U).
©2013 American Academy of Neurology
Dopamine-depleting Agents
Conclusions and Recommendations
 Tetrabenazine (TBZ) possibly reduces TDS
symptoms (2 consistent Class III studies). One
study (Class III) found reserpine and methyldopa effective in treating TDS.
 TBZ may be considered in treating TDS (Level C).
 Data are insufficient to determine the efficacy of
reserpine or -methyldopa in treating TDS (Level
U).
Clinical Context
 TBZ reduces TDS symptoms; there is no evidence
that long-term TBZ administration induces TDS,
but it can cause parkinsonism.
©2013 American Academy of Neurology
Dopamine Agonists
Conclusion and Recommendation
 Data are insufficient to support or refute the
use of bromocriptine for TDS treatment (Level
U).
©2013 American Academy of Neurology
Cholinergic Drugs
Conclusions and Recommendations
 Galantamine is possibly ineffective in treating
TDS (1 Class II study).
 Galantamine might not be considered in
treating TDS (Level C). Data are insufficient to
determine the effectiveness of other
cholinergic drugs in treating TDS (Level U).
©2013 American Academy of Neurology
Anticholinergic Drugs
Conclusions and Recommendations
 No controlled trials were reported examining the
efficacy of benztropine, biperiden,
chlorprothixene, and trihexyphenidyl in treating
TDS.
 Data are insufficient to determine the
effectiveness of anticholinergic drugs in treating
TDS (Level U).
©2013 American Academy of Neurology
Biperiden (Akineton) Discontinuation
Conclusion and Recommendation
 Data are insufficient to determine the
effectiveness of biperiden discontinuation in
treating TDS (Level U, 1 Class III study).
©2013 American Academy of Neurology
Antioxidants
Conclusions and Recommendations
 Ginkgo biloba (EGb-761) is probably useful in TDS
treatment (1 Class I study), but data are limited to
inpatients with schizophrenia (Level B).
 Based on 4 Class II and numerous Class III studies,
data are conflicting regarding vitamin E efficacy in
treating TDS. Data are insufficient to determine
the efficacy of vitamin E (Level U).
 Based on 1 Class II study, eicosapentaenoic acid is
possibly ineffective in treating TDS and might not
be considered (Level C).
©2013 American Academy of Neurology
Antioxidants, cont.
Conclusions and Recommendations
 Melatonin is possibly ineffective in treating TDS at
a 2-mg/day dose (1 Class II study) but is possibly
effective in treating TDS at a 10-mg/day dose (1
Class II study). Evidence regarding TDS treatment
with melatonin is conflicting (Level U).
 Data are insufficient to support or refute the use
of other antioxidants, including vitamin B6,
selegiline, and yi-gan san, in treating TDS (Level
U).
©2013 American Academy of Neurology
GABA Agonists
Conclusions and Recommendations
 Based on 1 Class I study, clonazepam is probably
effective in decreasing TDD symptoms short-term
(approximately 3 months) and should be
considered for short-term TDD treatment (Level
B).
 Data are insufficient to support or refute baclofen
use in treating TDD (Level U).
©2013 American Academy of Neurology
Levetiracetam
Conclusions and Recommendations
 Data are insufficient to recommend levetiracetam
as TDS treatment (Level U, 1 Class III study).
©2013 American Academy of Neurology
Calcium Channel Blockers
Conclusions and Recommendations
 Data are insufficient to support or refute
nifedipine use in treating TDD (Level U).
 Diltiazem probably does not reduce TDD and
should not be considered as treatment (Level B, 1
Class I study).
©2013 American Academy of Neurology
Buspirone
Conclusions and Recommendations
 Data are insufficient to support or refute
buspirone use in treating TDD (Level U, 1 Class III
study).
©2013 American Academy of Neurology
Clinical Question 4
 Do patients with TDS benefit from
chemodenervation with BoNT?
 BoNT injection is currently considered the

optimal treatment for focal dystonia. However,
efficacy data for use in TDS treatment derive from
open-label, retrospective studies (Class IV).
Data are insufficient to support or refute BoNT
use to treat TDS symptoms (Level U).
©2013 American Academy of Neurology
Clinical Question 5
 Do patients with TDS benefit from surgical
therapy?
 Data are insufficient to support or refute pallidal
deep brain stimulation use in treating TDS (Class
IV studies) (Level U).
©2013 American Academy of Neurology
Recommendations for Future
Research
 Comparison of the various TDS interventions is
difficult because different scales have been used to
measure TDS, statistical techniques used to assess
intervention efficacy have varied widely, and results
reporting lacks uniformity.
 Well-designed, double-masked randomized,
controlled trials with specific inclusion criteria are
needed to determine which interventions are most
effective for reducing TDS symptoms. Separate study
of certain TDS forms may be necessary, because not
all TDS are treated uniformly. Valid, reliable scales for
measuring TDS are critically needed.
©2013 American Academy of Neurology
References
1. Schooler NR, Kane JM. Research diagnoses for tardive dyskinesia. Arch Gen
Psychiatry 1982;39:486–487.
2. Stacy M, Jankovic J. Tardive tremor. Mov Disord 1992;7:53–57.
3. Stacy M, Cardoso F, Jankovic J. Tardive stereotypy and other movement disorders
in tardive dyskinesias. Neurology 1993;43:937–941.
4. Sachdev P. Tardive blepharospasm. Mov Disord 1998;13:947–951.
5. Fernandez HH, Friedman JH. Classification and treatment of tardive syndromes.
Neurologist 2003;9:16–27.
6. Burke RE, Kang UJ, Jankovic J, Miller LG, Fahn S. Tardive akathisia: an analysis of
clinical features and response to open therapeutic trials. Mov Disord 1989;4:157–
175.
7. Burke RE, Fahn S, Jankovic J, et al. Tardive dystonia: late-onset and persistent
dystonia caused by antipsychotic drugs. Neurology 1982;32:1335–1346.
8. Bharucha KJ, Sethi KD. Tardive tourettism after exposure to neuroleptic therapy.
Mov Disord 1995;10:791–793.
9. Chouinard G, Annable L, Ross-Chouinard A, Mercier P. A 5-year prospective
longitudinal study of tardive dyskinesia: factors predicting appearance of new
cases. J Clin Psychopharmacol 1988;8:21S–26S.
©2013 American Academy of Neurology
References, cont.
10. American Psychiatric Association. Diagnostic and Statistical Manual of Mental
Disorders: DSM-IV-TR. Washington, DC: American Psychiatric Association; 2000.
11. Correll CU, Rummel-Kluge C, Corves C, et al. Antipsychotic combinations vs
monotherapy in schizophrenia: a meta-analysis of randomised controlled trials.
Schizophr Bull 2009;35:443–457.
12. Morgenstern H, Glazer WM. Identifying risk factors for tardive dyskinesia among
long-term outpatients maintained with neuroleptic medications: results of the
Yale Tardive Dyskinesia Study. Arch Gen Psychiatry 1993;50:723–733.
13. Gardos G, Casey DE, Cole JO, et al. Ten-year outcome of tardive dyskinesia. Am J
Psychiatry 1994;151:836–841.
14. Guy W. Abnormal Involuntary Movement Scale. In: ECDEU Assessment Manual
for Psychopharmacology. Washington, DC: US Government Printing Office;
1976:534–537.
15. American Psychiatric Association. Tardive Dyskinesia: A Task Force Report of the
American Psychiatric Association. Washington, DC: American Psychiatric
Publishing; 1992.
16. Gilbert PL, Harris MJ, McAdams LA, Jeste DV. Neuroleptic withdrawal in
schizophrenic patients: a review of the literature. Arch Gen Psychiatry
1995;52:173–188.
©2013 American Academy of Neurology
References, cont.
17. Chouinard G, Jones B, Remington G, et al. A Canadian multicenter placebocontrolled study of fixed doses of risperidone and haloperidol in the treatment
of chronic schizophrenic patients. J Clin Psychopharmacol 1993;13:25–40.
18. Glazer WM, Hafez HM, Benarroche CL. Molindone and haloperidol in tardive
dyskinesia. J Clin Psychiatry 1985;46:4–7.
19. Tamminga CA, Thaker GK, Moran M, Kakigi T, Gao XM. Clozapine in tardive
dyskinesia: observations from human and animal model studies. The Journal of
clinical psychiatry 1994;55 Suppl B:102–106.
20. Gerlach J, Koppelhus P, Helweg E, Monrad A. Clozapine and haloperidol in a
single-blind cross-over trial: therapeutic and biochemical aspects in the
treatment of schizophrenia. Acta Psychiatr Scand 1974;50:410–424.
21. Bai YM, Yu SC, Chen JY, Lin CY, Chou P, Lin CC. Risperidone for pre-existing severe
tardive dyskinesia: a 48-week prospective follow-up study. Int Clin
Psychopharmacol 2005;20:79–85.
©2013 American Academy of Neurology
References, cont.
 For a complete list of references, please access
the full guideline at
www.aan.com/Guidelines.
©2013 American Academy of Neurology
Question-and-Answer Period
 Questions/comments?
©2013 American Academy of Neurology
Closing
 To access the complete guideline and related

guideline summary tools, visit
www.aan.com/Guidelines.
Thank you for your participation!
©2013 American Academy of Neurology